                           Psychedelic Chemistry
                         by Michael Valentine Smith
                         --------------------------

                        PREFACE TO THE FIRST EDITION

        The whole field of psychedelics, including areas of botany,
chemistry, and pharmacology, is still in a primitive state. Thousands of
potential psychedelics have been synthesized which have not been tested on
man, some of the more promising of which are indicated in these pages.
Also, anyone conversant with contemporary advances in synthetic methods
could devise better ways to synthesize most psychedelics. I have endeavored
to gather here all the more useful information on the synthesis and
structure activity relationships of the compounds loosely referred to as
psychedelics, of which LSD, mescaline, and the active constituents of
Cannabis are the most notorious prototypes. In each section, the simplest
methods, or those giving the highest yields, are given first. The many
synthetic routes contained in the literature, but omitted here, will
usually be found to involve greater difficulty, or lower yield. Each
synthesis is an abbreviated, reworded, and often translated extract from a
longer paper. While I have tried to make them accurate and coherent, a
fuller understanding as well as a correction of the inevitable blunders may
be achieved by consulting the original papers cited. Occasionally, material
will be found which is not contained in the cited work, and which is my
attempt to supplement the description.
        Though possessing little knowledge of chemistry, I have undertaken
this task because the only previous efforts of which I am aware are so
dismally inadequate. It is my fondest hope that some highly skilled chemist
will use the present effort as an outline in producing a thoroughly
competent work on psychedelic chemistry. Such a document should
significantly accelerate the psychedelic revolution.

                       PREFACE TO THE SECOND EDITION

        The scenario for the psychedelic revolution was completed in the
late sixties and nothing surprising has emerged since. Though the vast
majority of substances discussed here are clearly relatively harmless and
have tremendous potential for medical and psychological therapies as well
as for facilitating personal growth, there has been only a feeble trickle
of official research on them. This is due to the anti-drug laws, coupled
with the cowardice and stupidity of officialdom that is almost invariable.
One exception is Grof's superb book delimiting the parameters of
psychedelic psychotherapy (REALMS OF THE HUMAN UNCONSCIOUS), but for the
most part the field has been abandoned to unofficial research.
        I have included much new material that has come to my attention
since the first edition of this book, but with the field of organic
chemistry growing as it is, there are undoubtedly syntheses that have
eluded me. I would appreciate readers calling attention to these.
        I am indebted to Gyna Parthenos and her manuscript A NEW METHOD OF
LSD PRODUCTION (unpublished) for some of the intriguing new material in the
LSD chapter.

                             TABLE OF CONTENTS

               Preface to the First Edition
               Preface to the Second Edition
               Glossary
               Psychedelics and Society
               Marijuana: THC and Analogs
               Magic Mushrooms and Other Indole Trips
               Mescaline and Friends
               Harmaline and Other Beta-carbolines
               Muscimole and Other Isoxazoles
               LSD
               Cocaine
               Miscellaneous Psychedelics
               Literature and Chemical Hints
               Miscellany on Underground Laboratories
               Role of the DEA Laboratories in Drug Busts
               DEA Watched List of Chemicals

                                  GLOSSARY

cyclize - to form into a circle. Specifically, to link the OH group of CBD
   to the carbon atom to form the 3 ring compound THC, from the 2 ring
   compound CBD.

decarboxylate - to remove a carboxyl (-COOH) group from a molecule.
   Specifically, to remove the carboxyl group from THC acid or CBD acid, by
   heating, to give THC or CBD.

isomerize - to rearrange the atoms of a molecule such that the molecular
   weight remains the same, but the chemical or physical properties change.
   Specifically, when CBD is cyclized to THC, it has undergone
   isomerization.

polymers - a complex chemical compound formed of many simpler units.
   Cellulose is a sugar polymer and gelatin is an amino acid polymer.

synergize - the working together of two forces or chemicals to produce an
   effect greater than the sum of their individual effects. Specifically,
   THC and CBD together may synergize to produce redder eyes than the sum
   of the redness of the same amounts of the two, taken alone.

                          PSYCHEDELICS AND SOCIETY

        Primitive man likely began altering his consciousness with
psychedelics very soon after he first evolved into a creature that we
could term human. Virtually every area of the world possesses some
plants with psychedelic properties, and man seems to have a
remarkable ability to find just which roots and leaves are most
effective in blowing his mind. Unfortunately, Western Europe and
North America contain few psychedelic plants, and even though
primitive man may have brought marijuana seeds and the opium
poppy into these regions, he would have found them to be poor
psychedelics when grown in a cold, wet climate. In any case,
psychedelic use largely disappeared in Western societies and did not
reappear for several thousand years.
        Man has undoubtedly suffered considerably from the abuse of various
consciousness altering drugs, in particular alcohol and the opiates; but
less well known, at least in the West, are the benefits which psychedelics
have produced. It is gradually becoming evident that the world owes much of
its early art, music, literature, indeed perhaps the very fabric of many
ancient cultures directly to the effects of the psychedelic state. Many
millions of Westerners have recently gained personal experience with the
euphoria, aphrodisia, relaxation, and stimulation of creative imagination
which can result from psychedelic use. The failure of many otherwise
enlightened people to accept psychedelics has many causes, one of the more
important of which is probably that they are often among the fortunate few
to escape the neuroses, psychoses, abuse of amphetamines, tranquilizers,
barbiturates, and alcohol, which is the fate of the majority of the straight
world.
        While there are good reasons for supposing that psychedelics have
much to offer society and at worst have considerably less potential for
doing damage than many legal drugs such as tobacco and alcohol, an adequate
analysis of the total impact of psychedelics will not be possible for at
least several decades and perhaps not until they are legal. Legality could
come about very soon in some areas, since a town can pass laws against
manufacture, possession and sale which provide very light penalties (e.g.,
a $1 fine) for conviction.
        Presumably, anyone busted could be prosecuted under city laws and
thus double jeopardy might prevent state or federal laws from being
effective.
        Even though such laws will eventually be declared unconstitutional
because of conflict with state or federal laws, others could be passed, and
there are other legal grounds for challenging drug laws.
        For a useful article on ways of cross-examining the official chemist
in drug cases, see Contemporary Drug Problems 2,225 (1973), and
Microchemistry 4:555-67 (1960).

                                DRUG DAMAGE

        For virtually every drug there is a portion of the population which
will have an undesirable response. Medical journals are replete with
descriptions of drug damage and fatalities. In the US, penicillin and
aspirin each account for some 200 deaths yearly, and it was recently
estimated that prescription drugs are implicated in the deaths of some
29,000 Americans a year. The most toxic drug commonly ingested in large
amounts is probably nicotine; about three cigarettes contain a lethal dose
(although some brands now require two packs or more for a lethal dose). In
contrast, the psychedelics seem to be relatively safe and non-toxic. Some
people, perhaps one in a hundred, can develop a temporary psychosis which
rarely lasts more than a few hours or days, and which generally seems to
indicate preexisting psychopathology. In a more enlightened future,
psychedelics may be universally applied to expose latent mental illness.
There is no sound evidence that any psychedelic damages human brains,
genes, embryos, etc. Of course, all drugs are best avoided in the early
months of pregnancy, and excessive or prolonged use may have undesirable
effects.
        Psychedelics may cause subtle psychological changes leading to
apathy, fuzzy thinking, paranoia, etc., but the many studies noting such
effects in users are almost all worthless, since they lack adequate
controls. Psychiatric complications are common side effects of many
prescription drugs (e.g., see "Psychiatric Complications of Medical Drugs,"
R. Shaden (Ed.), 1972); and Heusghem and Lechat "Les Effets lndesireables
des Medicaments" (1973).
        Opiates (Heroin, Demerol, morphine, opium, etc.),
non-hallucinogenic amphetamines (Methedrine, Preludin, "bennies," etc.) and
barbituates ("reds," "yellows," etc.) are all addictive, lend themselves to
intravenous injection,  nd when used heavily usually lead to bodily damage
and frequently to death. Intravenous injection of anything under unsterile
conditions is a bad idea, since it will almost invariably lead eventually
to tetanus, hepatitis, bacterial or fungal infection of the heart and
arteries, partial paralysis, etc. The death rate among intravenous addicts
is extremely high (a recent English study found the rate for smack heads
thirty times higher than for a control group) and the best that can be said
for these drugs is that they are a rather expensive and unreliable way of
committing suicide.

                        Medical Use of Psychedelics

        It is often said that psychedelics have no recognized medical use.
Anyone who examines the technical literature with even a modicum of
critical competence realizes that this is true simply because there has
been virtually no adequate research. Psychedelics clearly have tremendous
potential in medicine (e.g., psychotherapy, antidepressants, appetite
stimulators, analgesics, aphrodisiacs, etc.) as well as in biology and
psychology. Psychotherapy is the most obvious area of application, and
though many studies have been done, very few deserved publication. Careful
selection of subjects, adequate controls, and careful followups are
uncommon, and the techniques used usually border on the idiotic. For
example, the use of LSD in the treatment of alcoholism: Four different
studies reported in 1969 found, in contrast to other work, that LSD was of
no use in the treatment of alcoholism. These four studies shared the
following characteristics: 1) there was little or no preparation for the
drug experience, and a large dose was given the first time; 2) the drug was
given in a hospital setting; 3) the patient had to trip alone, and had no
one present whom he loved or trusted; 4) there was little or no effort to
use psychotherapy before, during, or after the drug experience; 5) perhaps
the most important, the LSD was given only once. Since all five of these
conditions are contrary to what experience has shown to be the most
effective ways of using psychedelics, the negative results of the studies
are hardly surprising. To varying degrees, such inadequacies are present in
most medical research with psychedelics, and progress in this area can be
expected to be very slow, especially in view of the legal hindrances due to
neanderthaloid legislators.
        For a recent discussion of the potential value of LSD psychotherapy
and the relative lack of adverse side effects, see Psych. Bulletin
79,341(1973). Above all, see Stanislav Grof's definitive study REALMS OF
THE HUMAN UNCONSCIOUS (1976).

                           Synthetic Us. Organic

        Many people believe that organic or natural psychedelics such as
peyote, magic mushrooms and marijuana are safer or produce better trips
than synthetic compounds. This is almost certainly false, since any plant
material contains hundreds of compounds, many of which have a definite
toxicity, but few of which have psychedelic properties (they tend to make
you sick, not stoned). The various impurities or the additives (e.g.,
amphetamine, belladonna, strychnine) sometimes found in synthetic
preparations are probably no more toxic than many of the compounds found in
the psychedelic plants, and like these compounds, such additives or
impurities probably have relatively little effect on the trip.
        There is a great deal of superstition regarding purification of
psychedelics. Actually, any impurities which may be present as a result of
synthetic procedures will almost certainly be without any effect on the
trip. If there are 200 micrograms of LSD in a tablet, there could only be
200 micrograms of impurities present even if the LSD was originally only
50% pure (assuming nothing else has been added), and few compounds will
produce a significant effect until a hundred to a thousand times this
amount has been ingested. Even mescaline, which has a rather specific
psychedelic effect, requires about a thousand times this amount. It is
possible that iso-LSD may block LSD effects somewhat and inhibit the cosmic
trips that can result from high doses; this is however unproven.
Nevertheless, the prime reasons for a lack of cosmicity are undoubtedly low
doses and the development of tolerance. A single exposure to LSD or other
psychedelics may produce an adaptation or tolerance that lasts the rest of
your life (seeing the ocean for the first time is not a repeatable
experience). Furthermore, as seems to be the case with the active chemical
(THC) and its inhibitor (CBD) in marijuana,the presence of the inhibitor
may sometimes result in a more pleasant experience. Only careful studies in
which varying amounts of iso-LSD are added to LSD will decide the issue.

                              Trip Differences

        If a psychedelic is taken several days in succession, some degree
of tolerance (failure to produce a trip) develops. If a different
psychedelic is then taken and this also fails to produce a trip, the two
compounds are said to produce cross tolerance, which strongly indicates
that they act in the same way and create roughly the same kind of trip.
LSD, mescaline, and psilocybin (and probably the hallucinogenic
amphetamines) all produce cross tolerance, and there are some studies which
indicate that people are unable to tell them apart. In comparing trips, it
should be kept in mind that mescaline has seldom and psilocybin very rarely
been available on the black market. Virtually all "psilocybin," as well as
most of the "mescaline" has been LSD or one of the hallucinogenic
amphetamines (when they haven't been atropine, PCP, speed, etc.)
        PharmChem Dept. AA, 3925 Bohannon Drive, Menlo Park, CA 94025, will
qualitatively analyze any sample mailed in for $10 and will give results by
phone (415-328-6200) five days after the sample is received. Anonymity can
be achieved by assigning an arbitrary 6 digit number to your sample and
giving only this number when you call. They would like to know what you
think your sample is, its street price and general area of origin.
Envelopes with significant size specimens should be marked "Hand Cancel".
The feds won't let anyone give out quantitative results anymore. PharmChem
desires that letters be marked "Hand Cancel" and that you allow 5 days
after receipt for results. Their rates are now $10 for a qualitative and $15
for a quantitative analysis (for the latter, you must first get from them a
controlled drug transfer form to send with the sample and the $15).
        Perhaps the only reliable way to identify a psilocybin trip is by
its short duration; most trips are completely over in six hours or less.
THC, DMT, glycolate esters and very likely muscimole probably do not
produce cross tolerance with each other or with the
LSD-mescaline-psilocybin group, as would be expected from the distinct
kinds of trips produced by each of the former compounds. Other than the
synthesis of new compounds, the most fertile source of new trips lies in
the combination of varying amounts of known psychedelics.
        Although tranquilizers tend to inhibit the effects of psychedelics
if taken shortly before or during a trip, pretreatment (several hours to
several days) with a tranquilizer will often enhance the effects. This
enhancement is highly variable depending on the type and amount of
tranquilizer and psychedelic, time between ingestion, etc. Prior
administration of some tranquilizers is also useful in combatting the
nausea which, though transient, is a common unpleasant side effect of most
psychedelics. Certain phenothiazines (Stelazine, Compazine, Prolixin,
Vesprin, Trilafon) are most effective as antiemetics. Immediate relief of
nausea may be obtained from various nonprescription products, of which
Emertrol is perhaps the best.
        With most psychedelics, their activity can probably be considerably
enhanced by prior (or possibly concomitant) use of a monoamine oxidase
inhibitor (e.g., isocarboxazid (Marplan), nialamide (Niamid), phenelzine
(Nardil), and tranylcypromine (Parnate)). Some compounds (e.g., DMT) which
have no oral activity, can probably become orally active. These compounds
are often prescribed as antidepressants, but it is not a good idea to use
them frequently or in large doses. For antidotes to the hallucinogens see
Amer. J. Hosp. Pharm. 30,80(1973).

                Useful Books

THE ALKALOIDS, R. Manske and S. Holmes (eds).16 volumes, 1951-76.
CHEMISTRY OF THE ALKALOIDS, S. Pelletier (ed), 1970.
ETHNOPHARMACOLOGIC SEARCH FOR PSYCHOACTIVE DRUGS, D. Efron (ed.), 1967.
THE HALLUCINOCENS, A. Hoffer and H. Osmond, 1967.
MARIJUANA - THE NEW PROHIBITION, J. Kaplan (1970).
(The only competent study of legalization)
PSYCHOPHARMACOLOGICAL AGENTS, Vol. l, M. Gordon (ed.), 1964; Vol. 4, 1976.
PSYCHOTROPIC DRUGS AND RELATED COMPOUNDS, E. sdin and D. Efron, 1967,
and supplement.
SOMA: DIVINE MUSHROOM OF IMMORTALITY, R. Wasson, 1968.
THE NATURAL MIND, A. Weil, 1972.
FLESH OF THE CODS, P. Furst (ed.), 1972.
THE BOTANY AND CHEMISTRY OF HALLUCINOCENS, R. Schultes and A. Hofmann, 1973.
NARCOTIC PLANTS, W. Emboden, 1972.

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                         MARIJUANA: THC and ANALOGS

                                  History

        Cannabis sativa has been a cherished friend of an ever-increasing
proportion of mankind since prehistoric times. The genus Cannabis contains
only this one species, but its appearance and psychedelic properties vary
tremendously depending on growth conditions. It seems to have originated in
Asia, but its "medicinal" properties and the long fibers in its stem used
to make rope (hemp) have led to its being carried all over the world. The
early American colonists brought seeds with them and George Washington,
"the father of our country," was among its cultivators.
        There is evidence for Cannabis use as early as 5,000 B.C. in
Central Europe and there are probable references to it in the earliest
writings of China and Egypt. The frozen tombs of the inhabitants of Siberia
in about 500 B.C. have yielded quantities of seeds along with a variety of
devices for burning them. A very hot, dry climate appears necessary for
producing grass with high psychedelic activity, which may account for the
failure to use Cannabis as an intoxicant in Northwestern Europe.

                                Cultivation

        Grass seems to grow best in loose, well fertilized soil (manure,
superphosphates). The soil should be well tilled, and the seeds (actually
drupes or achenes, a type of nut) sown about one inch apart in rows about
one foot apart and covered with about 3/4 inch of soil. Some say it is best
to use dark (not green) seeds, and to soak them overnight in water before
sowing. They can be sown in flatboxes and transplanted when about two to
six inches high (about two weeks). After the plants have their first two
leaves they can be thinned by pulling up those which look the weakest.
        Cannabis is usually dioecious (male and female flowers on separate
plants). The female plants are widely believed to contain more THC than the
males, but this varies from strain to strain. In India, the males are
apparently weeded out before they have a chance to pollinate the females
and initiate seed development in the belief that the unfertilized females
produce stronger grass. This is unproven, and even if true, the total yield
of THC from a field of males plus fertilized females may well be greater.
The males are generally taller and thinner until almost mature (3 - 4
months), when the females may become taller. Males tend to yellow and die
some weeks before the females. Harvest takes place around September in
Europe and Japan and around July in North Africa. The sex of the plants can
be influenced by soil conditions, some experiments giving more males in
moist, heavily manured soils. Long light periods tend to masculinize,
whereas plants grown under short day conditions (for example, those seeded
in northern latitudes in winter) tend to produce intersexual flowers, males
changing to females; a condition also resulting from debudding males. It
has recently been found that male flowers tend to change to females after
early spraying with Ethrel (2-chloro-ethane-phosphonic acid). Under some
conditions, flowering may occur in as little as two weeks. A sizable
portion of the leaves can be harvested after about two months and the
plants will continue to grow. The effects of these various manipulations on
the THC yield of a single plant, or the crop as a whole, have yet to be
determined. "The Induction of Flowering," L. Evans (ed.), 205(1969) is a
good reference on Cannabis flowering.
        Pinching off the shoot tip when the plants are just beyond the
seedling stage, and pinching off subsequently developing side shoots at
about weekly intervals thereafter in order to keep the plant only a few
feet tall, can produce plants so altered in shape, color and leaf
morphology as to be unrecognizable as cannabis. The resins are said to
accumulate on the surface of such distorted plants to such an extent that
it looks crystalline, and the resulting grass is supposed to be as strong
as hashish.
        For definitive references on the cultivation and chemistry of
marijuana, see MARIJUANA GROWERS GUIDE, And/Or Press (1978) and MARIJUANA
POTENCY, And/Or Press (1977).

                               THC Extraction

        Some samples of grass have considerable THC acid. In order to
extract this it is first necessary to decarboxylate it by heating it to
110ø for fifteen minutes. Grass grown commercially for its fiber content,
as well as that grown in northern Europe or much of the U.S.A., contains
mostly the inactive cannabidiol and cannabidiolic acid. These compounds can
be extracted and used to synthesize the active THC and THC acid (by
smoking, not active orally) in one step. See TET 21,1228(1965) or the
following. To extract, add 50g grass/liter petroleum ether or benzene; soak
twelve hours with occasional shaking; filter and extract petroleum ether
three times with a solution containing 5% NaOH and 5% Na2SO3. Acidify the
aqueous extracts with cold dilute sulfuric acid and extract with ether or
chloroform which is dried, evaporated in a vacuum to yield the
cannabidiolic acid. THC and cannabidiol remain in the petroleum ether which
can be dried and evaporated in a vacuum and the residue added to grass. THC
acid is converted to THC by boiling in benzene for seven hours.

       THC Extraction for Smuggling or Converting Poor Grass to Good

        This is recommended to anyone who wants to smuggle or otherwise
conceal grass or hash. One hundred kilos of grass will convert to about two
or three kilos of resin, which can later be redissolved and absorbed on
alfalfa, etc. See Lloydia 33,453(1970) for a method of large scale
extraction.
        Cover grass or hash with methanol, benzene, petroleum ether, or
isopropyl (rubbing) alcohol. Allow to soak for about twelve hours, filter
and repeat soaking with fresh solvent. This process can be speeded up by
gently heating the solvent plus grass (no flames) for about three hours,
adding more solvent if necessary. Evaporate the combined solvent extracts
until a resin is obtained or until syrupy and absorb the syrup on grass,
etc. Repeat the process until no more resin is obtained, or until smoking
some of the residual grass indicates that all the THC has been extracted.
Methylene chloride works very well. Unleaded gas, preferably without
additives (white gas), paint thinner or remover, or turpentine should be
satisfactory. For a detailed discussion, see MARIJUANA POTENCY, And/Or
Press (1977).

                                   Dosage

        Smoking seems to destroy most of the THC, but even so, this is
several times more efficient than eating it, since the smoking dose of
delta-1 THC is about 2mg and the eating dose about 10mg. Based on a 5% THC
content, 1g of hash efficiently used should (by smoking) stone about 25
people.
        Partial tolerance to THC develops rapidly and most users observe
that they get much higher the first time a given batch of grass is smoked
than on subsequent occasions. However, for unknown reasons, tolerance to
grass of different origin seems less, leading some people to desire a
different batch for each day of the week.

                             Official THC Tests

        One-tenth gram powdered grass, 5ml petroleum ether; grind in mortar
and let soak fifteen minutes. Filter and add 1ml of the petroleum ether
carefully to 2 ml 15% HCl in absolute ethanol. Red color at boundary of two
layers indicates THC. After shaking, the upper layer is colorless and the
lower orange-pink which turns colorless after addition of 1 ml of water.
Alternatively, evaporate the petroleum ether, add 2 ml Duquenois reagent (
12 drops acetaldehyde, 1 g vanillin, 50 ml ethanol), 2 ml HCl and stir. Let
stand 10 minutes and add 2 ml chloroform; shake and let separate. A purple
chloroform layer indicates THC.
        Also useful but less specific is the fact that THC gives a purple
color with 5% KOH in ethanol. A few grains of sucrose will often intensify
color development in these tests. (See Bulletin on Narcotics 22,33(1970)).

                               THC Chemistry

[ Pictures of "some widely tested synthetic cannabinoids", not available in
  this ASCII version :) ]

                                Is It Legal?

        The delta-1 and delta-1(6) THC's with the n-pentyl in the 5'
position (obtained by using olivetol in the syntheses) are naturally
occurring and hence illegal, but the delta-3 THC's and the numerous
isomers, homologs and analogs of the delta-1 and delta-1(6) compounds are
probably legal.
        Apparently, recent federal legislation outlaws delta-1, delta-1(6),
delta-3,4-THC's, both cis and trans and D and L and compounds. This still
leaves hundreds of legal cannabinoids.

                      Structure-Activity Relationships

        THC refers to tetrahydrocannabinol, and delta refers to the position
of the double bond. Various numbering systems are used, so the following
equivalences should be noted: delta-1-THC = delta-1-3,4-trans-THC =
delta-9-THC and delta-6-THC = delta-1(6)-THC = delta-8-THC = delta-6-3,4-
trans-THC.
        Little careful human testing has been done, so data given here and
elsewhere on the relative psychedelic activity of various cannabinoids is
often only a rough guess. Delta-1-THC and delta-6-THC have about the same
activity which is about five times that of delta-3-THC. Cannabidiol,
cannabidiolic acid, cannabinol, cannabigerol and cannabichromene all have
very little or no activity. Only the L (-) isomer of THC seems to be
active. When the n-pentyl at the 5' position is replaced by
1,2-dimethylheptyl, potency and duration of action increases about five
times, giving the most active THC analog yet tested.
        It should be noted that recent testing has indicated that a
1,1-dimethylheptyl or 1-methyloctyl and probably similar side chains give
THC's of equal or greater activity than the 1,2-dimethylheptyl cpd.
However, the difficulty of synthesizing these compounds plus their very
long action (up to several days or more) makes it doubtful whether they
deserve all the interest they have generated among psychedelic enthusiasts.
More concern should be devoted to the shorter side chains, since they would
presumably allow one to get very stoned but to be straight again within a
few hours, thus allowing the drug to be more easily manipulated.
        Substituting N, O, or S atoms at various places or saturating the
double bond to produce hexahydrocannabinol probably retains activity. (See
CA 74,125667(1971) for S analogs.) Alkoxy side chains at 5' retain
activity. Unsaturated side chains are as active as saturated ones. Ether
moieties at the 5' position, but not at the 3', retain activity. Activity
is retained if an additional alkyl is placed at 4' but lost if placed at
6'. Activity is greatly decreased or lost if the H at the 4' or 6'
positions is replaced by carboxyl, carbomethoxyl, acetyl or acetoxyl; if
the hydroxyl is replaced by H; if the OH is at 5' and the side chain at 4'.
Methyl and/or ethyl at 1 and 5 retains activity, as does removal of the
methyl at 1. An hydroxyl in the side chain is active, but not on the first
carbon of the side chain. Esterifying the OH retains activity, but
etherifying eliminates activity.
        THC can be synthesized via cannabigerol and cannabichromene in low
yield (TET 24,4830(1968), TL 5349,5353(1969), Proc. Chem. Soc. 82,(1964)).
For several moderately difficult routes leading to delta-1(6)-THC via
cannabinol in about 10% yield, see LAC 685,126( 1965). For a synthesis of
delta-1(6)-THC from cinnamyl derivatives and isoprene see JACS
89,4551(1967). A rather difficult synthesis of delta-1 and delta-1(6)-THC
is given in JACS 89,5934(1967). For a variety of THC analogs of unknown
activity see BSC 1374, 1384(1968); JCS 952(1949); JACS 63,1971,
1977,2766(1941), 64,694,2031,2653(1942), 67,1534(1945), 70,662( 1948),
71,1624(1949), 82,5198( 1960); CA 75,48910 (1971); TL 3405(1967); JMC
11,377(1968); CT 2,167(1967); CA 76,126783(1972).
        Since 0 or 1 and perhaps 2 double bonds anywhere in the lefthand
ring below, as well as changes in the size and position of the alkyl groups
will probably all produce compounds with THC activity, many compounds
similar to menthadieneol, menthatriene, verbenol, epoxycarene, pulegone and
4-carbethoxy-1-Me-3-cyclohexanone can be used in the methods below to get
active THC analogs (e.g., isopipertinol will work (TL 945 (1972))). Also,
5-chlororesorcinol and 5-methylresorcinol (orcinol) have been shown to give
weakly active THC's (see CA 76,33946(1972), US Patent 3,028,410 (1962), and
TET 23,3435(1967) for syntheses of orcinol and related compounds).
Unfortunately, recent data indicate that orcinol gives a THC with very low
activity. It appears that delta-5 and delta-7 THC have very little
activity. If the methyl groups at carbon 8 in THC are changed to longer
alkyl groups, the activity decreases, but the replacement of the alkyl
groups by hydrogen or other groups has not been carried out. Open chain
analogs also have activity (see CT 2,167( 1967)).
        For new information on the structure-activity relationships of
cannabinoids see JMC 16, I 200( 1973), Arzneim, Forsch 22,1995 (1972), and
Chem. Revs. 76,75(1976).
        For THC analogs see JMC 19,445-71,549-53(1976); Eur. JMC
10,79(1975); Phytochem.14,213(1975); CA 82,57564,170672-3(1975); Diss.
Abst. 34B,1442(1973); J. Labelled Cpds. 11,551 (1975); Compt. Rend. Acad.
Sci. 281C,197(1975).
        For THC in one step from chrysanthenol see Experientia 31,16(1975).

[Nice picture of "two commonly used numbering systems for the same
 molecule", showing delta-1-THC and delta-9-THC, is deleted in this ASCII
 version :) ]

        The following gives the synthesis of a water soluble THC derivative
which is equipotent with THC and perhaps more rapidly acting (see Science
177,442(1972)). Stir equimolar amounts of THC, dicyclohexylcarbodiimide and
gamma-morpholinobutyric acid hydrochloride (or gamma-piperidinobutyric acid
hydrochloride) (JACS 83,2891 ( 1961 )) in methylene chloride at room
temperature for 16 hours and filter, evaporate in vacuum (can triturate
with ether and filter). The cost of synthetic THC will vary greatly
depending on many factors, but high quality grass can probably be produced
for under $20 a kilo.
        For good reviews of marijuana chemistry see Prog. Chem. Natural
Prod. 25,175( 1967), Science 168,1159(1970), C. Joyce and J. Curry (Eds.),
Botany and Chemistry of Cannabis ( 1970), JACS 93,217( 1971 ), JPS 60,1433(
1971 ), Ann. N.Y. Acad. Sci. 191(1971), Prog. Org. Chem. 8,78(1973),
Marijuana-R. Mechoulam (Ed.) (1973), and Chemical Reviews 76,75(1976).
        Only the first three methods below give the natural L (-) isomer of
THC. The other methods give the racemic produce and consequently their
yields of active THC are actually one-half that indicated.

                        Syntheses of THC and Analogs

      L-(-)-delta-1(6)-THC HCA 52,1123(1969), cf. JACS 96,5860(1974).

                                 Method I

        This method gives about 50% yield for THC and about 90% for the
1',1'-dimethylpentyl analog.
        Olivetol 4.74 g (or equimolar amount of analog), 4.03 g (+) cis or
trans p-methadien (2,8)-ol-1 (the racemic compound can be used but yield
will be one-half), 0.8 g p-toluenesulfonic acid in 250 ml benzene; reflux
two hours (or use 0.004 Moles trifluoracetic acid and reflux five hours).
Cool, add ether, wash with NaHCO3 and dry, evaporate in vacuum to get about
9 g of mixture (can chromatograph on 350 g silica gel - benzene elutes the
THC; benzene:ether 98:2 elutes an inactive product; then benzene:ether 1:1
elutes unreacted olivetol; evaporate in vacuum to recover olivetol).

                                  Method 2

        Dissolve the olivetol or analog and p-menthadienol or p-methatriene
(1,5,8) in 8 ml liquid SO2 in a bomb and fuse 70 hours at room temperature.
Proceed as above to get about 20% yield. L (-)-delta-1(6)-THC JACS
89,4552(1967), JCS (C) 579(1971), cf. Diss. Abst. 35B,3843(1974), and
Phytochemistry 14,213 (1975).
        Convert (-) alpha-pinene to (-) verbenol (see precursors section).
Add 1M(-) verbenol (racemic verbenol will give one-half yield), 1M olivetol
or analog with methylene chloride as solvent. Add BF3 etherate and let
stand at room temperature one-half hour to get approximately 35% yield
after evaporating in vacuum or purifying as above to recover unreacted
olivetol. Solvent and catalyst used in Method 1 above will probably also
work. Either cis or trans verbenol can be used. The JCS paper adds 1 g
BF3-etherate to a solution of 1 g olivetol and 1.1 g verbenol in 200 ml
methylene chloride and let stand two hours at room temperature. JACS
94,6164(1972) recommends two hours at -10øC, then one-half hour at room
temperature and the use of cis rather than trans verbenol (the latter
gradually decomposes at room temperature). The reaction is also carried out
under nitrogen, using twice as much verbenol as olivetol, 0.85 ml BF3
etherate and 85 ml methylene chloride/g verbenol (both freshly distilled
over calcium hydride) to give ca. 50% yield. See also JACS 94,6159(1972)
for the use of citral and Arzneim. Forsch. 22,1995(1972) for use of p-TSA.
        In the synthesis of THC with verbenol, the cis isomer is preferable
to the trans since the latter decomposes at room temperature. Pinene or
cawone give active THC's (JMC 17,287(74)).

                                  Method 3

        L(-)-delta-1 and delta-1(6) THC JACS 92,6061(1970), U.S. Patent
3,734,930.
        1M (+)-trans-2-carene oxide (2-epoxycarene), 1M olivetol or analog,
0.05 M p-toluenesulfonic acid in 10L benzene; reflux two hours and
evaporate in vacuum (or can separate the unreacted olivetol as above) to
get about 30% yield THC. Olivetol can also be separated as described below.
For synthesis of 2-epoxycarene (delta-4 carene oxide) from delta-4 carene
(preparation given later) see p-methadieneol preparation (Method 2).
3-carene oxide gives 20% yield of delta-1(6) THC.


                          Methods for Racemic THC

                      Delta-3 THC JACS 63,2211 (1941)

        1M pulegone, 1M olivetol or analog, 0.3 M POCl3, reflux four hours
in 1 L benzene and evaporate in vacuum or pour into excess saturated NaHCO3
and extract with dilute NaOH to recover unreacted olivetol. Dry, and
evaporate in vacuum the benzene layer to get the THC.

Delta-1(6) THC from Cannabidiol HCA 52,1123(1969)

        Reflux 1g cannabidiol, 60 mg p-toluenesulfonic acid (or 0.003 M
trifluoroacetic acid) in 50 ml benzene for 1 1/2 hours. Evaporate in vacuum
to get about 0.7 g THC. Alternatively, add 1.8g cannabidiol to 100 ml
0.005N HCl and reflux four hours. Proceed as above to get about 0.5 g THC
(cf. JACS 94,6159 (1972)).

                      Nitrogen Analogs of Delta-3 THC
            CA 72,66922(1970); JACS 88,3664(1966), TL 545(1972).

        5.4 g olivetol or 0.03M analog, 5.8 g 4-carbethoxy-N-benzyl-3-
piperidone hydrochloride or 0.03M analog (JACS 71,896(1949) and
55,1239(1933) give an old and clumsy synthesis, and Heterocyclic Compounds,
Klingenberg (Ed.), part 3, chaps. IX-XII (1962) gives information on
related compounds) in 10 ml concentrated sulfuric acid. The concentrated
sulfuric acid should be added dropwise, with cooling (cf. U.S. Patent
3,429,889). Add 3 ml POCl3 and stir at room temperature for 24 hours.
Neutralize with NaHCO3 to precipitate 2.3g (I). Filter; wash precipitate
with NaHCO3 and recrystallize from acetonitrile. Dissolve 4.3 g (I) in 30
ml anisole and add 0.1 M methyl MgI in 50 ml anisole. Stir 12 hours and
evaporate in vacuum or acidify with sulfuric acid, neutralize with NaHCO3
and filter; wash to get 2.4 g N-benzyl analog of THC. For other N-analogs
of unknown activity see JOC 33,2995(1968). Recover unreacted olivetol as
usual.

        The 5-aza analogs given in the JOC ref. seem to be active but they
use the pyrone intermediate from certain routes of THC synthesis for a
precursor. See U.S. Patent 3,493,579 (03 Feb 1970) for quinuclidine analogs
and JOC 38,440(1973) for a different approach to N-analogs. See JOC
39,1546(1974) and HCA 56,519(1973) for other N-analogs.

Delta-1(6) THC U.S. Patent 3,576,887

        This synthetic route allows one to proceed from the alkylresorcinol
dimethyl ether without using a compound of the verbenol or cyclohexanone
type.
        Synthesis of olivetol aldehyde (Aust. J. Chem. 21,2979 (1968)). To
a stirred solution of phenyllithium (1.6g bromobenzene and 0.16g Li) in 50
ml ether, add 0.01M olivetol dimethyl ether (or analog -- see elsewhere
here for preparation) in 5 ml ether and reflux 4 hours. Add 5 ml
N-methylformanilide, reflux 1 hour and wash with 2x50 ml dilute sulfuric
acid, 50 ml water, 25 ml saturated NaCl and dry, evaporate in vacuum the
ether (can dissolve in benzene and filter through 100g of alumina) to get
60% yield of the dimethylolivetol aldehyde (I) (recrystallize from
ether-pentane). Can recover unreacted starting material by refluxing the
vacuum distillate 3 hours with excess 10% HCl, removing the organic layer
and extracting the aqueous layer with ether: wash and dry, evaporate in
vacuum the combined ether layers.
        An alternative method for (I) (JACS 65,361(1943)). In a 200 ml 3
neck round bottom flask with a stirrer, a reflux condenser, a dropping
funnel and a nitrogen inlet tube, introduce a rapid stream of nitrogen and
in the stream issuing from the central neck, cut 1.5g of lithium into ca.
70 pieces and drop into the flask containing about 25 ml dry ether. Place
the fittings in position, slow the nitrogen stream and add 1/2 of the
solution of 9.2g n-butyl-chloride in 25 ml dry ether. Start the stirring
and add the rest of the n-butyl-chloride at a rate giving a gentle reflux.
Continue stirring and reflux 2 hours and add 15 ml olivetol dimethyl ether
in 25 ml dry ether. Reflux 2 hours and add dropwise a solution of 15 ml
N-methylformanilide in 25 ml dry ether with stirring at a rate sufficient
to produce refluxing. Continue stirring 1 hour, treat with 3% sulfuric acid
and then pour into excess of this acid. Remove upper layer and extract
aqueous layer twice with ether. Wash combined ether layers with dilute
aqueous NaHCO3 and water and dry, evaporate in vacuum the ether (can
distill 148-52/0.3) to get 78% (I).
        JACS 65,361(1943). A mixture of 6.5g (I) (or analog), 20 ml
pyridine, 1 ml piperidine and 9g malonic acid is warmed on a steam bath 1
hour. Add another 1 g malonic acid and heat another 1/2 hour. Reflux 1/2
hour and pour into excess iced 10% HCl, stirring occasionally over 2 hours.
Filter and dry to get 6 g 2,6-dimethoxy-4-n-amycinnamic acid (II)
(recrystallize from ethanol).
        10g (II), 40 ml 80% isoprene and 40 ml dry xylene or toluene is
heated in an autoclave at 185øC for 15 hours. Cool, dilute with 160 ml
petroleum ether and shake with 100 ml saturated aq. Na2CO3. Let stand and
separate the middle layer. Wash the middle layer with a mixture of
petroleum ether and dilute aq. Na2CO3 and again separate the middle layer
and treat with 75 ml 10% HCl and 75 ml ether. Shake, separate the aqueous
layer and wash the ether 3 times with water. Dry and evaporate in vacuum
the ether and dissolve the residue in petroleum ether. The solid which
ppts. after about 10 minutes is unchanged (II). Filter and let stand in
refrigerator overnight and dry and evaporate in vacuum to precipitate about
7 g of the 1-methyl-5 (2,6-dimethoxy-4-n-amylphenyl)-1-cyclohexene-4-COOH
(III) (recrystallize from petroleum ether).
        1g (III) in 5 ml dry ether is added to 10 ml 3M MeMgI (from 0.21 g
Mg and 1.2g methyl iodide) in ether, heated to 130øC to evaporate the
solvent and the oil kept at a bath temperature of 165ø C for 1/2 hour. Cool
in dry ice-acetone bath and cautiously add ammonium chloride-ice water mix
to decompose the excess Grignard reagent. Acidify with dilute HCl and
extract with ether. Wash with NaCl, dilute K2CO3, NaCl and dry, evaporate
in vacuum to get the dimethyl derivative (IV). Reflux (IV) in 25 ml benzene
with 100 mg p-toluenesulfonic acid for 1 hour with a Dean-Stark trap and
dry, evaporate in vacuum (or wash with NaHCO3, NaCl first) to get the THC
or analog.
        Hydrolysis of benzopyrones (for synthesis see elsewhere here) will
produce compounds of type (III) which will work in this synthesis. The
hydrolysis proceeds as follows (JCS 926(1927)): Add 10g of the benzopyrone
to 20g 30% NaOH, cool and shake 1 hour with 19 ml methylsulfate. Extract
the oil with ether and dry, evaporate in vacuum to get the ester. Acidify
the aqueous solution and filter, wash, dissolve ppt. in sodium carbonate
and acidify, filter to get the free acid. Both the acid and the ester will
work in this synthesis.
        For a possible route to benzopyrones via condensation of isoprene
and 3-CN-5-OH-7-alkyl-coumarin see JACS 82,5198( 1960). See JMC 16,1200
(1973) for another ref. on the pyrone route to THC.

Delta-3 THC Analogs TET 23,77(1967)

        11.6g 5-(1,2-dimethy))-heptyl resorcinol or equimolar amount of
olivetol or other analog, 9.2g 2-carbethoxy-5-methyl cyclohexanone
(4-carbethoxy-1-methyl-3-cyclohexanone), 5 g POCl3, 70 ml dry benzene
(protect from moisture with CaCl2 tube). Boil 5 minutes (HCl evolution) and
let stand at room temperature 20 hours. Pour into 10% NaHCO3, separate the
benzene layer and wash with 3x50 ml 10% NaHCO3. Dry and evaporate in vacuum
the benzene and recrystallize from 50 ml ethyl acetate to get 6.6 g of the
pyrone (I). 4.5g (I), 150 ml benzene; add dropwise to a solution prepared
from 7.8 g Mg, 18 ml methyl iodide, and 90 ml ether. Reflux 20 hours and
add 45 ml saturated NH4Cl. Separate the organic layer and extract the
aqueous phase with benzene. Combine the organic layer and benzene and dry,
evaporate in vacuum to get the THC analog.

