This manuscript is being offered for its informational and educational value
only, and it is intended and expected that the information will be used solely
by legitimate researchers and forensic chemists investigating these compounds.
No synthesis of these substances, the manufacture of which is illegal without
governmental license, should be undertaken without approval from the appropriate
governmental authorities. The authors do not want to assist, counsel, urge,
otherwise encourage or cause a criminal act, particularly in view of the fact
that manufacture of amphetamine(s) and methamphetamine(s) is punishable by
sentences up to life in prison.

A note on nomenclature utilized in the various syntheses. The literature
variously refers to amphetamine as beta-phenylisopropylamine, 1-phenyl-
2-aminopropane, beta-aminopropylbenzene, deoxynorephedrine, desoxynorephedrine,
PhCH2CH(NH2)CH3 or PhCH2CH(NH2)Me. The dextro isomer of amphetamine is the d,
(+), D or S isomer; the levo isomer is the l, (-), L or R isomer. The racemic
mixture may be referred to as d,l, (+,-), DL or (R)(S).

REDUCTIVE AMINATION

Reductive amination is the process by which ammonia is condensed with aldehydes
or ketones to form imines which are subsequently reduced to amines. Reductive
amination is utilized to produce amphetamine from 1- phenyl-2-propanone and
ammonia.

Diagram: Phenyl-2-propanone + NH3 --> imine + H2O
Imine + H2 --> amphetamine

Ammonia reacts with aldehydes and ketones to form compounds called imines
(a condensation reaction with the elimination of water). The first step is a
nucleophilic addition to the carbonyl group followed by a rapid proton transfer.
The resulting product, a hemiaminal, also sometimes called a carbinolamine, is
generally unstable and cannot be isolated. A second reaction occurs in which
water is eliminated from the hemiaminal and imine is formed.

Diagram: carbonyl group + NH3 <==> hemiaminal <==> H2O + imine

The subsequent reduction of imine to amine is typically accomplished by
treating with hydrogen and a suitable hydrogenation catalyst or treating
with aluminum-mercury amalgam or via sodium cyanoborohydride.

REDUCTIVE AMINATION VIA CATALYTIC HYDROGENATION

Reductive amination via catalytic hydrogenation of a mixture of aldehyde or
ketone and ammonia leads to a predominance of primary amine when excess ammonia
is present. At least five equivalents of ammonia should be used; smaller amounts
result in formation of more secondary amine.

A significant side reaction complicates the reductive amination method. As the
primary amine begins to build up, it may react with the intermediate imine to
form an imine which is reduced to secondary amine. The primary amine may also
condense with the starting ketone to give an imine which is reduced to secondary
amine. This side reaction may be minimized by using a large excess of ammonia in
the reaction medium.
Another possible side reaction is reduction of the carbonyl group to a hydroxyl
group (e.g., phenyl-2-propanone may be reduced to phenyl-2-propanol). Analysis
was performed on the reaction medium from a room temperature reductive amination
utilizing phenyl-2-propanone, methanol solvent, Raney nickel and a mixture of
ammonia and hydrogen bubbled through the solution at a slight overpressure and
on the amphetamine product which had been purified by repeated crystallization.
(fn.1) Due to the small quantities of the impurities in the amphetamine, the
reaction mixture, in which the impurities occurred in a much higher amount, was
utilized for analysis. The major impurity found was the Schiff base (imine) of
amphetamine and benzyl methyl ketone (phenyl-2-propanone), benzyl methyl ketone
phenylisopropylimine. This compound is the condensation product of
phenyl-2-propanone and amphetamine which had not been hydrogenated.
The minor impurity, surprisingly, was benzyl methyl ketone benzylimine. This
compound was found to be a by-product in the condensation of amphetamine with
benzyl methyl ketone.
Reductive amination does not usually produce a very high yield of primary amine,
although high yields have been reported for amphetamine. Raney nickel is
particularly useful in this regard, particularly at elevated temperature and
pressure. Reductive aminations carried out at low pressure with Raney nickel are
typically not very successful unless a large amount of catalyst is used.
It should be noted that the presence of an ammonium salt is necessary in
reductive amination with noble metals; in the absence of ammonium salts the
catalysts are poisoned or inactivated.
Isolation of imine and its subsequent reduction are sometimes reported to be
more effective than reductive amination, but typically the difficulties in
obtaining imines in high yield and their instability argue against that
procedure. Imines derived from ammonia tend to be unstable--they often rapidly
hydrolyze even with water to generate carbonyl compound and are often prone to
polymerization.