Delta-3 THC analogs from Resorcinol TET 23,83(1967)

        22g resorcinol,36 g 4-carbethoxy-1-methyl-3-cyclohexanone, 20g
polyphosphoric acid; heat to 105øC and when the exothermic reaction which
occurs subsides, heat at 140øC for one-half hour. Pour onto ice-water;
filter; wash with water and recrystallize-ethanol to get 34g of the pyrone
(I). 6.4g (I), 8 ml caproyl-Cl or analog (for preparation see above
reference, page 84); heat on oil bath (can use mineral oil) at 120øC until
the exothermic reaction subsides (HCl evolution). Cool and pour into
ethanol. Filter to get 8g precipitate (II). 3.2g (II), 4.4g dry AlCl3; heat
on oil bath at 170øC for one hour. Cool and add HCl; filter and dissolve
precipitate in 7 ml 2N NaOH. Filter and acidify with HCl to precipitate 1.4
g (III) (recrystallize-ethanol). Test this for activity. Use benzoyl-Cl or
benzoic anhydride to esterify the OH group (this may not be necessary),
methyl MgBr or methyl MgI to methylate the keto group, and sulfuric acid to
dehydrate and hydrogenate as described elsewhere here to get the THC
analog. Since the resulting THC analog has the side chain at the 6'
position, it may not be active. This paper also gives a synthesis for THC
analogs with the side chain in the 4' position, but again their activity in
man is unknown. Verbenol, etc., should work in this synthesis, thus
obviating the need for the methylation step.

Delta-1(6) THC JACS 88,367(1966)

        1 M olivetol or analog, 1 M citral in 10% BF3 etherate in benzene
about eight hours at 5-10øC. Extract unreacted olivetol with dilute
NaOH and evaporate in vacuum the ether to get about 20% yield of
the trans THC, and 20% of the cis THC which can be converted to
the active trans isomer by reacting with BBr3 in methylene chloride
at -20øC for 1 1/2 hours. (TL 4947(1969)). Alternatively, the
reaction can be carried out in 1 % BF3 etherate in methylene chloride
to get 20% Delta-1 THC.

Delta-3 THC Analogs JACS 63,1971(1941) cf. CA 82,170672-3 (1975)

        7.6g 5-n-heptyl resorcinol or equimolar amount analog, 6.6g
(0.037M) 4-carbethoxy-1-methyl-3-cyclohexanone or analog, 5.8g POCl3 in 60
ml benzene. Reflux 5 hours, cool and pour into NaHCO3 to get about 6 g THC
analog and 1 g more by concentrating the mother liquor, or proceed as
described elsewhere here to recover unreacted resorcinol.
3-carbethoxy-1-methyl-2 or 4-cyclohexanone, 2-carbethoxy-cyclohexanone,
etc. will probably also give active THC analogs.

Delta-3 THC Analogs JCS 952(1949)

        1.75 g 2-Br-4-methyl-benzoic acid, 1.5 g olivetol or analog, 10 ml
1N Na OH and heat to boiling; add 0.5ml CuSO4. Filter; wash with ethanol
and recrystallize from ethanol to get (I). 10g (I) in 150 ml benzene; add
to methyl-MgI prepared from 47.5 g methyl iodide, 8 g Mg, 120 ml ether.
Reflux fifteen hours, cool and pour on ice. Add saturated NH4Cl and
separate the ether. Wash two times with water and dry and evaporate in
vacuum the ether to get the THC.

                        Precursors For THC Synthesis

p-Menthatriene (1,5,8) BER 89,2493(1956)

        90g d(+) carvone (l(-) carvone or racemic carvone probably will
work also) in 150 ml ether; add dropwise with stirring to 7.5 g lithium
aluminum hydride in ether. Heat one hour on water bath; cool and carefully
add water and then ice cold dilute sulfuric acid. Separate the ether and
extract the aqueous layer with ether; dry and evaporate in vacuum the
combined ether to get about 60 g product (can distill 65/14).

(+) Cis and Trans p-Menthadien-(2,8)-OL-1

Method 1: LAC 674,93( 1964) cf. BSC 3961(1971), JOC 38,1684(1973)

        136g (+)limonene in 2 liters methanol; 2g bengal rose dye.
Illuminate with a high voltage Hg lamp (e.g., HgH 5000) for fourteen hours
or until about 1M of O2 is taken up. Evaporate the methanol at 0-10øC to
about 500 ml and then stir with ice cooling and add this solution dropwise
to solution of 250 g Na2SO3 in 1.5 liters water and continue stirring for
twelve hours. Heat two hours at 70øC and extract with ether and dry,
evaporate in vacuum (can distill with addition of Na2CO3 at 40-70/0.2) to
get about 100 g mixture containing about 40% product which can be purified
by fractional distillation.

Method 2: HCA 48,1665(1965)
        Convert (+) Delta-3 carene to (+) trans-4-acetoxycarane (I) via (+)
trans-4-OH-carane. Reflux 50 g (I) for 45 minutes (180øC oil bath under N2
or Argon). Cool and can distill (57/10) to get about 25 g mixture of
Delta-3 and Delta-4 carene (residue is unchanged starting material)
containing about 60% Delta-4 isomer.
        Alternatively, to 150 ml ethylene diamine add portionwise with
stirring at 110øC under Argon or N2, 5.3 g Li metal; after one hour add
dropwise 110g (+) Delta-3 carene. After one hour cool to 4øC and add water.
Extract with ether, wash the ether five times with water and dry, evaporate
in vacuum to get 100 g of a mix containing about 40% (+) Delta-4 carene
(can separate by fractional distillation).
        Delta-4 carene can also be obtained from Delta-3 carene as follows:
(JCS(C)46(1966)): Dissolve 1 g Delta-3 carene in 50 ml propionic acid and
heat at a suitable temperature (e.g., one-half hour at room temperature may
do) in presence of 1/2g Palladium-Carbon catalyst (5%) in ethanol and
filter, evaporate in vacuum (can distill 63.5/19.5). See J.Soc. Cosmet.
Chem. 22,249(1971) for a review of (+) Delta-3 carene chemistry.

Delta-2 Carene oxide (2-epoxycarene) LAC 687,22(1965), (cf. TL2335(1966),
and CA 68:22063(1968))

        To 136 g 04 carene in 330 ml methylene chloride and 120 g anhydrous
sodium acetate, add dropwise with vigorous stirring in an ice bath, 167 g
of 50% peracetic acid and continue stirring for ten hours. Heat to boiling
for two hours, cool, wash with water, sodium carbonate, water, and dry,
evaporate in vacuum the methylene chloride to get about 100 g
p-menthadieneol. Apparently (CA 68,22063(1968)) substituting sodium
carbonate for sodium acetate results in the production of Delta-2 carene
oxide (2-epoxycarene) in about 50% yield (can distill 63/7).

4-Carbethoxy-1-methyl-cyclohexanone LAC 630,78(1960)

        Cool 20 g of sodium metal in 325 ml ethanol to -15øC in an ice-salt
bath and add in small amounts over one hour a solution of 100 g
3-methyl-cyclohexanone and 150 g diethyloxalate (keep temperature below
-10øC). Keep three hours in cold and then twelve hours at room temperature.
Add solution of 1.3 L of water, 60 ml 2N sulfuric acid. Separate the
yellow-brown oil and extract the water with ether or CHCl3 until the yellow
is removed. Combine the oil and the extract and distill the solvent and the
unchanged starting material (100øC bath, 13 mm). Slowly heat the residue in
a one-half liter flask with air cooling. CO2 evolution starts at 160øC.
Continue heating to 220øC and keep at this temperature for 1 1/2 hours or
until a test with 1% ethanol-FeCl3 solution shows the end of the reaction
by a violet color (unconverted material gives a brown color). Can distill
two times in Vigreux column to give about 83 g of oily colorless product.

(-)Verbenol JCS 2232(1961)

        Racemic alpha-pinene will yield racemic verbenol which will give
one-half the yield of (-)verbenol.

        27 g (-)alpha-pinene in 500 ml dry benzene; heat and keep
temperature at 60-65øC throughout. Add with stirring over 20 minutes 84 g
dry (dry over P2O5) lead tetra-acetate. Stir one-half hour; cool and filter
and add filtrate to water. Filter and evaporate in vacuum the benzene layer
(can distill 96-7/9) to get 21.2 g cis-2-acetoxy-pin-3-ene(I). 5 g (I) in
25 ml glacial acetic acid; keep at 20øC for one-half hour and add water and
extract with ether. Wash the extract with aqueous Na2CO3 and evaporate in
vacuum the ether (can distill 97-8/9) to get 4.3 g trans verbenyl acetate
(II). Hydrolyze (II) with NaOH to give the (-) cis and trans verbenol. For
other methods of producing verbenol see CA 37,361(1943), CA 57,16772(1962)
and BSC 2184(1964), JCS (B) 1259(1967). The last paper also gives a method
for converting (-) beta-pinene to (-) alpha-pinene. See also CA
65,2312(66). 5-Alkyl Resorcinols from Acyl Resorcinols CA 72,66922(1970)

        Compounds I-III may be able to give active THC analogs if used in
place of olivetol for synthesis.

        45 g 1-(3,5-dimethoxyphenyl)-1-hexanone(I) or analog (for
preparation see the following methods) in 400 ml ether and 0.3 M methyl-MgI
in 150 ml ether react to give 49 g 2-(3,5-dimethoxyphenyl)-2-heptanol(II).
Heat 49 g (II) with 1 ml 20% sulfuric acid to 105-125øC/30mm for 1 1/2
hours to get 34 g of the 2-heptene compound (III). 33 g (III) in 100 ml
ethanol, 6 g Raney- Ni,1500 PSI hydrogen,150øC to get 26 g of the 2-heptane
(IV). 26 g (IV), 118 ml 57% hydrogen iodide; add 156 ml acetic anhydride
and heat at 155o C for two hours to get 22 g of the resorcinol.

5-Alkyl Resorcinals BER 69,1644(1936)

        25g ethyl-3,4,5-trimethoxybenzoyl acetate and 2.1 g Na in 100 ml
ethanol; warm to react. Add 2 g n-propyl iodide (or n-amyl iodide, etc.)
and heat twelve hours on steam bath; neutralize and distill off the
ethanol. Extract with ether and dry, evaporate in vacuum to get about 32 g
of the alkyl acetate (I). Heat 22 g (I) in 5% KOH in ethanol for one hour
at 50øC to get 14 g 3,4,5-trimethoxyvalerophenone (II), which crystallizes
on standing. 11 g (II), 600 ml ethanol, 60 g Na; warm and after Na is
dissolved, add 2 L water. Acidify with HCl, distill off the ethanol and
extract with ether. Dry, evaporate in vacuum the ether to get 7.8 g
olivetol dimethyl ether (or analog) (III). 7.2 g (III), 70 ml hydrogen
iodide; boil two hours and distill (164/760) to get Olivetol.

Olivetol HCA 52,1132(1969)

        Reduce 3,5-dimethoxybenzoic acid with lithium aluminum hydride to
3,5-dimethoxybenzyl alcohol (I). to 10.5 g (I) in 100 ml methylene chloride
at 0ø C add 15 g PBr3; warm to room temperature and stir for one hour. Add
a little ice water and then more methylene chloride. Separate and then dry,
evaporate in vacuum the methylene chloride. Add petroleum ether to
precipitate about 11.5 g of the benzyl bromide (II). To 9.25 g (II), 15 g
CuI, 800 ml ether at 0ø C, add butyl (or other alkyl)-Li (16% in hexane),
and stir for four hours at 0ø C. Add saturated NH4Cl and extract with
ether. Dry and evaporate in vacuum the ether (can distill 100/0.001) to get
about 4.5 g olivetol dimethyl ether (III) or analog. Distill water from a
mixture of 90 ml pyridine, 100 ml concentrated HCl until temperature is 21
0øC. Cool to 140øC and add 4.4 g (III); reflux two hours under N2. Cool and
pour into water. Extract with ether and wash with NaHCO3. Make pH 7 and
dry, evaporate in vacuum to get 3.8 g olivetol which can be chromatographed
on 200 g silica gel (elute with CHCl3) or distill (130/0.001) to purify.

5-Alkyl Resorcinols TET 23,77(1967)

        Since the method as given originally leads to 4-alkyl resorcinols
which do not produce an active THC, it is here modified to give the 5-alkyl
isomers. The method is illustrated for 1.2-dimethyl-heptyl resorcinol which
gives a much more active THC than olivetol.
        Convert 3,5-dihydroxyacetophenone (5-acetyl resorcinol) to
3,5-dimethoxyacetophenone(I) in the usual way with dimethylsulfate.

        To 24 g Mg, 1 crystal 12, 100 ml ether, add dropwise under N2, 180
g 2-Br-heptane in 100 ml ether over one hour and then reflux two hours. Add
over 1 1/2 hours a solution of 90 g (I) in 200 ml tetrahydrofuran and
reflux 10 hours. Cool and add 180 ml saturated NH4Cl; decant the solvents
and extract the residue with tetrahydrofuran. Combine the solvents and the
tetrahydrofuran and dry, evaporate in vacuum. Add a few drops 20% sulfuric
acid to the residual oil and evaporate in vacuum the water (oil bath
temperature 120-130øC/10mm). Distill the oil at oil bath temperature
285øC/0.2. Fraction boiling 128-140/0.2 yields about 60 g
2-(3,5-dimethoxyphenyl)-3-methyl-2-octene(II). If saponified and used to
synthesize a THC, this might give an active product, thus disposing of the
necessity of the next step. Hydrogenate 50 g (II) in 100 ml ethanol, 2-3
atmospheres H2, 0.6 g 10% Palladium-Carbon catalyst for two hours, or until
no more H2 uptake (or use the NaBH4-Ni method described at the start).
Filter and dry, evaporate in vacuum, and distill the residual oil
(110-17/0.1) to get 42g of the octane (III). 40 g (III), 100 ml 48% HBr,
320 ml glacial acetic acid and reflux four hours. Pour on ice and take pH
to 4.5 with 10 N NaOH and extract with ether. Extract the ether with 3x150
ml 2N NaOH; acidify the combined NaOH extracts with glacial acetic acid and
extract with ether. Dry and evaporate in vacuum, and distill the oil (
159/0.1 ) to get 20 g 5-1, 2-dimethylheptyl resorcinol.

5-Alkyl Resorcinols JACS 61,232(1939)

        Convert benzoic acid to 3,5-dihydroxybenzoic acid
(alpha-resorcyclic acid) (I). 50 g (I), 134 g dimethylsulfate, 60 g NaOH,
300 ml water; add 35 g NaOH and reflux to obtain about 50 g
3,5-dimethoxybenzoic acid (II) which is converted to dimethoxybenzoyl
chloride (III) with PCl5. Extract the (III) with ether and filter. Saturate
the ether with NH3 at 0øC and filter. Wash with ether and water and
recrystallize from hot water to get 3,5-dimethoxy-benzamide (IV). To a
solution of 1 M of n-hexyl bromide (or 1,2-dimethylheptyl bromide, etc.)
add 24.3 g Mg in 200 ml ether to prepare the Grignard reagent. Then rapidly
add 46 g (IV); add 300 ml ether and reflux and stir two days, excluding
moisture and air. Add a mixture of ice and water and 80 ml concentrated
sulfuric acid. Separate and dry, evaporate in vacuum the ether layer to get
about 50 g of the dimethoxyalkyl benzyl ketone (V). Recrystallize from
dilute ethanol. Add 0.2 M (V), 20.8 g 100% hydrazine hydrate, 75 ml
ethanol; reflux six hours. Evaporate in vacuum and heat the residual oil
with 82 g powdered KOH in oil bath about 225øC until N2 evolution ceases.
Can distill or recrystallize from 95% ethanol to get the dimethoxyalkyl
benzene (VI). 0.025 M (VI), 40 ml glacial acetic acid, 15 ml 48% HBr;
reflux four hours and pour into ice water; decolorize with a little Na
bisulfite, neutralize with NaHCO3 and extract with ether. Wash the extract
with 10% NaOH and separate and acidify the basic solution. Extract with
ether and dry, evaporate in vacuum the extract to get the 5-alkyl
resorcinol. Distill or recrystallize from water to purify. Dry, evaporate
in vacuum the first ether extract to recover starting material.

Olivetol LAC 630,77(1960), JCS 311(1945), cf. JACS 89,6734(1967)

        Dissolve 100 g malonic acid in 360 g dry pyridine and heat 48-52øC
for forty hours with 100 g n-hexaldehyde (n-capronaldehyde) or homolog.
Cool in ice bath and with good stirring add dropwise 150 ml ice cold
concentrated sulfuric acid (keep temperature below 5øC). After addition add
water to dissolve the precipitate and extract with ether two times. Dry,
evaporate in vacuum the ether and distill (70/0.7 or 102/5) to get about 98
g 2-octenoic acid (I). 95 g (I) in 300 ml ether; cool to -5øC and slowly
add a solution of an excess of diazomethane in ether dried over KOH and let
react for about one hour. Let stand twelve hours, evaporate in vacuum and
distill (91/17) to get about 94 g clear methyl-2-octenoate (II).
        To 16.3 g Na in 210 ml ethanol add 93 g ethyl-acetoacetate
(ethyl-3-oxo-butanoate), heat to boil and add dropwise 92 g (II) over 20
minutes. Stir and reflux five hours and cool to precipitate.Filter, wash
with ethanol and dissolve precipitate in 800 ml water. Cool to 0ø C and
slowly add 80 ml ice cold concentrated HCl to precipitate. Filter, wash
with water and ligroin to get about 108 g 6-carbethoxy-4,5-dihydro-olivetol
(III) (recrystallize from petroleum ether). To 104 g (III) in 260 ml
glacial acetic acid at room temperature with good stirring, add dropwise
over one hour 69 ml Bromine. Heat four to five hours at 60o C, cool and add
300 ml water and let stand twelve hours. Oil separates which will
precipitate on agitation and rubbing. Filter, wash with water until
colorless (recrystallize from ligroin, recrystallize from glacial acetic
acid and precipitate with water) to get about 86 g 6-carbethoxy-2,4-dibromo-
olivetol (IV). 0.035 g Palladium-Carbon catalyst in 25 ml hydrogenation
bottle. Saturate with H2 (pressure - 2.8 Kg/cm2) and add 0.33g (IV) in 5 ml
glacial acetic acid, which takes up 39.5 cm3 H2 at atmospheric pressure
over 1 1/2 hours at 60-70øC. Filter and acidify at 0øC with ice cold 6N
HCl. Extract with ether and dry, evaporate in vacuum. Recrystallize the oil
from ligroin and then from glacial acetic acid by adding water to get about
0.2 g 6-carbethoxyolivetol (V). (IV) can also be hydrogenated at room
temperature and atmospheric pressure over 1/2g Palladium-Carbon catalyst by
dissolving 70 g in 500 ml 1 N NaOH. Heat 35 g (V) with 45 g NaOH in 170 ml
water for two hours or until no more CO2 is evolved. Cool, acidify with 6N
HCl and boil 3 minutes. Extract the oil with ether and dry, evaporate in
vacuum the ether (can distill on Vigreux column 123/0.01, oil bath 160o C)
and let oil stand in refrigerator until crystalline to get about 21 g
olivetol. See CA 70,77495t(1969) for another variant of this procedure.

1',1'-Dimethyloliuetol HCA 52,1127(1969)

        Prepare 3,5-dimethoxy benzyl alcohol by reducing the acid with
lithium aluminum hydride as described elsewhere here, by hydrogenating the
aldehyde (2-3 atmospheres H2, room temperature, PtO2 in ethanol -- or by
the NaBH4 method), in five steps as described in JACS 70,666(1948), or
prepare (II) directly by the diborane procedure.
        Add with stirring 22.5 g SOCl2 in 100 ml ether in 20 ml portions to
a solution of 15 g 3,5-dimethoxybenzyl alcohol, 1 ml pyridine and 200 ml
ether. Let stand and wash with 2x100 ml cold water; separate and dry,
evaporate in vacuum the ether to get 16 g 3,5-dimethoxybenzyl chloride (I).
Recrystallize from petroleum ether. 16 g (I), 300 ml ethanol, 30 g NaCN, 75
ml water; reflux three hours and pour onto 400 g ice. After ice melts,
filter and recrystallize precipitate from petroleum ether to get about 14 g
3,5-dimethoxybenzyl CN (II). 5 g 50% NaH in mineral oil; wash three times
with pentane or hexane; fill flask with N2 or argon and add dimethoxyethane
or dimethylformamide (freshly distilled from K if possible). Stir and add 9
ml methyl iodide. Carefully add 8 g (II) and stir twelve hours. Add ice
water and neutralize with NaHCO3 to pH 7-8. Extract with ether and dry,
evaporate in vacuum the ether (can distill 170/0.1 ) to get about 9 g
alpha, alpha-dimethyl-3,5-dimethoxyphenylacetonitrile (III). Add 1.5 g
(III) to a solution of 0.45 g Mg, 2.5 g n-propyl Br (freshly distilled if
possible) in 30 ml ether. Reflux sixty-five hours. Add 2N sulfuric acid and
heat two hours on water bath. Cool and extract with ether and dry,
evaporate in vacuum (can distill 135/0.001) to get about 1.75 g
2-methyl-2-(3,5-dimethoxyphenyl) hexanone-3 (IV). Dissolve 4g (IV) in 50 g
ethane dithiol and saturate at 0øC with HCl gas (take care to exclude
water). Stir the solution in a sealed container forty-eight hours at room
temperature and then basify with NaHCO3. Extract with ether and dry,
evaporate in vacuum (or dry and evaporate in vacuum two hours at 70/12 and
distill at 130/0.001 ) to get about 5 g of the thioketal (V). Reflux 5.3 g
(V),100 g Raney-Ni, 2 L ethanol (or use NaBH4 procedure) for thirty hours.
Cool and filter (Celite), evaporate in vacuum and distill residue
(115/0.001) to get 3.7 g of the hexane which is saponified as described for
the dimethyl ether of olivetol above to give about 2.5 g of the title
compound (can distill 150/0.001).

Olivetol ACS 24,716(1970)

        Prepare 3,5-dimethoxybenzoic acid as described elsewhere here, and
to a solution of 18.2 g in 250 ml dry tetrahydrofuran under N2, add 1 g 85%
LiH, stir for fourteen hours and then reflux for one-half hour. Add a
solution of about 1.3 M butyllithium in ether (Org. Rxns. 6,352(1957)) with
stirring and ice cooling until the reaction mixture gives a positive Gilman
test (JACS 47,2002(1925)). Then add 500 ml ice water, extract with ether
and dry, evaporate in vacuum the organic phase to get a yellow oil which is
dissolved in an equal amount of absolute ethanol; left in refrigerator
twelve hours to precipitate. Filter and evaporate in vacuum the ethanol to
one-half volume to give more precipitate for a total of 18 g
1-(3,5-dimethoxyphenyl)-1 pentanone (I). 5.64 g (I) in 200 ml methanol;
0.66 g 20% Pd(OH)2 on carbon (TL 1663( 1967)) and hydrogenate at room
temperature and atmospheric pressure over two to three hours (or use other
reducing method as described here).Filter and evaporate in vacuum to get
olivetol dimethyl ether (II). 4.88 g (II), 40 ml HI (density 1.7,
decolorized with red phosphorous) and stir three hours at 115-125øC under
N. Dry, evaporate in vacuum or pour into 100 ml ice water and extract with
methylene chloride; wash methylene chloride with water and dry, evaporate
in vacuum (can distill 160-170/3-4) to get 3.5 g olivetol.

       5-Alkyl Resorcinols JOC 33,687(1968), JACS 71,1624,1628(1949)
                Illustrated for 1,2-dimethylheptyl compound

        110 g powdered 3,5-dimethoxybenzamide (preparation given elsewhere
here), five times excess of MethylMgI and reflux sixteen hours. Add 1.2 L
concentrated HCl and 1200 g ice and let stand sixteen hours with occasional
shaking. Extract with ether, dry, evaporate in vacuum and distill
(115-128/0.3). Let stand in refrigerator to precipitate. Wash precipitate
with petroleum ether and recrystallize from petroleum ether to get about 60
g 3,5-dimethoxyacetophenone (I). 83 g (I) in 50 ml methanol. Add dropwise
with stirring to solution of 18 g NaBH4 in 300 ml methanol and 1 g NaOH.
Reflux 30 minutes and concentrate by distilling. Add about 100 ml water
during distillation. Evaporate the methanol, cool and extract with ether.
Dry, filter, concentrate, and distill (124/0.65) to get about 80 g
3,5-dimethoxyphenyl ethanol (II).18 ml PBr3 in 70 ml ether; add dropwise
with stirring over one hour to 28.5 g (II) in 70 ml ether cooled in an ice
bath. Warm to room temperature; reflux two hours on steam bath; cool and
pour into 200 g ice. Shake and extract with ether 3 times; wash ether with
l0oþo NaHCO3 and water and dry, filter. Concentrate on steam bath and then
add with stirring under anhydrous conditions to 42 g diethyl-n-amylmalonate
in 300 ml ethanol in which has been dissolved 4.6 g Na metal. Stir 1 1/2
hours at room temperature and then heat to distill off the ether and
complete the reaction. When the distillation head temperature reaches 78øC
add water and continue distilling until temperature reaches 99øC. Cool and
extract with 3x250 ml ether and evaporate in vacuum the ether. Dissolve
residue in 180 ml ethylene glycol and 35 g NaOH by stirring six hours at
160øC. Cool and add 1500 ml water and wash with ether. Acidify the aqueous
phase and extract with 4x200 ml ether. Evaporate in vacuum the ether or
evaporate on steam bath and dissolve the residue in 150 ml xylene.
Evaporate residual ether and water until head temperature reaches 140o C
and reflux six hours. Evaporate in vacuum to get about 30 g oily
alpha-amyl-beta-methyl-hydro-cinnamic acid (III). 14.5 g (III), 5 g lithium
aluminum hydride, 250 ml ether; reflux 6 hours. Cool and carefully add
methanol, water and dilute HCl. Separate the aqueous layer, saturate with
NaCl and extract with ether. Wash ether with NaHCO3 (acidify NaHCO3 extract
to precipitate starting material) and dry, evaporate in vacuum the ether to
get about 12 g 2-amyl-3(3,5-dimethoxyphenyl)-butanol (IV). 1 I.7 g (IV) and
8.5 g p-toluenesulfonyl Cl each dissolved in 20 ml pyridine. Cool in ice
bath and combine. Place in freezer about sixteen hours, pour over ice and
extract with ether. Wash ether with cool, dilute HCl until HCl extract is
acidic. The combined HCl extracts are then acidified and extracted with
ether. Wash the ether with NaHCO3, dry and then add dropwise with stirring
to 3 g lithium aluminum hydride in 75 ml ether. Reflux 4 1/2 hours and work
up as for (IV). (Can chromatograph the undistilled product on activated
alumina and elute with 600 ml petroleum ether, then 200 ml methanol;
concentrate and distill (94/0.001) the petroleum ether to get product;
concentrate the methanol to give starting material). Yield is about 8 g
2-(3,5-dimethoxyphenyl)-3-methyl-octane (V). Convert (V) to the title
compound by refluxing in 48% HBr in glacial acetic acid as described
elsewhere here.

        An alternative route from (II) to (V) involves adding (II) and
diethylmethylmalonate to prepare dimethyl-3,5-dimethoxyhydro-cinnamic acid
as described for the preparation of (III). Then dehydrate and hydrolyze to
dimethyl-3,5-dimethoxycinnamic acid which is hydrogenated to the alcohol
and converted in several steps to (V).

5-Alkylresorcinols Aust. J. Chem. 21,2979(1968)

        Reflux 6.9 g triphenylphosphine and 6.6 g lauryl bromide (or
equimolar amount of homolog) in 40 ml xylene for 60 hours. Remove solvent
and wash residue with 5x20 ml ether (by decanting) to get 11 g lauryl
triphenylphosphonium bromide (I). To a stirred suspension of 5.6, g
(0.011M) (I) in 50 ml ether add 0.01M butyllithium solution (see Organic
Reactions 8,258(1954) for preparation). Stir 1/2 hour at room temperature
and slowly add 1.66 g 3,5-dimethoxybenzaldehyde (preparation given
elsewhere here) in 10 ml ether over 1/2 hour. After 15 hours, filter, wash
filtrate with water and dry, evaporate in vacuum. Dilute residue with
pentane, filter and remove solvent. Dissolve the residual oil in 25 ml
ethyl acetate and hydrogenate over 0.1 g Adams catalyst at one atmosphere
and room temperature for 2 hours. Filter and evaporate in vacuum to get the
5-alkylresorcinol dimethyl ether which can be recrystallized from pentane
and demethylated as described elsewhere here.

5-Alhylresorcinols Aust. J. Chem. 21,2979( 1968)

        Add 2.17 g 3,5-dimethoxybenzoyl chloride (see BER 41, 1329 (1980)
or elsewhere here for preparation) in 2.5 ml ether over 10 minutes to a
stirred solution of 0.42g diazomethane and 1.01 g triethylamine in ether at
-5øC. Keep 10 hours at 0øC, filter, wash precipitate with 20 ml ether and
evaporate in vacuum the combined filtrates to get 1.9g
diazo-3,5-dimethoxyacetophenone(I). Recrystallize from benzene-cyclohexane.
To 1.5g(I) in 15 ml ethanol add 1.23g pyridinium perchlorate in 2 ml
pyridine. Reflux 2 hours, cool and add 5 ml water. Filter to get 1.5g
3,5-dimethoxyphenylacyl pyridinium perchlorate (II). Recrystallize from
ethanol. To a stirred suspension of 0.13 g Na hydride in 10 ml dry, acid
free dimethylacetamide at 10øC under nitrogen, add 1.79g (II) in 10 ml
dimethylacetamide and shake for 15 minutes. Add 0.0075M propyl iodide or
homolog and keep 12 hours at room temperature. Heat 2 hours at 90øC and
cool to room temperature. Add 3g zinc dust and 5 ml glacial acetic acid;
stir at room temperature four hours and filter. Add 20 ml water to filtrate
and extract with 50 ml ether. Wash the ether layer with 2x50 ml 10% K2CO3,
50 ml water and 20 ml saturated NaCl. Dry and evaporate in vacuum to get
oily 3,5-dimethoxyphenylbutyl ketone (can chromatograph on 50 g alumina and
elute with 3:1 petroleum ether:ether). Recrystallize from ethanol.
Hydrogenolysis (see Aust. J. Chem. 18,2015(1965) or elsewhere here) gives
the olivetol dimethyl ether.

5-Alkylresorcinols Aust. J. Chem. 24,2655(1971)

        The method is illustrated for olivetol preparation, but substituted
thiophens can be used to get olivetol homologs.
        To a stirred solution of 45g 3,5-dimethoxybenzoyl chloride and
17.4g thiophen in 300 ml benzene at 0øC, add dropwise 10.5g freshly
distilled stannic chloride. Stir one hour at room temperature and add 200
ml 3% aqueous HCl. Separate the benzene layer and wash the aqueous layer
with benzene. Dry and evaporate in vacuum the combined benzene layers and
distill the red residue (250øC bath/4.5) to get 45g 2-(3,5-dimethoxybenzoyl)
thiophen(I). Recrystallize from petroleum ether. Add a solution of 21 g
AlCl3 in 160 ml ether to a stirred suspension of 6.1 g lithium aluminum
hydride in 140 ml ether. After 5 minutes add a solution of 39g(I) in 300 ml
ether at a rate giving a gentle reflux. Reflux and stir 1 hour; cool in an
ice bath and treat dropwise with 50 ml water, then 50 ml 6N aqueous
sulfuric acid. Separate the layers, extract the aqueous layer with 3x100 ml
ether and dry, evaporate in vacuum the combined ether layers. Can distill
the residue (230øC bath/5mm) to get 27g oily 2-(3,5-dimethoxybenzyl)
thiophen (II). Recrystallize from petroleum ether. Reflux a solution of 5g
(II) in 700 ml ethanol with W-7 Raney Nickel prepared from Ni-Al alloy (see
Org. Synthesis Coll. Vol III,176(1955)) for 6 hours. Filter, evaporate in
vacuum and can distill (140/0.01) to get about 2.2g oily olivetol dimethyl
ether which can be reduced to olivetol as described elsewhere here. The use
of the novel reduction methods described at the beginning of this section
would render this method much simpler.

5-Alkylresorcinols German Patent 2,002,815 (30 July 1970)

        In a 2 liter, 3 necked flask with a stirrer, dropping funnel,
thermometer, reflux head, nitrogen stream and mercury manometer (if
available) stir 230 ml dry methanol and 32.4g sodium methoxide under
nitrogen until dissolved. Add 110g diethylmalonate and stir 10 minutes. Add
portionwise 75g 90% pure 3-nonene-2-one (for olivetol-preparation below)
keeping the temperature below the boiling point (50-60øC). Stir and reflux
3 hours, then cool to room temperature, neutralize with about 50 ml
concentrated HCl and let stand overnight. Evaporate in a vacuum and
dissolve the residue in 200 ml 1N HCl and 800 ml ethylacetate. Separate and
wash the ethylacetate with 2x300 ml water and extract with saturated NaHCO3
until a small portion gives no turbidity upon acidification (about 5x200
ml). Carefully acidify the combined NaHCO3 extracts and then extract with
3x300 ml ether. Dry and evaporate in vacuum the ether (can dry under vacuum
several days) to get 6-n-pentyl-2-OH-4-oxo-cyclohex-2-ene-1-methyl-
carboxylate(I). 4.8 g (I) and 100 ml glacial acetic acid are stirred
vigorously at 75øC until dissolved. Cool and keep temperature between 5 and
10øC while adding a solution of 3.9g bromine in 10 ml glacial acetic acid
dropwise over 1 hour. Stir 1 hour at room temperature then 3 hours on a
steam bath. Evaporate in vacuum and dissolve the residual oil in 200 ml
ether. Wash with 2x25 ml 10% sodium dithionite, 2x25 ml saturated NaHCO3
and water and dry, evaporate in vacuum to get olivetol (or analog) (can
distill at 125-130/0.05).
        Alternatively, to 4.8g (I) ad 5.6g iodine in 200 ml glacial acetic
acid. Stir and reflux 10 hours, evaporate in vacuum, dissolve residue in
250 ml ether and proceed as above to get olivetol.
        A third alternative is to stir 12.2g (I) in 100 ml glacial acetic
acid at 25øC with vigorous stirring until well suspended. Cool and keep
temperature at 5-10øC while adding dropwise 22.4g cupric bromide dissolved
in 25 ml glacial acetic acid over 1 hour. Stir 1 hour at room temperature
then 3 hours on a steam bath and evaporate in vacuum. Dissolve the residue
in 200 ml water and 300 ml ether. Wash the ether layer with 2X50 ml 10%
sodium dithionite, 2x35 ml saturated NaHCO3 and 75 ml water and dry,
evaporate in vacuum to get olivetol (or analog).

For the 1,2-dimethylheptyl homolog proceed as follows.

Combine 15g 5,6-dimethylundec-3-ene-2-one with 19g diethylmalonate as
described above to get (I). Brominate 20.2g (I) with 12g bromine over 2
hours as described and stir 1 hour at room temperature. Add 500 ml water
and let stand overnight at 5-10øC. Filter, wash precipitate with about 4x75
ml cold water and dry in vacuum at 50øC to get 26g 3-bromo-2-OH-4-oxo-6-
(1,2-dimethylheptyl)-cyclohex-2-ene-1-methylcarboxylate(II).
In a 3 liter 3 necked flask with a stirrer, thermometer, reflux head and
Dean-Stark trap, add 350g (II) and 522g pyridine hydrochloride and heat on
oil bath at 90øC 4 hours. Heat with the heating mantle (removing volatiles
with the Dean-Stark trap) until the internal temperature reaches 190-200øC
and hold at this temperature 2 hours. Cool to room temperature and shake
with 3 liters ether and 660 ml 1.2N HCl and then 2x300 ml water. Extract
the ether solution with 4x350 ml 10% NaOH and then extract the combined
NaOH extracts with 2x300 ml ether. Acidify the alkaline solution with about
700 ml concentrated HCl and extract with 3x800 ml ether. Wash the combined
ether extracts with 3x300 ml 10% sodium dithionite, 2x300 ml saturated
NaHCO3 and 300 ml water and dry, evaporate in vacuum the ether to get the
5-(1,2-dimethyl-heptyl) resorcinol.

        To prepare the 3-nonene-2-one condense excess acetone with
n-hexaldehyde (or 2,3-dimethyloctanal for 5,6-dimethyl-undec-3-ene-2-one)
in the presence of NaOH in an inert medium if desired (benzene, toluene,
xylene, etc.), at 10-70øC to get (I). Dehydrate (I) with sodium sulfate or
cupric sulfate in an inert medium at reflux temperature or simply reflux in
benzene, xylene or toluene.

5-Alkylresorcinols JOC 37,2901(1972)
For 5-alkylresorcinols see Chem. and Ind. 685( 1973) also.

        This is an improved version of a previously given synthesis (LAC
630,71 (1960)). The ethanol used is distilled from Ca ethoxide;
dimethoxyethane from potassium. Cupric bromide is produced from cupric
oxide and 5% excess of HBr, plus sufficient bromine to remove the milkiness
on addition of a drop of the mixture to water; concentrate and dry,
evaporate in vacuum over KOH flakes.
        650g (5.3M) ethyl chloroacetate and 880g (5.3M) triethyl phosphite
are mixed and placed in a 3 liter flask fitted with a thermometer and
condenser under nitrogen. Heat and stir and slowly bring to 125øC.
Discontinue heating as ethyl chloride evolution proceeds over 1/2 hour.
Heat to 160øC over a 75 minute period and keep at 160o C 8 hours.
Cool,distill (e.g., through 12" Vigreux column) (74-7/0.03) to get 96%
yield of triethylphosphonoacetate (I). In a 3 liter flask fitted with a
stirrer, dropping funnel and condenser, place 45.3g NaH (1M in mineral oil)
and 1 liter of dry ether. Flush with nitrogen and keep at positive nitrogen
pressure. Stir in ice bath while 224 g (1M) (I) is added dropwise over 75
min. Stir and reflux 1 hour (H2 evolution stops). Cool in ice-salt bath and
add 1M of aldehyde (e.g., hexaldehyde for olivetol) over 1 hour. Continue
to cool and stir an additional 10 minutes and then slowly bring to reflux
and reflux for 10 minutes (ppt. prevents stirring). Decant the ether and
dissolve the oil layer in 500 ml warm water and separate the upper organic
layer. Extract the aqueous layer with 200 mI ether and extract the combined
organic solutions with 200 ml saturated NaHCO3. Dry and evaporate in vacuum
(can distill) to get the ethyl-á-alkylacrylates in about 90% yield (II).
        In a flask with nitrogen and fittings as in preceding step, add 156
g ethyl acetoacetate to Na ethoxide from 25.3g Na and 500 ml dry ethanol,
and stir and reflux 1/2 hour. Add 1M of (II) dropwise over 90 minutes and
reflux 20 hours. Cool in ice, filter, wash ppt. with 500 ml ice cold
absolute ethanol and several times with portions of ether and dry,
evaporate in vacuum to get the dione Na salt (III) in about 80% yield (for
olivetol precursor). In a 250 ml flask place 0.1 M (III),100 ml
1,2-dimethoxyethane and flush with nitrogen and stir at room temperature
while 45g of cupric bromide is added portionwise over 5 minutes, under a
nitrogen stream. Stir 1/2 hour and then reflux and stir 1 hour. Cool and
evaporate (keep temperature below 50øC) but do not remove more than about
65 ml dimethoxyethane. Dilute the remaining solution with 200 ml benzene
and filter. Wash the ppt. with 50 ml benzene and evaporate the combined
benzene filtrates (keep temperature below 50øC). Dissolve the bromodione in
100 ml dimethylformamide and put in 500 ml flask under nitrogen. Stir and
heat slowly until reflux and then heat to 150øC and reflux 4 hours. Cool,
pour into 500 ml water, extract with 3x100 ml dichloromethane and dry,
evaporate in vacuum to get the ethyl-6-alkyl-2,4-dihydroxybenzoate (IV).
Add a solution of 24g NaOH in 200 ml water to (IV) and stir and reflux
under nitrogen in hood for 3 hours. Cool in ice bath, acidify carefully
with a cold solution of 20 ml concentrated sulfuric acid in 80 ml water
while stirring under nitrogen in ice bath. Reflux under nitrogen 5 minutes,
cool, extract 3 times with ether and dry, evaporate in vacuum the combined
extracts to get about 80% yield of olivetol (or analog). The last step may
not be necessary since (IV) may yield an active THC.

Dimethylheptylresorcinol CA 65,20062(1966)

        This method is specifically designed to produce good yields of
dimethylheptylresorcinol, which provides, after synthesis by any of the
various routes, one of the most active THC analogs yet discovered. Note
that the synthesis may not have to be carried all the way to the
alkylresorcinol since the intermediate ketones etc. may give an active THC
analog.
        Mix 294g (1.6M) 1,3,5-trichlorobenzene, 184g (3.4M) Na methoxide
and 450g (3 3M) diglyme and reflux at 162øC for 42 hours. Cool to room
temperature, filter and distill the solvent to get 70% yield of
1-Cl-3,5-dimethoxybenzene (I). 43.2g (I) in 540 ml tetrahydrofuran is added
dropwise to 7.3g Mg, a small crystal of iodine and a few drops of ethyl
bromide (under nitrogen if possible) over 1/2 hour while the mixture is
heated to 75øC. Reflux 2 hours and cool to room temperature to obtain the
Grignard solution.
        To anhydrous liquid ammonia in a cooled flask, add Fe(NO3)3*9H2O
and then small pieces of sodium and bubble air through the solution until
reaction is observed. Add more sodium portionwise until 11.5g is in
solution. To the solution at its reflux temperature, add 27.6g (0.5M)
proprionitrile (or isobutyronitrile etc. for analogs) and add the resulting
solution dropwise to 53.3g 1-Cl-pentane (or 0.5M analog such as 2-Br-hexane
etc.) and let the ammonia evaporate. Add ether, then water to the residue
and separate the aqueous layer and extract with ether. Dry and evaporate in
vacuum the combined ether solutions to give 64% yield of
2-methyl-heptanonitrile (II) (or analog).
        Add 34.0g (0.27M) (II) in tetrahydrofuran to the Grignard solution
of (I) over 1/2 hour, heat 6 hours at 60øC and hydrolyze with 1600 ml 50%
sulfuric acid, keeping the temperature below 40øC. Evaporate in vacuum the
solvent and add another 400 ml 50% sulfuric acid. Heat 1 hour at 95-100øC,
cool, add ether, separate the aqueous layer and extract with ether. Dry and
evaporate in vacuum the combined ether layers to get 71% yield
2-(3,5-dimethoxybenzoyl) heptane (III) (can distill 133-8/0.2), which can
be demethylated as described for the preparation of (VII) below and
possibly used to synthesize an active THC analog (as can IV, V, or VI).
        21.8g (0.082M) (III) is added dropwise (keeping the temperature at
15-20øC) to 3 molar methyl-MgBr in ether and refluxed 1 hour. Pour into a
sulfuric acid-ice mix, add more sulfuric acid and stir. Separate and
extract the aqueous layer with ether. Wash, dry, filter and evaporate in
vacuum the combined ether layers to get 2-(3,5-dimethoxyphenyl)-3-methyl-
octanol (IV), which is dehydrated by mixing with anhydrous oxalic acid and
heating to 130-40øC. Extract the dehydrated reaction products with benzene
to get the octenes (V). Add 25g (V), 2.5g 65% Ni on kieselguhr in dry
hexane to hydrogenator and hydrogenate at 1750 psi and gradually increase
the temperature to 125o C. After 3 hours, increase the pressure to 1850 psi
and hold there 2 1/2 hours. filter and evaporate in vacuum to get
2-(3,5-dimethoxyphenyl)-3-methyl-octane (VI).
        Add 20g (0.08M) (VI) to 38% HBr in glacial acetic acid and stir and
reflux for 6 hours. Pour onto ice and water, neutralize with solid sodium
carbonate and extract with ether. Extract the ether with 10% aqueous NaOH,
acidify the aqueous solution with HCl, extract with ether and dry,
evaporate in vacuum (can distill) to get 2-(3,5-dihydroxyphenyl)-3-methyl-
octane (VII) (5-(1,2-dimethylheptyl)-resorcinol).
        As an alternative process for getting from (III) to (VI), combine
64.2g (0.18M) methyltriphenylphosphonium bromide in dry benzene with 11.6g
(0.18M) (in 14% solution) butyllithium in benzene. Heat to 60øC and cool.
49.0g (0.176M) (III) in 40 ml dry benzene is added (keep temperature below
40øC) and then reflux 2 hours. Cool, filter and evaporate in vacuum to get
the octene, which after catalytic hydrogenation as described for (V) yields
(VI).

5-A Alkylresorcinols Aust. J. Chem. 21,2979(1968)

        Mix 50g 3,5-dihydroxybenzoic acid, 250 g K2CO3, 200 ml
dimethylsulfate and one liter acetone and reflux 4 hours. Remove the
acetone, add one liter water and one liter ether to the residue and
extract. Wash the ether extract with 2x100 ml concentrated NH4OH, 2x100 ml
dilute HCl and 100 ml water and dry, evaporate in vacuum to get 48g
methyl-3,5-dimethoxybenzoate (I). Recrystallize from aqueous methanol. To a
stirred suspension of 19g lithium aluminium hydride in 200 ml ether add
78.4g (I) in 300 ml ether at a rate which gives gentle refluxing. Reflux 2
1/2 hours, cool and add 50 ml wet ether; then 100 ml dilute sulfuric acid.
Wash and dry, evaporate in vacuum the ether extract to get 62g oily
3,5-dimethoxybenzyl alcohol (II). Recrystallize from ether-pentane. To a
cooled stirred slurry of 15g CrO3 and 250 ml pyridine add 8.4g (II) in 25
ml pyridine and let stand 1 hour at room temperature. Add 60 ml methanol,
let stand 2 hours, and dilute with 500 ml 5% NaOH and 500 ml ether. Extract
the aqueous layer with ether and wash the combined ether layers with 500 ml
water, 3x500 ml 5% sulfuric acid, 500 ml water and 200 ml saturated NaCl
and dry, evaporate in vacuum to get 7g 3,5-dimethoxybenzaldehyde (III).
Re-crystallize from ether-pentane. To a flask with a dropping funnel and
condenser add 0.58g Mg turnings and 10 ml ether. Add a few drops of a
solution of lauryl bromide (5.7g) or equimolar amount of homolog in 15 ml
ether and start reaction by adding 2 drops methyl iodide. Add the remaining
bromide solution with stirring and gentle refluxing over 15 minutes and
then reflux 3 hours. Cool in an ice bath and add 3.1g (III) in 5 ml ether
dropwise with stirring over 45 minutes. Reflux 4 hours, cool and dilute
with ice water. Wash the organic layer with 2x25 ml 3N sulfuric acid, 2x25
ml 10% K2CO3, 25 ml water, 25 ml saturated NaCl and dry, evaporate in
vacuum to get 5g 3,5-dimethoxyphenyldodecyl methanol (IV) or homolog.
Recrystallize from methanol. Hydrogenate 4.2g (IV) in 50 ml ethyl acetate
with 5 drops concentrated sulfuric acid and 0.5g 10% Palladium-Carbon
catalyst at room temperature and 5 atmospheres hydrogen for 4 hours. Filter
and evaporate in vacuum to get the aklylresorcinol dimethyl ether.
        Aust. J. Chem. 26,799(1973) gives a 2 step synthesis of
5-alkylresorcinols by condensation of beta-ketosulphones with
3,5-dimethoxybenzyl bromide and then reduction. Aust. J. Chem. 26,183(1973)
gives a synthesis from 3,5-dimethoxy-N,N-dimethylbenzylamine in 7 steps
(but perhaps only 4 will reach a cpd. that can give an active THC analog).

5-alkylresorcinols CPB 20,1574(1972)

        To a solution of 0.02M ethyl-á-ketocaprylate (or homolog) in 20 ml
tetrahydrofuran, add 1.02g (0.02M) (53% oil) NaH with stirring and cooling
and then add a solution of diketene (1.68g, 0.02M) in 20 ml tetrahydrofuran
dropwise, keeping the temperature between -5 and 0øC. Stir 1 hour at this
temperature and then 1 hour at room temperature. Neutralize with 10% HCl
and extract with ether. Dry and evaporate in vacuum to get about 38% yield
of ethyl-olivetol carboxylate (I). (I) can be purified on silica gel, the
impurities being eluted with petroleum ether (30-35øC) and the produce with
8:1 petroleum ether:ether. Recrystallize from n-hexane. Dissolve 0.2g (I)
in 10 ml 10% NaOH and reflux 30 minutes. Acidify with 10% HCl and extract
with ether. Wash the extract with water and dry, evaporate in vacuum (can
distill 126-129/3) to get 96% olivetol (or homolog)

        For new, simple, high yield syntheses of 5-alkyl resorcinols see TL
4839(1973), 2511 (1975) and CJC 52:2136(1974). A superior, high yield, 3
step synthesis of olivetol and analogs has recently appeared in JOC
42:3456(1977).

-------------------------------------------------------------------------

		   MAGIC MUSHROOMS AND OTHER INDOLE TRIPS

        Various trees, vines, etc. and mushrooms containing
dimethyltryptamine (DMT) and analogs have been used by the natives of
Central and South America for millennia. Precise chemical and botanical
identification have been made on a number of species, the first and most
famous of these being certain species of mushrooms of the genus Psilocybe,
species of which are found in the U.S.A., Canada, Scotland, Australia, etc.
as well as Central America. Psychedelic species of the closely related
genera Conocybe, Stropharia, Pholiota, Copelandia and Panaeolus are found
widely scattered around the world. Not all species of each genus
necessarily contain significant amounts of hallucinogens, but it seems that
most do. A general test is that the stem of indole containing species tends
to turn blue several hours after it is picked and slightly crushed. These
are generally found in late summer and fall in the U.S.A. Pictures are
given in many mushroom books including R. Heim, LES CHAMPIGNONS
HALLUCINOGENES DU MEXIQUE (1958), and L. Enos, A KEY TO THE AMERICAN
PSILOCYBIN MUSHROOM (1971).

	It turns out that the home cultivation of psilocybin mushrooms is
quite easy. See Oss and Oeric PSILOCYBlN: MAGIC MUSHROOM GROWER'S GUIDE
(1976 - And/Or Press) or THE COMPLEAT PSILOCYBIN MUSHROOM CULTIVATOR'S
BIBLE (1976 - Hongero Press). Strains of Stropharia cubensis being grown on
the West Coast are sufficiently strong that I have seen people who were
very experienced with acid get higher than they had ever been on three
fresh mushrooms. Remember that psilocybin is cross-tolerant with LSD, so
you won't get off as well if you've done acid recently.

	Puffballs of the genus Lycoberdon are also hallucinogenic, and
activity has been claimed for Boletus satana, which occurs in the
southeastern U.S.

	In THE TEACHINGS OF DON JUAN, Don Juan seems to have taught Carlos
to smoke the mushrooms, which might provide a different or heavier trip
than ingesting them since they undoubtedly contain many compounds like DMT
and 5-methoxy-DMT which are not orally active.

	Puffballs seem to usually produce only auditory hallucinations. L.
marginatum found over much of Europe and America is active ( 1 or 2
constitutes a dose).

	New Guinea "mushroom madness" is apparently due to species of
Boletus, Russula and Heimiella. See R. Heim NOUVELLES INVESTICATIONS SUR
LES CHAMPIGNONS HALLUCINOGENES (1967). Also see FIELD GUIDE TO THE PSILO-
CYBIN MUSHROOM (available from P.O. Box 15667, New Orleans, LA 70175).

	Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) and psilocin
(4-hydroxy-DMT) are among the active indoles in the mushrooms. Upon
ingestion, psilocybin is hydrolyzed to psilocin; consequently there is no
point in carrying the synthesis past the psilocin step. All the active
naturally occurring compounds in this group seem to have the dimethylamine
moiety, which is usually obtained in the course of chemical synthesis by
using dimethylamine (DMA). If however, the DMA is replaced by diethylamine
(DEA), dipropylamine (DPA), methylethylamine (MEA), pyrrolidine, etc., the
potency and duration of action might be considerably increased. Likewise,
an increased activity might be seen when the OH position of psilocin is
replaced by methoxy or acetoxy. Human data are lacking for most of these
compounds, but judging from animal experiments, the order of potency should
be roughly as follows (MET is methylethyltryptamine, DET is
diethyltryptamine):

4 or 5 AcO-MET > 4 or 5 MET > 4 or 5 MeO-DET >4 or 5 MeO-DMT > 4-OH-DMT > DMT
                  5-AcO-DMT                                               DET

	Compounds with a low relative activity (e.g., DMT, DET, 5
methoxy-DMT) have very little activity orally and must be smoked or
sniffed. Unfortunately, these compounds taste and smell like burning
plastic when smoked and are harder to smoke than hash. There is, however,
no evidence for the notion that they are damaging. With the exception of
DMT, DET, psilocin and psilocybin, most of these compounds are probably
legal in most states.

[Picture of Psilocin deleted]

	In the case of the unsubstituted N, N-diakyltryptamines, duration
of action increases as the chain gets longer in the order DMT, DET, DPT,
and seems to decrease with further increase in length. The trip produced by
a good dose of DMT typically lasts about one-half hour, whereas that for
DPT can last three to four hours or more. There is some evidence that DET
produces a better (i.e., more meditative and euphoric) trip than DMT.

	If the alkyl side chain at the 3 position of the indole nucleus is
shortened (e.g., gramine) or lengthened (e.g., 3-(3-dimethylamino)-propyl
indole) activity seems to decrease strikingly. Also, as the substituents
are moved around the benzene ring of indole, activity decreases greatly in
the order 4,5,6,7. For example, whereas 4-OH-DMT(psilocin) is active at
about 5 mg orally (i.e., about as active as STP), 5-OH-DMT (bufotenin) is
not psychedelic at all.

	The effects of 5-methoxy-DMT are unpleasant for most people
(smoking it gives me nausea plus the feeling that I'm being sat on by an
elephant), but it is not known whether other substituents in the 5 position
or in the 4 and 5 positions simultaneously will be similarly distressing.

	DMT, DET, etc. are remarkably fast acting (peaking in ca. 2 minutes
after a good toke or snort) and produce very strong visual effects (my
first toke of DMT produced a large grinning green dragon with red ruby eyes
that lasted as long as the Stones' "Sympathy for the Devil"). It is
unfortunate that it is usually DMT rather than the longer acting DET or DPT
that is available, especially since the latter cpds. are no more difficult
to produce. Also, it is rumoured that N,N-dibutyl and longer alkyls are not
only active but (along with the dipropyl, diisopropyl etc. cpds.) orally
active.

	Ken Kesey has reputedly said that alpha-methyltryptamine, in oral
doses of ca. 30 mg, peaks in about 12 hours, produces a trip similar to
psilocybin, but nicer, and is the "Rolls Royce of psychedelics," but others
find it unpleasant. Alpha-ethyltryptamine produces minimal LSD-type effects
at 150 mg orally, but effects of these when smoked or inhaled are unknown.
N,N-disubstituted tryptamines which have substituents in the alpha or beta
positions should also be quite interesting.

			 Identification of Indoles

				Keller Test

	Add a little of the powdered substance (about 0.2 mg to 1 ml
glacial acetic acid containing 0.5% FeCl3, layer underneath with 1 ml
concentrated sulfuric acid and shake. The color varies with the indole,
being olive green for psilocin and red-violet for psilocybin.

			       Van Urk Test

	Prepare Van Urk reagent by adding 0.5 g p-dimethylaminobenzaldehyde,
100 ml water, 100 ml concentrated sulfuric acid. Dissolve 1 mg substance in
1 ml ethanol and mix with 2 ml Van Urk reagent and illuminate for 10
minutes with an ultraviolet lamp (black light). Psilocin gives a blue-grey,
psilocybin a red-brown color.
	Colors produced in these two tests by many indole derivatives are
given in HCA 42,2073(1959).

	      Quick, Easy, On-the-Spot Test JPS 56,1526(1967)

	Saturate strips of filter paper with 2% p-dimethylaminobenzaldehyde
in 45% ethanol; air dry and store in tightly stoppered amber bottles (or
keep in stoppered container in dark) which will keep them useful for
several months. Put a little of the suspect substance in a few drops of
ethanol (gin may do, but do a control), wet a filter paper strip in this
and allow to dry. Put one drop concentrated HCl on the dried paper (don't
let it touch anything). Alternatively, the powder can be placed directly on
the strip and the HCl dropped on it. A violet red or violet blue spot
indicates indole derivatives such as LSD. With DMT or psilocybin the color
is redder. The color must be observed soon after adding the HCl since it
rapidly changes.

			Dialkyltryptamine Syntheses

	   Dialkyltryptamines HCA 42,2073(1959) and many others

	To 25 g indole (or 50 g 4-benzyloxyindole or 0.21 M other indole)
in 1 L dry ether at 0ø add a solution of 50 ml (75 g) oxalyl chloride in
1 L dry ether carefully and with good stirring a little at a time over 1/2
hour and stir until bubbling ceases (about one-half hour more). Some
indoles require a longer reaction time (e.g., 4-Cl-indole requires fifteen
hours refluxing) and some will not react (e.g., 4-Br-indole). Add
portionwise, carefully with stirring at 0ø, a solution of 225 ml (160 g)
diethylamine (DEA) (or 0.46M dipropylamine, pyrrolidine, etc.) in 100 ml
dry ether at 0ø. Stir and let warm to room temperature; cool, filter, and
wash precipitate two times with ether to get (I). This can be
recrystallized by dissolving in the minimum volume of 1:1 methanol:benzene
(or 95% ethanol), gently heated, cooled to 0ø and filtered (or add
petroleum ether to induce precipitation). Dissolve 25 g (or 0.102 M) (I) in
the least volume (about 200 ml) THF and add very carefully and slowly
(preferably dropwise) to 20 g lithium aluminum hydride dissolved in the
least volume (about 200 ml) tetrahydrofuran at room temperature. Stir and
heat under reflux for about fifteen hours. Cool to Oø and slowly and
carefully add a little cold methanol and water until no more bubbles are
formed. Filter, wash precipitate with hot tetrahydrofuran and add washings
to filtrate. Dry, evaporate in vacuum the tetrahydrofuran (or add petroleum
ether) to precipitate the dialkyltryptamine. To purify, add 500 ml
saturated sodium sulfate and filter. Wash precipitate with tetrahydrofuran;
acidify with a few ml 0.1 M HCl and shake with ether. Separate the organic
layer and neutralize with 0.1 M NaOH. Extract with CHCl3 and dry, evaporate
in vacuum the extract (or can evaporate until a few ml left and precipitate
by adding petroleum ether). The 4-benzyloxy-DET which would be produced if
4-benzyloxyindole is used as the starting material is probably a good
psychedelic. lf however, it is desired to change this to 4-OH-DET, add
37.5 g 4-benzyloxy-DET in 1.2 L methanol to 20 g 5% Palladium catalyst on
alumina (or 14 g 10% Palladium-Carbon) with 2.8 kg/cm2 H2 in a Parr
hydrogenator and shake twelve hours. Filter, evaporate in vacuum. Other
hydrogenating methods might also split off the benzene ring. Other methods
(LAC 576,69(1952)) must be used for reducing a methoxy group to a OH group
(another demethylation method is given here later).

        If (I) has an alkyl group in position 1 (as in some of the
following syntheses), reduction will give the indolylhydroxylamine. This
may be active, but if the indolamine is desired (I) (substituted or not)
may be reduced with the diborane method given later in this section.
Dialtryltryptamines JCS (C) 2220(1967)

	This procedure gives about 20% yield with indole, but the yield
with substituted indoles (e.g., 4-OH-indole for producing psilocin) has not
been reported.

        Cool 32 g ethyl iodide to 0øC; dissolve in 50 ml anisole (other
solvents won't work) and add 8 ml to 5.28 g Mg turnings in 50 ml anisole,
and add the rest gradually. Warm gently to start the reaction, and if
necessary add a crystal of iodine or a small amount of ether for a rapid
rate. Stir well and heat at 50-60ø for one hour (under N2 if possible).
Cool to 10ø and add dropwise over one-half hour 12 g (0.1 M) indole in 50
ml anisole (keep temperature below 25ø). Stir forty-five minutes at 50ø and
cool to -5ø. Finely grind 0.2 M (34 g) 1-Cl-2-diethylaminoethane-HCl (or
the corresponding diisopropyl, pyrrolidyl, etc. compounds) and suspend in
about 20 ml benzene at Oø. The free base in benzene can also be used, if
obtainable. Stir and take pH to 8.5 with 40% NaOH. Add anhydrous potassium
carbonate until the water layer is semisolid. Decant the benzene and
extract the residue with 4X 15 ml benzene. Dry the combined benzene
extracts with KOH pellets for less than an hour and quickly proceed to the
next step. Add the benzene solution (about 80 ml) slowly over one hour to
the above solution of indole in anisole at -5ø. Stir three hours at -5ø and
let sit five hours at -5ø. Then let warm to room temperature and dry,
evaporate in vacuum (or to purify, break up the precipitate and pour the
solution on 500 ml saturated aqueous NH4Cl. Stir one-half hour; separate
the organic layer and extract the aqueous layer with ether. Combine the
organic solutions and extract three times with 10% HCl. Wash HCl extract
with ether; cool to Oø, basify with 40% NaOH and extract three times with
ether. Dry, evaporate in vacuum this second ether extract to get the oily
DET or analog).

	       4-Substituted Dialkyltryptamines CT 279( 1970)
			  (cf. JOC 30,339( 1965))

	Beta-carbomethoxypropionyl chloride (Org. Synth. 25,19 (1945)).
Dissolve 400 g succinic anhydride in 190 ml methanol in 1 L round bottom
flask and reflux (steam bath) one-half hour. Stir until homogeneous (about
twenty minutes) and reflux one-half hour. Evaporate in vacuum and cool the
residual liquid to precipitate about 500 g methyl-hydrogen succinate (I).
Dissolve 264 g (I) in 200 ml SOCl2 in a 1 L round bottom flask with a
reflux condenser and warm at 30-40ø in water bath for three hours.
Evaporate in vacuum the SOCl2 (can heat flask in steam bath) to get 270 g
of the title compound (can distill 92/ 18).

	Add excess diethylamine to beta-carbomethoxypropionyl-Cl in dry
ether to get (see above JOC reference) 3-carbo-methoxy-N,N-
diethylpropionamide (I). 206 g (I) in 3 L, three-necked round bottom flask
in ice bath with stirrer, dropping funnel and reflux head. Keep temperature
at 10-20ø and add 169 g POCl3 dropwise over fifteen minutes. Remove ice
bath and stir fifteen minutes and replace ice bath. Add 250 ml ethylene
chloride, cool to 5ø. Stir and slowly add 67 g pyrrole in 250 ml ethylene
chloride over 1 hour. Remove ice bath and reflux fifteen minutes (HCl
evolution). Cool to room temperature and add solution of 750 g sodium
acetate trihydrate in 1 L water dropwise at first, then as rapidly as
possible. Reflux fifteen minutes with stirring, cool and remove ethylene
chloride in separatory funnel. Extract aqueous phase with 3x200 ml ether
and wash combined ethylene chloride and ether with 3x100 ml saturated
aqueous Na carbonate (add carefully at first). Dry, evaporate in vacuum the
organic phase to get 132 g methyl (pyrrolyl-2')-4-keto-4 butyrate (II) (can
distill 135-45/0.2) (recrystallize from cyclohexane). Alternatively, (Chem.
Commun. 1429(1968)), condense 1,3-cyclohexanedione and aminoacetaldehyde
dimethylacetal in benzene with p-toluenesulfonic acid. Azeotropic removal
of water gives a compound which, when treated with 3N HCl, gives compound
(IV). But it has been claimed that this alternative method does not work.

	94 g (II), 1.5 L diethylene glycol, 93 g hydrazine hydrate and heat
at 100ø fifteen minutes. Add 150 g potassium carbonate a little at a time
and raise temperature slowly. Heat four hours at 190-200ø and pour onto 5
kg ice. Acidify and then extract with 5x400 ml ether. Wash extract with a
little saturated NaCl and evaporate in vacuum to get about 48 g
4-(pyrroly-2')-butyric acid (III) (recrystallize-cyclohexane). Can purify
the oily compound by filtering through 80 g silica and 80 g Celite (elute
with benzene). 24 g (III) in 400 ml 1,2-dichloroethane; cool to -5ø and add
15.8 g triethylamine and 17 g ethyl chloroformate. Let stand 1 hour at 15ø;
filter and wash precipitate with 100 ml dichloroethane. Add 0.5 L anhydrous
ZnCl2 (freshly fused) and let stand two hours at -5ø. Add 0.5 L 2N HCl,
decant and wash the aqueous phase three times with CHCl3; dry, evaporate in
vacuum (can chromatograph as for (III)) to get about 11 g
4,5,6,7-tetrahydro-4-indolone (IV). 7.35 g (IV), 5 g 10% palladium-carbon,
700 ml mesitylene and reflux eight hours or more. Filter hot, wash
precipitate with methanol, cool and evaporate in vacuum (can chromatograph
as for (III)) to get 5 g 4-OH-indole (V) (recrystallize from petroleum
ether), which can be converted to the diakyltryptamine by any of the
methods described here or as follows (the first step leading to (VI) may
not be necessary). 5 g (V), 20 ml pyridine, 10 ml acetic anhydride and heat
in water bath 10 minutes. Pour on ice, stir and add NaHCO3. After one-half
hour extract with ethyl acetate, wash extract with NaCl and dry, evaporate
in vacuum to get about 6.3 g 4-acetoxy-indole (VI). 6 g (VI), 150 ml ether;
cool in ice-salt bath and add carefully 6 ml oxalyl-Cl. After four hours
add 20 g dry dimethylamine or equimolar amount other amine and stir twenty
hours. Filter, wash precipitate with ether and then water to get about 2.8
g 4-acetoxy-3-indolyl-N, N-dimethylglyoxylamide (VIIa) (recrystallize-
isopropanol). Shake the ether with water and filter to get about 5 g of the
4-OH compound (VIIb) (recrystallize-isopropanol). 7.8 g (VIIa or b or
mixture obtained by evaporating in vacuum the ether above), 17 g lithium
aluminum hydride, 150 ml tetrahydrofuran or dioxane; reflux seventeen
hours, carefully add water and stir until bubbling ceases and evaporate in
vacuum to get about 4.7 g of psilocin or analog (about 5% overall yield).
For other methods of synthesizing (1V) see JOC 36,1232(1971) and references
therein. For another method of reducing (IV) see Chem. Het. Cpds.
(Russian), 572(1972).

		      4-Substituted Dialkyltryptamines
	      HCA 42,2073(1959), 38,1452 (1955), CT 276( 1970)


        Method is illustrated for 4-benzyloxyindole (I) but will probably
work for most other substituted indoles.

        A: Convert (I) to 4-benzyloxygramine (II) as described elsewhere
here.
	B: Add 30 g (II) over one-half hour to 420 ml methyl iodide and let
stand fifteen hours at 5ø. Separate the iodomethylate which precipitates,
dry briefly at 50ø and heat with vigorous stirring at 80ø for two hours
with 60 g NaCN in 1 L water. Extract with CHCl3, dry and evaporate in
vacuum the extract and dissolve the residue in 250 ml ether. Filter,
evaporate in vacuum to a few ml and precipitate the acetonitrile (III) by
adding petroleum ether. The acetonitrile can also be prepared directly from
the indole via the Grignard reagent as given elsewhere here.
	B (Alternative): 0.05 M (II), 0.76 ml glacial acetic acid in 75 ml
tetrahydrofuran (dry) are added slowly with stirring and cooling over
one-half hour to a solution of 25.2 ml dimethylsulfate and 0.76 ml glacial
acetic acid in 30 ml dry tetrahydrofuran. After two hours, filter and wash
the precipitate with ether. Dissolve precipitate in 10% aqueous solution of
KCN and heat one hour at 70ø. Filter, wash precipitate with water and dry
to get (III).
	C: 0.04 M (III) in 200 ml 33% ethanol solution of DMA or other
amine, 2.5 g Raney-NI, 40o, 100 kg/cm2 (about 100 atmospheres) H2. Heat
about three hours; filter and evaporate in vacuum to get the
dialkyltryptamine.
	C (Alternative): 5.8 g (III), 12 g KOH, 36 ml ethanol, 28 ml water;
reflux fifteen hours, add 15 ml glacial acetic acid, filter and add 150 ml
water to precipitate 4-benzyloxyindole acetic acid (IV). Filter, wash
precipitate with water and recrystallize from methanol.
	D 1.76 g (IV), 1.4 g PCl5, 50 ml ether at Oø. Stir until dissolved
and add dropwise to solution of 5.36 g DEA (or equimolar amount other
amine) in 10 ml ether. Let warm to room temperature, let stand one-half
hour and precipitate by adding water. Filter, dry, evaporate in vacuum the
ether and add the residue to the precipitate to get the diethylacetamide
(V) (recrystallize-benzene).
	D (Alternative): 20.6 g (IV) in 50 ml methanol; add excess
diazomethane in ether, evaporate in vacuum and dissolve the oil in 90 ml
dry hydrazine. Heat at 135ø 1 1/2 hours, add 150 ml water and cool to
precipitate the hydrazide (recrystallize-aqueous methanol). 14.7 g of the
hydrazide in 250 ml tetrahydrofuran or dioxane and add 50 ml 1 N NaNO2.
Cool to 4ø and add dropwise over 4 minutes with vigorous stirring, 60 ml 1N
HCl; let stand fifteen minutes at 4ø and add 500 ml water. Extract the oily
azide with ether and dry, evaporate in vacuum. Add 77 ml (0.75 M) DEA (dry)
to the azide and let stand three hours at 5o with care to exclude moisture.
Evaporate in vacuum and take up the residue in NaHCO3. Extract with CHCl3
and dry, evaporate in vacuum the extract to get (V).
	E. 0.7 g (2.28 mM) (V) in 20 ml dry tetrahydrofuran; add slowly to
a well stirred solution of 0.35 g lithium aluminum hydride in 20 ml
tetrahydrofuran and keep one hour at 40ø. Carefully add 5 ml water and stir
twenty minutes. Add 15 ml 20% NaOH and extract with ether. Dry, evaporate
in vacuum the extract to get 4-benzyloxy-DET or analog
(recrystallize-ether).
	E (Alternative): To 0.4 g (V) in 15 ml tetrahydrofuran add 2.9 ml
1M borane in tetrahydrofuran and reflux one hour. Cool and heat with 5 ml 2N
HCl; evaporate in vacuum to get about 0.15 g product.

	  4-Nitro and 4-Amino-Dialkyltryptamines CJC 41,2585(1963)

	153 g alpha-Cl-butyryl-Cl, 16 g Pd on BaSO4, 1.66 ml sulfurquinoline
(Org. Synthesis 21,84(1941)), 900 ml toluene; reflux and stir while
bubbling H2 through for seven hours or until HCl evolution ceases (can
bubble effluent HCl through water to monitor evolution). Filter, wash
toluene with water, NaHCO3, water and dry, evaporate in vacuum to get 100 g
gamma-Cl-butyraldehyde (I) (can distill 28/2). 10 g (I), 20 g
3-nitro-phenylhydrazine; dissolve in the minimum volume of hot ethanol
containing 10% glacial acetic acid. Heat on steam bath one hour; cool and
add water until dark oil separates. Evaporate in vacuum the ethanol and
decant the water to get the oily gamma-Cl-butyraldehyde-3-intro-phenyl-
hydrazone(II). 29 g (II), 300 ml concentrated HCl, 200 ml benzene; stir
three hours, replace benzene with fresh benzene and stir four hours.
Combine the two benzene portions, wash with water and dry, evaporate in
vacuum to get 4 g 3-(beta-Cl-ethyl)-4 and 6-nitroindole (III). 3.56 g
(III), 200 ml ethanol, 200 ml 34% aqueous DMA (or other amine) and let
stand at room temperature for one week. Evaporate in vacuum the ethanol,
filter, dissolve the precipitate in dilute HCl and filter. Basify the
filtrate with dilute NaOH to precipitate 3 g 4 and 6-nitro-DMT (IV). 5.2 g
(IV), 350 ml ethanol, 100 ml 1N NaOH; heat to 50ø and add a solution of 3 g
Na dithionite in 15 ml 0.2N NaOH. filter hot and evaporate in vacuum to get
2 g 4 and 6 amino-DMT (can purify by dissolving in HCl, filter, basify,
extract with ether and dry and evaporate in vacuum the extract).

			5-Acetyl-DMT JMC 7,144(1964)

	40 g p-aminoacetophenone, 250 ml water, 143 ml concentrated HCl.
Slowly add 21 g NaNO2 in 200 ml water and keep temperature at 0-5ø. Add
70 g ethyl-alpha-(2-dimethyl-amino-propyl)-acetoacetate, then 63 g sodium
acetate and keep pH at 5.5-6.0 with 3N NaOH. Stir in cold two hours; basify
with NaOH and extract with 3x400 ml CHCl3. Dry, evaporate in vacuum the
extract to get 70 g ethyl-alpha-keto-delta-dimethylaminovalerate (I)
(recrystallize-benzene-petroleum ether). 50 g (I), 430 g polyphosphoric
acid and heat slowly with stirring. Foaming starts about 60ø. Slowly raise
temperature to 105ø and keep two hours. Cool to 70o; pour into 700 ml ice
water; stir to dissolve; cool, basify, extract with 3x400 ml CHCl3 and dry,
evaporate in vacuum to get 10 g 5-acetyl-2-carbethoxy-DMT (II). Test for
activity. 11.2 g (II) in 190 ml 20% HCl; reflux four hours; cool and
filter. Basify with 40% KOH and extract with 4X125 ml CHCl3 and dry,
evaporate in vacuum to get 5-acetyl-DMT.

			1-Methyl-DET BSC 1056(1962)

	135 g acetoacetic acid in two-necked flask fitted with two
condensers atop one another, the upper air cooled only, and a dropping
funnel with a tube running to the bottom of the flask. Heat to boiling and
add over forty minutes, as a vapor, 80 g DEA dried (e.g., with Na wire).
The residue can be distilled (120-140/12) and redistilled (123-4/12) to
give 100 g N,N-diethylacetoacetamide (I). 15.7 g (I) in 80 ml CHCl3 and add
dropwise 16 g Br2 in 10 ml CHCl3. Heat gently to a boil for one-half hour
and cool to precipitate.Filter, wash precipitate with CHCl3 and dry to get
25 g gamma-Br-diethylacetoacetamide (II) (use crude since decomposes on
distillation). 4.72 g (II), 4.28 g N-methyl-aniline, 20 ml dimethyl
formamide and let stand twelve hours (or 90 ml ethanol and reflux eighteen
hours) at room temperature. Slowly add 300 ml water and extract the oil
which forms with benzene. Wash with water and dry, evaporate in vacuum the
benzene extract to get 4 g precipitate (recrystallize-80% ethanol). 4 g
precipitate, 4 g ZnCl2 finely ground; heat in oil bath and keep temperature
100-110ø for forty-five minutes. Cool and dissolve precipitate in 40 ml 4N
HCl and 160 ml benzene. Separate the benzene and wash with water; basify
and dry, evaporate in vacuum to get 1.3 g 1-methyl-3-indole-N, N-diethyl-
acetamide (III) (recrystallize-ethanol). Test for activity. Recover
N-methyl-aniline by basifying the water or ethanol, extract precipitate
with ether, wash extract to neutrality and dry, evaporate in vacuum. 1.1 g
(III), 0.38 g finely ground lithium aluminum hydride, 300 ml ether and
reflux two days. Carefully add a little water and filter, evaporate in
vacuum to get 1-methyl-DET (recrystallize-ethanol). (III) can probably also
be reduced by the method described in the chemical hints section or even
more simply as follows: Dissolve 1M NaBH4 and 0.1 M (III) in 500 ml
pyridine or other solvent and reflux eight hours or more.


		      Alpha-alkyl-DMT TET 29,971(1973)

	21.6 g (0.1M) alpha-bromopropionyl (or butyryl etc.) bromide is
added dropwise over 1 hour to a well stirred mixture of 11.7 g (0.1 M)
indole and 8.1 ml (0.1 M) pyridine in 300 ml toluene at 60ø. Stir 1 hour,
cool and pour into 500 ml water. Separate the oil and dissolve in methanol.
Let stand 1-24 hours until crystals separate. Filter (recrystallize from
acetonitrile) to get 18.4 g (72%) 3-(2-bromopropionyl)indole (I). 5.2 g
(0.02M) (I), 7 ml 33% aq. dimethylamine and 3 g NaI in 100 ml ethanol are
refluxed for 20 hours, concentrated to 25 ml and poured into 200 ml aqueous
0.5M HCl. Extract with ether and basify with concentrated NH4OH.
Recrystallize from ethanol to get ca. 3g (50%) 3-(2-dimethylaminopropionyl)-
indole (II). 2.7g (II) in 50 ml tetrahydrofuran is added to a well stirred
mixture of 2.7 g lithium aluminum hydride in 60 ml tetrahydrofuran. Reflux
23 hours, carefully add 5 ml 2N KOH, filter and wash the the ppt. with
ether and dry, evaporate in vacuum the ether to get 1.65 g (66%)
alpha-methyl-DMT (recrystallize-benzene-n-hexame).

		      Alpha-methyl-DET JMC 9,343(1966)

	46.8 g (0.4 M) indole in 100 ml toluene; add to 54.5 g ethylbromide
and 12.5 g Mg turnings in 125 ml ether. After one-half hour convert the
indolyl-Mg-Br to 3-indolyl-2-propanol with propylene oxide (CA 56,3455(1962)).
8.8 g of the indolyl-propanol, 200 ml ether; add 4.4 g PBr3 and let stand
four hours. Add excess DEA and stir for a few minutes. Evaporate in vacuum
or extract with dilute HCl and basify the extract with NaOH to precipitate
the alpha-methyl-DET.

	   Dialkyltryptamines from Tryptamines BCSJ 11,221(1936)

        Illustrated for 5-methoxy-tryptamine (I). 1.5 g (I), 30 ml ethanol;
add 5 g methyl iodide (or equimolar amount ethyl iodide) and 4.5 g dry
sodium carbonate and heat five hours on water bath. Filter hot, heat
precipitate with ethanol and filter hot again. Evaporate in vacuum to get
2.5 g 1-methyl-5-methoxy-DMT.

		    Dialkyltryptamines AP 294,486(1961)

	Convert indole to indolyl-3-methyl-ketone (I) by treating indolyl-
Mg-Br (preparation already described) with acetyl-Cl, by treating indole in
POCl3 with dimethylacetamide (Vilsmeier reaction), or by reacting indole
with diketene (ACS 22,1064(1968)). 15.9 g (I) in 50 ml methanol; cool, stir
and add dropwise 16 g Brz. Reflux 1 1/2 hours on water bath; cool, filter,
wash with ether and recrystallize-methanol to get 18 g
indolyl-3-Br-methyl-ketone (II). Dissolve 11.9 g (11) in 60 ml warm
isopropanol and add 11 g 38% aqueous DMA (or equimolar amount other amine);
reflux one hour on water bath. Filter (recrystallize-ethanol) to get 8.5 g
indolyl-3-dimethylamino- methyl ketone (III). Add 4.6 g (0.02 M) (III) in
30 ml tetrahydrofuran to 2.3 g lithium aluminum hydride in 50 ml
tetrahydrofuran, stir one-half hour at room temperature and reflux two
hours. Add a little water dropwise and extract the precipitate with
acetone. Dry, evaporate in vacuum the combined organic phases to get an oil
which will precipitate with ether-petroleum ether to give DMT. (III) should
be tested for psychedelic activity.

	    Dialkyltryptamines BCSJ 11,221(1936), BSC 2291(1966)

	30 g 5-methoxy-indolyl-3-acetonitrile is heated with KOH in aqueous
methanol until no more ammonia is evolved (about 20 hours). Evaporate the
methanol in vacuum and extract the water remaining with ether. Acidify the
aqueous layer with HCl to precipitate 28 g 5-methoxy-tryptophol (I).
Alternatively, dissolve 2.3 g indole in 15 ml glacial acetic acid and 5 ml
acetic anhydride. Add with stirring 0.025M ethylene oxide, heat to 70ø for
25 hours, then hold at 20o for 50 hours in a closed flask. Pour into water
and extract with ether. Wash with water, dry, evaporate in vacuum and
saponify (e.g., heat with NaOH) the residue to get 1.5 g tryptophol (can
purify on alumina; benzene elutes indole, ether elutes tryptophol). 2g (I)
or tryptophol in 100 ml ether. Mix with 1 g PBr3 dissolved in ether and let
stand 12 hours at room temperature. Decant the liquid from the precipitate;
wash with water and NaHCO3 and dry, evaporate in vacuum the ether to get
1.3 g of the oily bromide (II). 1 g (II), 4 ml methanol, 4 ml 33% aqueous
DMA (or DEA etc.) and heat on steam bath in sealed container 15 hours.
Acidify with about 50 ml dilute HCl, extract with ether and dry, evaporate
in vacuum the ether to get about 0.5 g DMT or analog.

		     Dialkyltryptamines BSC 1335(1966)

	To 600 ml liquid NH3 add 23.5 g Na: 40 g Na-amide are thus prepared
and the NH3 evaporated in vacuum. Mix 170 g 5-CI-2-methoxy-phenylaceto-
nitrile (preparation given elsewhere) in 900 ml benzene with the Na-amide
and stir and reflux two hours. Cool to 40ø and add dropwise 111 g
2-dimethylaminochloroethane (or diethyl etc. analogs) prepared freshly in
benzene as described in a previous method, or use the base freshly
distilled. Reflux two hours, cool and add a little ethanol and water and
extract the amine by evaporating in vacuum or pouring on cool water and
filtering to get 157 g (I) (recrystallize-petroleum ether). 105 g (I) in
150 ml methanol containing 15% NH3. Hydrogenate at 50ø, 70 kg pressure, in
presence of Raney-Ni. Filter, dry and evaporate in vacuum to get 97 g of
the phenethylamine (II). Cyclise (II) with Na and naphthalene as described
later for 4-methoxyindole to get the yellow, oily indoline (111)
(recrystallize-ethanol). Test this for activity. If desired, the
noncyclised material can be eliminated by tosylation. 3.1 g (III),
preferably as the HCl salt, 200 ml water; stir and heat fifteen hours with
10 g Raney-Ni and 1.5 g maleic anhydride. Filter, dry and evaporate in
vacuum to get 4-methoxy-DMT.

			     Dialkyltryptamines

	A: CCCC 22,1848 (1957). 5.5 g indole, 15 ml cyclohexan, 1/2 g
copper. Reflux and add dropwise 2.9 g diazoacetone. After a time, the
reaction goes very rapidly and forms two layers. Filter, evaporate in
vacuum or distill (130-145/0.2) to get 2.6 g 3-indolyl-acetone (I). A
(Alternative): JCS 3175( 1952). 2 g 3-indolyl-acetic acid (preparation
given elsewhere here), 1.55 g freshly fused sodium acetate, 5 ml acetic
anhydride. Heat I 35-140ø on oil bath for eighteen hours; cool, wash with
water and extract with CHCl3-ether ( 1:4). Wash organic phase with 3x20 ml
saturated KHCO3 and dry, evaporate in vacuum to get the 1-acetyl-3-indolyl-
acetone, which can be reduced to the alpha-methyl-tryptophol derivative
with lithium aluminum hydride, and then converted to the dialkyltryptamine
as already described (as can (I)), or used in step B, or reduced to (I) as
follows: dissolve 1 g in 1 ml 1 N Na-methoxide in methanol and 60 ml
methanol, and keep at 40ø for 10 minutes: acidify with dilute HCl and
extract with ether. Dry, evaporate in vacuum to get (I)
(recrystallize-methanol).