High Pressure Reductive Amination of 1-Phenyl-2-Propanone Utilizing Raney Nickel:

Organicum: Practical Handbook of Organic Chemistry (Addison-Wesley Publishing
Co., Inc., 1973), English translation by B. J. Hazzard, 458-9 and 686.

In working with Raney nickel, Hazzard states that a highly basic catalyst (e.g.,
that of Urushibara prepared from 30% nickel alloy, see catalyst preparation
below) gives the best results.

134.2 g. (1.0 mole) of phenyl-2-propanone is dissolved in 500 ml of methanol
that has been saturated with ammonia at 10C (about 94 g. or 5.5 moles). After
the addition of Raney nickel from 30 g. of alloy, hydrogenation is carried out
in a shaking or stirring autoclave at 90C and 100 atm. After the uptake of
hydrogen has ceased, the pressure is released, the catalyst is filtered off, and
the solvent is distilled off. The residue is acidified with 20% hydrochloric
acid to Congo Red (i.e., to pH 3; Congo Red is blue- violet at pH 3.0 and red at
pH 5.0) and the non-basic impurities are extracted with ether. The ethereal
extract is discarded and, with efficient cooling, the aqueous solution is made
alkaline with 40% sodium hydroxide solution and is repeatedly extracted with
ether. The extract is dried over potassium hydroxide. After the solvent has been
evaporated off, the product is distilled through a 20-cm Vigreux column to
obtain a 90% yield of DL-1-phenyl-2- aminopropane, b.p. 12mm. 92C.

Hazzard notes the amphetamine is better stored in the form of the hydrochloride.
To obtain the hydrochloride, the amphetamine base was dissolved with cooling in
an excess of absolute alcohol saturated with hydrogen chloride and precipitated
with absolute ether to obtain the racemic DL amphetamine hydrochloride, mp 152C.

Preparation of alkaline highly active Raney Nickel (Urushibara nickel): In a
vessel as large as possible (5 liters or larger), 50 g. of aluminum- nickel
alloy containing 30-50% nickel is slurried in 500 ml water. Then solid sodium
hydroxide is added without cooling at such a rate that the mixture just does not
foam over. Caution: There is an induction period of 0.5-1 minute before the very
violent reaction. The mixture boils vigorously. When the further addition of
sodium hydroxide does not give rise to any appreciable reaction, which requires
about 80 g., the mixture is allowed to sit for 10 minutes and then kept for 30
minutes on the water bath at 70C. The nickel settles to the bottom as a spongy
mass. The supernatant aqueous layer is decanted off and, with shaking, the
catalyst is washed by decantation two or three times with water and then two or
three times with the solvent to be used for the hydrogenation. If the solvent is
immiscible with water, a suitable intermediate washing liquid is used.

Although the catalyst can be stored for some time under a solvent, it is always
desirable to prepare it directly before use, since storage leads to a marked
fall in activity.

Low Pressure Reductive Amination of 1-Phenyl-2-Propanone Utilizing Raney Nickel:

Haskelberg, Aminative Reduction of Ketones. J. Am. Chem. Soc., 70 (1948) 2811-2;
C.A. 43: 1349f (1949).

Phenylacetone (1-phenyl-2-propanone) was catalytically converted to
beta-phenylisopropylamine (amphetamine) using ethanolic ammonia, hydrogen at
about atmospheric pressure and Raney Nickel. A yield of 85% was obtained.
Phenylacetone, 118 g. (0.89 mole) in 400 cc. 17% NH3 in ethanol was hydrogenated
with 22 g. Raney Nickel at a hydrogen pressure of 1 atm. or slightly above and a
temperature of 20C or slightly above. After removal of the catalyst, the product
was isolated by fractionation of the mixture. Beta- phenylisopropylamine was
obtained in 85% yield, b.p. 10mm. 80C, hydrochloride m.p. 146. A higher-boiling
by-product of 10.2 g. (8%) bis-(1- phenyl-propyl-2)-amine, C18H22N, b.p. 2mm.
154C was also obtained.