	A (Alternative): JCS 2834(1962). 4.8 g Mg turnings, 32 g ethyl
iodide in 20 ml dry anisole. Cool to 0ø and add dropwise 15.6 g indole in
20 ml anisole. Stir one-half hour at 20ø; cool to 0ø and treat with 20 ml
prop-2-ynyl-bromide in 10 ml anisole over 20 minutes. Continue stirring one
hour at 0ø and let stand at room temperature twelve hours. Cool to 0ø, add
100 ml ether, 200 ml water, 12 ml glacial acetic acid, 100 ml water, and
extract with 5x25 ml ether. Wash with NaHCO3 and dry, evaporate in vacuum
the extract to get 8 g oily material which precipitates on standing in
refrigerator. Add 1/2g HgSO4 to 100 ml 2N sulfuric acid; stir and heat on
steam bath and add 15 g of the precipitate in 100 ml ethanol. Stir and heat
two hours and pour into water. Basify with NaHCO3 to get 3 g (I)
(recrystallize-benzene).

	B: JMC 9,343(1966). 3.3 g (I) in 100 ml ethanol; reduce over
palladium-carbon catalyst in presence of 0.04 M DEA (or other amine). After
two hours filter and evaporate in vacuum to get the DET or analog.

		  Methylethyltryptamines HCA 49,1199(1966)

	82 ml acetic anhydride, 35 ml formic acid; heat two hours at 50-60ø
with stirring and then add dropwise a solution of 100 g
4-benzyloxytryptamine (or equimolar amount other tryptamine) in 250 ml
tetrahydrofuran. Cool to room temperature and stand twelve hours. Evaporate
in vacuum, add 100 ml water and let stand two hours to precipitate the oily
N-formyltryptamine (I) (recrystallize- 700 ml 50% ethanol). 35 g (I) in I
50 ml tetrahydrofuran; add dropwise to 20 g lithium aluminum hydride in 400
ml tetrahydrofuran and reflux twelve hours. Cool to 15o, slowly add 35 ml
ethyl acetate and reflux two hours. Slowly add 10 ml water, 10 ml 15% NaOH,
30 ml water. Filter, wash precipitate with tetrahydrofuran and evaporate in
vacuum to get 20 g 4-benzyloxymethylethyltryptamine (II) or analog (can
recrystallize by dissolving in 100 ml methanol and precipitating with 10 g
oxalic acid (anhydrous)).

	Alternatively, dissolve 220 g 4-benzyloxy-3-indoleacetic acid (or
equimolar amount other indoleacetic acid) in 2 L absolute methanol and
reflux six hours in the presence of 20 g Dowex 50x8 sulfonic acid resin.
Filter (decolor with carbon if desired) and concentrate below 35ø until
precipitation starts; then cool to precipitate and filter to get 200 g of
the methyl ester. Add 200 g of the ester to 600 ml 40% aqueous methylamine
over twelve hours with vigorous stirring. Filter, wash precipitate with
water and dry to get 187 g of the N-methyl-acetamide (reflux two hours in
500 ml benzene to remove unreacted ester). 24 g of the acetamide in 300 ml
tetrahydrofuran is added dropwise to 10 g lithium aluminum hydride in 300
ml tetrahydrofuran; reflux ten hours, cool to 15ø and add dropwise with
stirring 50 ml ethyl acetate. Reflux two hours and proceed as above to get
15 g (II) or analog.

		   Dialkyltryptamines JACS 84,4917(1962)
		Illustrated for the piperidine analog of DMT

	2.5 g methyl or ethyl-indoleacetic acid (see previous method and
elsewhere for preparation), 12 ml dry piperidine and reflux twentyfour
hours. Evaporate in vacuum, dissolve residue in CHCl3; wash with dilute
HCl, NaHCO3, and dry and evaporate in vacuum to get 2.6 g
3-indolyl-aceto-piperidide (I) (test for activity). 2.6 g (I) in 80 ml
tetrahydrofuran; add 2.5 g lithium aluminum hydride in 200 ml ether and
reflux five hours. Carefully add a little water until bubbling stops.
Filter, dry and evaporate in vacuum to get the piperidine analog of DMT.

		 Tryptamine from Tryptophan JCS 3993(1965)

	10 g tryptophan in 500 ml diphenyl ether; reflux one hour under N2;
cool and extract with 3x40 ml 2N HCl. Wash extract with ether, basify with
6N NaOH and extract with 5X50 ml ether. Wash extract with water, NaCl; dry
and evaporate in vacuum and recrystallize-benzene to get tryptamine which
can be alkylated to dialkyltryptamine as described previously. (Tryptophan,
if oxidized by H2O2 and cyclised with HCl, gives a psychedelic compound.)
Much interest has been generated by the mention of tryptophan oxidation to
a psychedelic compound, but the original reference gives no details of the
method.

		   Dialkyltryptamines CCCC 24,3984(1959)

        A: 4 g 3-indoleacetic acid (I) in ether. Treat with PCl5 as
described elsewhere here to get 2.7 g of the chloride (II). Dissolve 2.7 g
(II) in 40 ml ethyl acetate and add 2 ml piperidine (or equimolar amount
other amine), 3.5 ml N-ethyl-piperidine in 40 ml ethyl acetate. Let stand
three hours at room temperature and filter. Wash filtrate with 1N HCl, 10%
Na carbonate and evaporate in vacuum to get 1 g of the amide (III) (test
for activity). Add 1 g (III) in 25 ml ether to 1.4 g lithium aluminum
hydride in 50 ml ether; stir four hours at room temperature and reflux
one-half hour. Cool and carefully add water until no more bubbling. Add 3
ml 20% NaOH and dry, evaporate in vacuum to get 1 g piperidine analog of
DMT (IV).
	A (Alternative): Treat 4 g (I) in pyridine with SOCl2 as described
elsewhere here to get (II). Treat (II) with 2.3 g triethylamine and 2 g
piperedine (or other amine) in 5 ml ether. Stir fifteen hours at room
temperature; extract with 200 ml water, and after precipitation, wash
precipitate with 10% Na carbonate, 3N HCl and dry, evaporate in vacuum the
ether solution to get (III). Reduce (III) to (IV) as above or with the
NaBH4 method or possibly with hydrogenation.

	A (Alternative): To 6 g (I) in 250 ml ether add 3.1 g piperidine
(or other amine) in 20 ml ether. Let precipitate form and filter. Heat 7 g
precipitate three-and-one-half hours at 190-215ø; cool and dissolve in 100
ml ether. Wash with 10% K carbonate and 5N HCl and evaporate in vacuum to
get (III), which is reduced to (IV) as above.

		  Dialkyltryptamines JCS 7175,7179( 1965)

	6.3 g N-Methyltryptamine in 40 ml methylformate; heat in autoclave
six hours at 100ø and evaporate in vacuum to get 7.4 g precipitate (test
for activity). Dissolve precipitate in 50 ml tetrahydrofuran and add to 2.6
g lithium aluminum hydride in 50 ml tetrahydrofuran and reflux three hours.
Carefully add a little water or methanol; filter, evaporate in vacuum to
get DMT or analog. This paper also gives four ways to prepare hydroxylamine
analogs of DMT, but their activity is unknown.

			5-Methoxy-DET BSC 1062(1962)

	If 3-methoxy-aniline is used, 6-methoxy-DET will probably result,
but if 3,5-dimethoxyaniline is used, 4,6-dimethoxy-DET should be obtained.
	A: 1M p-methoxy-aniline (p-anisidine), 0.5 M
ethyl-gamma-Br-acetoacetate (brominate as described above for 1-methyl-DET
synthesis); cool and add 250 ml ether. Filter, evaporate in vacuum and
reflux residue fifteen hours with 60 g ZnCl2 in 250 ml ethanol. Evaporate
in vacuum, wash precipitate with water and dissolve residue in benzene.
Wash with 4N HCl and water and dry, evaporate in vacuum. Reflux precipitate
two hours in ethanol-KOH to get about 70% yield of 5-methoxy-indoleacetic
acid (I).
	B: Dissolve 4.26 g triethylamine and 8 g (I) in 200 ml CHCl3; cool
to -5ø, add rapidly 4.58 g ethyl-CI-carbonate and agitate fifteen minutes.
Bubble dry NH3 through for five minutes (can possibly substitute
concentrated NH4OH) and let stand one hour at room temperature. Add water,
wash with NaHCO3 and water and dry, evaporate in vacuum the CHCl3 to get
5-methoxy-diethyl-indolyl-acetoacetamide(II). Test this for activity.
	B (Alternative): 0.5 g (I) and 0.28 g triethylamine in 5 ml
methylene Cl. Add 0.33 g dicyclohexylcarbodiimide and let stand for sixteen
hours at room temperature. Add a little glacial acetic acid, wash with
dilute HCl, NaHCO3 and water and dry, evaporate in vacuum to get (II).
	B (Alternative): Do not reflux the precipitate in ethanol-KOH in
the last part of step A. Heat 8 g of the precipitate with equimolar amount
DEA (or other amine) in 80 ml methanol in a sealed bomb or tube in
autoclave for twenty-four hours at 105ø and filter, evaporate in vacuum to
get (II) (recrystallize-ethanol).
	B (Alternative): 20 g of the unrefluxed precipitate (ethyl-ester of
(I)) from last part of step A in 100 ml ether. Add dropwise to a solution
of 4 g lithium aluminum hydride in 900 ml ether at 0ø. Reflux three hours
and isolate the resulting tryptophol as described earlier. Dissolve 3 g of
the tryptophol in 140 ml ether and stir at 0ø. Add dropwise 1.8 g PBr3 in
30 ml ether and let stand sixteen hours at room temperature. Decant the
ether and wash the precipitate with ether. Wash ether with water, NaHCO3
and water, and dry, evaporate in vacuum the ether to get the bromide
(recrystallize-ethanol). 2 g of the bromide and 1.5 g piperidine (or
equimolar amount DEA, etc.) in 65 ml methanol and heat in sealed tube
fifteen hours at 100ø (or let stand room temperature twenty-four hours).
Evaporate in vacuum to get the 5-methoxy-dialkyltryptamine.
	C: Reduce (II) to 5-methoxy-DET or analog with lithium aluminum
hydride or diborane as described previously.

		       Tryptamine CA 54,13018( 1960)

	15.4 g indole (or substituted indole) in 40 ml ether under N2; add
to 50 ml methyl MgBr in ether (2.62 M) and reflux fifteen minutes. Cool on
ice bath and add 68 ml ethyleneimine in 30 ml dry xylene. Stir 1 1/2 hours
at room temperature (add xylene to keep volume constant), reflux one hour
and cool to room temperature. Add dropwise 75 ml water and take pH to 1
with HC1. Filter, wash precipitate with ether and dissolve in 150 ml hot
water. Cool to 10ø for fifteen minutes and decolorize. Filter, neutralize
with 80 ml 10 N NaOH and stir at 5ø. Filter and dry to get the tryptamine
which can be converted to the dialkyltryptamine as described previously.
More tryptamine can be had by adjusting pH of solution to 10 with NH3 (or
NH4OH) and extract with methylene Cl: evaporate in vacuum.

		     Dialkyltryptamines BSC 1417(1965)

	Dissolve 456 g o-vanillin (2-OH-3-methoxy-benzaldehyde) and 150 g
NaOH in 1 L water and add dropwise 660 g benzenesulfonyl-Cl. Filter, wash
precipitate with water, ethanol and recrystallize-acetic acid to get 805 g
of the benzenesulfonate (I). Can probably also protect the OH group by
methylating with dimethylsulfate as described elsewhere here. However, OH
protection may be unnecessary to yield an active final product. Quickly add
250 g (I) to 2.5 L fuming HNO3 at 0ø and let stand five minutes. Pour onto
ice and filter after melting. Wash precipitate with water, ethanol and
recrystallize-acetic acid to get 171 g (II). Dissolve 170 g (II) in 2 L
methanol and reflux ten minutes. With vigorous stirring add 100 g K2CO3 in
200 ml water and 400 ml methanol. Reflux one-half hour, filter and dissolve
precipitate in boiling water; acidify to precipitate 6-NO2-o-vanillin
(about 86 g) (III). Dissolve 50 g (III) and 40 g K2CO3 in 1.2 L DMF and 60
ml water. Stir 1 1/2 hours and add dropwise benzyl-Cl and continue stirring
eighteen hours under N2 if possible and in the presence of NaI. Precipitate
by pouring on ice; filter, dry and recrystallize-benzene-petroleum ether to
get about 52 g 2-benzyloxy-3-methoxy-6-NO7-benzaldehyde (1V). Again,
methylation can probably be done instead, and this step may be unnecessary.
To 50 g (1V) in 1 L ethanol add 18 ml nitromethane, and then at -15ø add 25
g K2CO3 (or KOH) in 40 ml water and 400 ml ethanol in small portions over a
period of one hour. Keep two hours at -10ø, then acidify with 50 ml
concentrated HCl (keep temperature below 0ø). Add 2 L water, filter (or
extract five times with ether and dry, evaporate in vacuum). Heat
precipitate five minutes at 140ø with 60 g anhydrous sodium acetate and 250
ml acetic anhydride and pour on ice, filter to get 52 g of the nitrostyrene
(V) (recrystallize-methanol). 60 g (V) and 300 g iron filings in 1 L 80%
acetic acid and heat forty minutes at 95ø. Add 1 L saturated Na bisulfite
and extract with benzene; dry and evaporate in vacuum (can chromatograph on
alumina with benzene) to get 33 g 4-benzyloxy-5-methoxy-indole (VI)
(recrystallize-benzene-petroleum ether), which can be converted to the
dialkyltryptamine by any of the methods described here or as follows. 320
ml dioxane, 320 ml glacial acetic acid, 24.8 g 40% formaldehyde, 25 g DMA
(or other amine) in 40% aqueous solution. To this stirred mixture at 0ø add
34 g (VI) in 300 ml dioxane, let stand twelve hours and pour on ice.
Basify, filter and extract with HCl; basify and extract with ether (or just
dry and evaporate in vacuum after pouring on ice) to get 30 g of the
gramine (VII) (recrystallize-ethyl acetate). To 20 g (VII) in 400 ml
methanol add a solution of 9 g KCN in 20 ml water and 25 g methyl iodide
below 10ø. Stir at room temperature for twenty-four hours and evaporate in
vacuum. Dissolve residue in ether, wash with dilute HCl, NaHCO3, water and
dry, evaporate in vacuum to get the acetonitrile (VIII)
(recrystallize-ethanol). Dissolve 14 g (VIII) in 300 ml 33% ethanol
solution of DMA (or other amine) and hydrogenate at 40o and 100 atmospheres
pressure in presence of 3 g Raney-Ni for about three hours. Filter,
evaporate in vacuum (can dissolve residue in ether, dry and evaporate in
vacuum) to get 7 g of the dialkyltryptamine.

		    Indoleacetonitrile BER 58,2043(1925)

	To the Grignard reagent prepared from 2.4 g Mg, 10 ml anisole and
16 g ethyl iodide, add 7.8 g indole in 10 ml anisole. Stir and cool to 0ø.
Slowly add dropwise 5.5 g Cl-acetonitrile in 40 ml anisole. Warm to room
temperature and stir; heat to 60-70ø on water bath (a reddish precipitate
forms over about twenty minutes). Cool and purify and convert to the
dialkyltryptamine as described earlier.

			Tryptamines JOC 24,894(1959)

	Add a 1 M excess of nitroethylene dropwise to liquid
5-benzyloxyindole (or other indole) on a steam bath over two hours. Cool,
filter and recrystallize from methylene chloride-petroleum ether.
Hydrogenate at two atmospheres over 10% palladium-carbon catalyst to get
5-OH-tryptamine in 30% yield. Can probably also reduce with lithium
aluminum hydride or diborane methods.

	       4-Nitration of 5-methoxy-DMT JMC 12,321 (1969)

	Dissolve 35 g 5-methoxy-DMT (or analog) in 100 ml glacial acetic
acid, cool to 10ø, stir and add dropwise a solution of 30 ml concentrated
HNO3 in 50 ml glacial acetic acid over one-half hour. Let warm to room
temperature, stir eight hours and dilute with 1 L ice-water. Filter, wash
precipitate with water and dry to get 4.5 g 5-methoxy-4-NO2-DMT
(recrystallize-methanol).

      Methylation of OH indoles JOC 23,1977(1958), CA 74,53525 (1971)

	The procedure will not work for tryptamines. This and the two
following procedures may be used to protect the OH group during subsequent
steps, or simply to give the alkyloxy compounds which may be more active
than the OH compounds. Dissolve the OH-indole in ethanol (0.14 M in 50 ml)
and add 28 ml dimethylsulfate and 1.2 g Na hydrosulfite. Add slowly with
stirring and cooling (under N2 if possible) 12 g NaOH dissolved in 26 ml
water (keep temperature at 20-25ø). Heat to 70ø for one-half hour, cool and
dilute with an equal volume water. Extract the yellow oil into
ether-benzene and dry, filter, and evaporate in vacuum to get the
methoxyùindole.

	      Methylation of OH-tryptamines LAC 513,16( 1934)

	This should work well with OH-dialkyltryptamines Dissolve 1 g
OH-tryptamine in methanol or ether; add 2.5 g diazomethane in ether and
heat twenty hours. Evaporate in vacuum to get the methoxy-tryptamine.
Acetylation of OH-tryptamines May require modification for OH-indoles, but
probably not for OH-dialkyltryptamines. Dissolve 4.1 g OH-tryptamine in 20
ml 1 N NaOH and evaporate to dryness under N2. Dry in vacuum at 90ø and
dissolve in 50 ml dimethoxyethane. Add to 1.9 g acetyl-Cl in 50 ml
dimethoxyethane and stir four hours at room temperature. Add to dilute
NaHCO3 and CHCl3; shake and dry, evaporate in vacuum the CHCl3 layer to get
the acetyltryptamine. This will also work with benzoyl-Cl for benzoylation
and with chlorsulfonic acid for sulfonylation. Acetylation can also be done
with acetic anhydride in NaOH at 5ø.

            Demethylation of methoxy-oxyindoles BER 96,253(1963)
    The procedure may require modification for tryptamines, and indoles.

        Mix 1.63 g 4-methoxy-oxyindole and 1.5 g finely ground AlCl3 and
heat ten minutes at 220-230ø in oil bath. Cool, powder and dissolve in ice
water, evaporate in vacuum to get 4-OH-oxyindole (recrystallize-water).

                  4-Substituted Indoles from 5-OH-indoles
HCA 51,1209(1968); see also: TL4459(1966), JOC 35,3764(1970), TET 26,3685(1970)

        This method, although described for indoles, probably also works
with 5-OH-tryptamine (serotonin), and 5-OH-DMT (bufotenin); with compounds
of the latter type, orally active psilocybin analogs will be obtained in
one step. Dissolve 5 g 5-OH-indole (or analog) in 25 ml ethanol. Add 5.5 g
33% aqueous dimethylamine (or other amine, e.g., piperidine) and add slowly
dropwise with stirring 3.5 g 38% aqueous formaldehyde. Two minutes after
the end of the addition shake with water and CHCl3: dry and evaporate in
vacuum the CHCl3 phase to get 5 g oily 4-dimethyl-aminomethyl-5-OH-indole
(I) (can chromatograph on 100 g alumina and elute with ethyl acetate). It
has been claimed that this method does not work.

        Alternatively (CA 72,66732(1970)), add 1.6 g 5-OH-indole, 1g
bis-dimethyl-aminomethane in 5 ml dioxane. Heat 2 1/2 hours on water bath
to get 1 g (I) (recrystallize-methanol-dimethylformamide). For the
transformation of the dimethylaminomethyl substituent of (I) into methyl,
aminomethyl, formyl or cyanomethyl see BSC 2046(1973).

              4-Hydroxydimethyltryptamine (Psilocin) from DMT
                    C.R. Acad. Sci. Paris 275,613(1972)
            See also C.R.A.S.P. 269,51(1969) and BSC 1523(1959).

        Mix 0.01 M dimethyltryptamine, 0.02 M phosphate buffer pH 7.2
containing 5 mM ascorbic acid, 0.02 M disodium EDTA and 0.01 M ferrous
sulfate (CuCl may substitute) and add with stirring at 20-22ø 0.02M H2O2
(0.01 M may increase yield). Let reaction proceed to completion (2 hours or
less) and extract with ethyl acetate. Dry and evaporate in vacuum to get
about 30% yield of psilocin. The product, which contains the other OH-DMT's
as well, can be chromatographed on silica thin layer with t-butanol-acetic
acid-water (ACS 22,1210 (1968)) or on a 5% alumina-Nickel column or 10%
alumina-Nickel plate with CHCl3-methanol and the psilocin eluted with
methanol.

            Tryptamine from Tryptophan Synthesis 475(Sept. 1972)

        Cently reflux a suspension of 250 mg L-tryptophan in 10g warm
diphenylmethane in a stream of nitrogen (if possible) for 5-20 minutes
until there is no more CO2 evolution. Cool and evaporate in vacuum or treat
with 20 ml benzene saturated with dry HCl and filter, wash precipitate with
hexane and dry to get about 60% yield of tryptamine.

              4-Acetylation of 5-OH-indoles BCSJ 44,550(1971)

        To 2 g 5-OH-indole (or analog) in 50 ml nitrobenzene add 4 g AlCl3
in 50 ml nitrobenzene. Add 1.26 g Acetyl-Cl and heat three hours at 50ø;
evaporate in vacuum or add dilute HCl to get 1g 4-Acetyl-5-OH-indole
(recrystallize-ethyl acetate).

                 4-Substituted Tryptamines JMC 8,200(1965)

        Heat 85.5 g 3-carbethoxy-2-piperidone and 30 g KOH in 1 L water for
twelve hours at 30o. Filter, cool to 0ø, add 50 ml 6N HCl. Prepare a fresh
solution by diazotizing at 0-5ø a mixture of 85 g 3-amino-4-Cl-acetophenone,
250 ml concentrated HCl and 750 ml water with a solution of 36 g Na nitrite
in 125 ml water. Add the piperidone solution at 0ø to the diazonium salt
solution and stir five hours at 10ø. Filter, wash precipitate with water to
get 80% yield of the hydrazone (I) (recrystallize-95% ethanol). Reflux 62 g
(I) in 310 ml 88% formic acid to get 40 g of the carboline (II)
(recrystallize-absolute ethanol) (test for activity). Reflux 40 g (II), 100
g KOH, 480 ml ethanol and 360 ml water for eighteen hours and evaporate in
vacuum. Add 480 ml water to the residue, cool and adjust pH to 6 with
glacial acetic acid. Scratch glass to precipitate; filter, wash precipitate
with cold water to get 41 g 4-acetyl-2-COOH-7-Cl-tryptamine
(recrystallize-50% ethanol) which can be alkylated to the active
dialkyltryptamine as described elsewhere here.

Alpha,alpha-DMT from Gramine or Indole-3-aldehyde JCS 7165 (1965),3493(1958)

        81 g (0.465 M) gramine (or analog), 405 ml 2-nitropropane and 20.4
g NaOH are stirred and boiled under nitrogen for 20 hours. Cool and treat
with excess 2N acetic acid and ether and wash the ether Iayer with 2N
acetic acid and water and dry, evaporate in vacuum to get ca. 90%
3-(2-methyl-2-nitropropyl)indole (1a) (recrystallize-benzene-light
petroleum). See JCS 3493( 1958) for the use of the indole-3-aldehyde to get
the corresponding nitronium salt (1b). (1a) is then reduced (e.g., with PtO
at 20ø/1 Atm. in EtOH or one of the methods given elsehwere here) or (1b)
is reduced (e.g., with lithium aluminum hydride as described many times,
e.g., JMC 6,378(1963)) to give the tryptamine, which can be alkylated as
described. This paper also gives a route to other alpha and beta mono and
disubstituted tryptamines.

Reduction of Indolyglyoxamides with Diborane JOC 38,1504(1973),TET 1145(1968)

        A solution of 7mM of the indolyglyoxamide in 160 ml tetrahydrofuran
and 30 ml (30mM) 1.0M borane in THF is refluxed 2 hours and cooled.
Carefully add water, then evaporate in vacuum and dissolve residue in
ether. Wash twice with saturated saline, dry and evaporate in vacuum.
Triturate with ether and filter to get the tryptamine-borane in ca. 30%
yield. Diss. 200 mg in 2 ml xylene and 2 mI octene-1 and reflux 4 hours.
Cool, dilute with hexane and filter to get ca. 80 mg white tryptamine (or
dialkyltryptamine) (recrystallize-acetone-hexane etc.).

        Alternatively, 63 g (0.45M) BF3 etherate in 180 ml diglyme is added
dropwise with stirring to 0.15 M of the indolyglyoxamide and 12 g NaBH4 in
300 ml diglyme. Stir 12 hours at room temperature and evaporate in vacuum.
Boil residue 2 hours with methanolic NaOH and evaporate in vacuum. Take up
residue in ether, wash with water and dry, evaporate in vacuum to get the
dialkyltryptamine in ca. 80% yield.

                              Indole Syntheses

                 4-7-Dimethoxyindoles Farmaco 25,972(1970)

        Heat 1 g Cl-acetone and 7 g 2,5-dimethoxyaniline (or analog) at
boiling until complete fusion; then one-half hour at 180ø on a metal bath.
Cool, dissolve in a little ethanol and pour into 100 ml 7% HCl. Cool,
filter and dry (can distill 100/.001) to get 160 mg 4,7-dimethoxy-2-methyl-
indole (recrystallize-benzene:petroleum ether, 1:1).

                  4-Carboxyindoles CJC 49,2784,2797(1971)

        To a stirred solution of 0.05 M 2-methyl-5-nitroisoquinolinium
iodide in 250 ml water, add a solution of 11.2 g KOH in 110 ml water and
immediately add a solution of 49.4 g K ferricyanide in 300 ml water; stir
one hour at room temperature. Add 50 ml methylene chloride and 100 ml
benzene and stir until solids dissolve. Separate organic phase and extract
aqueous phase with benzene. Wash combined organic layers with 10% HCl,
water and dry and evaporate in vacuum to get about 90% yield of
2-methyl-5-nitroisocarbostyril (I) (recrystallize-cyclohexane). Mix 8.16g
(I), 18 ml acetic anhydride, 5 drops concentrated sulfuric acid and heat on
steam bath four hours. Cool to room temperature, add 25 ml water and heat
on steam bath until a single phase is produced (about ten minutes). Pour
into a large volume of water, extract with methylene chloride, wash
methylene chloride five times with water and dry and evaporate in vacuum to
get 6.8 g 2-methyl-4-acetyl-5-nitro-isocarbostyril (II) (recrystallize-
benzene). 1.64 g (ll), 200 mg 10% palladium-carbon in 100 ml ethanol and
hydrogenate at room temperature and initial pressure of 60 pounds per
square inch for one hour. Transfer to 500 ml round bottom flask under N2.
Evaporate in vacuum and add solution of 8.4 g KOH in 120 ml 50%
dimethylsulfoxide to residue. Stir and reflux seventeen hours under N2 and
then add concentrated HC1 until the dissolved silica precipitates from the
basic solution. Filter, wash precipitate with water and acidify filtrate
with concentrated HCl. Extract filtrate with ethyl acetate and then shake
ethyl acetate with Na carbonate (100g/L). Acidify solution with
concentrated HCl and extract with ethyl acetate. Wash extract with water
and dry, evaporate in vacuum to get 400 mg 2-methyl-indole-4-COOH
(recrystallize-60% ethanol). Can dissolve in methanol and chromatograph on
5 g silica gel-250 ml ethyl acetate elutes the indole.

4-OH-Indole JCS 1605(1948)

        Dissolve 0. 7 g KOH in 10 ml ethanol, cool to -10ø and add with
stirring over twenty minutes to 1 g 2-nitro-6-OH-benzaldehyde and 0.4 g
nitromethane in ethanol at -10ø. Acidify with cold HCl, add water and
extract with ether. Dry and evaporate in vacuum the ether to get a yellow
oil. Warm the oil with 2 g Na acetate and 3 ml acetic anhydride for fifteen
minutes. Add 20 ml water, separate the precipitate and add water to
crystallize about 1.3 g 2,beta-dinitro-6-acetoxy-styrene (I)
(recrystallize-ethanol). Warm gently a solution of 0.5 g (I), 2 g iron
filings, 4 ml ethanol and 4 ml glacial acetic acid until hydrogen evolution
is vigorous and continue to warm gently for ten minutes. Filter, wash
precipitate with a little warm ethanol and add water to filtrate. Basify
with Na carbonate, extract three times with ether and dry and evaporate in
vacuum the ether to get about 0.1 g 4-acetoxyindole (II)
(recrystallize-petroleum ether). If 4-OH-indole is desired, dissolve 0.1 g
(II) in 3 ml methanol and saturate at 0ø with NH3 and keep below 5ø for
sixteen hours. Evaporate in vacuum, add 50 ml water and extract with ether,
dry and evaporate in vacuum to get 4-OH-indole (recrystallize-petroleum
ether).

4-Substituted Indoles MON 100,1599(1969),101,161(1970)

        To a solution of 1.84 g Na metal in 60 ml ethanol at 5-10ø add over
1/2 hour with vigorous stirring a mixture of 0.08 M ethyl azidoacetate and
0.02 M 2 (or 2,5; 2,3 etc. but not 6) substituted benzaldehyde and continue
stirring at 5-10ø until nitrogen evolution ceases (about 1/2-1 hour); then
stop immediately and rapidly evaporate in vacuum 1/2 the ethanol (keep
temperature below 30ø). Basify the solution with solid NH4Cl, dilute with
500 ml water and extract 3 times with ether. Filter, wash with water to
neutrality and dry, evaporate in vacuum the ether (or can dissolve the
residue in petroleum ether, or 1:1 petroleum ether:benzene for methoxy
compounds, and filter through silica gel) to get the ethyl-alpha-azido-
cinnamates (I) in about 50% yield. Store in freezer until used in next
step. Dissolve 1g (I) in 100 ml p-xylol and reflux 10 minutes. Evaporate in
vacuum (or add 5 ml pentane, filter, evaporate in vacuum) to get about 90%
yield of the 4-substituted 2-carbethoxyindole which can be decarboxylated
as described elsewhere here.

                      4-Methoxy-indole JCS 3909(1952)

        4.5 g 2-methoxy-6-nitro-benzyl-Cl (JOC 6,217(1941)), 4.5 ml
ethanol, 1.6 g KCN, 1.5 ml water; reflux six hours, cool and extract with
ether. Wash with water, dry and evaporate in vacuum the extract to get 4 g
of the cyanide (I). 4.2 g (I), 125 ml concentrated HCl; reflux six hours,
cool and filter. Add precipitate to dilute aqueous Na carbonate; stir and
warm until dissolved and filter. Acidify and let stand one hour at 0ø;
filter to get 1.8 g 2-methoxy-6-nitro-phenylacetic acid (II). 5 g (II) in
100 ml glacial acetic acid catalyzed with palladium-carbon at room
temperature gives 3.8 g 4-methoxy-indole. Filter, evaporate in vacuum and
recrystallize-1:5 ethanol/water.

                         Indoles CA 74,87819(1971)

        To 30 g polyphosphoric acid (prepared by adding 2:1 P2O5:85%
phosphoric acid) add 3.3 g phenylhydrazine and 4 g phenylacetone (or
equimolar amount ethylacetone) and heat twenty minutes at 130-140ø in N2
stream. Pour over 200 ml water and extract with methylene chloride to get
about 45% yield 2-benzylindole or 30% 2-ethyl-indole (recrystallize-ether).

Indole-3-acetic acid CA 72,66815(1970)

        To 21.6 g phenylhydrazine dissolved in 300 ml 0.3N sulfuric acid,
add 9.8 g concentrated sulfuric acid. Add dropwise with stirring and
heating at 100ø, 11.6 g methyl-beta-formyl-propionate in 300 ml 0.3 N
sulfuric acid and continue heating six hours to get 14 g indole-3-acetic
acid. Convert to the dialkyltryptamine as already described.

Alpha,alpha-Dimethyl-indoleacetic acid ACS 8,122( 1954)

        117 g indole in 1 L acetone; add 220 g NaOH pellets and stir in
three-neck, 3 L flask with thermometer and dropping funnel. Cool in ice
bath and add CHCl3 dropwise over about two hours, keeping temperature below
15ø. Let warm to room temperature over one hour with stirring and continue
stirring four hours. Warm on water bath and evaporate the acetone. Dissolve
the residue in 1.5 L water and extract four times with ether (dry and
evaporate in vacuum the extract to get about 50 g unreacted indole).
Acidify the aqueous phase with dilute sulfuric acid and extract the oil
with ether. Wash with water and dry and evaporate in vacuum the extract to
get the title compound (recrystallize-aqueous methanol), which can be
converted to the dialkyltryptamine as described elsewhere here.

4-Nitroindole JACS 80,4621 (1958) -cf. Chem.Het.Cpds.(Russian) 37(1973).

        21 g ethyl-pyruvate-meta-nitro-phenylhydrazone (I) in 100 g
polyphosphoric acid; warm in oil bath with stirring and cool to keep
temperature below 125o. Stir at 105-11 So for one-half hour and then add
ice water. Filter, extract water with ether to remove unreacted (I), wash
precipitate with water and dry to get 9.5 g
ethyl-4-nitroindole-2-carboxylate (II) (recrystallize-ethanol or 800 ml
benzene). It may be possible to use this directly for diakyltryptamine
synthesis, otherwise proceed as follows. Dissolve 9.7g (II) in 75 ml hot
ethanol and add solution of 7.5 g KOH in 18 ml water, let stand six hours
at room temperature. Add 350 ml warm water and add the mixture to excess
dilute HCl so that the pH is acid. Filter, wash precipitate with water and
dry to get 9 g 4-nitroindole-2-COOH (III). 11.3 g (III) and 1.1 g CuO or Cu
powder in 90 ml quinoline and reflux 2 hours. Add 100 ml concentrated HCl
and 200 g ice; filter and extract both precipitate and filtrate with ether.
Evaporate in vacuum or wash with dilute NaHCO3, water and dry and evaporate
in vacuum to get the title compound (recrystallize-dilute ethanol).

Methoxyindoles from Methoxynitrostyrenes JOC 22,331(1957)

        Illustrated for 5,6,7-trimethoxyindole (for the trimethyl-indole
see JOC 25,1542(1960)). 2-methoxy-beta-nitro-styrene, if nitrated at the
6 position and used in place of (I), should give 4-methoxy-indole.

        7.9 g 3,4,5-trimethoxy-beta-nitrostyrene (preparation described in
mescaline section) in 40 ml acetic anhydride at -8o: stir well and add
dropwise 5 ml fuming HNO3. Stir twenty minutes and pour on 200 ml ice
water. Add some solid Na carbonate, filter, wash with water to get the
2-nitro derivative (I) (recrystallize-aqueous ethanol). 2.5 g (I) in 18 ml
ethanol; add 8.8 g iron powder and 18 ml glacial acetic acid and stir and
warm (cooling is eventually necessary). Stir about ten minutes until
solution thickens and about five minutes more, then add 50 g Na bisulfite
in 220 ml water and extract the indole with 5x200 ml ether. Wash combined
extracts with NaHCO3, water, and dry and evaporate in vacuum to get the
indole (can purify on alumina, eluting with 1:1 benzene:petroleum ether,
discarding the precipitate that won't dissolve in the benzene-petroleum
ether).

4-Substituted Indoles from Pyrrolyl Aldehydes J. Prakt. Chem. 315,295(1973)

        A mixture of 9.5 g pyrrolyl-2-aldehyde, 29.2 g dimethyl-succinate
and NaH (9.6 g of 50% suspension in oil) in 100 ml benzene is stirred at
room temperature 6 hours, cooled and carefully acidified with glacial
acetic acid. Add water and ether and dry, evaporate in vacuum or work up
(JACS 72,501 (1950), JCS 1025(1959)) to get ca. 17 g (80%)
3-methoxycarbonyl-4-(2'-pyrrolyl)-3-butenoic acid (I)
(recrystallize-acetone-benzene). A mixture of 12 g (I), 7 g sodium acetate
and 70 ml acetic anhydride is left overnight at room temperature with
occasional shaking. Then gradually raise the temperature to 70-75ø over 2
hours, maintain for 4 hours and work up (see JCS 1714(1955), 986(1958)) to
get ca. 8 g (60%) methyl-4-acetoxy-indole-6-carboxylate (II)
(recrystallize-petroleum ether). If desired, this can be converted to
4-OH-indole-6-COOH and 4-methoxyindole-COOH as described in the ref. or
decarboxylated as described elsewhere here. If the 1-methyl cpd. is used,
1-Me-indole results.

Dialkyltryptamines from Indoles BSC 1424(1973)

        Dissolve 2.75 g anhydrous sodium carbonate in a mixture of 50 ml
acetic acid and 25 ml propionic acid. Add 11. 7 g (0.1 M) indole and 8.8 g
(0.11M) dimethylamine hydrochloride (or other amine) in 5 ml diglyme. Cool
to between zero and minus 5ø and add 11 g chloracetaldehyde hydrate
(containing 75% chloracetaldehyde-0.1 M). Stir 1 hour, keeping temperature
below zero and put in refrigerator at ca. 5ø for ca. 5 days. Pour on
crushed ice and filter out the white, flocculent ppt. Shake the cold acid
filtrate with cold ether (vigorous cooling) and separate the ether. Slowly
with stirring neutralize by adding NaOH dropwise. Rapidly decant the ether
phase, dry rapidly over sodium sulfate and quickly, with stirring, at a low
temperature add HCl in ether. Decant the ether and treat the thick oil
which formed with a small amount of absolute ethanol to bring about
crystallization (add dry ether if necessary). Can recrystallize 3 times
from ethanol-ether or acetonitrile to get 8.2 g (32%)
alpha-chloromethylgramine (I).

        Add 1 g (I) to a suspension of 2.5.g NaBH4 in 75 ml diglyme heated
to 55ø with stirring. Heat to 85-90ø and keep at this temperature for 48
hours (the yellow color disappears). After 24 hours, cool and pour on ice.
Extract with ethyl acetate and evaporate to get about 37% yield of the oil
DMT (or analog). Can purify on 1:1 silica:celite column; benzene elutes the
skatole, methanol the DMT (recrystallize-hexane).

4-Acetylindoles from 5-Hydroxyindoles BCS 2046( 1973)

        Heat 1.1 g 2-ethoxycarbonyl-5-hydroxyindole/5-OH-indole and perhaps
5-OH-DMT will work) and 0.9 g powdered AlCl3 at 145ø in
orthodichlorobenzene. Add 2-3 ml acetylchloride and keep the temperature at
145-150o for 2 hours. Cool and hydrolyze with ice cold 2N HCl. Extract with
chloroform and dry, evaporate in vacuum to get 4-acetyl-2-ethoxy-carbonyl-
5-hydroxyindole in ca. 50% yield. This paper also gives a method for
brominating the starting cpd. in the 4 position.

5-Methoxy-indole REC 81,317(1961)

        Again, if 3,5-dimethoxyaniline is used, 4,6-dimethoxy-indole should
result. To 123 g p-anisidine (p-methoxy-aniline) in 1L 15% HCl; add 1 Kg
ice and while stirring, quickly add dropwise below the surface, a solution
of 75 g NaNO2 in 200 ml water (temperature below 5ø). Add 5 g activated
carbon, stir and filter and quickly add filtrate with stirring to a mix of
160 g ethyl-alpha-methyl-acetoacetate in 1 L methanol, 1Kg ice and 820 g Na
acetate. Stir two hours and extract with 4x500 ml benzene. Wash extract
with water, dry and evaporate in vacuum and dissolve residue in 1/2 L
ethanol. Cool to 0ø and quickly add 1/2 L cold ethanol saturated with dry
HCl gas (violent boiling). Stir one hour, add 100 ml hot water and
refrigerate twelve hours. Filter, wash precipitate with 2x100 ml ethanol,
2x200 ml hot water and dry to get 135 g ethyl-5-methoxy-indole-2-COOH (I).
(I) might be used directly to synthesize a dialkyl-tryptamine. 135 g (I)
and 56 g KOH in 1 L 90% ethanol; reflux 1 1/2 hours and pour into 6 L
water. Acidify with concentrated HCl, filter, wash with water and dry to
get 108 g 5-methoxy-indole-2-COOH (II). To a stirred mixture of 45.6 g (II)
in 60 ml fresh quinoline, add 2 g Cu chromite and heat to 210-230ø in a
metal bath until CO evolution stops (or just heat at 210-230ø five minutes
under N2. Cool, filter, dry and evaporate in vacuum or add 1/2 L ether,
filter and extract filtrate with 3x200 ml 2N HCl, 3x200 ml water, 2x100 ml
2N NaOH, 2x100 ml water and dry, filter, evaporate in vacuum to get 24 g
5-methoxy-indole.

5-Nitroindole JGC 29,2508(1959); see also JOC 20,1541(1955)

        11.9 g indoline dissolved in 150 ml acetic anhydride. Add 8.5 ml
concentrated HNO3 dropwise with stirring (temperature 10-12ø). Pour the
mixture into water and filter. Add the precipitate (or 1-acetyl-indoline,
prepared by boiling indoline in acetic anhydride) to 100 ml concentrated
HCl and boil one-half hour. Basify with NaHCO3 (can filter to remove black
precipitate formed after adding first portion of NaHCO3) to get 12 g
5-nitro-indoline (I) (recrystallize-heptane). 7.9 g (I) and 11.7 g
chloranil in xylene. Reflux ten hours, cool, evaporate in vacuum or wash
two times with 20% NaOH, filter, wash xylene with water, 50% HCl, water and
dry, evaporate in vacuum to get 5.4 g 5-nitro indole (II). Can reduce (II)
to the aminoindole as described for preparation of 4-amino-DMT or as
follows. To 5.4 g (11) in 50 ml ethanol add a little Raney-Ni and add
dropwise over two hours 100 ml hydrazine hydrate to the boiling solution.
Filter, evaporate in vacuum (can distill 190/6) to get 5-NH2-indole
(recrystallize-heptane). Can benzoylate by dissolving in benzene and
shaking with 20% NaOH and excess benzoyl-Cl, let stand twelve hours and
dry, evaporate in vacuum (recrystallize-benzene). The dialkyltryptamine of
the benzoylated compound may be more active than that of the amino
compound.

                       4-CN-indole JACS 71,761 (1949)
     (See BER 89,270 (1956),90,1980(1957) for a more involved method.)

        To 23 g Na in 350 ml ethanol add 146 g ethyl-oxalate and 171 g
2-nitro-6-Cl-toluene and reflux forty minutes. Dilute the red solution with
water and steam distill until no more starting material is distilled. The
aqueous residue is filtered, acidified with HCl and filtered to get 102 g
2-nitro-6-Cl-phenylpyruvic acid (I) (recrystallize-benzene). Add 81 g (I)
in dilute NH4OH to a solution of 560 g FeSO4*7H20 and 230 ml concentrated
NH4OH and 2 L water and boil five minutes. Filter, wash precipitate with
dilute NH4OH, water and acidify filtrate with dilute HCl to get 60 g
4-Cl-2-indole-COOH (II) (recrystallize-aqueous ethanol). 9.78 g (ll) and
6.7 g CuCN in 35 g quinoline and reflux (about 237ø) for twenty hours. Pour
the hot solution into a mixture of 25 ml concentrated HCl and ice. Stir and
filter; wash precipitate with water and extract the filtrate and
precipitate three times with ether. Wash the ether with HCl, water and dry,
evaporate in vacuum to get 3.6 g 4-CN-indole (recrystallize-water). Or,
heat (II) alone at 290ø until fusion; then heat at 250ø for ten minutes
until CO2 evolution ceases to get 4-CN-indole. For conversion to
4-formyl-indole see HCA 51,1616(1968).

           4-Alkyloxyindoles TET 24,6093(1968), JMC 13,983(1970)
                    and a longer route in CT 274(1970).

        Add solution of 150 g 2-amino-6-nitrotoluene (prepared by reduction
of 2,6-dinitrotoluene with H2S in ammoniacal ethanol and recrystallize-
water or ethanol) in 550 g concentrated sulfuric acid slowly to 5 Kg
crushed ice and then add dropwise a solution of 75 g Na nitrite in 100 ml
water with stirring and cool (0-5ø). Continue stirring two hours and add 2
L 10% sulfuric acid containing 0.1 % Cu sulfate. Heat at 75-80ø twelve
hours or until N evolution ceases. Filter, cool to precipitate 135 g
2-OH-6-nitrotoluene (I) (recrystallize-aqueous ethanol) (can also prepare
by nitrating o-cresol). Add 20 g (I) in 100 methanol to a solution of 5.8 g
Na metal in 60 ml methanol or ethanol. Add dropwise with stirring, 34 g
diethyl or dimethylsulfate. After addition reflux one hour, evaporate in
vacuum most of the methanol, add 100 ml water and extract with 3x50 ml
ether. Wash ether with 50 ml 5% NaOH, 2x50 ml water: dry, filter, evaporate
in vacuum (can distill 116/2.2 for ethyl-, 94-6/0.5 for methyl-) to get 20
g 2-alkyloxy-6-nitrotoluene (11). Can also use 1-Br-propane and reflux four
hours; evaporate in vacuum the ether extract and distill residue (180/17)
to get the 2-n-propoxy-6-nitrotoluene (recrystallize-aqueous methanol). To
a suspension prepared from 7.8 g K metal (Na may do) and 25 ml absolute
ethanol in 160 ml dry ether, add dropwise a solution of 0.1 M (II) and 29.2
g diethyloxalate in 50 ml dry xylene. Stir four hours and let stand at room
temperature three days. Extract the precipitate with 100 ml ice water and
extract the resulting dark red aqueous layer with 3x50 ml ether. Filter and
remove the residual ether by blowing air through the aqueous solution. Cool
in ice bath and treat alternately with a little 20% NaOH and 30% H202 (16
ml each total) until the dark red color is gone. Filter and acidify with
concentrated HCl to get 9 g of the 2-alkyloxy-6-nitrophenylacetic acid
(III). 2 g (III) in 40 ml glacial acetic acid. Add 0.1 g 10%
palladium-carbon and hydrogenate at room temperature and atmospheric
pressure about one hour. Filter, evaporate in vacuum to get 1.2 g
4-alkyloxyindole (recrystallize-toluene). For the n-propoxy compound,
hydrogenate one-half hour in 30 ml 5% NaOH, filter, acidify with
concentrated HCl and heat on steam bath for one-half hour. Cool and filter
and recrystallize-aqueous ethanol. If desired, these indoles can be
dealkylated as described elsewhere here. Alternatively, dissolve 45 g (III)
in 600 ml water with the minimum amount of 2N NaOH (about 80 ml). Add
Na2S2O4 to the well stirred solution in small amounts until no further
increase in temperature occurs. Add 2N NaOH dropwise, at the same time add
further Na hydrosulfite, until the red color disappears (about 80 ml NaOH,
70 g Na hydrosulfite). This takes about one hour and final temperature is
about 35ø. Stir in 200 ml dilute (1:1) HCl to precipitate the
alkyloxyindole-COOH (IV) which can be used as is, or decarboxylated with
quinoline and Cu powder by heating to 245ø and cool, filter and evaporate
in vacuum as described elsewhere here.

Methoxyindoles from Methoxyanilines JOC 20,1454(1955), 23,19 (1958)

        Illustrated for preparation of 4,5,6-trimethoxyindole (IV). 1.8 g
3,4,5-trimethoxyaniline in 10 ml glacial acetic acid; add 1.9 g
ethyloxomalonate-dihydrate and heat ten minutes on steam bath. Let stand
two hours at room temperature and add 125 ml water and then solid ammonium
carbonate till pH is 8 to precipitate 2.7 g 4,5,6-trimethoxy-3-OH-3-
carbethoxyindole (I) (recrystallize-benzene-petroleum ether). 4.5 g (I) in
50 ml 5% NaOH and heat on water bath with aeration ten minutes. Take pH to
4 with dropwise addition of formic acid. Filter, wash with water and
recrystallize from aqueous ethanol to get 1 g 4,5,6-trimethoxyisatin (II).
To a stirred suspension of 7.2 g (II) in 30 ml boiling water, add 7 g Na
hydrosulfite and let clear solution stand twelve hours in refrigerator.
Filter, recrystallize the precipitate from boiling water and dry to get the
dioxindole (III). To a stirred slurry of 1.9 g lithium aluminum hydride in
100 ml dry ether add 4.3 g (III) in 120 ml dry benzene and reflux four
hours. Cool and carefully add a little water. When bubbling stops, filter
and dry, evaporate in vacuum the organic layer to get (IV).

                      4-Methoxyindole BSC 1335(1966)

        Methylate p-Cl-phenol to get p-Cl-methoxy-benzene which is then
converted (BSC 643(1953)) to 5-Cl-2-methoxy-benzyl-Cl (I). 50 g (I) in 50
ml dimethylformamide is added to a solution of 16 g KCN in 80 ml
dimethylformamide and 70 ml water at 70ø. Add a pinch of KI and heat at
85-90ø 1 1/2 hours. Pour on cold water; filter, dry (can purify by
distilling 167/12) to get 38 g 5-Cl-2-methoxy-phenyl-acetonitrile (II).
Alternatively, dissolve 29 g (I) in 200 ml acetone, add 8 g NaCN and 1.6 g
NaI and reflux twenty-four hours. Cool, filter, and evaporate in vacuum to
get 21 g (II). 174 g (II) in 174 g concentrated sulfuric acid, 174 ml water
and 174 g glacial acetic acid; reflux and stir three hours. Cool, filter
and dissolve the brown crystals in Na carbonate solution (can add
decolorizing carbon and filter) and acidify to precipitate I 79 g (III)
(recrystallize-ethanol) (2-methoxy-5-Cl-phenylacetic acid). Alternatively,
dissolve 50 g (II) in 350 ml methanol containing 15% NH3 and hydrogenate at
70 Kg pressure, 50ø in presence of Raney-Ni (or other reducing method) to
get 40 g colorless liquid (after filtering, and evaporating in vacuum)
2-methoxy-5-CI-á-phenethylamine (VIb). 76 g (III) carefully mixed with 60 g
SOCl2 and heated until dissolved. Let stand twelve hours and evaporate in
vacuum to get 58 g yellow oily 2-methoxy-5-Cl-phenylacetyl-Cl (IV) (can
distill 145/10). See preparation of mescaline for alternatives to this and
other steps. 6 g (IV) and I 4 ml 10% NaOH are added at the same time to 10
ml 33% aqueous methylamine at 0ø and stirring is continued for one-half
hour. Filter, wash precipitate with water and dry to get 5 g of the
N-methyl-phenylacetamide (V). Carefully add 20 g pure and dry (V) to 10 g
lithium aluminum hydride in 800 ml dry ether (can first reflux lithium
aluminum hydride and ether twelve hours under N2 and filter), reflux about
four days and carefully add a little water until no more bubbles. Filter,
extract filtrate with 2N HCl and extract the HCl with ether (evaporate in
vacuum the ether to recover 3 g (V)). Basify the HCl extract and extract it
with ether. Dry and evaporate in vacuum the ether to get 8 g oily
N-methyl-2-methoxy-5-CI-beta-phenethyl-amine (VIa) (can distill 110/0.5).12
g (VIa or b) and 4.5 g DEA or DMA in 500 ml ether; mix rapidly with 270 ml
0.9 M phenyl-Li, boil fifteen hours and extract as for (VI) or as described
previously to get 8 g oily 4-methoxy-indoline (or its 1-methyl derivative)
(VII). Alternatively, add 36 g naphthalene to 300 ml tetrahydrofuran and
add 1 I g Na metal cut in small pieces. Reflux and stir three hours and add
18 g (VI) and 8 g DEA in 200 ml tetrahydrofuran rapidly and boil twelve
hours. Evaporate in vacuum, dissolve the oily residue in 2N HCl and extract
with ether. Proceed as described to get (VII). 4 g (VII) in 200 ml dry
pyridine; add to 6 g Cu chloride in 400 ml pyridine and reflux 1 1/2 hours.
Pour on water and extract with ether. Wash extract with 4N HCl and then
water and dry and evaporate in vacuum the ether to get 2 g of the indole
(VIII). Alternatively, dissolve 4 g (VII) and 9.5 g cinnamic acid in 700 ml
mesitylene, add 1 g 5% palladium-carbon and reflux five hours. Filter, wash
with HCl and NaHCO3 and dry and evaporate in vacuum the mesitylene to get
the red, oily (VIII) (can chromatograph on alumina and elute with
benzene-petroleum ether).

                         5-OH-indole JCS 2525(1952)

        To a solution of 4.3 g 2,5-dihydroxyphenylalanine and 2 g NaHCO3 in
150 ml water, add with stirring during ten minutes, a solution of 13 g K
ferricyanide and 3 g NaHCO3 in 200 ml water (dark solution turns pale
yellow). Extract with 3x200 ml ether and dry, evaporate in vacuum to get
2.3 g 5-OH-indole.

                 4-Indolecarboxylic Acid CPB 20,2123(1972)

        Heat 3-nitrophthalic anhydride with ammonium carbonate to get
3-nitrophthalimide (I). Dissolve 4.3 g (I) in 50 ml 90% methanol and add
1.9 g sodium borohydride over 30 minutes while stirring vigorously at room
temperature. Stir 2 hours, acidify with 20% HCl, evaporate in vacuum and
treat the dry residue with acetone. Evaporate in vacuum to get 3.9 g (88%)
3-OH-4-nitrophthalimidine (II) (recrystallize from acetone). Dissolve 3.9 g
(II) in 40 ml 20% HCl and stir for 10 hours on water bath at 80-90ø.
Distill off HCl and stir residue with acetone. Filter and evaporate in
vacuum to get 3.4 g 3-OH-4-nitrophthalide (III) (recrystallize from CHCl3
and can purify on column). Prepare an ether solution of CH2N2 and add to
1.93 g (III) in a 100 ml flask until a reaction is no longer evident. Add
acetic acid to decompose excess diazomethane and evaporate in vacuum to get
about 2 g of 2-methoxycarbonyl-6-nitrostyrene oxide (IV) (can purify on
column). Dissolve 560 mg (IV) in 50 ml absolute methanol, add 50 mg PtO2
and hydrogenate as described elsewhere here (other reducing methods should
work). Filter, evaporate in vacuum and recrystallize from benzene to get
270 mg methyl-4-indolecarboxylate(V). Dissolve 250 mg (V) in 2 ml 0.05M KOH
and stir at room temperature 6 hours. Neutralize with 10% HCl carefully to
prevent excessive heat and collect the crystals by filtration. Dry to get
126 mg 4-indolecarboxylic acid.

                Indole Russian Patent 306,126(29 July 1971)

        To a stirred suspension of 1.9 g orthocarbamoyl cinnamamide in 50
ml methanol add 26 ml 0.77 N NaOCl and heat in a distillation apparatus at
40ø for 2 hours, or until no more indole is distilled off (can use the
indole tests described earlier). Extract the distillate with CHCl3 and dry,
evaporate in vacuum (or steam distill the solvent) to get about 45% indole.

Indole German Patent 2,052,678(6 May 1971)

        A molar ration of 2-(o-nitrophenyl)-ethanol to reducing gas of 1:5
is best (greater than 90% yields). The catalyst is Al2O3 or silica gel
containing 7-14% by weight of copper (or Ni, Co, Cu chromite, etc.), with
some potassium sulfate if necessary. Reducing gas is NH3 or H2, which can
be mixed with nitrogen. The temperature is 250-300ø. The
2-(o-nitrophenyl)-ethanol is vaporized over 30 ml catalyst in a quartz tube
56 cm long with an inner diameter of 15 mm, containing along its whole
length a thermoelement tube with an outer diameter of 8 mm. The tube is
filled to 28 cm with quartz glass fragments. The gas flow rate is 80-240
ml/minute with a contact time of 7-14 seconds. Compare CA
79,105065-66(1973).

               Indole Analogs

        Replacement of one or more of the C or N atoms of the indole
nucleus by atoms of N, C, O or S will result in dialkyltryptamine analogs
some of which are very likely to be psychedelic. Among the indole analogs
are isoindole, indene, indazole, diazindoles, benzofuran, benzothiophene
and benzimidazole. The syntheses of several such compounds follows.

Benzimidazole Analog of DET JCS 1671 (1957)

        17.3 g benzimidazole dissolved in 300 ml ethanol containing 3.4 g
Na metal. Slowly add 22.4 g alpha-Cl-N, N-diethyl-acetamide (or 18.2 g
dimethyl analog) in 100 ml ethanol and reflux four hours. Filter, evaporate
in vacuum to get 2-1'-benzimidazolyl-N,N-diethylacetamide (I)
(recrystallize-acetone). Add 16 g (I) to 6 g lithium aluminum hydride in
300 ml tetrahydrofuran and reflux six hours. Cautiously add a little water
and filter, evaporate in vacuum to get the DET analog
(recrystallize-water). (I) may be active.

        Alternatively, dissolve 10 g N,N-diethyl-N'-o-nitrophenyl-ethyl-
enediamine in 100 ml ethanol. Add Raney-Ni and 5 atmospheres hydrogen and
hydrogenate one hour. Filter, evaporate in vacuum and reflux the oil forty
minutes with 100 ml 4N HCl and 20 ml 87% formic acid. Basify with NH4OH;
extract four times with CHCl3 and evaporate in vacuum to get the DET analog
(recrystallize-water).

         Indene Analogs of DETJMC 10,856(1967), JOC 30,3231 (1965).
                   Illustrated for 6-methoxy-DET analog.

        Prepare 6-methoxy-1-indanone (I) (JCS 1986(1962)) using
polyphosphoric acid made by diluting 500 g of the commercial acid with 120
g 85% phosphoric acid. 2.5 g (I) in 176 ml ether and reflux one hour with
0.27 g lithium aluminum hydride. Cool and carefully add water and filter
when bubbling stops (can use Celite filter aid). Dry and evaporate in
vacuum and store twelve hours at 15ø (under N2 if possible) to precipitate
the white 6-methoxy-1-indanol (II) (recrystallize-n-hexane). 2.5 g (II) in
73 ml benzene and reflux one-half hour with 0.2 g p-toluenesulfonic acid.
Cool, add water and separate the phases. Extract the aqueous phase with
ether and combine with benzene phase and dry, evaporate in vacuum to get
5-methoxy-indene (III) (can distill 110-45/10). 1.53 g (III) and 1.39 g
N,N-diethyl-aminoethyl-CI-HCl in benzene (prepare the free base in benzene
as described previously). Reflux four hours with 0.42 g sodamide, cool,
wash with water and dry, evaporate in vacuum to get the indene analog of
6-methoxy DET as a dark liquid (can crystallize as oxalate). Alternatively,
dissolve 2.51 g (III) in ether and treat (under N if possible) with 12 ml
1.6M butyl-Li in hexane at 0-10ø. After two hours cool to -30ø and add 12
ml more of butyl-Li. Add ether suspension of 2.5 g N,N-diethylaminoethyl-Cl.
HCl over one-half hour and warm to room temperature. Filter, evaporate in
vacuum to get the 6-methoxy-DET analog.

	 The following are some other syntheses of indole analogs:

Indene JOC 37,1545(1972); TL 2869(1972); CT 7,205(1972)
Indazole analog of 5-benzyloxy-DMT JACS 79,5246(1957),80,966(1958)
Benziminazole analog of 5-OH-trybtamine JCS 1671(1957)
5-BR-benzothiophene analog of DMT JMC 10,270(1967)
Tryptamine analogs using pyrrolidine and piperidine JMC 10,1015 (1967)
Benzoluran derivatiues LAC 662,147(1963), CA 60,2901 (1963)
Benzothiophene preparation JOC 10,381 (1945)
4-Azindoles CA 72,66934(1970),73,56000(1970)
Isoindoles J.Prakt. Chem. 312,440(1970)
Various analogs JMC 9,819(1966),10,856(1967 ),13,1205 (1970);
ACS 17,2724(1963); JACS 77,4324(1955); J.Het.
Chem. 6,775(1969); JCS (C) 2317(1959), 1612(1969), 498 (1970);
JOC 37,51(1972). CT 7,205(1972)

        The following are syntheses of indoles and derivatives: For an
extensive review of indole syntheses and reactions see CHEMISTRY OF
HETEROCYCLIC COMPOUNDS (W.J. Houlihan, Ed.), 25, parts 1, 2 and 3 (1972-3).

5-OH-DMT (which can be substituted in the 4 position as described
here) from 2,5-dimethoxybenzaldehyde JCS 1165(1954)
5-Nitro-DMT (in six steps from tetrahydrofurfuryl alcohol) JACS 75,1880(1953)
N-acylation of tryptamines JPS 58,563( 1969), cf. JACS 74,101 (1952)
4-Acetylindole-3-acetic acid (in ten steps from m-amino-benzyl alcohol)
BER 87,229(1954)
4,5-Benzindole JOC 24,565(1959)
5-methyl-indole JOC 24,2030(1959)
Indolyl-3-acetaldehyde JCS 3172(1952)
DMT derivatiues JACS 77,4322(1955)
5-substituted indoles JCS 1424(1965), Israel J. Chem. 5,129(1967)
5-6-Methylenedioxyindole JCS 78 (1949)
Dibhenyltryptamine CA 73,109616 (1970)
Tryptamines (via ethyleneimine) CA 55,19897(1961)
Indoles (from phenylhydrazones) CA 72,66814(1970)
Indoles (possible route to methylethyltryptamine, using N-ethyl-aziridinium
tetraflouroborates) Angew. Chem. 79,188 (1967)
3-(4-pyridyl)indoles (if this is not active, the 4-n-alkyl-pyridyl analog
will probably be) J. Het. Chem. 7,1071 (1970), ACS 22,1064(1968)
Indoles (from o-acylanilines and dimethylsulfonium methylide)
GCI 100,652(1970), TL 679(1969)
Indoles BSC 643, 741 (1960), 1051,2263(1962), 861,2175 (1965), 3359(1966)
Indole Crignard Reagents (review) Adv. Het. Chem. 10,43(1969)
Indoles (reviews) Het. Compounds (Elderfield-Ed.) 3,1(1952);
Prog. Drug Res. 6,75(1963); THE INDOLE ALKALOIDS, W.
Taylor (1966); THE CHEMISTRY OF INDOLES, R. Sundberg (1970)
4-Aminoindole from 5-Br-indole C.R. Acad. Sci. Paris 265,110(1967)
Indole derivatives JPS 60,304(1971); AP 304, 73(1971)
5-OH-indoles from substituted phenylethylamines TL 723(1970)
4-Alkylindoles from 4-Br or iodoindoles BER 104,2027(1971)
Indoles from cyclohexanones and allylamines C.R. Acad. Sci. Paris
272,1509(1971)
For a general, simple high yield indole synthesis from anilines and
methylthioacetaldehyde etc. see JACS 95,588,591,2718,6508
(1973). For indoles from N-(á-hydroxy-ethyl aniline esters see BSC
2485(1973). For a 2-acyl-indoles in one step from orthoaminoketones and
alpha-haloketones or 2-carboxyindoles from sulfonamides of ortho-amino-
carbonyls see JOC 38,3622-24(1972).
Indole and 5-Br-indole in 4 steps from beta-naphthol see Chem. Het.
Cpds. (Russ.) 753(1973). Indole-JOC 37,3622(1972).
4-substituted indoles: from N-methylpyrrole in 5 steps Compt. Rend.
276C,1327(1973); in 20% yield by irradiation of 1-substituted
indoles TL 2451 ( 1973); in one step Swiss Patent 536,840(29 June
1973); French Patent 2,154,485(15 June, 1973); from parabenzoquinone etc.
German Patent 2,145,573(15 March 1973);
from 4-aminobenzofurans CA 78,147795(1973) (Japanese Patent 73 08,777
(03 Feb 1973)).
Indoles Review: lnt. Rev. Sci. Orgn. Chem. Ser. 14,29(1973).
Sulfur analog of psilocin JCS (P.T.1) 3011(1972); JHC 10,297
(1973); DMT analog CPB 19,603(1972). Benzothiophenes from thiophenes
JOC 38,1056(1973).
Dialkyltryptamines from tryptamines: CA 78,147730(1973).
Tryptamines: J. Het. Chem. (Russ.)213(1973).
Indoles from Nitrosoanilines JHC 10,883(1973); from N-(beta-hydroxyethyl)-
aniline by thermal cracking: BSC 2485(1973); from isonitrile and
diazomethane: TL 2133(1973).
CA 79,146321(1973) gives a one step synthesis of tryptamine from
phenylhydrazine and 4-chlorobutyraldehyde by refluxing in aqueous
ethanol for 6 hours (70% yield). CA 80,3381(1974) gives the
preparation of DMT analogs.
JPS 62,490(1973) gives an indoline synthesis which can be carried one step
further (dehydrogenation described in this chapter) to give DMT
derivatives. See JOC 41,1118( 1976) for indoles from betaketosulfoxides.
Indoles JOC 2,235(1937), TET 27,775,1167(1971); CA 75, 35735,63605,88424,
98445,11 8230(1971), 76,14237(1972); ACS 25,1277(1971); JOC 37,43(1972); CA
77,75123(1972); CPB 20,1395(1972); J. Heterocyclic Chem. 8,903(1972); Diss.
Abst. Int. 31 B,5871 (1971); AP 305,159(1972); JCS (Chem. Comm.) 415(1972).
4-Fluorotryptamines Israel J. Chem. 2,25(1964)
Tryptophan 4-acetic acid from tryptophan JACS 88,3941 (1966)
Indoles from o-azidobenzaldehydes JOC 37,719(1972)
Indoles from isatins or oxindoles via diborane Synthesis 2,84(1972)
Indoles from 2-oxindoles TL 1081 (1972)
Indole Derivtives JOC 37,2010(1972)
Psilocin Derivatives Diss. Abst. Int. 32B,2606(1971)
Benzothiobhene and Benzofuran TET 28,5397(1972)
Isoindoles TL 4295(1972); JCS(C) 1149(1972)
5-OH-indoles Diss. Abst. lnt. 33B,107(1972)
Alkoxyindoles from Hydroxyindoles CA 77,151,914(1972)

-------------------------------------------------------------------------

			   MESCALINE AND FRIENDS

	Mescaline and related alkaloids are found in varying amounts in
cacti of the genera Lophophora, Cymnacalycium, Stensonia, Mammillaria,
Ariocarbus, Obuntia, Trichocereus, Pelecyphora, and probably others.
Members of the Native American Church do quite well with the dried cactus,
but extraction of mescaline is desirable since the pure compound seems to
produce fewer unpleasant side effects (e.g., nausea). For an excellent
review on the occurrence and chemistry of the mescaline type compounds, see
JPS 59, 1699(1970) (cf. JPS 60,655(1971)). Various species of these cacti
occur in southwestern U.S. as well as Central and South America and have
been used by the Aztecs and others for millennia. For a good review of
peyote see Lloydia 36, 1-58(1973).

		    Extraction of Mescaline from Cactus
		 JACS 88,4218( 1966), Lloydia 29,318(1966)

	Dry and grind the top of the cactus and add 50 g to 250 ml methanol
and let soak one day. Filter and add 100 ml 1N HCl to the wet powder and
let stand about two hours. Meanwhile, evaporate in vacuum the methanol.
Filter the HCl solution until clear and add to the residue remaining from
the methanol. Make pH about 7 with 2N KOH and add 100 ml CHCl3. Shake in
separatory funnel and separate the bottom CHCl3 layer. Add 40 ml water to
the CHCl3 and shake in separatory funnel. Dry and evaporate in vacuum the
CHCl3 layer to get the mescaline (and other compounds).

	The most detailed directions for cactus extraction are contained in
PSYCHEDELIC GUIDE TO THE PREPARATION OF THE EUCHARIST by R. Brown,
obtainable for $5.50 from L.S.l. Co., PO Box 4374, Austin, TX 78765.

	Another source pressure cooked the peyote in acidic water 15
minutes at 15 lbs. and poured off the liquid. This process was repeated 5
more times and the combined water extracts evaporated slowly to a tar which
is cooled until able to be formed into small pills. The pills are dipped in
Salol (phenyl salicylate), which has been liquefied by heating, and allowed
to dry. This forms an enteric coating which is said to allow ingestion
without nausea. Others merely put the tar in gelatin capsules. Either way
the nausea of whole peyote is greatly diminished. Three or four tabs are
supposed to have the impact of 15-20 buttons.

Methoxyphenethylamines and Derivatives

	Of the nineteen possible methoxyphenethylamines, only three are
known to be psychedelic in man at reasonable doses. These are the
3,4,5-trimethoxy-(mescaline), 2,3,4,5 and 2,3,4,5,6 compounds. There are,
however, a vast number of possible psychedelic derivatives with methyl,
ethyl, Br, and other groups replacing methoxy groups. In addition,
innumerable amphetamine derivatives which closely resemble mescaline in
their structure and psychedelic properties have been synthesized. This
similarity can be seen in the structures of mescaline and
3,4,5-trimethoxyamphetamine.

	These amphetamine derivatives have the advantage that they are
almost all more active than mescaline, STP being about 80x more active
(i.e., requiring only about 5 mg as contrasted with about 400 mg for
mescaline), and that they are often easier to synthesize. They do, however,
seem to produce somewhat more of the effects of speed (e.g., anxiety,
restlessness, sweating) than mescaline. The methylenedioxy compounds, on
the other hand, produce some of the mildest trips of any psychedelic.

	2-5,dimethoxy-4-Br-amphetamine (prepared by bromination of
2,5-dimethoxy-amphetamine -- see JCS 200(1953)) is about ten times more
active than STP but it produces a trip similar to that of MDA and is not
truly hallucinogenic. The phenethylamine analogs of this compound and of
STP are ten times less potent than the corresponding amphetamines and
produce only MDA type effects without the intense sensory alterations.
Beta-hydroxy-3,4-methylenedioxyphenylethyl amine is said to be a very fine
trip.

	When the amino group of amphetamine is methylated, one gets
methamphetamine which is considerably more stimulating. The corresponding
hallucinogenic analogs of methamphetamine have not yet been shown to have
any special stimulating properties, having on the contrary less potency
than the unmethylated forms (see JMC 13,134(1970)), but human tests should
be done (preliminary results show these compounds to be very pleasant).

	N-methyl-MDA is extremely pleasant, producing more euphoria than
cocaine, lasting much longer and having a very easy down. N,N-dimethylation
or N-ethylation diminish activity drastically and the latter appears to
have sedative effects. The methylenedioxy compounds are generally free of
marked visual changes, allow considerable voluntary control of the
experience and are more potent than the dimethoxy counterparts.

	It is probably best to avoid p-methoxyamphetamine (PMA) and
2,5-dimethoxy-4-methylamphetamine (STP), the former because it seems to
have a high toxicity and the latter because it lasts too long (e.g., 24
hours for a minimum dose). Other 4-alkyl amphetamines also seem to be
toxic. A number of apparent fatalities due to MDA have been noted, but the
reports usually involve very large amounts, often in combination with other
drugs (e.g., 7 g MDA plus barbiturates) and screening for other, more toxic
drugs (in particular, PMA) has not been done.

	These amphetamine analogs can be produced by using the
appropriately substituted benzaldehyde in place of 3,4,5-triù
methoxy-benzaldehyde, and nitroethane in place of nitro-methane in the
aldehyde method for mescaline synthesis (using nitropropane, etc., to give
a longer chain results in less activity). However, easier synthetic routes
from the naturally occurring (therefore cheap and commercially available)
ring substituted propenylbenzenes are given here.

	The following table lists common names, position of ring
substitution, and approximate activity of the amphetamine derivatives for
some readily available allyl and propenyl benzenes (see J. Chromatography
30,54(1967) for further information on these compounds). Activity is
relative to mescaline which equals 1 (an activity of 12 means a dose of
about 25 mg). Parentheses indicate a methylenedioxy bridge; other
substituents are methoxy groups.

	Allyl		Propenyl	Substituents	Activity

	Safrole 	Isosafrole	(3,4)		2
	Croweacin	---		2(3,4)		2
	Myristicin	Isomyristicin	3(4,5)		2
	Dillapiole	Isodillapiole	2,3(4,5)	6
	Estragole	Anethole	4		6
	---		Asarone 	2,4,5		12
	---		Apiole		2(4,5)		12
	Apiole		Isoapiole	2(3,4)5 	12

Amphetamines from Allylbenzenes JACS 91,5648(1969)

	To a cooled and stirred solution of 100 ml acetonitrile and 64.8 g
mercuric nitrate, add slowly 0.2M of the allylbenzene (keep temperature
below 30ø). Stir one hour at room temperature, cool and add 200 ml 3N NaOH,
then 200 ml 0.5M NaBH4 in 3N NaOH. After one hour saturate the water layer
with NaCl and extract with ether. Dry and evaporate in vacuum the extract
to get the N-acetyl-amphetamines. This procedure may not work with the
propenylbenzenes.
	If it is desired to remove the N-acetyl group see CJC 51,1407
(1973).

	    Amphetamines from Propenylbenzenes CA 52,11965(1958)

	Use of N-methyl-formamide in place of formamide will give the
corresponding N-methyl-amphetamine which is nicer. Exemplified for
3,4-methylenedioxyamphetamine (MDA). To a cooled mixture of 34 g 30% H202
and 150 g formic acid, add dropwise a solution of 32.4 g (0.2M) isosafrole
in 120 ml acetone (keep temperature below 40ø). Let stand about twelve
hours and evaporate in vacuum. Add 60 ml methanol and 360 g 15% sulfuric
acid to the residue and heat on water bath three hours. Cool, extract with
ether or benzene and evaporate in vacuum the extract to give 20 g
3,4-methlenedioxybenzyl-methyl ketone (I) (can distill 115/2). Add 23 g (I)
to 65 g formamide and heat at 190ø for five hours. Cool, add 100 ml H2O,
extract with benzene and evaporate in vacuum the extract. Add 8 ml methanol
and 75 ml 15% HCl to residue, heat on water bath two hours and evaporate in 
vacuum (or basify with KOH and extract the oil with benzene and dry, 
evaporate in vacuum) to get about 11 g MDA. In this, as in the other syntheses, 
either the cis or trans (alpha or beta) propenylbenzenes (or a mixture) may be used.

	     Amphetamines from Probenylbenzenes JMC 9,445(1966)

	If the allyl isomer is at hand, it must first be converted to the
propenyl as follows (CJC 43,3437(1965)): Add equal weights of the allyl
compound and KOH flakes, and absolute ethanol and heat on steam bath or
reflux for twenty-four hours; dry and evaporate in vacuum or add two times
the volume of water and extract with ether or methylene chloride and dry,
evaporate in vacuum (recrystallize-hexane).

	0.034M propenylbenzene in a mixture of 3.3 g pyridine and 41 g dry
acetone is cooled to 0ø and 6.9 g tetranitro-methane added over one minute
with vigorous stirring, and stirring continued for two minutes. Add 2.2 g
KOH in 40 ml water, add more water and extract the nitropr”pene with
methylene chloride and dry, evaporate in vacuum (recrystallize-methanol).
The nitropropenes (which seem to have little activity themselves) can be
reduced to the active amphetamines with lithium aluminum hydride or Zn-Hg
as described later, or reduced by another method (hydroboration,
hydrogenation, Na-ethanol, electrolytic, etc.).

       Mescaline and Amphetamines from Styrenes and Propenylbenzenes
			     JACS 86,3565(1964)

	The yield of mescaline should be about 50%; that for amphetamines
will vary. 0.1 M of ring substituted styrene or propenylbenzene in 30 ml
tetrahydrofuran in 1/2 L flask. Flush with N2 and add 33 ml 1 M borane in
tetrahydrofuran (see procedure below for preparation). Stir one hour, add 3
ml water and 50 ml 3N NaOH, and then 215 ml 0.31 M fresh chloramine
solution (prepared by treating dilute aqueous NH4OH with Na hypochlorite at
Oø; see BER 40,4586 (1907)). Keep at room temperature one hour, acidify
with HCl, extract with ether, basify with NaOH and extract with ether and
dry, evaporate in vacuum (or just basify and extract with ether and dry,
evaporate in vacuum) to get the amine. To prepare the diborane in
tetrahydrofuran, add 0.3 M NaBH4 (or LiBH4) and 0.4 M BF3 in total 200 ml
tetrahydrofuran and keep dry in refrigerator, or generate the diborane in
the reaction flask as follows: To a well-stirred suspension of 3.4 g NaBH4
in 150 ml tetrahydrofuran and 0.3M of the styrene or propenylbenzene, add
over one hour at room temperature, 15.1 ml BF3 in ether in 20 ml
tetrahydrofuran (keep temperature at room temperature); let stand one hour
at room temperature and decompose the excess hydride with water; then add
the NaOH and chloramine (or hydroxyl-amino-O-sulfonic acid) and proceed as
above to get the amine.

	Other references on organoboranes: JACS 82,4710( 1960),
88,5853(1966), Org. Reactions 13,28(1963). Amines from Alkenylbenzenes by
Aminoboration BSC 2668 (1973)

	Styrenes will give phenethylamines, 1-propenylbenzenes will give
amphetamines. The tetrahydrofuran should be dried over KOH pellets and, if
desired, distilled from sodium then from lithium aluminum hydride. The
diglyme can be vacuum distilled from calcium hydride and stored with
calcium hydride. Hydroxylamine-O-sulfonic acid can be purchased or prepared
(LAC 702,131 (1967); Inorg. Synth. 5,122(1957)). To a 3-necked flask
flushed with a nitrogen stream add 0.096M styrene or 1-propenylbenzene in
200 ml diglyme, and then a solution of 1.52 g (0.04M) NaBH4 in 70 ml
diglyme. Keep the temperature at 25ø and add with stirring over 1/2 hour
7.3 g (0.052M) 48% BF3 etherate. Let temperature rise over 3 hours and then
reflux 3 hours. Cool and carefully add 11.86 g (0.105M)
hydroxylamine-O-sulfonic acid dissolved in 50 ml diglyme. Reflux 3 hours,
cool and take up in 10% HCl. Extract with ether, basify the cold acid phase
with excess NaOH, extract with chloroform, and dry, evaporate in vacuum to
get about 40% yield of the amine.

	     Amphetamines from Phenylacetates CA 35,5868(1941)

	Add 0.44 moles ring substituted phenylacetate, 100 g acetic
anhydride and 30 g sodium acetate and heat at 145-150ø for 18 hours to get
ca. 0.4 moles of the methyl-phenylacetate (I). Add (I) and formamide (or
N-methyl-formamide for the N-methyl cpd.), heat 4-5 hours at 180-195ø, cool
and extract with CHCl3. Evaporate in vacuum, dissolve residue in 40%
sulfuric acid and heat at 90-125ø for 5-6 hours. Neutralize and add solid
NaOH to precipitate about 50% amphetamine. Treat with 10% sulfuric acid
to get the sulfate.

	     Amphetamines from Phenylacetones CA 61,6953(1964)

	Exemplified for 2,4,5-trimethoxyamphetamine (I) preparation. Mix 25
g 2,4,5-trimethoxyphenylacetone, 9.3 g hydroxyl-amine-HCl, 15.6 g K-acetate
and 400 ml 70% ethanol and reflux 3 1/2 hours. Evaporate in vacuum and
extract the residue with 4x150 ml benzene. Wash combined extracts with 2x75
ml water; dry and evaporate in vacuum the benzene (can purify the oil by
dissolving in benzene and precipitate by adding petroleum ether) to get out
20 g precipitate (test for activity). Dissolve 18.1 g precipitate in 200 ml
methanol and hydrogenate. Acidify to get about 15 g (I).

		     Amphetamines from Propenylbenzenes
	 J. Prakt. Chem. 137,345, 138,271(1933), JACS 54,273(1932)

	Illustrated for 2,4,5-trimethoxyamphetamine (I) preparation. Add a
saturated solution of 40 g Na nitrite to 10 g asarone in 90 ml ether. Add
dropwise over four hours 75 ml 20% sulfuric acid with stirring. Let stand
eight hours; filter and wash precipitate with water, ether, ethanol, and
dry. Dissolve 10 g precipitate in 60 ml 8% K carbonate in ethanol with
stirring and gentle (below 30ø) heating. Add 150 g ice, acidify with 100 ml
dilute HCl and let stand one-half hour at Oø. Filter, wash with water and
dry to get about 7 g yellow crystals (recrystallize-methanol)
(2-nitropropenylbenzene). Add 4 g crystals to 100 ml ethanol and 50 ml
glacial acetic acid; then add 10 ml concentrated HCl or 50 ml concentrated
sulfuric acid for the catholyte in a 40 cm2 Hg-cathode in a porous cell
surrounded by 3N sulfuric acid anolyte with a water cooled lead anode and
reduce at 4 amps (about 0.07 amps/cm2 cathode surface) at 30-40ø for twenty
hours or until solution is colorless. Evaporate in vacuum to about 20 ml;
cool with ice, basify with NaOH and extract with ether. Wash, dry and
dilute the ether (or dry, evaporate in vacuum) to get (I).

	Note that this provides an alternative to tetranitromethane for
nitration of propenylbenzenes, and an alternative to lithium aluminum
hydride or Zn-Hg for reduction of nitropropenes.

	     Amphetamines from Bromobenzenes JACS 63,602(1941)

	0.2 M p-methoxy (or other group)-Br-benzene (see this paper for
preparation) and 4.6 g Mg. Rapidly add 18.5 g chloroacetone in 50 ml ether.
Evaporate the ether by heating in oil bath and then at about 135ø for one
hour. Cool and add ice and dilute HCl; extract the oil with ether and dry,
evaporate in vacuum to get about 11 g product (can distill 106/18). 0.057 M
of the ketone product in 16 g formamide in 100 ml round bottom flask, with
an air condenser. Heat twelve hours at boiling and then reflux with 35 ml
30% NaOH eleven hours and separate the amine layer and dry, evaporate in
vacuum to get the amphetamine.

	The following papers often employ a glass apparatus called a
Soxhlet extractor to get maximum yields in a reduction with lithium
aluminum hydride; it is, however, unnecessary.

	 Phenyisopropylamines and Phenethylamines JMC 13,134(1970)

	Mix 5.5 g 3,4,5-trimethoxybenzaldehyde (or analog), 2.5 g NH4
Acetate, 25 ml nitroethane (or equimolar amount nitromethane for the
analog), 25 ml benzene and reflux about twenty hours; water being removed
with a Dean-Stark tube. Cool and wash with 2x25 ml water, 2x25 ml saturated
NaHSO3 and 2x25 ml water and dry and evaporate in vacuum the benzene to get
(I). Reduce the nitropropene (or nitrostyrene) by any method such as
follows: To a stirred suspension of 3 g lithium aluminum hydride in 50 ml
tetrahydrofuran, add 4.4 g (I) in 50 ml tetrahydrofuran and reflux one
hour. Cool in ice bath and treat slowly with wet tetrahydrofuran until
bubbling stops. Filter and evaporate in vacuum (or filter and extract
precipitate with 3X25 ml hot tetrahydrofuran and evaporate in vacuum
combined tetrahydrofuran) to get the amine.

	For a catalytic reduction of (I) see AP 270,340,410(1932) or
proceed as follows (AP 273,481(1935)): Dissolve 0.02 M (I) in 250 ml
glacial acetic acid and add 10 ml concentrated sulfuric acid and 1g
palladium-carbon (or other catalyst). Reduce at 2 atmospheres H2 and I5o
(about fifteen minutes); filter, add 36 ml 5N NaOH and evaporate in vacuum
to get the amine. For Zn-Hg reduction of (I) see below. See also JOC
37,1861(1972) for another catalytic reduction of (I).