Mastagli et al., Study of the Aminolysis of Some Ketones and Aldehydes.
Bull. soc. chim. France (1950) 1045-8; C.A. 45: 8970g (1951).
Primary amines were prepared by the ammonolysis of ketones.
Reaction was carried out in methanol saturated with ammonia by the method of
Haskelberg (see above). Where ammonolysis was not complete, the nonamine portion
is a mixture of ketone and the corresponding alcohol (1- phenyl-2-propanol).
1-Phenyl-2-propanone (PhCH2Ac) 15 g. (0.11 mole) in 60 cc. methanol saturated
with NH3 was hydrogenated over Raney nickel at 65C for 5 hours. An 86% yield of
amphetamine (PhCH2CH(NH2)Me) was obtained, b.p. 12mm 92-95C.

Low Pressure Reductive Amination of 1-Phenyl-2-Propanone Utilizing Platinum
Oxide:

Alexander et al., A Low Pressure Reductive Alkylation Method for the Conversion
of Ketones to Primary Amines. J. Am. Chem. Soc., 70, 1315-6 (1948); C.A. 42:
5411d (1948).

Reductive amination was carried out in the presence of ammonium chloride, in the
hopes that the more basic primary amine reaction product would react and form an
alkylammonium ion, thereby tending to stop the process at the formation of
primary amines. Nevertheless, considerable amounts of secondary amine were
observed. The reaction medium was methanol saturated with ammonia and the
catalyst was platinum oxide. A 52% yield of phenylisopropylamine was obtained.

An apparatus similar to the one described by Adams et al. (fn.2) was used for
the reaction. The phenyl-2-propanone was redistilled before use. In a 300-ml
reduction bottle containing 10 ml of distilled water, 0.2 g. of platinum oxide
was prereduced to platinum by shaking in an atmosphere of hydrogen for 10
minutes (when an attempt was made to omit this step a long induction period
occurred and reduction appeared to proceed much more slowly than normal).

Phenyl-2-propanone (40.2 g., 0.3 mole), ammonium chloride (20.0 g., 0.37 mole),
225 ml of absolute methanol saturated with ammonia, and 25 ml of aqueous ammonia
were added and the mixture was reduced by shaking with hydrogen at one to three
atmospheres. Hydrogenation was continued until a constant pressure reading
indicated that reduction had ceased. Shaking was stopped, the bottle vented, and
the catalyst allowed to settle. Filtration was through a Hirsch funnel into a
round-bottomed flask, and the catalyst and salt which collected was rinsed down
with water or methanol. The flask and contents were then removed to a hood and
refluxed under a condenser for one hour to remove the excess ammonia (nitrogen
entrainment can help here).

The solution was then cooled and acidified to Congo red paper with concentrated
hydrochloric acid, forming an insoluble salt. The mixture was cooled, and the
salts were filtered with suction and washed thoroughly with water and saved. The
aqueous filtrate was extracted with three 25-ml portions of benzene. The benzene
extracts were discarded (one likely side product here is phenyl-2-propanol, the
result of direct reduction of the ketone starting material).

The aqueous filtrate was then recombined with the insoluble salts and made
strongly basic with 50% sodium hydroxide solution. The two layers which formed
were separated and the water layer was extracted three or four times with ether.
The ether extracts and the oily layer were then combined, washed with water and
dried over potassium hydroxide. The primary amine (amphetamine) was purified by
distillation through a 13-cm column packed with glass helices and obtained in a
52% yield. Considerable amount of secondary amine was observed to remain in the
boiling flask.

High Pressure Reductive Amination of 1-Phenyl-2-Propanone Utilizing Raney
Nickel and Ammonium Acetate:

Green, Reductive Amination of Ketones. U.S. Pat. No. 3,187,047, June 1, 1965;
C.A. 53: 9873f (1965).

A process for the reductive amination of ketones was described in which the
NH4 (ammonium) salt of an organic acid was used as the source of amine.