   Substituted Amphetamines From Substituted Benzenes JACS 68,1009(1946)

	4M of the substituted benzene and 32.4 g dry FeCl3. Cool to -21ø in
an ice-salt bath and add dropwise with stirring over two hours, 76.5 g
allyl-Cl and continue stirring three hours. Add about 2 lbs. crushed ice
and 100 ml concentrated HCl. Agitate and separate the organic layer and
wash with dilute HCl, then water and filter, dry and evaporate in vacuum
(or distill 100-115/ 10 with Claisen flask, etc.) to get the
substituted-1-phenyl-2-Cl-propane (I). Dissolve 0.16 M (about 27 g) (I) in
450 ml ethanol saturated with NH3 (125 g/L, seal in an iron pipe in
autoclave and agitate and heat about nine hours at 160ø. Cool and filter
and evaporate in vacuum to get the amphetamine in about 20% yield.

	 Amphetamines from Benzylmethyl ketones JACS 70,1315 (1948)

	10 ml water and 0.2 g Pt oxide (or other catalyst) in 300 ml Parr
hydrogenation bottle. Shake in H2 atmosphere ten minutes and add 0.3 M
p-methoxy-benzyl-methyl ketone (1-p-methoxy-phenyl-2-propanone) (or
analog), 20 g NH4Cl, 225 ml methanol saturated with NH3, 25 ml NH4OH and
shake with 1-3 atmospheres H2 until uptake ceases. Filter, wash precipitate
with methanol or acidify with HCl and dry, evaporate in vacuum to get
p-methoxy-amphetamine or analog.

	For the preparation of phenylacetones from nitropropenes see JOC
15,8( 1950). Mescaline J. Chem. U.A.R. 11,401(1968) and many others. Obtain
3,4,5-trimethoxybenzoic acid or synthesize as follows (Org. Synth. Coll.
Vol 1,537( 1946)): To a cold solution of 80 g NaOH in 500 ml water in 1 L
flask, add 50 g gallic acid; tightly stopper to exclude O and shake
occasionally until all acid dissolves. Add 89g (67 ml) dimethyl sulfate,
shake twenty minutes, releasing pressure occasionally, and cool to keep
temperature below 30ø. Again add 89 g dimethyl sulfate and shake ten
minutes. Reflux two hours, add 20 g NaOH in 30 ml water and reflux two
hours more. Cool, acidify with HCl; filter and wash with water to get 50 g
3,4,5-trimethoxybenzoic acid (recrystallize-2 L hot water) (can recover
more by concentrating the filtrate).

	A. Do a Fisher esterification by refluxing 100 g
3,4,5-trimethoxybenzoic acid in ethanol with concentrated sulfuric acid for
several hours. Cool, filter, to get the ester (I) (recrystallize-ethanol).

	A. (Alternative) 100 g 3,4,5-trimethoxybenzoic acid, 20 g NaOH, 55g
NaHCO3 and 300 ml water and add with stirring 94 ml methyl or ethyl sulfate
over twenty minutes and reflux one-half hour. Cool, filter, dissolve the
precipitate in a small amount hot methanol or ethanol and cool to
precipitate (I) (acidify the filtrate to recover unreacted
trimethoxybenzoic acid).


        B. 1 M (I), 10 M NaBH4; dissolve in methanol, reflux four hours and
filter, dry and evaporate in vacuum to get 3,4,5-trimethoxybenzyl alcohol
(II).

	B. (Alternative) To 4.6 g lithium aluminum hydride in 200 ml ether,
add over one-half hour a solution of 23 g (I) in 300 ml ether. Slowly add
50 ml ice water; decant the ether and add 250 ml ice cold 10% sulfuric
acid. Extract with 3x50 ml ether and dry, evaporate in vacuum (can distill
135-137/0.25) to get (II).

        C. To a stirred solution of 39.6 g (11) in 150 ml CHCl3 (or CCl4 or
benzene), at 0-5ø, add 35 g SO2Cl3 in CHCl over one-half hour; let warm to
room temperature and stir for one hour. Evaporate in vacuum and pour
residue on ice cold water. Filter and wash precipitate 3X with water to get
the trimethoxybenzyl-Cl (III) (recrystallize-benzene-hexane).

	C. (Alternative) 25 g (II) and 125 ml ice cold concentrated HCl is
shaken vigorously until a homogeneous solution is obtained. Let stand four
hours until gummy precipitate forms and dilute with 100 mI ice water.
Decant the water and extract with 3x50 ml benzene. Dissolve precipitate in
this benzene, wash benzene with water and dry, evaporate in vacuum. Suspend
the residue in a small amount ice cold ether, filter throuþh cold funnel
and wash with cold ether. Let filtrate stand in refrigerator to get more
precipitate of (III) (recrystallize-benzene).

	D. 43.2 g (III), 40 g KCN, 300 ml 85% formic acid (or DMSO,
acetonitrile, 70% methanol, but lower yield for these). Add 150 ml water
and reflux two hours. Cool, filter, and extract filtrate with 3X50 ml
CHCl3. Wash CHCl3 with 3x50 ml water and dry, evaporate in vacuum to get
the phenylacetonitrile (IV) (recrystallize-benxene-hexane, yield about
34g).

	E. HCA 53,50(1970) (see JMC 14,375(1971) or the following for other
methods of reducing (IV)). 40 g (IV) in 90 ml methanol and 10 g aqueous 50%
Raney-Ni (or substitute catalyst described in chemical hints section). Add
dropwise over ten minutes with vigorous stirring a solution of 7.6 g NaBH4
in 25 ml 8N NaOH and cool to keep temperature at 50ø. H2 evolution stops in
about five minutes. Filter, wash with methanol and evaporate in vacuum to
get mescaline (V).

	E. (Alternative) Dissolve 10 g lithium aluminum hydride in 300 ml
tetrahydrofuran or ether. Stir and add 20.4 g (IV) in 60 ml tetrahydrofuran
or ether over one-half hour. Reflux three hours and cool. Slowly (dropwise
at first) add 10 ml concentrated sulfuric acid in 40 ml water; separate the
aqueous layer and basify with concentrated NaOH. Filter off any precipitate
and extract brown oil with 3x30 ml ether. Wash ether with water, dry and
add 1 ml concentrated sulfuric acid and 25 ml ether. Filter and wash the
white precipitate with ether to get (V) (recrystallize-ethanol).
(Alternatively, add 1.5N sulfuric acid dropwise until bubbling stops,
filter (wash precipitate with solvent and add washings to filtrate), and
dry, evaporate in vacuum (or bubble HCl gas through, or add a little
concentrated HCl and evaporate in vacuum) to get (V)).

                  Mescaline and Amphetamines via Aldehydes
	       J. Chem. U.A.R. 11,401(1968) and many others.

Illustrated for mescaline

	A. To 39.6 g trimethoxybenzyl alcohol (see preceding method for
preparation) (or other analog) in 250 ml methanol. stirred and cooled to
Oø, carefully add 54 ml Br2 over one hour at Oø. Let temperature rise to
room temperature, stir for two hours and add 30 ml saturated Na
thiosulfate. Filter off the aldehyde (I) (recrystallize-benzene).

	A. (Alternative) To 11 g hexamethylenetetramine in 70 ml CHCl3, add
18 g trimethoxybenzyl-Cl (or other analog) and reflux four hours. Evaporate
in vacuum and add 35 ml acetone to cause precipitation. Filter and heat
precipitate with 100 ml water for twenty minutes. Add 17.5 ml concentrated
HCl and reflux five minutes. Evaporate in vacuum the acetone, cool and
filter to get (I).

	B. To 40.4 g (I) and 16 g nitromethane (or equimolar amount
nitroethane for amphetamines) in 100 ml methanol, add 14 ml 3% methylamine
in methanol (under N2 if possible) and let stand at room temperature one
day. Cool to -10ø, filter, wash precipitate with cold methanol and dry in
vacuum or warm oven to get the nitrostyrene (or nitropropene) (II), which
can be reduced as described previously, or as in step C.

	B. (Alternative) 40.4 g (I) and 16 g nitromethane (or equimolar
amount nitroethane) in 150 ml glacial acetic acid and 15 g NH4 acetate.
Reflux 1 1/2 hours; cool, filter, and recrystallize from acetic acid or
methanol to get (II).

	C. CPB 16,217(1968). Suspend 0.2 M (II) and Zn-Hg from 200 g Zn and
20 g HgCl2 in 2 L ethanol and add with vigorous stirring portions of
concentrated HCl until the yellow color disappears. Continue stirring
one-half hour, filter, evaporate in vacuum to get about 0.14 M of the
amine.

	    Phenethylamines from Acetophenones JOC 22,331(1957)

	Acetophenones can be obtained by various routes such as by reacting
acetic anhydride with the substituted benzene (Shirley-PREPARATION OF
ORGANIC INTERMEDIATES, 1951, pg. 190) and may then be isomerized, if
necessary, with aluminum chloride (JCS 232(1944)).

	A mixture of 0.33M of the acetophenone, 39 g of redistilled
morpholine and 14.4 g sulfur is refluxed for 12 hours and the warm solution
poured into 175 ml hot ethanol. Cool to precipitate about 80% yield of the
substituted phenylacetothiomorpholide (I). Mix about 50 g (I), 110 ml
acetic acid, 16 ml sulfuric acid and 25 ml water and reflux 5 hours. Decant
from the small amount of tar formed with stirring into 850 ml water.
Filter, wash the precipitate with water and heat the precipitate with 225
ml 5% aqueous NaOH. Filter and acidify the filtrate with dilute HCl to give
about 80% yield of the substituted phenylacetic acid (II). Mix about 21 g
(II) and 25 g phosphorus pentachloride (caution), and after the initial
reaction subsides, warm on the steam bath 10 minutes. Distill under reduced
pressure to remove the POCl and gradually add the residue to ice cold
concentrated NH4OH. Filter, wash precipitate with water and air dry (can
recrystallize from benzene with a little ethanol added) to get about 18 g
(85%) of the substituted phenyl-acetamide (II). (III) may be reduced by
various means such as the following. To a stirred suspension of 8.6 g
lithium aluminum hydride in 500 ml dry ether add a solution of 10 g (III)
in 600 ml boiling reagent benzene, adding additional hot benzene to
redissolve any precipitate. Stir and reflux for 22 hours and then hydrolyze
by adding water cautiously and 10% sulfuric acid. Filter, heat the
precipitate with concentrated HCl to dissolve and cool to preicipitate the
substituted phenethylamine.

		    Phenylethylamines from Benzaldehydes
	      Indian J. Chem. 5,471 (1967), JMC 11,534( 1968)

	A. 0.02 M substituted benzaldehyde, 27 g acetic anhydride,12 g
fused K acetate in 250 ml round bottom flask with air condenser and CaCl2
tube. Heat on oil bath at 160ø one hour and then at 175ø for four hours.
Pour into water (neutralize with Na carbonate and steam distill to recover
unreacted aldehyde), cool, acidify and filter to get about 60% yield
substituted cinnamic acid (I).

	B. Dissolve 10 g (I) in 100 ml water containing 10% NaOH and add
with stirring, 300 g 3% Na-Hg portionwise at intervals of one hour and stir
for ten hours. Filter, concentrate to one-half volume and acidify to
precipitate the hydrocinnamic acid (II) in about 50% yield.

	C. 10 g (ll) and 15 g SOCl2 are refluxed on water bath two hours
and evaporated in vacuum on water bath. Pour residue into cold liquid NH3
or NH4OH with stirring. Filter, wash precipitate with water to get about
80% yield substituted hydrocinnamamide (III) (recrystallize-benzene or
dilute ethanol).

	C. (Alternative) To O.1M ethyl-chloroformate in 100 ml CHCl3 at
-30ø add a cold solution of 0.1 M (Il) and 0.1 M triethylamine in 100 ml
CHCl3 over forty minutes. Stir 1 1/2 hours at -20ø to 5ø and bubble NH3
through the cold mixture for twenty minutes. Stir one-half hour at room
temperature, filter and extract the solid with CHCl3. Combine CHCl3
extracts and filtrate and wash two times with cold NaOH solution and two
times with water. Dry and evaporate in vacuum to get (III).

	D. Pass the chlorine from 3 g KMnO4 and excess HCl into 120 ml 10%
NaOH to make a solution of hypochlorite (Clorox may do). Add 10 g finely
powdered (III) and stir to dissolve amide, while warming to 50ø. Heat one
hour at 85ø, add 30 g KOH and heat two hours. Separate the oil and extract
the aqueous layer with ether. Add ether to oil and dry, evaporate in vacuum
to get the substituted phenylethylamine (IV).

	D. (Alternative) To a stirred and cooled solution of 0.1 M NaOH in
100 ml water at -5ø add 0.04 M bromine over five minutes and stir one-half
hour at 0ø. Add 0.02 M (III) and stir 1 1/2 hours at 0-5ø. Stir sixteen
hours at room temperature and 70ø for one hour. Cool and extract with
ether, dry and evaporate in vacuum to get (IV).

	Phenylethylamines from Substituted Benzenes CA 57,6721(1963)

	0.1 M m-methoxy-toluene (or analog), 30 ml HCl, 30 ml benzene; cool
to 0ø and with cooling and stirring saturate with HCl. Add 0.15 M
formaldehyde and then more HCl for fifteen minutes. Stir at room
temperature for two hours and dry, evaporate in vacuum the benzene layer to
get about 30% 2-methyl-4-methoxy-benzyl-Cl (or analog). 0.5 M (I), 0.8 M
NaCN, 5 g NaI or KI in 250 ml dry acetone; stir and boil twenty hours.
Filter, wash precipitate with 100 ml acetone and dissolve precipitate with
75 ml benzene. Wash with 100 ml water and dry, evaporate in vacuum to get
about 80% yield 2-methyl-4-methoxy-benzyl-CN (II). 0.1 M (II) in 60 ml 10 N
NH3 in methanol; 4 g Ni-Cr2O3 and shake in autoclave at 70-100 atmospheres
H2 and 120ø to get about 80% yield of the phenethylamine.

	      Phenylethylamines from Phenols CA 68,86944(1968)

	To 5.1 g omega-phthalimidoethyl-Br and 3.1 g 2,6-dimethoxyphenol
(or analog) in 500 ml ether add 2.66 g dry AlCl3 portionwise and let stand
twenty-four hours at room temperature. Heat two hours at 60ø, filter, wash
to recover starting material and dry, evaporate in vacuum to get 25% yield
of (I). To an ether solution of diazomethane from 8 g H2N-CON(NO)CH3 add 4
g (I) portionwise and filter, evaporate in vacuum to get about 100% yield
of (II). Heat 2 g (II) in 20 ml aqueous HCl for four hours and cool,
precipitate, filter, evaporate in vacuum the filtrate to get about 30%
yield mescaline.

		      Phenethylamines JMC 15,214(1972)

	This is a rapid, convenient procedure. If trimethoxybenzyl alcohol
is used in place of p-anisyl alcohol, mescaline will result. Shake 100 g
p-anisyl alcohol (or 0.72 moles analog) with 500 ml concentrated HCl for 2
minutes. Wash the organic phase with water, 5% NaHCO3 and water, and then
add over 40 minutes to a stirred slurry of 49 g NaCN in 400 ml
dimethylsulfoxide with ice water cooling to keep temperature at 35-40ø.
After completing addition, remove cooling bath, stir for 90 minutes and
then add to 300 ml water. Separate the small upper layer and extract the
aqueous-DMSO layer with 2x100 ml ether. Add the ether extracts to the small
upper layer, wash once with water and dry (MgSO4). Add 600 ml ether to a
dry flask and chill in ice as 80 g of anhydrous AlCl3, is added
portionwise, followed by 23 g of lithium aluminum hydride. Add the washed
and dried ether extracts at such a rate as to give gentle reflux without
external heat (ca. 1 hour). Stir for 2 hours, ice chill and treat dropwise
with 25 ml water then 250 ml 20% aqueous NaOH, with periodic addition of
ether through the condenser to replenish losses and facilitate stirring.
Filter and wash precipitate with ether; add ether to filtrate and mix with
one third its volume of absolute ethanol. Slowly and with continuous
swirling and ice cooling add 60 ml concentrated HCl. Cool to 0ø and filter
to get the amine hydrochloride in ca. 75% overall yield (or can obtain the
crude amine by filtering and drying, evaporating in vacuum the final ether
solution). Note the use of concentrated HCl to obtain the crystalline end
product in contrast to many other papers which employ HCl gas.

	   N-Methylation of Amines JMC 13,134(1970), 15,214(1972)

	Either phenethylamine or phenylisopropylamine will work. If the
hydrochloride salt is available, this should first be changed to the free
amine by stirring with concentrated aqueous NaOH.

	Treat 0.54 moles of the amine with 100 ml of benzene and 70 g of
benzaldehyde in a flask fitted with a Dean-Stark trap and reflux until no
more water is present in the condensate (ca. 1 hour) (alternatively, reflux
1/2 hour and then distill until the temperature reaches 100ø): remove the
trap and add a solution of 82 g dimethylsulfate in 200 ml benzene through
the condenser at a rate sufficient to maintain reflux (ca. 15 minutes).
Reflux 30 minutes (or heat 90 minutes on a steam bath), add 200 ml water
and reflux (or heat on steam bath) for 1/2 hour more. Separate the aqueous
layer, extract it twice with ether or benzene, basify with 50% NaOH and
extract twice more. Add the extracts to the organic layer and dry,
evaporate in vacuum to get ca. 70% yield of the N-methyl-amine. Can
crystallize by dissolving in 500 ml 20% absolute ethanol-ether and treating
with 50 ml concentrated HCl while swirling and cooling. The crystals can be
further purified by washing with ice cold 20% ethanol-ether and
recrystallizing from ethanol.

	N-methylation of hallucinogenic amphetamines seems to produce a
very smooth, mellow, euphoric trip, and the same is probably true for
phenylethylamines.
	For N-methylation via the imides see JOC 38, I 348(1973).
N-methylation appears to decrease the potency. Larger N-alkyl groups seem
to have a sedative action.

		    N,N-Dimethylamines JMC 13,134( 1970)

	To 14 g formic acid, cooled in an ice water bath, add dropwise
0.016 mole of the amine and then 3.6 g of formaldehyde (ca.10 ml of
formalin) and reflux for 5 hours. Cool to room temperature, add 7 ml
concentrated HCl and evaporate in vacuum. The resulting oily dimethylamine
can be purified by dissolving in 25 ml water, extracting with 2x25 ml
CHCl3. Basify the aqueous layer with 2N NaOH and extract with 3x25 ml
ether, and proceed as described above for the N-methylamines. This
procedure should work for both phenethylamines and phenylisopropylamines,
and should affect the trip similarly to N-monomethylation. See the
following method for another easy route to N-alkylation which will probably
work for dialkylation. Although N,N dialkyl compounds have very little
activity, they are probably worth further investigation.

		      Amphetamines via phenylacetones
	   CT 3,313(1968) CF. JACS 58,1808(1936) and JCS 18(1930)

	Note that the following procedure leads from the aldehyde to the
amine or N-substituted amine without involving a troublesome catalytic
hydrogenation for reducing the intermediate nitropropene. Mix 0.25M
substituted benzaldehyde, 0.3M nitroethane, 50 ml dry toluene and 5 ml
n-butylamine (or other amine), and reflux 3 hours with a Dean-Stark trap
(or prepare the nitro-propene as described elsewhere here). Add 50 g iron
powder and 1 g FeCl3 (optional) and reflux while adding 90 ml concentrated
HCl over 3 hours. Reflux 1 hour more, add 2 liters of water and extract 3
times with ether, then dry and evaporate in vacuum (or steam distill until
about 3.5 liters of distillate is obtained; extract the distillate 3 times
with toluene; wash the toluene layers with 7 g NaHSO3 in 225 ml of water,
then 3 times with water and dry, evaporate in vacuum) to get the ketone.
Mix 0.13M ketone, 28 g formamide (or dimethyl-formamide if the
N,N-dimethylamine is desired) and 3 ml formic acid and heat at 160ø. Add 3
more ml formic acid and heat 16 hours at 170-180ø adding formic acid from
time to time to keep the pH acid. Distill off the water formed (about 16
ml), cool and extract with 3x70 ml benzene. Distill off the benzene and
reflux the residue 7 hours with 30 ml concentrated HCl. Chill, basify with
10% NaOH and extract with 3X70 ml ether. Dry and evaporate the ether in
vacuum to get the amine. Since some amines are unstable to heating, it is
perhaps best just to dry and evaporate the benzene extract.

	To obtain an N-substituted amine reflux 0.1 M ketone, 17 g aluminum
filings or foil, 50 ml ethanol, 40 ml 30% aqueous n-butylamine (or other
amine), and 0.5 g of mercuric chloride for 3 hours. Cool and pour on 500 g
crushed ice and 200 ml 10% KOH. Extract 3 times with ether and dry,
evaporate in vacuum (or wash combined ether layers 2 times with 1O% HCl,
basify acid extract with 15% NaOH and extract 3 times with ether and dry,
evaporate in vacuum) to get the n-butyl-amine (or other amine).

			    Alkoxybenzaldehydes
		2,4,6-Trimethoxybenzaldehyde JCS 4964(1952)

        This method should also work for 3,4,5-trimethoxybenzene and other
symmetrically substituted benzenes. To 42 g 1,3,5-trimethoxybenzene, 30 g
formanilide and 200 ml ether add 19 g POCl3 and let stand twelve hours.
Evaporate in vacuum, add 900 ml 5% NaOH and steam distill residue to get
the aldehyde (recrystallized benzene-ligroin). For a different synthesis
see Org. Synth. 2,11 (1940).

Methylenedioxybenzaldehydes

        Substituting methyl sulfate for methylene sulfate will probably
give the dimethoxybenzaldehydes. Dissolve 4 g 3,4-dihydroxybenzaldehyde (or
any other benzaldehyde having adjacent OH groups) and 7.6 g KOH in 50 ml
water. Heat to 50ø (under N2 if possible) with stirring and add 5 g
methylene sulfate; stir and heat two hours. Add 500 ml water and sufficient
K sulfate to dissolve the precipitate. Extract with ether, acidify the
aqueous phase with HCl to precipitate unreacted aldehyde, and dry,
evaporate in vacuum the ether to get the title compounds
(recrystallize-methanol).

            2,4,5-Trimethoxybenzaldehyde JACS 57,1126,2739(1935)

        To 13 g 3,4-dimethoxyphenol in 20 ml methanol add a solution of 5.3
g KOH in 100 ml methanol and then 12 g methyl iodide. Reflux two hours, add
300 ml water and make pH 10 with 5% NaOH. Extract with ether and dry,
evaporate in vacuum the pooled extracts to get a clear oil. Mix 17.3 g
N-methyl-formanilide and 19.6 g POCl3 and let stand at room temperature for
one-half hour. Add 8.5 g of the oil, heat two hours on steam bath (or
boiling water) and pour black viscous product on 800 g cracked ice and let
stand three hours, or until no more precipitation to get title compound.
Filter (recrystallize-methanol).

        Simple methods of preparing phenylacetonitrile from
diazoacetonitrile and triphenylboron are given in JACS 90,6891 (1968) and
from the borophenyl-9-borabicyclo (3.3.1) nonane (BBN) and Cl-acetonitrile
in JACS 91,6854(1969). These methods should work with substituted phenyl
compounds to give mescaline and analogs. Likewise (JACS 90,5936(1968)), a
preparation of phenylketones from triphenylboron or BBN and diazoacetone,
or bromo-acetone (JACS 91,6852( 1969)) may be used to prepare the
phenylacetones which can be reduced to the amphetamines in one step as
already described. For synthesis of BBN see JACS 91,4304(1969) and for
borabicyclononane see JACS 90,5280(1968). The amphetamine and mescaline
analogs which can be obtained by replacing carbon atoms with O, N, or S
atoms may also be active, but little work has been done on this. For the
synthesis of thienyl analogs see JACS 64,477(1942).

Other Syntheses
N-Methyl Mescaline HCA 35,1577(1952) p-Methylephedrine Pharmazie
24,735(1969) 4-Nitropropenylbenzene CCI 100,846(1970) Amphetamines and
Phenylethylamines JMC 11,186(1968), 13, 26,134(1970); JOC 19,11 (1954),
20,102,1292(1955), 22,331 (1957), 23,1979,2034(1958), 25,2066(1960); Alab.
J. Med. Sci. 1,417(1964); JCS 18(1930); BSC 835(1962); BER 63,3029 (1930),
65,424(1932), 67,696(1934); CA 6953(1964); Arznei. Forsch. 9,157(1959);
JACS 51,2262( 1929), 63,602(1941), 76,5555(1954); Pharmazie 22,19(1967); CT
3,313(1968). Bromoamphetamines JMC 15,413(1972) N-substituted mescaline
derivatives and methamphetamine analogs Diss. Abst. Int.
32B,5704,5706(1972). Methambhetamine analogs JMC 16,14(1973), MMDA CJC
46,75 (1968). See CT 8,308(1973) for a route from phenethyl or
phenylpropylchlorides to the amines. For older MDA syntheses see JACS
62,425(1940); JCS 15(1943), 1527(1951). For other compounds related to STP
see CJC 51,1402(1973), and Psychopharmacology Communications 1,93(1973) MDA
Japanese Patent 8573 (5 Oct 1956)

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                    HARMALINE AND OTHER BETA-CARBOLINES

        Although some of the compounds of this group occur in plants used
as hallucinogens for millenia by the aborigines of South America and
elsewhere, very little scientific work has been done on them. The Homa of
Asia Minor appears to be syrian rue (Peganum harmala) from which harmaline
was first isolated. Harmaline (1-methyl-7-methoxy-3,4-dihydro-beta-carboline)
is about three times less potent than the 6-methoxy isomer, and very
probably the 5-methoxy isomer will be even more active. The 6-methoxy
isomer is also called 10-methoxy-harmalan. Activity appears to be greater
when the methoxy group is replaced by a longer chain alkoxy group. If a
double bond is also placed in the 3-4 position of harmaline, one obtains
harmine. These compounds are active at about 200 mg orally. Most of these
compounds are probably legal.

                  Harmaline and Isomers CJC 37,1856( 1959)

        Dissolve 3.3 g 4,5, or 6 methoxy (or ethoxy, methyl, etc.)-
tryptamine or its HCl salt in 350 ml 0.1 N HCl: heat on steam bath two
hours with 1.1 g glycoaldehyde (reaction over when aliquot no longer gives
a precipitate with dinitrophenylhydrazine). Filter, concentrate by heating
on water bath or evaporate in vacuum; basify with 20% NaOH and extract with
ether (best to do in an extractor for eighteen hours). Dry and evaporate in
vacuum the extract to get about 5 g residue or oil which may precipitate on
standing. Add 250 ml 90% phosphoric acid and heat on steam bath two hours.
Evaporate in vacuum (or dilute with water, basify with 20% NaOH; extract
with ether in extractor and dry, evaporate in vacuum the extract) to get
about 2.5 g harmaline (or analog).

                Norharmaline and Isomers JACS 72,2962(1950)

        To 24 ml acetic anhydride in 80 ml formic acid add 22 g 4,5 or 6
methoxy (or analog) tryptophan and reflux 1/2 hour. Concentrate to thick
syrup on steam bath with vacuum and add slowly with stirring 180 ml water
and let stand twelve hours at Oø. Filter, wash with 2% HCl and water to get
about 18 g N-formyl-methoxy-tryptophan (I) (recrystallize-benzene-ethanol).
10 g (I), 119 g polyphosphoric acid, 10 ml POCl3 mixed in 500 ml flask with
vigorous stirring. Heat on oil bath at 125ø for eighty minutes (HCl and CO2
evolution). Add ice, cool, filter and neutralize filtrate with concentrated
NH4OH to get about 5 g norharmaline or isomer. To get harmaline isomers,
use 1.4 g N-acetyl-methoxy-tryptophan, 14 g polyphosphoric acid and 3 ml
POCl3 and proceed as above.

                  Harmaline and Isomers JACS 70,223(1948)

        Dissolve 27 g 4,5, or 6 methoxy (or ethoxy, methyl, etc.)
tryptophan in 50 ml freshly distilled acetaldehyde and 1 L water and heat
at 50ø in loosely stoppered flask three hours. Heat on steam bath five
hours to remove acetaldehyde, then add 5 L water and heat to boiling. Add
1.2 L 1O% K-dichromate and 240 ml glacial acetic acid and continue heating
three minutes. Cool and add excess Na-sulfite; take pH to 8 with Na
carbonate Extract with 5 L ether and dry, evaporate in vacuum (or simply
evaporate in vacuum after cooling) to get the harmaline isomer.

                   1,2-Dihydroharmaline JPS 57,269(1968)

        Dissolve 4 g glyoxylic acid monohydrate in 220 ml water and add
with stirring to a solution of 10 g 4,5, or 6 methoxy-tryptamine-HCl in 80
ml water. Adjust pH to 4 with 1O% KOH and stir five hours at room
temperature. Filter and wash with water to get about 4.5 g precipitate.
Melt to decarboxylate or to 4 g precipitate add 30 ml concentrated HCl and
100 ml water and heat at 65ø one hour. Add water to dissolve the solid and
add excess 10% KOH. Filter to get the title compound or analog.

                     Harmaline analogs BSC 2262( 1962)

        Brominate cyclohexanone-2-COOH (JACS 72,2127( 1950)) and cover to
the ethyl ester. Add 1M ethyl-3-Br-cyclohexanone-2-carboxylate to 2M
p-methoxy-aniline in cold benzene. Recrystallize the product from
ether-petroleum ether and reflux sixteen hours in presence of ZnCl2 in dry
ethanol. Filter, evaporate in vacuum and recrystallize-petroleum ether.
Dehydrogenate with 5% palladium-carbon and then treat with NaOH (JCS
530(1945)). Heat at 180ø to get the analog of 6-methoxy-norharmine.

   Sulfur Analogs ol Harman and Other beta-Carbolines JACS 72,4999(1950)

        To synthesize 6-methoxy-3,4-dihydro-beta-carboline (10-methoxy-
harmalan), add 5-methoxy-tryptamine to acetic anhydride and let stand
twelve hours at 10ø. Dilute with water, basify and extract with methylene
Cl and dry, evaporate in vacuum to get melatonin (I). Reflux (I) in xylene
in the presence of P2O5 to get the title compounds. Other References: JMC
7,136(1964); JPS 57,1364 (1968), 59,1446(1970); JACS 70,219(1948); JCS
1602(1921), 1203(1951), 4589,4593( 1956); Organic Synthesis 51, 136 (1971).
For the preparation of tryptophan-4-acetic acid from tryptophan see JACS
88,3941 (1966).

Sulfur isomeres of harmine, harmaline, etc. J.Het. Chem. 9,1265 (1972).
Harmaline and analogs BSC 2058(1973). Beta-carbolines from sugars and
tryptamines in 1 step BER 106,2943(1973).

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                       MUSCIMOLE AND OTHER ISOXAZOLES

        It appears likely that mushrooms were the source of man's first
psychedelic experiences. The "soma" praised in the Rig Veda of ancient
India (about 2,000 BC) is now thought to be a mushroom (the fly agaric,
Amanita muscaria, and possibly other Amanita species). Much of the Eurasian
religion and mythology may have had its origin in the psychedelic
properties of these mushrooms. Probably all members of the genus Amanita are
psychedelic, but ingesting them is unwise since there is probably not a
great difference between the psychedelic and lethal dose of mushroom for
some species. Amanita muscaria itself is seldom lethal but be very careful
if you eat it. It is said to be active if dried, powdered, and smoked. In
the USA it fruits in early summer and again in late summer (in fall and
winter on the Pacific coast). Since muscimole is very water soluble, it can
be extracted from the dried, powdered mushroom (or perhaps even fresh ones)
by soaking in water (hot or even boiling water may be OK) and straining ùù
but drink cautiously. Most of the muscimole is contained in the red "skin"
and the underlying yellow tissue. Some Russian peoples regarded thorough
drying of Amanita as a necessary preliminary to ingestion. It has recently
been suggested that there are significant chemical differences between New
and Old World A. muscaria.

        The main psychedelic component of these mushrooms appears to be
muscimole (5-aminomethyl-3-OH-isoxazole), which is active in an oral dose
of about 10 mg. See HCA 48,920(1965) for extraction of muscimole from the
fungus.

        The value of muscimole as a psychedelic is diminished by the
dizziness and muscle twitching which seem to occur (at least in some
people), but a small dose in conjunction with another psychedelic should be
very interesting. Ibotenic acid also occurs in Amanita, and though not
itself a desirable psychedelic, it can be converted to muscimole by
dissolving in dimethylsulfoxide or refluxing in water.

        Its synthesis is generally more difficult than that of muscimole
(see CA 65,2266(1966) and CPB 15,1025(1967), 19,46(1971)). Several routes
for the synthesis of muscimole (also called agarin or pantherine) follow.
For a good review of this subject see Prog. Chem. Org. Nat. Prod.
27,262(1969). Muscimole is probably legal everywhere.

                            Muscimole Synthesis

Method 1 Rend. Ist. Lomb. 93A,150(1959), 94A, 735(1960), JCS 172(1968)

        Dissolve 100 g 1-Cl-3-Butanone (JACS 75,5438(1953)) in 300 ml
dimethylformamide; stir and add 77.5 g NaNO2 with cooling. Stir five hours
and let stand twelve hours. Add 300 ml water; extract with ether and dry,
evaporate in vacuum the extract (can distill residue 86/2) to get 50 g
1-N02-3-butanone (I). Dissolve 18 g (I) in 90 ml 48% HBr and reflux ten
minutes. Add 100 ml water and steam distill. Dry, extract with ether and
dry, evaporate in vacuum the extract (can distill 67-8/18) to get 4.8 g
3-Br-5-methyl-isoxazole (II). 32.4 g (II) and 85.5 g KOH in 220 ml methanol
and reflux twenty four hours (under N2 if possible). Add 1 L water, extract
with 4x250 ml ether and dry and evaporate the combined ether extracts to
get 13 g liquid 3-methoxy-5-methyl-isoxazole (III). Add 100 ml
n-butyllithium in hexane (2 moles) with stirring over twenty minutes below
-65ø to 22.6 g (III) in 100 ml dry tetrahydrofuran. Stir at -75ø one hour
and pour onto a stirred mixture of 1 kg dry ice (solid CO2) and 1 L ether.
Let stand twelve hours or until CO2 evaporates and extract with 3x200 ml 2N
NaOH. Acidify with dilute HCl and extract with 3x100 ml ether. Dry and
evaporate in vacuum the extract to get 25 g 3-methoxy-isoxazole-5-acetic
acid (1V) (re-crystallize-petroleum ether-ethyl acetate). Dissolve 5.2 g
(IV) in 100 ml 3% HCl in methanol and reflux three hours. Evaporate in
vacuum and recrystallize-petroleum ether (or dissolve residual oil in
ether, wash with NaHCO3 and dry, evaporate in vacuum) to get 4.5 g of the
methyl ester (V) (can distill 80/0.1 ). Add 6.5 g (V) in 20 ml methanol to
3 g hydrazine hydrate in 20 ml methanol and reflux four hours. Evaporate in
vacuum and dry in exsiccator over concentrated sulfuric acid for twelve
hours to get 6 g 3-methoxy-isoxazole-5-acetohydrazide (VI)
(recrystallize-ethyl acetate). Dissolve 5.13 g (VI) in 50 ml dry
tetrahydrofuran and treat with 50 ml 1.75 N HCl in tetrahydrofuran. Cool to
-40ø and add over ten minutes with stirring 5 ml tertiary butyl nitrite in
20 ml tetrahydrofuran (temperature rises to about 10ø). Evaporate in vacuum
and dissolve the yellow oil in 100 ml ethyl acetate. Wash with 50 ml NaCl
containing 1% NaHCO3 and dry, evaporate in vacuum to get the azide.
Dissolve the azide in 50 ml toluene and heat at 100ø until N2 evolution
stops (about thirty minutes). Add 10 ml ethanol and reflux two hours.
Evaporate (room temperature/15) to get 4 g 5-(ethoxy-carbonylamino)-
methyl-3-methoxy-isoxazole (VII) (can distill 129/0.2). Test for
psychedelic activity. Dissolve 4 g (VII) and 2.5 g KOH in 12 ml ethanol and
reflux eight hours. Dissolve in 20 ml water, acidify with dilute HCl and
evaporate to dryness. Dissolve residue in hot ethanol and evaporate to get
3 g 5-aminomethyl-3-methoxy-isoxazole (VIII). Test for activity. 1 g (VIII)
in 10 ml glacial acetic acid and 4.5 g HBr and reflux one hour. Evaporate
in vacuum to get muscimole.

Method 2 JACS 62,1147( 1940), TL 2077( 1963), CA 65,2267 (1966)

        Pass chlorine gas into an ice cold, well-stirred solution of 5 ml
acetylketene in 30 ml CCl4 until there is a 4.5 g increase in weight
(solution is slightly yellow). Pour slowly into excess methanol or ethanol
at 0ø and distill at 118/17 to get 6 ml methyl (or ethyl)-4-Cl-acetoacetate
(I). To 2.7 ml methanol saturated with dry HCl at 0ø, add a mixture of 10 g
(I), 20 g methyl orthoformate (trimethoxymethane) and 13 g methanol and
reflux four hours. Pour hot into 200 ml ice water and adjust pH to 8 with
30% NaOH. Extract four times with ether and evaporate and distill to get
methyl (or ethyl)-4-Cl-3,3-dimethoxy-butyrate (II). Dissolve 40 g (II) in
20 ml methanol and add hydroxylamine-HCl in methanol. After ninety-six
hours at room temperature (under N2 if possible), evaporate in vacuum. Can
purify the residue by dissolving in water and put on anionic column; wash
column to neutrality and elute with 2N acetic acid; just before the acid
elutes, the alkaline fraction giving a positive FeCl3 test appears;
evaporate in vacuum this fraction below 40ø and dry at 40/0.5 for twelve
hours. Dissolve 5 g product in 130 ml glacial acetic acid and saturate at
room temperature, then at Oø with dry HCl. Let stand sixteen hours at room
temperature and evaporate in vacuum at 40øC. Dilute with water and
evaporate three times. Extract with 2x130 ml hot ether and filter,
evaporate in vacuum to get 3-Cl-methyl-5-OH-isoxazole (III) (recrystallize
in acetone). Heat (III) sixteen hours at 90ø in concentrated NH4OH in
autoclave and evaporate to get muscimole.

                  Method 3 GCI 91,61 (1961), JCS 172(1968)

        To 1 g 3-CI-5-methyl-isoxazole in 14 ml 1.4 N NaOH add with
stirring 1.1 g KMnO4 in 20 ml water. Filter, decolorize with NaHSO3 and
acidify with dilute sulfuric acid. Extract with ether and dry, evaporate in
vacuum to get 0.8 g 3-Cl-isoxazole-5-COOH (I). To 2.5 g (I) in 7.5 ml water
add 15 g KOH in 43 ml methanol and reflux four hours (under N2 if
possible). Cool, acidify with concentrated HCl and extract with ether five
times. Dry and evaporate in vacuum to get 2 g oil which precipitates to
give 3-methoxy-isoxazole-5-COOH (11). Dissolve 5.2 g (ll) in 100 ml 3% HCl
in methanol and reflux three hours. Evaporate in vacuum and
recrystallize-petroleum ether (or dissolve residual oil in ether, wash with
NaHCO3 and dry, evaporate in vacuum) to get the methyl ester (III). Add
with stirring 0.8 g (III) to 40 ml aqueous NH3 (density about 0.88) and
stir thirty minutes at room temperature. Filter, wash with cold water and
dry to get 0.5 g 3-methoxy-isoxazole-5-carboxamide (IV). Dissolve 37.8 g
NaBH4 in 100 ml diglyme (dimethyl ester of diethylene glycol) and 23 ml BF3
etherate in diglyme; add to 4.6 g (IV) in 100 ml tetrahydrofuran and reflux
forty-eight hours. Add HCl, evaporate in vacuum and dissolve residue in
water. Basify with 50% KOH and extract with ether. Dry, filter, evaporate
in vacuum or treat with HCl to give (VIII) of method 1 which converts to
muscimole as described.

                         Method 4 CA 65,2266(1966)

        Dissolve 626 g 2-(2-nitrovinyl) furan in 3.13 L 48% HBr and 6.26 L
glacial acetic acid and heat on steam bath nine hours. Evaporate in vacuum
to 3 L; add 3 L water; boil; decolorize; cool and filter. Extract filtrate
with 2L CHCl3 and evaporate in vacuum the extract. Add residue to
precipitate. Filter out to get 3-Br-isoxazole-5-proprionic acid (I)
(recrystallize-benzene-cyclohexane). Dissolve 44 g (I) in 440 ml
concentrated sulfuric acid and add 80 g CrO3 in 80 ml water dropwise over
three hours at 15-20ø. Pour onto 800 g ice and extract the aqueous solution
with 3x500 ml ether. Evaporate in vacuum to get 3-Br-isoxazole-5-COOH (II)
(recrystallize-benzene-toluene). Dissolve 30.7 g (II) and 27 g KOH in 500
ml methanol and stir two hours at 140ø. Cool, add 1.5 L water and extract
with 3X 1.5 L ether. Can decolorize aqueous solution by boiling briefly
with carbon, then filtering and acidifying with concentrated HCl. Filter
and recrystallize-benzene to get 3-methoxy-isoxazole-5-COOH, which is the
analog of (IV) in method 1 and is identical to (II) in method 3 and can be
converted to muscimole by either method.

                  Method 5 Rend. Ist. Lomb. 94A,737(1960)

        This method gives a somewhat lower yield than method 1. Dissolve
14.1 g 1-nitro-3-butanone in 30 ml glacial acetic acid and heat to 35ø; add
slowly with stirring to a solution of 5.3 g bromine in 10 ml glacial acetic
acid. Evaporate in vacuum, dissolve residue in ether and wash with water,
NaHCO3 and water. Dry and evaporate in vacuum the ether (can distill 84/2)
to get 6 g 1-nitro-4-Br-3- butanone (I). Add 4.4 g (I) to 25 ml 48% HBr and
reflux three hours. Add 50 ml water and steam distill. Neutralize the
distillate with K carbonate and extract with ether. Dry and evaporate the
extract (can distill 128/20) to get 5.6 g 2-Br-5-Br-methyl-isoxazole (II).
To a warm solution of 5.2 g urotropine (hexamethylenetetramine) in 45 ml
CHCl3, add 8 g (II) in 10 ml CHCl3 and let stand four hours at room
temperature. Filter, wash with CHCl3 and dry. Dissolve 2.3 g precipitate in
10 ml concentrated HCl and let stand two hours at room temperature. Add 30
ml water, basify with NaOH and extract with ether. Precipitate with dry HCl
gas to get 3-Br-5-aminomethyl-isoxazole (III). Test for activity. Dissolve
8.8 g (III) and 5.6 g KOH in 60 ml methanol and reflux thirty hours.
Dissolve in 100 ml water, acidify with dilute HCl; evaporate in vacuum and
dissolve residue in hot methanol to get 3-methoxy-5-aminomethyl-isoxazole
(IV). Test for activity. Convert (IV) to muscimole as described in method 1
or as follows: reflux in concentrated HCl four hours and evaporate in
vacuum (recrystallize-methanol:tetrahydrofuran 1:1). Can add
tetraethylamine to precipitate.

         Method 6 (best yield) CPB 19,46(1971), JCS 121,1638(1922)

        To prepare diethylacetone dicarboxylate (I) proceed as in method 3
for cocaine synthesis, substituting 720 ml ethanol for methanol. To 197 g
(I), add rapidly with stirring and cooling 208 g PCl5, keeping temperature
below 50ø. When HCl evolution stops, pour into water and add ice as
necessary to cool. Extract the red oil with ether and dry, evaporate in
vacuum. Boil residue 2 1/2 hours with 20% HCl, evaporate the water and
dissolve the residue in ether. Dry and evaporate in vacuum to get 100 g
3-Cl-glutaconate (II). 100 g (II), 300 g ethanol, 50 ml sulfuric acid and
reflux while passing in ethanol vapor until 1.5 L collects. Add water,
extract with ether, wash with aqueous Na carbonate and dry, evaporate in
vacuum to get 113 g diethyl-3-CI-glutaconate (Ill). Mix 28 g NaOH, 140 ml
water, 10.4 g hydroxylamine-HCl, 280 ml ethanol and cool to -35ø in
acetone-dry ice bath. Stir and add 30.3 g (III) in 50 ml ethanol over two
minutes; stir one hour (can let stand twelve hours). Neutralize with 60 ml
concentrated HCl while cooling in ice bath. Evaporate in vacuum and then
add 62 ml dry ethanol, 130 ml benzene and 1/2 ml concentrated sulfuric acid
to residue and reflux twenty-four hours to remove 80 ml of the azeotrope.
Cool, pour into 60 ml ice water and separate the organic layer. Extract the
aqueous layer with 30 ml benzene and add to organic layer. Wash organic
layer with 2x15 ml NaHCO3 (2%), 2x30 ml water and dry, evaporate in vacuum
to get 14 g ethyl-3-OH-5-isoxazoleacetate (IV) (recrystallize-ether). Add
3.36 g (IV) portionwise to 1.35 g hydrazine hydrate which has been heated
at 94ø on water bath and heat 3 hours. Cool, filter and recrystallize in
methanol to get 2.6 g of the hydrazide (V) (concentrate filtrate to get
more). Dissolve 3.41 g (V) in 30 ml tetrahydrofuran and mix with 6.55 ml of
a solution of dry HCl in tetrahydrofuran (9.94M). Cool to -50ø in dry
ice-acetone bath and add dropwise 2.81 g isoamyl nitrite in 10 ml
tetrahydrofuran over five minutes. Remove cooling bath, let stand fifteen
minutes and stir fifteen minutes and filter. Evaporate in vacuum the
liquid, dissolve the residue in 80 ml ethyl acetate; wash with 2x20 ml 1:9
mixture of saturated aqueous NaHCO3 and saturated aqueous NaCl and dry,
evaporate in vacuum. Dissolve oily residue in 40 ml dry ethanol and reflux
on oil bath forty-five minutes. Cool, evaporate in vacuum, filter and wash
with benzene to get 1.2 g 3-OH-5-(carbeth-oxyamino)-methyl-isoxazole (VI)
(recrystallize-benzene). 3.83 g (VI) in 80 ml 20% Ba(OH)2. Reflux fifteen
hours and evaporate in vacuum (or cool and acidify with 10% sulfuric acid,
filter, and evaporate in vacuum) to get muscimole (recrystallize-methanol).

Other References

        The following papers describe the preparation of various muscimole
analogs which may have activity: CJC 48,3753(1970); TL 21 O1 (1970); JOC
35,1806(1970); JMC 13,738(1970); BSC 2685(1970). For a simple two-step
synthesis of 3-OH-5-methyl-isoxazole (which may substitute for (III) in
method 1) see CA 74,76407(1971) (cf. CA 74,12552 I (1971)). The antibiotic
Oxamycin (cycloserine) is often psychedelic (see Merck Index for
synthesis).




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                                    LSD

        Since Hofmann's first trip in 1943, great deal of interest has been
generated in the occurrence and properties of various lysergic acid
derivatives. Fungi of the genus Claviceps, which grow on rye wheat, rice
and other grasses, were the first natural source of these alkaloids to be
discovered. In recent years related compounds have been found in the genera
Penicillium (the blue-green mold that also produces penicillin),
Aspergillus, and Rhizobus (the black bread mold). These compounds are now
produced commercially by culturing certain strains of Clavicebs which
produce as much as 4 g of ergotamine per Liter of culture medium. Growing
pure cultures of fungi is not for amateurs, but those interested will find
these references useful: JPS 58,143(1969); App. Microbiol. 18,464 (1969);
HCA 47,1052(1964); Lloydia 32,327,401(1969); Can. J. Microbiol.
16,923(1970); CA 61,15314c-f, 67,84858e, 69, 36323w; Biotech. Bioeng.
13,331(1971); CA 76,57736(1972); U.S. Patent 3,483,086; Planta Med.
23,330(1973); J. Pharm. Educ. 36,598(1972); CA 78,41492(1973); French
Patent 1,531, 205; German Patents 1,806,984 and 1,909,216; British Patent
1,158,380.
        For a description of a wild American Claviceps species see
Mycologia 66,978(1974).

        The occurrence of hallucinogens in the seeds (and to a lesser
degree in the leaves and stems) of various members of the family
Convolvulaceae (morning glories, etc.) was known to the Aztecs. Seeds of
the genera Rivea, Impomoea, and Argyria (Hawaiian baby woodrose) contain
lysergic acid derivatives; the woodrose being champion with about one
hundred times as much as the other genera (about 7 mg alkaloids/g seeds).
In view of the low yield (maximum 10 mg alkaloids/ 100 g seeds) even the
famed pearly gates variety of morning glory is not worthwhile extracting,
and the trip is commonly a bummer, resembling that produced by scopolamine
or ibogaline and unlike that of LSD. However, the lysergic acid amide,
etc., can be extracted, hydrolyzed to lysergic acid (as described below for
ergot alkaloid hydrolysis), and converted to LSD by any of the methods
described. For species variation of alkaloid content see Lloydia
29,35(1966). Crude ergot or woodrose seeds should yield ca. 1 g LSD/kg
after conversion of the isolated alkaloids.

                     Alkaloid Extraction (short method)

        Finely grind seeds (preferably woodrose) and add NaHCO3. Extract
with ethyl acetate by soaking about one day. Filter and extract the ethyl
acetate with tartaric acid solution. Basify the extract with NaHCO3 and
extract it with ethyl acetate. Dry and evaporate in vacuum the ethyl
acetate to get the alkaloids. Repeat this procedure on the seeds until no
more residue is obtained.
        Alternatively, add 100 ml petroleum ether to 100 g finely ground
seeds and let soak about two days. Filter, discard petroleum ether and let
seeds dry. Add 100 ml methanol to the seeds and let soak about two days.
Filter, repeat extraction with another 100 ml methanol and evaporate in
vacuum the combined methanol extracts. The residual yellow oil contains the
alkaloids.

        For chromatographic purification of ergot alkaloids from seed
extracts see Phytochem. 11,1479( 1972). For ergot extraction and separation
see also Fr. Patent 2,089,081 (11 Feb 1972) and CA 79,105,457(1973). For a
recent review of the ergot alkaloids see R. Manske (Ed.) The Alkaloids,
vol. 15: 1-40(1975).

  Extraction of Lysergic Acid Amides from Woodrose Seeds or Powdered Ergot

        Reduce the seed material to a fine powder in a blender, and spread
it out to dry. Grind it again if it is not fine enough after the first time
due to dampness. Saturate the powdered seed material with lighter fluid,
naphtha or ligroine. When completely saturated, it should have the
consistency of soup. Pour it in a chromatography column and let it sit
overnight. Remove the fatty oils from the material by dripping the lighter
fluid or other solvent through the column slowly and keep testing the
liquid that comes through for fats by evaporating a drop on clean glass
until it leaves no greasy film. It will take several ounces of solvent for
each ounce of seeds. Mix 9 volumes of chloroform with 1 volume of
concentrated ammonium hydroxide and shake it in a separatory funnel. When
it settles the chloroform layer will be on the bottom. Drain off the
chloroform layer. Discard the top layer. Drip the chloroform wash through
the column and save the extract. Test continuously by evaporating a drop on
clean glass until it ceases to fluoresce under a black light. Evaporate the
chloroform extracts and dissolve the residue in the minimum amount of a 3%
tartaric acid solution. If all the residue doesn't dissolve, place it into
suspension by shaking vigorously. Transfer the solution to a separatory
funnel and wash the other vessel with acid in order to get all the alkaloid
out. Pour the washings in the funnel also. Basify by adding sodium
bicarbonate solution, and add an equal volume of chloroform. Shake this
thoroughly, let it settle, remove the bottom layer and set it aside. Once
again, add an equal portion of chloroform, shake, let it settle and remove
the bottom layer. Combine the chloroform extracts (bottom layers) and
evaporate to get the amides.

               The Culture and Extraction of Ergot Alkaloids

        Make up a culture medium by combining the following ingredients in
about 500 milliliters of distilled water in a 2 liter, small-neck flask:

        Sucrose..........................100 grams
        Chick pea meal...................50 grams
        Calcium nitrate..................1 gram
        Moriopotassium phosphate.........0.25 grams
        Magnesium sulphate...............0.25 grams
        Potassium chloride...............0.125 grams
        Ferrous sulphate heptahydrate....8.34 milligrams
        Zinc sulphate heptahydrate.......3.44 milligrams

        Add water to make up one liter, adjust to pH 4 with ammonia
solution and citric acid. Sterilize by autoclaving. Inoculate the
sterilized medium with Claviceps purpurea under sterile conditions, stopper
with sterilized cotton and incubate for two weeks periodically testing and
maintaining pH 4. After two weeks a surface culture will be seen on the
medium. Large-scale production of the fungus can now begin. Obtain several
ordinary 1 gallon jugs. Place a two-hole stopper in the necks of the jugs.
Fit a short (6 inch) glass tube in one hole, leaving 2 inches above the
stopper. Fit a short rubber tube to this. Fill a small (500 milliliter)
Erlenmeyer flask with a dilute solution of sodium hypochlorite, and extend
a glass tube from the rubber tube so the end is immersed in the
hypochlorite. Fit a long, glass tube in the other stopper hole. It must
reach near the bottom of the jug and have about two inches showing above
the stopper. Attach a rubber tube to the glass tube as short or as long as
desired, and fit a short glass tube to the end of the rubber tube. Fill a
large, glass tube (1 inch x 6 inches) with sterile cotton and fit 1-hole
stoppers in the ends. Fit the small, glass tube in end of the rubber tube
into 1 stopper of the large tube. Fit another small glass tube in the other
stopper. A rubber tube is connected to this and attached to a small air
pump obtained from a tropical fish supply store. You now have a set-up for
pumping air from the pump, through the cotton filter, down the long glass
tube in the jug, through the solution to the air space in the top of the
jug, through the short glass tube, down to the bottom of the Erlenmeyer
flask and up through the sodium hypochlorite solution into the atmosphere.
With this aeration equipment you can assure a supply of clean air to the
Clauiceps purpurea fungus while maintaining a sterile atmosphere inside the
solution. Dismantle the aerators. Place all the glass tubes, rubber tubes,
stoppers and cotton in a paper bag, seal tight with wire staples and
sterilize in an autoclave. Fill the 1-gallon jugs 2/3 to 3/4 full with the
culture medium and autoclave. While these things are being sterilized,
homogenize in a blender the culture already obtained and use it to
inoculate the media in the gallon jugs. The blender must be sterile.
Everything must be sterile. Assemble the aerators. Start the pumps. A slow
bubbling in each jug will provide enough oxygen to the cultures. A single
pump can, of course, be connected to several filters. Let everything sit at
room temperature (25øC.) in a fairly dark place (never expose ergot
alkaloids to bright light -- they decompose) for a period of ten days.
After ten days adjust the cultures to 1% ethanol using 95% ethanol under
sterile conditions. Maintain growth for another two weeks. After a total of
24 days growth period the culture should be considered mature. Make the
culture acidic with tartaric acid and homogenize in a blender for one hour.
Adjust to pH 9 with ammonium hydroxide and extract with benzene or
chloroform/iso-butanol mixture. Extract again with alcoholic tartaric acid
and evaporate in a vacuum to dryness. The dry material is the salt (i.e.,
the tartaric acid salt, the tartrate) of the ergot alkaloids, and is stored
in this form because the free basic material is too unstable and decomposes
readily in the presence of light, heat, moisture and air. To recover the
free base for extraction of the amide or synthesis to LSD, make the
tartrate basic with ammonia to pH 9, extract with chloroform and evaporate
in vacuo. If no source of pure Claviceps purpurea fungus can be found, it
may be necessary to make a field trip to obtain the ergot growths from rye
or other cereal grasses. Rye grass is by far the best choice. The ergot
will appear as a blackish growth on the tops of the rye where the seeds
are. They are approximately the same shape as the seeds and are referred to
as "heads of ergot." From these heads of ergot sprout the Claviceps
purpurea fungi. They have long stems with bulbous heads when seen under a
strong glass or microscope. It is these that must be removed from the
ergot, free from contamination, and used to inoculate the culture media.
The need for absolute sterility cannot be overstressed. Consult any
elementary text on bacteriology for the correct equipment and procedures.
Avoid prolonged contact with ergot compounds, as they are poisonous and can
be fatal.

                             LSD Identification

        Since LSD is an indole derivative, it gives a positive reaction
(violet color) to the tests given in the indole section. LSD also
fluoresces under an ultraviolet light (black light), but so do many other
compounds. For infrared spectra of LSD and related compounds, see JACS
78,3087(1956) and J. Forensic Sci.12,538 (1967). For other information on
identification see JPS 56,1526 (1967) and JAOAC 50,1362(1967),
51,1318(1968). For a microcrystalloscopic test see J. Pharm. Pharmacol.
22,839(1970). In order to make LSD, lysergic acid is needed. This can
sometimes be obtained, but generally one of the lysergic acid containing
ergot alkaloids such as ergotamine is more readily available. Ergot is the
dried sclerotium of various species of fungi which infect rye (and other
grasses), leading to the formation of large purple growths in place of the
rye grains. These growths are collected, dried, powdered and the alkaloids
extracted. For the extraction procedure see HCA 28,1283(1945), J. Pharm.
Pharmacol. 7,1 (1955), JPS 50,201(1961), CA 75,137422(1971). Proc. Indian
Acad. Sci. 71B,28,33(1970) gives production from artificially infected rye.
Ergot is produced mainly in Europe (especially Switzerland) but some has
been grown in the USA (e.g., in Minnesota). This production occurs
primarily because of the use of ergotamine and related compounds in
medicine (contracting the post-partum uterus, terminating
migraineheadaches, etc.). Many of the ergot alkaloids are derivatives
(amides) of lysergic acid. Unfortunately, these compounds have little
hallucinogenic activity and it is necessary to hydrolyze (split with water)
off the amide, producing lysergic acid, and to synthesize a different amide
with greater psychedelic activity. This hydrolysis can be done with any of
the following compounds or a mixture of them: ergometrine, ergine,
ergotamine, ergosine, ergocristine, ergokryptine, ergonovine (ergo-
metrine) and methysergide (Sansert). When -ine is added to the name (e.g.,
ergotaminine) this indicates the isomers which will lead to the production
of the inactive iso-LSD. The papers cited here give simple techniques for
converting these to the active forms (or see the technique for converting
iso-LSD to LSD in method 1 following): HCA 37,820,2039(1954); CA
69,36322(1968); CCCC 34,694 (1969). For a review of the ergot alkaloids see
THE ALKALOIDS, Manske and Holmes (Eds.), 8,725(1965), and F. Bove, THE
STORY OF ERGOT (1970).

Ergot Alkaloid Hydrolysis

        JBC 104,549(1934); HCA 47,1929(1964). Perhaps the best method is
Hofmann's modern hydrazine hydrolysis given later, since this disposes of
the necessity for isolating the lysergic acid (I); otherwise the following
alkaline hydrolysis can be used: Dissolve 20 g of the alkaloid (e.g.,
ergotamine) in 200 ml 1M KOH in methanol (i.e., dissolve 56 g KOH pellets
in 1L 100% methanol) in a 1 L heavy walled vacuum flask and evaporate in
vacuum the methanol at room temperature. To prevent the solution from
cooling, and thus greatly prolonging the evaporation time, put the flask in
a pan of water kept at room temperature by gentle heating or by running
warm water through it. Add 400 ml 8% KOH in water to the residue and boil
for one hour (under N2 if possible, this can be done by filling the flask
with a N2 stream and loosely stoppering or by allowing a gentle stream of
N2 to flow through during heating). Cool, acidify with dilute sulfuric acid
and shake in separatory funnel with 1 L ether. Discard the upper ether
layer and filter with vacuum the aqueous suspension of lysergic acid (I).
Wash precipitate with 20 ml dilute sulfuric acid. To recover the small
amount of (I) remaining in solution, basify with Na carbonate and bubble
C02 through it. Filter and add precipitate to first batch. Some isolysergic
acid will remain in solution and can be precipitated by adding 10% HNO3. It
can be converted to (I) by adding 3 ml 10% KOH for each 0.1 g acid, boiling
on steam bath for one hour under N2 (if possible) and precipitating by
acidifying with glacial acetic acid. Maximum yield is about 9 g (I) for 20
g ergotamine. A shorter method of hydrolysis which may work as well
follows: dissolve 20 g alkaloid in 300 ml methanol and 300 ml 40% KOH and
reflux two hours under N2 (if possible). Cool, saturate with CO2 and
evaporate in vacuum. Extract the residue with hot ethanol three times and
dry, evaporate in vacuum the combined ethanol extracts to get (I). Under
ordinary conditions, about 20% of (I) will be converted by the action of
hot water, etc., to the inactive isolysergic acid. Most of this remains in
solution and can be isomerized to (I) as described above, or it can be
converted to iso-LSD by any of the methods described later and isomerized
to LSD (see method 1). It is unnecessary to purify (I), but this can be
done as follows: dissolve 9 g (I) in 20 ml NH4OH, filter and concentrate in
vacuum at room temperature to precipitate (I). After filtering, the grey
crystals can be further purified by dissolving in boiling water and cooling
in ice bath to precipitate (I). Melting point should be about 240o
(decomposes). Alternatively, the dark-colored (I) resulting from hydrolysis
can be shaken with 2x400 ml 2 M NH4OH in ethanol, and the combined extracts
evaporated in vacuum to give (I). Dissolve the remaining residue in 500 ml
hot methanol, cool to 0ø and filter out the (I) (recrystallize-water). Can
remove colored impurities by shaking solution with decolorizing carbon and
filtering. Recently a method for increasing the yield of (I) about 10%
using 2.5% hydrazine hydrate was described (CA 69,36323(1968)). Dissolve 7
g alkaloid in 200 ml 6 N KOH in methanol and 200 ml ethanol, add 10 ml
hydrazine hydrate and boil four hours under N2 (if possible) and proceed as
above. Finally, the (I) must be thoroughly dried by heating at about 110ø/1
mm for two hours or 150ø if ordinary lab vacuum of 15 mm is used. A forced
water vacuum (about 25 mm) can be used here as elsewhere. An oil bath
(e.g., mineral oil) will allow temperature regulation.

                               LSD Synthesis

                                  Dangers

        There are certain aspects of LSD production which are common to all
synthetic methods. The first is a certain degree of danger; each uses
dangerous reagents and solvents. Hydrazine and hydrazine hydrate are both
violent poisons, and each can cause severe skin burns and eye damage. The
vapor of each is irritating, and can cause severe eye irritation as well as
liver and blood damage, but the symptoms don't always manifest right away,
sometimes appearing three or four days after exposure, so it is easy for
exposure to be much more dangerous than is immediately realized. In
addition, anhydrous hydrazine is a sensitive and violent explosive, the
explosion of which can be set off by certain types of stainless steel and
such common things as wood and rust. Both trifluoroacetic acid and sulfur
trioxide will cause very severe skin burns, and their vapors are extremely
irritating. Sulfur trioxide is such a strong dehydrating agent that it
chars organic material, and its heat of dehydration is so high that it will
start a fire if spilled on wood, which could prove fatal were flammable
solvents in use at the time or stored nearby. Phosgene is very poisonous;
so insidious that it was used as a war gas in World War I. One deep breath
can cause immediate collapse and death, and as it is not irritating there
is no gag reflex to prevent one from taking that deep breath. Doses which
are not high enough to be immediately lethal may not be noticed at all at
the time of exposure, yet lead to death within 24 hours. Sub-lethal doses
cause pulmonary edema and serious respiratory disability; again, the
symptoms can appear well after an exposure which was hardly noticed.
Diethylamine, used in every LSD synthesis, has a very low flash point, and
its vapor is irritating. The vapor of DMF is also irritating, and prolonged
exposure can cause liver damage. In fact, most of the solvents used in LSD
production are either flammable or toxic or both. In addition to all the
above, the starting material, the ergot alkaloids, is as a class quite
toxic, and clean working conditions are necessary when working with it.
Ergot alkaloid poisoning, known in the Middle Ages as Saint Antony's fire,
can actually cause one's limbs to blacken, shrivel, and fall off! Any woman
working with these compounds should also be aware that many of them are
oxytoxics, that is, they cause uterine contractions, and are so used to
induce labor, etc.

                             Working Conditions

There are certain procedures common to all syntheses of LSD which are based
upon the sensitive nature of ergot compounds in general. Natural ergot
alkaloids, lysergic acid, LSD, and the intermediate products associated
with the various syntheses are all to a varying degree unstable. Even the
most stable of these compounds will readily decompose under any but
moderate conditions. Thus precautions must be taken against light,
moisture, oxygen, and heat. Light of the ultraviolet region promotes
addition of water at the delta-9-10 double bond to form the lumi-compounds.
Thus reactions are best carried out in the light of red or yellow
photographic darkroom bulbs, and storage should be in opaque or amber
bottles. Most of the reactions involved in LSD synthesis require anhydrous
conditions for good yield, and so protection must be made against moisture
during the actual production. Furthermore, the final product must be
thoroughly dried to prevent possible formation during storage of the
lumi-compounds as mentioned above. Oxidizing agents, including atmospheric
oxygen, will decompose ergot compounds. For this reason, all reactions are
carried out in an atmosphere of an inert gas such as nitrogen. The danger
of oxidation increases with temperature, so this precaution is of course
most important with those reactions proceeding at elevated temperature.
Various methods have been devised to prevent oxidation during storage. The
most obvious is to store the LSD in nitrogen filled containers, but the
excellent protection thus afforded is of course lost when the bottle or
ampule is opened. Another method is to use an antioxidant; Brown and Smith
recommend ascorbic acid. A more sophisticated method, recommended on the
highest authority, is to make LSD maleate rather than the tartrate. Both
maleic and tartaric acids are dicarboxylic, but the pK2 of maleic acid is
too low to form a salt with LSD. Thus there is a free carboxyl group in LSD
maleate, which group will serve to prevent oxidative decomposition.
Excessive heat will cause decomposition of LSD and its precursors, and will
also increase the possibility of racemization. Thus reactions at elevated
temperature are not unnecessarily prolonged, nor are temperatures
unnecessarily raised. All drying is done in vacuo in an inert atmosphere,
and long term storage should be under refrigeration.

                                 Legal Acid

        I want to emphasize that "legal acid" can be obtained if other
amines are substituted for diethylamine in LSD synthesis. These other
lysergamides should give identical trips, but most of them are less potent
than LSD. Precise potency data do not exist, so it remains for an
enterprising chemist to gain immortality by adding each of the following
amines (and any others that come to mind) to separate aliquots of the final
step of LSD synthesis (they could easily be done simultaneously), isolating
the tartrates and assaying them for potency: piperidine, diisopropylamine,
ethylisopropylamine, ethylpropylamine, methylethylamine,
methylisopropylamine, tetrahydrooxythiazine, tetrahydroisoxazine,
dioxazole, 2-methylmorpholine, 2,5-dimethyl (or dimethoxy) pyrrolidine,
cyclo-butyl-amine, cyclopentylamine, etc. Published potency data expressed
as a fraction of LSD activity follow: pyrrolidide (1/20), dimethylamide
(1/20), morpholide (1/10 or 1/3), ethylpropyl (1/3), dipropyl (1/10),
methylethyl (less than 1/10), methylpropyl (less than 1/10).

                                  Methods
          LSD via the Hydrazide HCA 38,429(1955), HCA 26,953(1943)
              CA 57,12568(1962), U.S. Patent 3,239,530(1966).

        Perhaps the simplest method is the following devised by Hofmann,
which proceeds directly from the ergot alkaloid via hydrazine, and is not
to be confused with his earlier use of hydrazine under more violent
conditions which led to a racemized product and reduction of the yield by
one-half.

        Add 1.16 g ergotamine HCl to 4 ml anhydrous hydrazine and heat one
hour at 90ø. Add 20 ml water and evaporate in vacuum. Can proceed to the
next step or can purify by adding ether and aqueous tartaric acid, basify
the aqueous phase and extract aqueous phase with CHCl3 to get mainly
d-iso-lysergic hydrazide (I). Can chromatograph on alumina and elute with
0.5% ethanol in CHCl3 to purify. To 1 g (I), finely ground, in 40 ml 0.1 N
ice cold HCl, add with good stirring at 0ø 4 ml 1N Na nitrite. Quickly over
two-three minutes, add 40 ml 0.1 N HCl so pH is about 5. Let stand five
minutes, basify with 1N NaHCO3 and extract with 100 ml ether, then 50 ml
ether. Wash ether with water and dry and evaporate in vacuum at 10ø.
Dissolve the resulting yellow azide in about 5 ml diethylamine (DEA) at 0ø
and heat one hour at 60ø in a bomb (sealed metal pipe), or heat 3 to 4
hours at 45øC in a vented flask. Let stand several hours and evaporate in
vacuum to get about 0.7 g d-LSD and 0.15 g d-iso-LSD (which can be converted
to d-LSD as described in method 1 following). Alternatively, the DEA can be
added to the cooled ether solution of the azide and let stand several hours
or overnight at room temperature in the dark in a vented flask. An
alternate method of proceeding from the hydrazide follows (U.S. Patent
3,085,092). To a solution of 1.4 g (I) in 5.5 ml 1 N HCl, 5 ml water, 5 ml
EtOH, add 1 g acetylacetone (2,4 pentanedione), let stand 1 hour at room
temperature and neutralize with 5.5 ml 1 N NaOH. Filter off the lysergyl
pyrazole (II) and wash with water. Can purify by drying in vacuum at 60øC
and recrystallizing from chloroform by the addition of ether. Heat 0.4 g
(ll) and 2.5 ml DEA at 100ø C for 2 hours (or let stand 15 hours at room
temperature, evaporate to dryness and heat a few minutes at 100øC in
vacuum). Can recrystallize from CHCl3, petroleum ether or as described
elsewhere here.

      Technical Scale Details For This Method // Hydrazide Production

        In dim yellow light, (preferably) three tared and fully dried 250
ml round-bottom flasks containing stirring bars are each charged with 30 g
dry ergotamine tartrate and 120 ml anhydrous hydrazine. The flasks are
fitted with gas inlet tubes adjusted to just above the liquid level and
streams of nitrogen passed through, the exhaust gas being led through wash
bottles equipped with traps and containing dilute acid to remove hydrazine
vapors. The flasks are lowered into oil baths preheated to 90øC, and heated
with slow stirring for one hour. The contents of the three reaction flasks
are then emptied into a 2000 ml beaker containing 900 ml distilled water,
and this solution transferred to a 3000 ml two-neck round bottom flask. An
additional 900 ml water is used to rinse the residue in the flasks, beaker,
etc. into the 3000 ml flask. This large flask is fitted with siphon tube,
gas inlet tube, and gas outlet connected to wash bottle and trap.
        The aqueous hydrazide solution is evaporated from a tared 2000 ml
flask on an efficient rotary evaporator, using a bath temperature of 40øC
and an ice-cooled condenser; the 3000 ml siphon flask assembly is used as
storage for the vacuum feed. The weight of the crude hydrazide so obtained
is determined, it is dissolved in about 170 ml 1 N tartaric acid, the
aqueous solution washed with three 30 ml portions ether, made alkaline with
190 ml 1 N ammonium hydroxide, and exhaustively extracted with successive
portions of chloroform, the first two portions being 100 ml each, the
following 50 ml.
        Completeness is ensured by testing with UV light, extraction
ceasing only when the chloroform extract exhibits no blue fluorescence. The
chloroform solution is washed with three 30 ml portions distilled water,
dried over chloroform moistened magnesium sulfate, and the hydrazide
recovered by vacuum evaporation in tared 500 ml flasks, one such flask
being used for each two 90 g batches. These flasks are flushed with
nitrogen, stoppered, and stored in a dark and dry refrigerator. As the
hydrazide is stable, all the ergotamine tartrate will be converted to it
prior to the next step. Theoretical yield from 1000 g ergotamine tartrate
is 429.65 g; 80% yield is 343 g.

Pyrazole Production

        In dim red light, the weighed hydrazide contained in one of the 500
ml flasks (ca. 67 g; 95% of theory) is washed into a 1000 ml beaker with
263 ml 1N hydrochloric acid. 239 ml distilled water, 239 ml ethanol (95%),
and 37 ml 2,4-pentanedione are added, and the well-mixed solution left to
stand in the dark at room temperature until the reaction is complete, i.e.,
about 30 minutes. The reaction mixture is neutralized with the addition of
263 ml 1 N sodium hydroxide, and the beaker covered with parafilm and
refrigerated to ensure complete precipitation. The pyrazole is filtered at
the pump, the mother liquor being returned to the beaker and used to wash
out the last few crystals, washed with cold water, and sucked dry under a
stream of dry nitrogen. The product is dried in vacuo over barium oxide or
phosphorus pentoxide for at least twelve hours before proceeding to the
next step, wherein anhydrous conditions will increase yield. Hofmann calls
for drying the pyrazole in vacuo at 60øC, which indicated the product to be
fairly stable. So all the hydrazide is converted prior to aminization.

Amide Production

        In dim red light, 50 g of the well-dried pyrazole and 700 ml
freshly dried diethylamine are placed in a tared and well-dried 1500 ml
flask equipped with gas inlet tube and stirring bar. The flask is lowered
into a bath preheated to 45øC, and the contents stirred under a stream of
nitrogen for four hours. On a rotary evaporator, using a 6 atm temperature
of 40øC and an ice-cooled condenser, the diethylamine is removed in vacuo
and set aside for purification and re-use. Briefly and in high vacuum the
flask is heated to 100øC, the split-off pyrazole being thereby driven off.
        The residue so obtained is immediately placed in solution with
methanolic potassium hydroxide to effect interconversion of the
stereoisomers. Amination and Transposition will proceed simultaneously, the
first batch being transposed while the second is aminated.

Production Scale Isomerization of iso-LSD to LSD

        In dim red light, the amide residue from the last step is dissolved
in the least possible amount of dry methanol and washed into a 1500 ml
round-bottom flask. A two-fold volume of 4 N methanolic potassium hydroxide
is added, and the well-mixed solution left to stand at room temperature, in
the dark and under a slow stream of nitrogen, for four hours. At the end of
this period, the solution is neutralized with methanolic hydrogen chloride
(ca. 5 N), washed into a 4000 ml Erlenmeyer flask, and dried over
methanol-moistened anhydrous magnesium sulfate (0.10 g MgSO4 per ml KOH
solution). The methanolic acid should be added slowly and with good
stirring to prevent possible hydration of the 9-10 double bond to give
lumi-LSD. Together with 100 ml dry isopropanol (to remove the last trace of
water azeotropicly) the dried solution is transfered to a 3000 ml siphon
flask assembly, and the solvent removed in vacuo in a tared 500 ml two-part
freeze-dry flask. The weighed gummy residue is scraped into the thimble of
a Soxhlet extractor, the adhering residue being washed into the thimble
with portions of warm chloroform, the total volume of which is 12.5 ml per
gram amide (total weight minus weight KCl). A 3000 ml flask is used with
the extracter, and it is previously charged with 37.5 ml dry benzene per
gram amide. Under a stream of dry nitrogen, the solvent is in vacuo at 40øC
refluxed through the thimble, thus extracting the amide from the inorganic
salt and at the same time preparing the solution for use in the
chromatographic separation of the stereoisomers. The above solution is
stored over a small amount of benzene-moistened calcium sulfate in a
nitrogen flushed flask which is placed in a dark refrigerator. All the
pyrazole is converted to this benzene-chloroform solution prior to
separation of the isomers.

        The following methods all proceed from lysergic acid (I). Methods
1, 2, 4, and 6 give less than 20% iso-LSD in the product but methods 2, 5,
and 9 seem to have the highest total yield (about 80%) of LSD plus iso-LSD.
Since unreacted lysergic acid can be recovered and run through the
synthesis again, and iso-LSD isomerized to LSD as described here, it is
probably best to use the simplest methods. These comparative yields come
mostly from the reference to method 9.

From Lysergic Acid - Method 1 CA 50,10803d( 1956) (Pioch)

        Dissolve 5.3 g dry (I) in 125 ml acetonitrile (or dimethylformamide
or proprionitrile) and cool to -20ø (freezer or dry ice-acetone or ethanol
mixture). Add 8.82 g trifluoroacetic anhydride in 75 ml acetonitrile cooled
to -20ø carefully. Let stand at -20ø 1 1/2 hours or until all the (I)
dissolves. Then add 7.6 g DEA in 150 ml acetonitrile and let stand at room
temperature in dark two hours. Evaporate in vacuum to get LSD. If
purification is desired, dissolve the residue in 150 ml CHCl3 and add 20 ml
ice water. Pour into 1/2 L separatory funnel and drain out the lower CHCl3
layer into a beaker (after shaking). Add 50 ml CHCl3 to funnel, shake and
drain bottom layer into same beaker. Repeat with 3x50 ml CHCl3 and discard
the water. Extract the combined CHCl3 extracts with 4x50 ml ice cold water
and dry, evaporate in vacuum the CHCl3 to get 3.5 g d-LSD. This is composed
partly of the inactive d-iso-LSD, which, while it will not effect the trip,
can be recovered and converted to d-LSD as follows: dissolve the residue in
120 ml benzene and 40 ml CHCl3 (or 200 ml methanol), add tartaric or maleic
acid and shake to precipitate mainly d-LSD (add a little ether and cool in
refrigerator several days if necessary to ensure complete precipitation;
evaporate in vacuum the solvent to get d-iso-LSD. Add 50 ml ethanol and 5
ml 4N KOH per g iso-LSD and let stand at room temperature two hours;
evaporate in vacuum (or extract with CHCl3 as above) to get LSD. 4 hours in
2.66 N methanolic KOH is said to be optimal for isomerization.

From Lysergic Acid - Method 2 JOC 24,368(1959) (Galbrecht)

        This method is supposed to give little iso-LSD but it gives some of
the monomethylamide.
        Add 1 L dimethylformamide (freshly distilled, if possible) to dry
flask fitted with stirrer, ice bath, dropping funnel and condenser, both
protected from water by Ca chloride drying tubes. Add dropwise with
stirring over four-five hours at 0ø 0.21 lbs (90.7 g) SO3 (sulfuric
anhydride, available as Sulfan from Allied Chem. Co.). If precipitate
forms, stir until it dissolves. Sulfan may be made in larger amounts and is
good for several months if kept dry and cool. Molarity of fresh 503-DMF
reagent should be about 1M, but for precise determination, add a little
water to an aliquot and titrate with standard NaOH to phenolphthalein end
point. Add 6.45 g dry (I) (or 7.15 g (I) monohydrate) and 1.06 g LiOH
hydrate (or NaOH or KOH but these absorb water so they must be dissolved in
absolute methanol, titrated and added in equimolar amounts) to 200 ml
methanol in a 1 L vacuum flask and evaporate in vacuum. Dissolve residue in
400 ml anhydrous dimethylformamide and distill off 200 ml DMF at about 15
mm Hg through a twelve inch column packed with glass helices or other
material. Cool to 0øC and rapidly add 50 ml SO3-DMF solution (1 M). Stir at
0øC for ten minutes and add 91.5 g (12.9 ml) DEA and stir ten minutes. Add
400 ml of water stir and add 200 ml saturated NaCl. Extract the LSD by
shaking with several 500 ml portions ethylene dichloride (can use indole
test given in indole section to show completeness of extraction). Combine
extracts (lower layer in separatory funnel) and dry, evaporate in vacuum to
get LSD (can purify as above).

From Lysergic Acid - Method 3 JOC 24,368(1959) (Garbrecht)

        This route is said to give a lower yield than method 2. Dissolve
13.4 g dry (I) in 250 ml dry dimethylformamide and cool to 0ø. Add cooled
solution of 3.4 ml 0.35 M methane-sulfonic acid anhydride in dry
dimethylformamide. After thirty minutes at 0øC add 14.6 g (20.4 ml) DEA and
keep at 0øC one hour. Evaporate in vacuum to get LSD and proceed as above.

From Lysergic Acid - Method 4 CA 57,5979(1962) (Hofmann)

        Dissolve 0.536 g (I) in 10 ml freshly distilled POCl3; stir and add
416 mg powdered, freshly sublimed PCl5. Hold two minutes at room
temperature, two minutes at 90øC, and evaporate in vacuum. Extract the
residue with hexane to give the lysergic acid chloride-HCl (can also
extract the reaction mixture with hexane instead of evaporating in vacuum).
Alternatively, use 6 ml POCl3 and 240 mg SOCl2 and heat three minutes at
90øC to get the acid chloride. To 5 g of the acid chloride add 1.4 ml DEA
in 50 ml methylene chloride and cool to 0ø. Stir and add 27.5 ml pyridine
and stir one-half hour at 0øC. Warm to room temperature and stir 1 1/2
hours; evaporate in vacuum to get LSD.

                       From Lysergic Acid - Method 5
        CCCC 27,1590(1962) (Cerny and Semonsky) cf. CA 75,77110(1971)

        To a suspension of 13.4 g dry (I) in 800 ml dry dimethylformamide
(DMF) in a 2 L vacuum flask at 20ø, add a solution of 8.9 g
N,N'-carbonyldiimidazole in 250 ml DMF and stir at 20ø in dark for one-half
hour. Add a solution of 4 g DEA in 50 ml DMF and let stand two hours at
20ø; then twenty hours at 5ø. Evaporate in vacuum to get LSD. Can purify as
above or dissolve residue in 2 1/2 L 2% tartaric acid; extract with ether
and discard ether. Filter, basify with NH4OH and extract with a 9:1
solution of ether:ethanol. Dry and evaporate in vacuum to get LSD in 81%
yield.

       From Lysergic Acid - Method 6 JMC 16,532(1973) (Johnson et al)
                   This method gives very little iso-LSD.

        To a refluxing slurry of 3.15 g dry (I) or monohydrate) in 150 ml
CHCl3 add 0.1 mole of the amine in 25 ml CHCl3 and 2 ml POCl3
simultaneously from separate dropping funnels over 2 to 3 minutes. Reflux 3
to 5 minutes more till a clear amber solution results. Cool to room
temperature and wash with 200 ml 1M NH4OH. Dry and evaporate in vacuum
(below 40ø). Can dissolve in the minimum amount of methanol and acidify
with a fresh solution of 20% maleic acid in methanol. Filter and wash
crystals with cold methanol to get the LSD or other amide. This method
works with a wide variety of amines. For LSD itself, the POCl3 can be added
first. The yield is about 50%.

From Lysergic Acid - Method 7 German Patent 1.965,896 (1970) (Julia et al.)
               See end of total synthesis of LSD given below.

From Lysergic Acid - Method 8 U.S. Patent 3,141,887 (Patelli and Bernardi)

        Note: Phosgene is very hazardous and only professional chemists
working with a fume hood should even think about using this method. It can
be dissolved in a weighed container of DMF (dimethylformamide) and a second
weighing will give the phosgene concentration.
        0.5 g anhydrous lysergic acid suspended in 10 ml DMF or
acetonitrile at -10øC are reacted with 2 ml of DMF containing 0.34 g of the
phosgene-DMF complex for 20 minutes. Add 0.7 g diethylamine in 10 ml DMF
(or acetonitrile), keep at -10øC for ten minutes and then at room
temperature for 10 minutes. Dilute with chloroform, wash with NaOH (1
normal), then water and distill off the solvent in a vacuum. Dissolve the
oily residue in methanol, acidify with tartaric or maleic acid; add ether
to start crystallization. Keep overnight at 0øC, filter and wash with
ether. Dissolve the product in methanol, decolorize with charcoal and
precipitate with ether to obtain the tartrate or maleate (tartrate melts
192-198 C). D20 = + 25ø (C = 1 in water).

     From Lysergic Acid - Method 9 CT 13,373(1978) (Losse and Mahlberg)
      This method gives about 2/3 iso-LSD, and about 80% total yield.