An autoclave was charged with 3 kg. 2,5-dimethoxyphenylacetone (2,5-dimethoxy-
phenyl-2-propanone), 1.2 kg. AcONH4 (ammonium acetate), 180 ml. AcOH (acetic
acid), 9500 ml. MeOH (methanol), 300 ml. H2O, and 500 g. Raney nickel catalyst.
The autoclave was closed, heated to 90C, and H2 (hydrogen) introduced to a
pressure of 1200 psi. When the reaction was completed an analysis showed a 95%
yield of 2,5-dimethoxyamphetamine, 3% distillation residues, and 2% acid
insolubles.

REDUCTIVE AMINATION VIA DISSOLVING METAL REDUCTIONS

Dissolving metal reductions, in particular aluminum, continue to be utilized
although not without their difficulties (such as trying to filter the aluminum
hydroxide formed in the reaction).

Although molecular hydrogen is produced as the metal dissolves, this is
generally considered to be a detriment to the reduction of the substrate.
The actual reduction mechanism evidently does not involve molecular H2 but is a
result of an "internal electrolytic process." In one theory, electron transfer
to a heteroatom results in a radical carbon which abstracts hydrogen from
solution to complete reduction. (fn.3), (fn.4)

"Poisoning" via amalgamation is one approach used to minimize rapid dissolution
of the metal and to abate formation of H2. Aluminum-mercury amalgamation serves
to give an activity somewhere between the extremes of the over-active metal and
the inactive metal oxide. Amalgamation between aluminum and mercury has the
additional benefit of preventing oxide formation on the surface of aluminum in
contact with air. (fn.5)

Aluminum-Mercury Reduction of Imine From Phenyl-2-Propanone and Ammonia:

Wassink et al., A Synthesis of Amphetamine. J. Chem. Ed., 51, 671 (1974).
Amphetamine was obtained in a one step synthesis. Although the yield of the
reaction was not as high with reduction utilizing ammonia instead of methylamine
(30% yield versus 70%), the easiness of the procedure made the method
worthwhile. Note that it may be possible to recover unreacted phenyl-2-propanone
from the initial ether extract. A mixture of 40 g. (0.3 mole) phenyl-2-propanone,
200 ml ethanol, 200 ml 25% ammonia, 40 g. (1.5 mole) aluminum-grit and 0.3 g.
(0.001 mole) mercuric chloride (HgCl2) was warmed with vigorous stirring until
reaction took place, after which warming was stopped immediately. Cooling was
applied if the reaction became too violent. When the violence of the reaction
had diminished, the mixture was refluxed with vigorous stirring for about 2
hours, concentrated in vacuo to 200 ml and poured into ice water, alkalinized
with 120 g. potassium hydroxide (KOH), and extracted with diethyl ether. The
extractions were shaken with 20% HCl (pressure), the resulting water layer
alkalinized (e.g., with 50% sodium hydroxide) and then extracted with 150 ml
ether. The organic layer was dried over Na2SO4 (sodium sulfate; KOH is probably
a better choice), the ether evaporated and the residue distilled in vacuo.
Yield: 12.5 g. (0.09 mole or 30% of theoretical yield). Preparation of
amphetamine sulfate yielded 96-98% product with a purity of 99.2-99.8% according
to the USP.

(1) Theeuwen et al., Impurities in Illicit Amphetamine. 7. Identification of
    Benzyl Methyl Ketone Phenylisopropylimine and Benzyl Methyl Ketone
    Benzylimine in Amphetamine. Forensic Science International, 15, 237-41
    (1980).
(2) Adams et al., Organic Syntheses (John Wiley and Sons, Inc., 1941) p. 61.
(3) See Allen et al., Synthetic Reductions in Clandestine Amphetamine and
    Methamphetamine Laboratories: A Review. Forensic Science International, 42,
    183-99 (1989) for a more extensive discussion of dissolving metal reductions.
(4) Another theory utilizing implications of Feynman diagrams holds that if you
    add up all the probabilities of an electron appearing in the electron clouds
    for all the atoms in the universe, you find there is only one electron in
    the universe, only you can't tell if it's an electron going forward in time
    or a positron traveling backward in time.
(5) Allen et al., supra.

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