        Add 134 mg (0.5 mM) dry (I), 103 mg (0.SmM) N,N-dicyclohexylcarbo-
diimide, 90 mg (0.67mM) 1-hydroxybenzotriazol (N-hydroxybenzotriazol) and
0.5 mM diethylamine to 2.5 ml CH2Cl2 and 2.5 ml tetrahydrofuran and stir in
the dark at 20ø C for 24 hours. filter, wash precipitate with CH2Cl2 and
evaporate the filtrate at 15 mm Hg, 30ø C to get LSD.

                            LSD Via SO3 METHOD I

        This and the following method are expanded versions of Garbrecht's
method. My own prejudice is that it makes much more sense to use one of the
other, simpler methods since the unreacted lysergic acid can be recycled,
and the initial yield is consequently of little import. However, the
details as presented here derive from the practical experience of
underground chemists and contain many points of interest for any technique.

Notes on Processes:

1. Chemicals to process one kilogram of ergotamine tartrate:

  Alumina, Activity II, 100-200 mesh...................8 Lbs.
  Benzene, Reagent..................................20 Liters
  Charcoal, activated powder, Norit A...............100 Grams
  Congo red papers.....................................1 Vial
  Dichloromethane (methylene chloride), Purified....60 Liters
  Diethylamine, Reagent..................500 Grams or 725 ml.
  Dimethylformamide, Reagent........................12 Liters
  Ergotamine tartrate..............................1 Kilogram
  Ether, Absolute......................................5 Lbs.
  Ethyl alcohol, Anhydrous, Denatured................10Liters
  Lithium hydroxide hydrate, Reagent................200 Grams
  Methanol, Reagent..................................24 Pints
  Molecular sieve, Linde 4 A............................1 Lb.
  Petroleum ether, B.P. 40ø=70øC...................2.5 Liters
  Phenolpthalein, White................................1 Gram
  Phosphorus pentoxide, Reagent.....................100 Grams
  Potassium hydroxide, Reagent.........................2 Lbs.
  Sodium Chloride, Reagent.............................5 Lbs.
  Sulfuric acid, Fuming 33%............................3 Lbs.
  Sulfuric acid, Reagent...............................4 Lbs.
  Tartaric acid, natural, powder, Reagent...........200 Grams

2. Cylinder gasses:
   Ammonia, anhydrous...................................1 Lb.
   Nitrogen, Dry.....................1 small welding cylinder

3. Notes on preparing reagents:

        Ammoniacal ethanol is prepared by chilling ten liters of anhydrous
denatured ethyl alcohol as commercially purchased in a freezer to well
below 0ø C. Next, 600 to 750 ml of liquid ammonia is drawn from a pressure
cylinder into a 1000 ml graduate in a well ventilated area. The contents of
the graduate are carefully poured into the chilled alcohol. The solution is
then stirred to mix and warmed to room temperature. The solution should be
at least two molar as determined by titration against standard acid
solution to a methyl red endpoint. If titration is to be attempted, a
little methyl red should be added to the chemical list.
        Dilute sulfuric acid is prepared by pouring 750 ml of sulfuric acid
into about 11.25 liters of ice cold water in a large acid resistant
container such as a polyethylene jug or 5 gallon gasoline container, etc.
Anhydrous dimethylformamide for making up sulfur trioxide-DMF reagent is
prepared by shaking three liters of reagent dimethylformamide with 100 to
200 grams of Linde molecular sieve, and allowing the mixture to stand
overnight with occasional shaking. Next, the dimethylformamide is decanted
off and poured into a five liter boiling flask. The flask is fitted with a
helices packed fractionating column and distilled at 25 millimeters
pressure. 800 ml is distilled off as a forerun and discarded or re-dried
over molecular sieve. The next fraction of about two liters is collected
and kept so as to protect from atmospheric moisture (drying tube, etc.). A
little dimethylformamide is left in the boiling flask. Dimethylformamide
when prepared in this manner is excellent for preparing the sulfur trioxide
reagent. Commercially available spectro-quality or pesticide quality
dimethylformamide may also be used if the water content is specified to be
less than .O5%, but the reagent obtained from these products has always
appeared darker in color than that made by the above method. Commercial
reagent quality dimethylformamide is suitable for the main reaction.

4. Preparation of the sulfur trioxide-dimethylformamide reagent (503-DMF).

        Sulfur trioxide is distilled from fuming sulfuric acid. About 200
grams are necessary and can be obtained from varying amounts of fuming
sulfuric acid depending upon the concentration of sulfur trioxide in the
commercially available product. Occasionally it is possible to purchase
fuminþ sulfuric acid which contains as much as 70% sulfur trioxide (S03).
Fuming sulfuric acid containing 30-33% is usually easily available and 200
grams of 503 can be obtained by distilling about one kilogram of it. The
distillation is done at atmospheric pressure in a simple distillation
apparatus which utilizes a large bore condenser of the West or similar
typ;. The receiving flask should be connected to the condenser in a closed
fashion as in a vacuum distillation and vented to the atmosphere through a
drying tube or similar device. Corks, rubber stoppers and any kind of joint
grease cannot be used in contact with sulfur trioxide or fuming sulfuric
acid as they will char. Tapered glass fittings should be used throughout
without grease. All fittings should be cleaned in benzene to remove grease
before distilling. Sulfur trioxide fumes are very irritating and good
ventilation is a must. Glass stoppers and small empty flasks with tapered
fittings should be used to close openings in the distilling apparatus when
changing receiving or boiling flasks. This will help considerably to keep
fumes out of the atmosphere.

Experimental procedure:

        200 grams of sulfur trioxide are distilled from the appropriate
amount of fuming sulfuric acid. The boiling range should be 5ø or less. The
200 grams are collected in a small round bottom flask previously weighed
with a glass stopper in place. Next, a small unweighed portion of
phosphorus pentoxide is added to the sulfur trioxide in the flask (1
teaspoonful). The flask is swirled and then placed on the distilling
apparatus as the boiling flask. A forerun of 5 ml is distilled into a small
receiving flask. This is returned to the boiling flask and the apparatus is
fitted with a receiving flask (3 liter boiling flask) already containing
1500 ml anhydrous dimethyl-formamide and a magnetic stirring bar teflon
coated. The flask is surrounded by an ice water bath in a nonmagnetic
container and a magnetic stirring motor is placed underneath to rotate the
stirring bar in the flask. The remaining sulfur trioxide is distilled into
the receiving flask containing the dimethylformamide. The receiving flask
should be absolutely dry before filling it with the dimethyl-formamide. The
sulfur trioxide should distill off over a 2ø boiling range the second time.
A hot water bath or an oil bath is convenient when heating the boiling
flask and prevents overheating. When the distillation is complete, the
receiving flask is removed carefully and stoppered. The flask is warmed and
swirled to dissolve any crystalline material and then cooled to around 5øC.
and left several hours. If any material precipitates, a little anhydrous
dimethyl-formamide is added to dissolve the residue. The flask is swirled
and the contents decanted into a storage bottle. The temperature in the
storage bottle is recorded and a ten milliliter aliquot withdrawn with a
pipette. The aliquot is run into a 250 ml Erlenmeyer flask and diluted with
10 ml water to decompose the complex. The mixture is then titrated to a
phenolpthalein endpoint with a standard base solution. A convenient
standard base solution can be made by dissolving 1 mole of lithium
hydroxide hydrate (41.96 gr) in distilled water to make one liter in a
volumetric flask. Three consecutive titrations should be done and an
average taken. One mole of sulfur trioxide reacts with two moles of lithium
hydroxide. The reagent bottle should be labeled as to sulfur trioxide
concentration (about 1.5 molar) and the temperature at which the
concentration was determined since the reagent has a rather high
coefficient of expansion.

        If at any time during the distillation of the sulfur trioxide,
crystals of solid sulfur trioxide form in the condenser or receiving flask,
they may be melted by careful local heating with a propane torch flame or
by running hot water through the condenser jacket. The water in the
condenser should be above 23øC during distillation of sulfur trioxide to
prevent crystallization of sulfur trioxide polymers.

5. Notes on changing the scale of reactions:

        The ergotamine to lysergic acid reaction may be scaled up or down
by multiplying the quantities involved by a proportionality constant: all
quantities should be multiplied by the same constant. It has been found
that the quantities of water and potassium hydroxide used in the hydrolysis
of ergotamine are not particularly critical and their relative
concentrations may be varied somewhat to meet other considerations. As a
rule, ergotamine should be hydrolysed with about a 1.5 to 2.5 molar
potassium hydroxide solution.
        The lysergic acid to lysergic acid amide reaction has been designed
to utilize minimal quantities of solvents in order to squeeze as much
material as possible into ordinary laboratory glassware.
        Some workers have suggested that the quantity of dichloromethane
(or chloroform) can be further reduced and still effectively extract the
amide, but this may prove difficult, especially if emulsions are
encountered. When scaling down the reaction, if desired, the quantities of
methanol, dimethylformamide, saline solution, and dichloromethane may be in
greater quantity than calculated by direct proportion to the other
reagents. The proportional relationship between lysergic acid, lithium
hydroxide and sulfur trioxide must be strictly adhered to. The molar
proportions are: lysergic acid, 1 mole; lithium hydroxide, 1 mole; sulfur
trioxide, 2 moles. Diethylamine should be added in at least five molar
equivalents. 6.5 equivalents are used in the example given. In general, two
thirds of the dimethylformamide should be distilled off from the
lithiumlysergate solution. It is convenient to do the reaction in a small
quantity of dimethylformamide if doing large quantities of lysergic acid
since the product is contained in smaller volume and extraction may be done
with less solvent.

6. Notes on purification of amide

        The chromatography detailed in the example has been used and works
fairly well, however, the removal of all colored impurities is not achieved
and there is room for improvement. It is suggested that further
experimentation be done to improve the process. An ultraviolet light is
indispensable when doing experimentation with these compounds. The lysergic
acid amide displays a blue fluorescence. Benzene has been used successfully
as an eluant on activity 4 alumina, but the results were no better than the
example given. Chloroform and chloroform-benzene mixtures also have been
used on varying grades of alumina but no useful data is available.

7. Notes on crystallization of tartrate

        Methanol and methanol-ether mixtures have both been used to
crystallize the amide tartrate. Crystallization proceeds more readily if
ether is present. Usually, the quantity of solvent from which the tartrate
is crystallized should be around 4.0 to 6.0 times the weight of the free
base amide (in grams) expressed in milliliters. For example, if the free
base lysergamide weighs 20 grams, then the crystallization should be done
in 80 to 120 milliliters of solvent. The purer the free base amide, the
less solvent that may be effectively used and the higher the yield. The
solvent is reagent grade methanol containing 10% to 25% ethyl ether. It is
usually preferable to dissolve the amide in the methanol and then to add
the ether. Ether should not be added after the tartaric acid is added since
it precipitates the impurities at the site of addition. Crystallization
occurs more slowly with impure preparations. Considerable time should be
allowed in the cold before filtering. Overnight is excellent.

Lysergic Acid Monohydrate

        350 grams of potassium hydroxide are dissolved in 3500 ml of water
in a five liter three-neck boiling flask equipped with a reflux condenser
and a small tube introducing a slow stream of nitrogen gas. The mixture is
then heated to about 80øC, when 500 grams of ergotamine tartrate is added
to the flask. The temperature is maintained at 80ø for about 2 1/2 hours
while continuously bubbling nitrogen gently through the mixture.
        The reaction mixture is next poured into a ten liter polyethylene
bucket and diluted by addition of ice to an approximate volume of six
liters. The bucket is then placed in an ice water bath and the mixture
cooled below 10øC, after which the mixture is slowly neutralized by the
careful addition of cold dilute sulfuric acid (15 parts water:1 part acid)
to a congo red endpoint (pH 4.0 - 4.4). Lysergic acid and considerable
potassium sulfate precipitates at this time. The bucket is allowed to stand
in the ice water bath several hours when the precipitate is filtered off on
a large buchner funnel (15 cm or larger) and sucked as dry as possible on
the funnel. The slightly moist filter cake is broken up and placed in a
four liter beaker containing 2 1/2 liters of two molar ammoniacal ethanol
(about 300 ml liquid ammonia poured into 5.0 liters of chilled anhydrous
denatured ethanol). The contents of the beaker are stirred for one hour and
then filtered. The filtrate is kept and the filter cake is broken up and
extracted in the previous manner with a second portion of two liters
ammoniacal ethanol. This extract is filtered using 500 ml of ammoniacal
ethanol to wash down the filter cake and the combined filtered extracts are
taken to total dryness in a rotary vacuum evaporator over a boiling water
bath. The tan colored residue is easily scraped from the sides of the
evaporator flask by means of two bent wire rods, one bent less than 90ø and
one bent greater than 90ø. The residue is scraped into a large mortar as
well as possible with the bent rods and then 225 ml of methanol mixed with
75 ml of water is used in divided portions to wash the remaining residue in
the flask into the mortar. The last portion of the methanol-water mixture
(about 100 ml) is left in the evaporator flask to be used to wash the
mortar clean later. The slurry in the mortar is ground with a pestle to an
even consistency free of lumps when it is then poured and scraped into a
large Buchner funnel (15 cm or larger) and filtered. The remaining portion
of the methanol-water mixture is used to wash down the mortar and the
filter cake. Next the filter cake is washed with at least 250 ml of water
and sucked dry for an hour. The filter cake is broken up and dried to a
constant weight under high vacuum at 90øC in a dessicator.

Yield: 125 to 150 grams of lysergic acid monohydrate, MW.286.35. A slightly
       off-white powder.

N,N-Diethyllysergamide (LSD)

        143.20 grams of lysergic acid monohydrate (0.5 mole) and 21.0 grams
of lithium hydroxide hydrate (0.5 mole) are dissolved in 2500 ml of
methanol with stirring and warming in a four liter beaker. When the
lysergic acid is completely dissolved, the contents of the beaker are
admitted to a rotary vacuum evaporator and taken to total dryness over a
boiling water bath. A little methanol is used to rinse any lysergate
residue that may remain in the beaker into the evaporator. The crumbly, tan
colored dry residue is dissolved and rinsed into a five liter boiling flask
with three liters of anhydrous dimethylformamide. Considerable care should
be exercised when transferring solutions from one vessel to another to
avoid loss of lysergate since small deviations from the calculated
quantities of reagents result in considerable reduction in overall yield.
The five liter flask is next fitted with a 600 mm helices packed
fractionating column and about 2050 ml of dimethylformamide is carefully
distilled off at 10.0 millimeters pressure to remove water from the
lysergate solution. The boiling flask containing lithium lysergate in the
remaining dimethylformamide is tightly stoppered and chilled in an ice
water bath to below 5øC. 1.0 mole of sulfur trioxide is now added to the
flask by addition of the appropriate amount of sulfur
trioxide-dimethylformamide reagent (previously prepared by double
distilling sulfur trioxide from fuming sulfuric acid and slowly adding it
to anhydrous dimethylformamide to make a solution of approximately 1.5
molar strength as determined by titration against standard base solution).
Cooling and swirling are continued for 15 minutes when 335 ml of
diethylamine is added. Cooling and swirling are continued 15 minutes longer
when the reaction mixture is poured into 3800 ml of a 20% saline (sodium
chloride) solution to break the reaction complex. The reaction mixture is
now extracted with 10.0 to 12.0 liters of methylene chloride
(dichloromethane) or chloroform in divided portions in a separatory funnel.
A scheme for division of the extraction solvent is as follows:

        Extract         Quantity        Total Solvent Used

        First           2000ml          2000ml
        Second          1800            3800
        third           1500            5300
        Fourth          1200            6500
        Fifth           1000            7500
        Sixth           1000            8500
        Seventh         800             9300
        Eighth          700             10,000
        etc.            etc.            etc.

Continue until clear lower layer appears.

        The extracts from the reaction are combined and shaken up with a
little anhydrous magnesium sulfate (120 grams) and filtered. The filtrate
is evaporated to dryness in the rotary vacuum evaporator, care being taken
not to heat the extracts or the residual syrup above 55øC. A good
mechanical vacuum pump and effective cold traps in the line are necessary
to remove the residual dimethylformamide from the residue. A brown to black
bubbly residue should remain when evaporation is complete. This residue
contains the amide product and considerable impurities. A general method of
purifying the amide follows.

Method A

        The material to be purified (the above residue or other material
containing N,N-diethyl lysergamide) is taken up in 1200 ml of methylene
chloride containing 20% benzene and applied to a chromatographic column
containing two pounds of basic alumina 100-200 mesh Brockmann activity two
or three. The column is eluted with nine liters of methylene chloride
containing 20% benzene. At this point, the column when viewed with visible
light should display three distinct color bands. The uppermost band will be
a dark brown or greyish color, the next band will be a reddish brown color,
and the lowest band will be a light brown or tan color. The eluant should
be amber colored. The column may now be eluted with about one liter
methylene chloride containing 0.5% methanol. This will bring the reddish
band nearly to the bottom of the column. At no time should any portion of
the reddish band be eluted from the column. If any of the reddish band
reaches the bottom of the column, elution should be stopped. Next, the
total eluant is shaken up with 30 grams of activated charcoal (Norit A)
mixed with 30 grams of alumina and filtered. The filter is washed with 600
ml of methylene chloride and the total filtrate taken to dryness on the
rotary vacuum evaporator. Care is taken not to heat the residue or solution
above 55ø C. The residue is taken up in one liter of benzene and
immediately taken to near dryness when another liter of benzene is added to
dissolve the residue and the solution is again taken to near dryness. This
procedure is repeated until four to five liters of benzene have been added
and evaporated. The residue is finally taken to complete dryness at about
45ø C. If sufficient benzene has been added and evaporated, a light tan
bubbly, crystalline material will fill the interior of the evaporator
flask. It is important that this residue be completely dry before
proceeding. The evaporation of benzene from the residue aids removal of
solvents and other volatile materials (as azeotropes) which promotes
formation of the bubbly crystalline structure in the residue. 700 ml of
petroleum ether is next added to the evaporator flask which is then removed
from the evaporator and tightly stoppered. The flask is shaken vigorously
to loosen the residue from the sides of the flask. Usually all the material
comes loose from the flask and forms a slurry in the petroleum ether. If
necessary, a bent wire rod may be used to scrape material from the flask.
The slurry is now decanted into a buchner funnel and filtered. The filtrate
is used to further wash material from the flask into the filter funnel. The
filter cake is sucked as dry as possible and then dried to a constant
weight under high vacuum at 45øC in a dessicator.

Yield: approximately 130 grams N,N-diethyllysergamide MW 323.42.

        The material remaining on the column may be removed with methanol,
evaporated in a vacuum and recycled through the isomerization and
subsequent procedures by itself or combined with fresh material. Also, all
leftover solutions and residues may be neutralized with sodium bicarbonate,
evaporated in vacuo, extracted with ammoniacal chloroform, the extract
evaporated to dryness, and the residue re-used.

N,N-Diethyllysergamide Tartrate

        130 grams of N,N-diethyllysergamide is dissolved in 400 ml methanol
and filtered. The filter is washed with 30 ml methanol and the filtrate and
washing is poured into a one liter beaker. 30 ml more methanol is used to
further wash the filter and filter flask and the wash is also poured into
the beaker. 130 ml of diethyl ether is now added to the contents of the
beaker. The beaker is gently warmed on a hot plate and 32.0 grams of
tartaric acid are then added with constant stirring and warming until they
are completely dissolved. The beaker is then allowed to cool.
Crystallization of the tartrate usually begins as soon as the tartaric acid
dissolves completely. The beaker and contents are refrigerated for at least
four hours. Occasional stirring of the crystallizing solution will produce
smaller crystals, whereas if the solution is left unstirred during the
crystallization, larger crystals will grow. Either is satisfactory. After
the beaker has been allowed to stand in the cold four hours or more, the
contents are filtered off on a 110 mm buchner funnel with suction. The
crystals are washed on the funnel with first 200 ml of a two part
methanol:one part ether mixture, and then with 250 ml of a two part
ether:one part methanol mixture. Next the crystals are washed with 600 ml
of ether and sucked dry. The filter cake is broken up and allowed to air
dry in a warm, dark place.

First crop yield: Approximately 80 grams pale yellow to white needles.

        The mother liquors and the two washes containing methanol are
collected and combined. A one normal solution of potassium hydroxide in
methanol is added in approximately equal volume to the combined washes and
mother liquors. The solution is then filtered and the filter washed with a
few ml of methanol. The filtrates are allowed to stand at room temperature
for two to three hours to re-equilibrate the iso-lysergic acid amides from
the mother liquors. About 500 ml of water is then added and the mixture
extracted with 2.5 liters of methylene chloride in divided portions in a
separatory funnel. The combined extracts are shaken with 25 grams of
anhydrous magnesium sulfate and filtered. The filtrate is taken to dryness
on the rotary vacuum evaporator, care taken not to heat above 55øC. The
material is purified in the same manner as that from the original reaction
mixture using approximately one fourth the quantities of solvents and
alumina as for the original.

Second crop yield: Approximately 20 grams white needles.

        The mother liquors may again be worked up as before, or
alternatively, they may be saved and included in subsequent batches.

Third crop yield: Approximately 5 grams white needles.

Total yield: Approximately 105 grams N,N-diethyllysergamide tartrate
MW = 430.51 (includes one mole methanol per mole of amide).

Method B

        The residue from the previous step is taken up in two liters of
chloroform and filtered with suction through a column 50 millimeters in
diameter packed with 400 grams of basic alumina, Brockman activity 1. The
filtrate is then refiltered through the same column in the same manner four
or five times until the filtrate appears light amber and further repetition
of this process fails to remove significant color from the filtrate. The
column is now eluted by adding several liters of fresh chloroform to the
top and sucking it through into the previous filtrate. Sufficient
chloroform should be added to remove all blue fluorescent material from the
column but not greenish or yellow (use a blacklight in a darkened room). A
band of greenish yellow material should remain in the upper 2/3 of the
column when viewed in ultraviolet light (blacklight). The total filtrate is
taken to dryness in vacuo in a three liter round bottom flask on a rotary
evaporator over a 60ø hot water bath. The residue is taken up in 500 ml of
benzene and again taken to dryness in the same manner. 500 ml of benzene is
again added and taken to dryness. The flask is left on the evaporator under
full vacuum for a considerable length of time after the residue appears dry
to remove any traces of dimethylformamide that may still remain. A bubbly,
crystalline residue should fill the interior of the flask at the end of
this step. If any tarry, gummy appearing material appears to remain on the
sides of the flask, repeat the addition of 500 ml of benzene and evaporate
to dryness again to get a glassy, crystalline appearance. When the material
in the flask is totally dry, remove the flask from the evaporator and add
sufficient petroleum ether (a commercial mixture of hexanes is excellent
for this purpose) to the flask to be able to swirl the crysþalline material
around and loosen it from the sides of the flask. Filter this slurry on the
buchner funnel with a fritted glass disk and use the filtrate to further
wash the remaining material from the evaporator flask into the buchner
funnel. Suck the material dry on the funnel and then place in a vacuum
dessicator and dry to a constant weight. Record the dry weight of this
material N. Calculate the weight of one equivalent of tartaric acid as
follows:

  Weight of tartaric acid =.232N

        Add methanol to a small beaker in a quantity equal to four times N
in milliliters. Dissolve the dried material of weight N in this. Dissolve
one equivalent of tartaric acid in the same solution, warming the solution
gently and stirring. Slowly with stirring, add ether to the solution in the
quantity of no greater than.5 N ml. Addition of ether causes a precipitate
which dissolves quickly. Ether should be added dropwise with stirring
between drops to dissolve any precipitate before addition of the next drop.
Crystallization of LSD tartrate should begin shortly after or during
addition of the ether. This precipitate does not dissolve and should not be
confused with the precipitate caused by the addition of ether. The mixture
should be stirred until the solution becomes thickened by formation of
crystals. Once crystallization of LSD tartrate is begun it is unnecessary
to continue addition of ether. The beaker should be refrigerated several
hours and the contents then filtered on a buchner funnel with a fritted
glass disk. The crystals are sucked dry and washed with 2.0 N milliters of
methanol previously chilled below -5øC and then with 4 N milliliters of a
1:1 mixture of cold ether and methanol. The crystals are sucked completely
dry, washed with 8 N ml of ether, sucked dry, and placed in a vacuum
dessicator to remove last traces of solvent.

        The total filtrates from the crystals (mother liquors plus
washings) are made basic by addition of 2 molar ammoniacal ethanol in
approximately equal volume and allowed to stand several days at room
temperature when the mixture is filtered and taken to dryness and treated
in the same manner as the residue from step 2 for a second crop of
crystals.

                            LSD Via SO3 Method 2
                               Lysergic Acid

        Ergotamine tartrate (10g) is added to a stirred de-aerated
(nitrogen stream) solution of 38 g potassium hydroxide in 100 ml of
methanol and 200 ml of water. The solution turns pink to red. The solution
is heated to reflux and the methanol is slowly removed using a partial
takeoff. Methanol is allowed to distill until the pot temperature reaches
90-95ø C. The mixture is then maintained at total reflux until the
evolution of ammonia ceases (hold pH paper in outlet of reflux condenser to
test for ammonia). Nitrogen should be bubbled through the mixture to
entrain the ammonia.
        The hot dark solution is then allowed to cool somewhat and then
cautiously acidified with a mixture of 60 ml acetic acid and 60 ml water.
The resulting hot solution is quickly treated with Norite "A" decolorizing
carbon and filtered hot.
        The clear purple-hued filtrate is allowed to cool to room
temperature (crystallization begins) and then in an ice bath or
refrigerator. The crystalline precipitate of lysergic acid (grey to
purplish white) is collected, washed with a small amount of cold water (5
ml), followed by cold methanol (5 ml) and ether. Yield 3.2 to 3.8 g.
        Digestion of the crude acid with about 50 ml of methanol (to remove
some of the colored impurities) gave after cooling to 0-10øC and filtering
an almost quantitative recovery of lighter colored acid. This material is
suitable for conversion into LSD.

                         Lysergic Acid Diethylamide

1. Sulfur Trioxide-Dimethylformamide Comþlex

        Into a carefully dried two liter three necked round bottomed flask
fitted with a mechanical stirrer, thermometer and a pressure equalizing
dropping funnel protected from the atmosphere with a CaCl2 drying tube, was
placed approximately one (I) liter of freshly distilled dimethylformamide
(DMF) (a one to three degree fraction BP ca. 62-63øC/20 mm). The DMF was
cooled to 0-5ø C by means of an external ice-salt-water bath. Sulfur
trioxide (Sulfan B) (ca. 100 g) was then placed in the dropping funnel and
added dropwise over a period of 30 to 40 minutes to the stirred DMF. The
temperature is carefully maintained between 0 and 5ø C throughout the
course of the addition. Stirring is continued thereafter until all of the
crystalline material is brought into solution.
        The resulting reagent solution is then transferred into a suitable
reservoir fitted with an automatic burette (protected from the atmosphere
with a Drierite tube) and refrigerated. If kept dry, the reagent will be
good for a month or two even though it will turn yellow and then orange in
color.
        The molarity of the reagent is then determined by titration against
standard base. An aliquot (1 or 5 ml) is first diluted with water (20 or
100 ml) to convert the sulfur trioxide-DMF complex into sulfuric acid. The
resulting solution is titrated to phenolphtalein end-point with standard
0.1 or 0.01 N aqueous alkali (NaOH or KOH) to determine the molarity (1/2
of the Normality). It should be in the range of 0.9 to 1.2 depending on the
amounts of 503 and DMF used.

2. Lysergic Acid Diethylamide (LSD)

        For best results all lysergic acid and LSD solutions should be
protected from direct light (yellow light is non-damaging) and the working
temperatures should never exceed 25ø C.
        Lysergic acid monohydrate (7.15 g, 25.0 mmol on a 100% basis) and
lithium hydroxide monohydrate (1.06 g, 25.0 mmol) were added to 200 ml of
anhydrous methanol and stirred until complete solution occurs. Use magnetic
stirrer and keep solution under dry nitrogen in the dark. The solvent
methanol is then removed by evaporation under reduced pressure to leave a
frothy glass-like residue of lithium lysergate.
        A solution of the calculated amount of tartaric acid is prepared in
methanol (ca. 8 ml/g). Approximately 1/2 of the methanol to be used and 20%
of the tartaric acid solution is added to the flask containing the LSD
base. The flask is swirled and/or shaken until the solid material has
dissolved (5-10 minutes) and the solution is then transferred into an
Erlenmeyer flask. The balance of the methanol, in two portions, is used to
complete the transfer. At this point the rest of the tartaric acid solution
is added. lt may be helpful to titrate the solution to an end-point pH of
5.3, since adding excess tartaric acid solution inhibits crystallization
somewhat. However this is optional. If seed crystals are available, they
should be added at this point. Crystallization should begin within a 1/2
hour: The flask should then be refrigerated for 12-24 hours at 5-10ø C and
then for another 12 hours at -10 to -20øC. For 5 g of LSD base 1 g of
tartaric acid in 7-8 ml methanol and an additional 17-18 ml of methanol are
used.
        The crystalline mass of needles is broken up and the cold solution
filtered (suction). The filter cake is sucked dry and then washed with
anhydrous ether. lf necessary the product may be recrystallized from
methanol using 5 ml for each gram. The snow white product melts at
198-200øC.

3. Recrystallization Procedure

        The crude tartrate (10 g) is placed in a 125 ml Erlenmeyer flask
and boiling methanol (50 ml) is added and the mixture stirred and heated
for a minute or two (no longer) until solution is complete. The hot
solution is quickly filtered through a previously warmed buchner funnel and
the filtrate cooled immediately by swirling in a cold water bath until the
temperature drops to 25ø C. Crystallization should be well on the way by
this time. The mixture is further cooled to 5 to 10øC and then to -10 to
-20øC as previously described, to complete the crystallization. Recovery
is between 50 and 70%.

4. Additional Crops of Crystals

        The mother liquors from initial crystallizations and from
re-crystallizations of LSD can be concentrated by evaporation under reduced
pressure to produce additional crops of crystals. The second and third
crops of crystals are usually dirty enough to require re-crystallization.
After three crops, the mother liquors usually become very syrup-like. They
then contain mostly iso-LSD (as the tartrate salt).
        The iso-LSD salt can be converted back into the base by the
addition of methanolic KOH or potassium methoxide to the mother liquor. The
resulting mixture should be added to a separatory funnel containing salt
solution and ethylene dichloride. The LSD base is extracted into the
ethylene dichloride layer (the lower layer). The lower layer is removed and
fresh ethylene dichloride used to extract the last traces of LSD base from
the salt water-base mixture. The ethylene dichloride extracts are combined,
dried with MgSO4, decolorized and filtered through diatomaceous earth as
earlier. The resulting ethylene dichloride solution may be combined with
the chloroform solutions of iso-LSD which eluted from the chromatographic
column. The combined solution may be evaporated to dryness under reduced
pressure.

5. Isomerization

        The dry iso-LSD base can then be dissolved in methanol and
potassium methoxide added. The resulting mixture is stirred for about 30
minutes. During this time isomerization takes place; about 70% of the
iso-LSD is converted into the desired "normal" form of LSD.
        The methanolic solution is poured into a separatory funnel
containing salt water solution and ethylene dichloride. The salt water
layer is repeatedly extracted with ethylene dichloride to separate the LSD
base from the water-base mixture. The ethylene dichloride extracts are
combined, dried with MgSO4, decolorized and filtered. The ethylene
dichloride solution is then evaporated to dryness under reduced pressure.
        The resulting dry LSD base is chromatographed on basic alumina
(activity grade 1) as previously described. The blue band is collected as
before, evaporated and converted into the tartrate salt. The iso-LSD band
may be collected and saved for further re-cycling.
        NOTE: If you only have mother liquors to isomerize, the second
mixing with potassium methoxide is unnecessary. Simply prolong the
initial mixing to about 1/2 hour.

  Total Synthesis of Lysergic Acid

        Of the many attempts at the total synthesis of lysergic acid from
simple starting materials, only two have been successful (JACS
78,3087(1956), which is very complicated, and CA 74,3762 (1970), which
follows). However, it is very likely that some of the intermediates in each
attempt are psychedelic. ln fact, this is one of the most promising and
least investigated areas of psychedelic chemistry. Following are some
references to the synthesis of intermediates: CCCC 33,1576(1968); HCA
33,67,375,1796, 2254,2257(1950), 34,382(1951), 35,1249,2095(1952), 36,839
1125,1137(1953), 37,1826(1954), 38,463,468(1955), 44,1531 (1961); JCS
3399,3403(1954); BSC 861(1965); JOC 10,76 (1945), 26,4441(1961),
29,843(1964); Chem. and Ind. 1151 (1953); CJC 41,2585(1963); CPB
12,1405,1493(1964),13,420 (1965), 14,1227(1966); JACS 61,2891(1939),
67,76(1945), 71,761(1949), 73,2402(1951), 78,3087(1956), 79,102(1957),
82,1200(1960), 88,3941 (1966); BER 86,25,404(1953), 87,882 (1954),
88,370,550(1955), 89,270,2783(1956), 90,1980,1984 (1957), 93,2024,2029
(1960), 96,1618(1963),100,2427(1967), 101,2605(1968); JMC 8,200(1965); C.R.
Acad. Sci. Paris 264 (C), I 18(1967), 265 (C), 110( 1967); BSC 1071 (1968);
CJC 41,2585(1963); CPB 12,1405,1493(1964), 13,420(1965), 14, 1227(1966);
JCS (P.T.1.) 1121(1972), 760(1973), 438(1973); CA 78,71830,72200(1973).

        Various analogs containing part of the LSD structure have been
synthesized, but few have any activity. See JPS 60,809(1971) for a review
of these compounds.
        For other LSD analogs see JMC 16,804,1015(1973); BSC 2046(1973); CA
48,4489(1954); JPS 62,1881(1973).
        Some other useful references on LSD chemistry: U.S. Patents
3,856,821 and 3,856,822; Swiss Patent 517,680(1970); Belgian Patent
738,926; French Patent 1,368,420 and addition 91,948 (1968).
        Total Synthesis of LSD German Patent 1,965,896 (1 Oct 1970). German
Patent 1,947,063 is the same as 1,965,896.
        For synthesis of 5-Br-isatin from isatin see CA 33,2516(1939) or
BER 40,2492(1907).
        For the use of cycloaliphatic or aromatic esters in place of
methyl- 6-methylnicotinate or of isatin or 4 or 5 chloroisatin or
4-bromoisatin in place of 5-bromoisatin see French Patent Addition
#2,052,237 (14 May 1971).

  Total yield of LSD from starting materials is probably about 1%

        Mix 32.8 g (0.217M) methyl-6-methylnicotinate (other alkyl groups
can replace either methyl group) with 45.2 g (0.2M) 5-bromoisatin
(apparently 4-Br or 4 or 5 Cl isatin will also work) in a 250 ml flask at
100ø in an oil bath and raise the temperature of the bath to 180ø over 15
minutes. Lower temperature to 170ø and let react for 70 minutes. Cool and
then grind the solid as fine as possible in a mortar. Recrystallize from
150 ml dimethylformamide and wash with ether to get 40 g (57%)
methyl-a(5-bromo-3-isatylidene)-6-methylnicotinate (I). Suspend 10 g (I) in
250 ml glacial acetic acid and heat to boiling. Add in small portions over
30 minutes excess powdered zinc. Reflux 1 hour, filter and evaporate in
vacuum and recrystallize the residue from dioxane to get 9.7 g (95%)
methyl-a-(5-bromo-2-oxindol-3-yl)-6-methylnicotinate (II). To a suspension
of 18 g dry NaBH4 in 300 ml dry tetrahydrofuran add with stirring at 0ø
over 30 minutes about 75 g BF3 etherate. Stir 3 hours at 0ø, add 18 g (II)
and heat exactly 20 minutes at precisely 22-24ø. Add carefully 150 ml
concentrated HCl while cooling in an ice bath. Add 200 ml water and stir 12
hours. Basify, extract the product with ethyl acetate and dry, evaporate in
vacuum to get 11 g of residue which recrystallizes from methanol to give
methyl-a-(2,3-dihydro-5-bromo-3-indolyl)-6-methylnictotinate (111).

        The following step may be unnecessary but it gives stability to
(III). The acetyl group can be split off at the end of synthesis, but this
is unnecessary since the 1-acetyl-LSD is as active as LSD.

        Treat 12 g (Ill) at room temperature for 24 hours with acetic
anhydride then hydrolyze and extract to get 11.5 g residue which is ground
in petroleum ether and recrystallized from cyclohexane (can chromatograph
on alumina and elute with petroleum ether to wash out an oil, then with
benzene containing 5% ethyl acetate to elute the produce) to give
methyl-a-(1-acetyl-5-bromo-2,3-dihydro-3-indolyl)-6-methylnicotinate (IV).
Heat 5 g (IV),12.5 ml acetone,12.5 ml methanol and 1.8 ml methyl iodide for
18 hours in a Carius tube at 70-80ø. Cool, filter, wash with acetone and
recrystallize from methanol to get methyl-a(1-acetyl-2,3-dihydro-5-bromo-3-
indolyl)-1,6-dimethylnicotinate iodide (V). To 9.4 g (V) in 250 ml water
and 250 ml methanol at 35ø add over 5 minutes 2.9 g KBHþ and stir 10
minutes. Add 2.9 g more KBH4 and stir 30 minutes. Evaporate in vacuum and
extract the residue with methylene chloride to get 6.2 g oily mixture
containing about 2 g of the d isomer (can separate by chromatography if
desired) of methyl-a(1-acetyl-2,3-dihydro-5-bromo-3-indolyl)-6-methyl-
1,2,5,6-tetrahydronicotinate (VI).
        To a suspension of finely powdered NaNH2 (6.1 g) in 2 liters dry
ammonia, add with stirring 8 g (VI) in 50 ml dry tetrahydrofuran. Stir 1
hour, add NH4Cl and evaporate the ammonia as fast as possible in a nitrogen
stream. Extract at pH 8 with methylene chloride to get 6 g (can
chromatograph on 300 g silica gel and 250 g Celite and elute with 98%
benzene-2% absolute ethanol and evaporate in vacuum) of
methyl-1-acetyl-2,3-dihydro-lysergate (VII). (VII) can be converted to
2,3-dihydro-LSD (not to be confused with 9,10-dihydro-LSD, which is
inactive), which is about ten times less active than LSD. (VII) can be
converted to lysergic acid prior to conversion to LSD, which will triple
the yield in terms of LSD activity (considering 30% yield). The process
(which follows) is somewhat complicated and an easier dehydrogenation
process may work. 2,3-dihydro-LSD can be converted directly to
12-hydroxy-LSD, which has about the same activity as LSD and this process
is also given below.

Lysergic Acid from 2,3-Dihydrolysergic Acid JACS 78,3114 (1956)

        Dissolve 4 g (VII) in 78 ml 1.5% KOH and reflux five minutes
(under N2 if possible). Add 8.5 g Na arsenate hydrate and 16 g
Raney-Ni (wet) (deactivated by boiling in xylene suspension - see
JOC 13,455(1948)) and reflux twenty hours (under N2 if possible).
Filter, precipitate lysergic acid by taking pH to 5.6 with HCl; filter
and wash precipitate with water to get 1 g lysergic acid. Evaporate in
vacuum the filtrate to get more product.

12-Hydroxylysergamides from 2,3-dihydrolysergamides HCA 47,756(1964)

        Warm to dissolve 1.5 g 2,3-dihydro-LSD in 5 ml acetone, 40 ml water
and 40 ml saturated NaHCO3. Cool to 20ø and add all at once with vigorous
stirring 2.46 g potassium nitro-sodisulfonate dissolved in 90 ml water and
10 mI saturated NaHCO3. After 1 minute, extract 7 times with ethylacetate,
wash the combined extracts with water, dry and carefully remove solvent to
get a mixture of 12-OH-LSD, LSD and starting material which can be
chromatographed to give about 0.2 g 12-OH-LSD.
        The following method of converting (IV) to the diethylamide (which
can probably be used in place of (IV) to give the diethylamide of (V),
(VI), and (VII)) will probably also work admirably for (VII) or lysergic
acid.
        Reflux 0.5 g (IV) with 0.5 g KOH in 30 ml methanol for 4 hours.
Evaporate in vacuum and add water to the residue. Adjust the pH to between
5 and 6 and filter or centrifuge to get 0.3 g of the free acid. Suspend 1.8
g of the acid in 125 ml chloroform, cool to -5ø and add 0.5 g
triethylamine, then 0.6 g ethylchloroformate and stir 45 minutes. Add 2 ml
diethylamine and stir 3 hours at room temperature to get, after the usual
workup, 1 g of the diethylamide (recrystallize from benzene).

Summary of Procedures and Materials For 1 Kilogram Ergotamine

* Starred chemicals are carefully watched.

   **** diethylamine                        500 g (725 ml)
        methylethylamine                     50 g (75 ml)
        ethylisopropylamine                  50 g (75 ml)
        diethyl ether                         5 lbs
        potassium hydroxide pellets           2 Ibs
        methanol                              5 L
        activated charcoal powder           100 g
        tartaric or maleic acid powder      200 g
        small cylinder N2 or N2O or freon
        HCL or sulphuric acid concentrated  500 ml
        chloroform                            5 L  (optional but desirable)
        ethanol                               9 L  (optional but desirable)
        NH4OH concentrated                  500 ml (optional but desirable)

IN ADDITION AT LEAST ONE OF THE FOLLOWING SETS OF REAGENTS

First choice
        N,N-dicyclohexylcarbodiimide 500 g
        N-hydroxybemotriazol         500 g
        (1-hydroxybenzotriazol)
        tetrahydrofuran               10 L
        methylene chloride            10 L

Second choice
        N,N carbonyldiimidazole      200 g
        dimethylformamide             15 L

Third choice
     ** anhydrous hydrazine            4 L
        HCl conc.                      1 L
        sodium nitrite                 1 kg

Fourth choice
     ** phosphorous oxychloride      200 ml
        chloroform                    10 L
        methanol                       5 L

Fifth choice
        acetonitrile or DMF           15 L
     ** trifluoroacetic anhydride    500 g

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