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.

INTRODUCTION

A note on nomenclature utilized in the various syntheses.
Methamphetamine is variously referred to as beta-phenylisopropylmethylamine,
1-phenyl-2-methylaminopropane, N-methyl- phenylisopropylamine,
alpha,N-dimethyl-phenethylamine, N,alpha- dimethylbenzeneethanamine,
N-methylamphetamine, deoxyephedrine, desoxyephedrine, PhCH2CH(NHCH3)CH3 or
PhCH2CH(NHMe)Me. The dextro isomer of methamphetamine is the d, (+), D or S
isomer; the levo isomer is the l, (-), L or R isomer. Racemic mixtures may be
referred to as d,l or (+,-) or DL or (R)(S).

REDUCTIVE ALKYLATION

Reductive alkylation (alkamination) is related to reductive amination. During
reductive amination a carbonyl compound and ammonia form a primary amine; during
reductive alkylation a mixture of a primary or secondary amine and a carbonyl
compound form a secondary or tertiary amine, respectively. Reductive alkylation
is utilized to produce methamphetamine from phenyl-2-propanone and methylamine.
Alkylation of a primary amine proceeds in the same manner as reductive
amination--through an addition product or through an imine (also called a Schiff
base) after splitting out water.

REDUCTIVE ALKYLATION VIA CATALYTIC HYDROGENATION

Like reductive amination, reductive alkylation is dependent on the reactivity of
the carbonyl function. The basicity of the amine is also a factor. A more basic
amine generally preferentially reacts with the carbonyl function (in the absence
of factors such as steric hindrance, etc.). Thus a ketone such as phenyl-
2-propanone will preferentially react with a more basic primary amine such as
methylamine as opposed to the less basic secondary amine reaction product,
methamphetamine (methamphetamine is also more sterically hindered).

Platinum oxide or 5% platinum on carbon may be the catalyst of choice for these
reactions. In a number of reductions there appeared to be little difference in
uptake time whether 5% palladium on carbon or platinum on carbon was used, but
the alkylation of methylamine with phenyl-2-propanone utilizing palladium gave
poor results (see below).

There are reports that platinum oxide should be prereduced before use in
reductive alkylation. Other reports state that there did not seem to be any
difference in a number of comparable reactions whether using the catalyst
immediately or prereducing it.

When utilizing 5% rhodium on carbon or on alumina, the reaction period, which
is longer than that of platinum or palladium catalyzed alkylations, can be
shortened by running the reaction in the presence of weak acid. Rhodium is
generally less efficient than other catalysts, but is of value in alkylations in
the presence of chlorine containing compounds, since it does not usually cause
dechlorination. Rhodium may also be useful in alkylations in the presence of
bromine under acidic conditions.

Although some have reported good results from alkylations in the presence of
Raney nickel at low pressure, alkylations at low pressure usually require a
large amount of catalyst. Raney nickel was generally efficient at elevated
temperature and pressure, however. Low pressure reductive alkylations with Raney
nickel may be promoted by the use of one equivalent of acetic acid to neutralize
the effect of the nitrogen base on the catalyst (note, however, that a basic
Raney nickel catalyst is usually more active than a neutral catalyst). The
effectiveness of Raney Nickel may also depend on its age and activity.

Reductive Alkylation of Methylamine with 1-Phenyl-2-Propanone via Platinum Oxide
at Low Pressure:

Freifelder, Catalytic Hydrogenation in Organic Synthesis: Procedures and
Commentary (John Wiley & Sons, Inc., 1978) 101-2; Freifelder, Practical
Catalytic Hydrogenation: Techniques and Applications (John Wiley & Sons, Inc.,
1971) 366.

This appears to be the highest yielding published procedure for synthesizing
methamphetamine from phenyl-2-propanone and methylamine. This is not surprising,
considering Mr. Freifelder's vast knowledge of and experience with heterogenous
catalytic hydrogenation and his many years as head of catalytic hydrogenation at
Abbott Laboratories, maker of Desoxyn(r) brand d-methamphetamine.

1-Phenyl-2-propanone, 68.5 g. (~0.5 mole) in 150 ml ethanol was reacted with
51.8 g. (0.5 mole) 30% w/w aqueous methylamine solution, (fn.1),(fn.2) and
hydrogenated at 3 atm. pressure (fn.3) with 1.4 g. of platinum oxide. (fn.4)
There was a lag period of 1-2 hours, during which time there was little or no
uptake of hydrogen (prereduction of catalyst did not change the lag period).
Thereafter uptake was usually complete in an additional 2-4 hours. (fn.5) After
removal of catalyst and concentration of filtrate and washings, high yields of
the racemic N- methylphenylisopropylamine (methamphetamine) were obtained (90%
or greater yield).

Reductive Alkylation of Methylamine with 1-Phenyl-2-Propanone via Raney Nickel
at High Pressure:

Organicum: Practical Handbook of Organic Chemistry (Addison-Wesley Publishing
Co., Inc., 1973), English translation by B. J. Hazzard, 458-9. There is little
advantage to using this procedure as compared to the Freifelder procedure above,
but it may be useful for those who have easy access to high-pressure
hydrogenation equipment and Raney nickel. In working with Raney nickel, Hazzard
states that a highly basic catalyst (e.g., that of Urushibara prepared from 30%
nickel alloy, see Reductive Amination) gives the best results.

134.2 g. (1.0 mole) of phenyl-2-propanone is treated with a solution of 31.1 g.
(1.0 mole) of methylamine in 200 ml of methanol. 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 an 80% yield of DL-1-phenyl-2-methylaminopropane,
b.p. 15mm. 93C.

Hazzard notes the methamphetamine is better stored in the form of the
hydrochloride. To obtain the hydrochloride, the methamphetamine 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
methamphetamine hydrochloride, m.p. 140C.

Reductive Alkylation of Methylamine with 1-Phenyl-2-Propanone via Raney Nickel:

Novelli, Sympathicomimetics. Preparation of Nitrogen-Substituted beta-
Phenylisopropylamines. Anal. Assoc. Quim. Argentina 27 (1939) 169-171;
C.A. 34: 16278 (1940).
Amines were obtained in 50-70% yields. Methamphetamine was obtained as the
hydrochloride salt, m.p. 133-5, and purified by solution in absolute alcohol
and precipitation by anhydrous diethyl ether.

Reductive Alkylation of alpha-Methylbenzylamine with 1-Phenyl-2-Propanone
Followed by Hydrogenolysis:

Nichols et al., Asymmetric Synthesis of Psychotomimetic Phenylisopropylamines,
J. Med. Chem. 16(5) (1973) 480-3. This procedure offers a route to
dextro-amphetamine from phenyl-2-propanone.

In this procedure imine is preformed from the phenylacetone and the
alpha-methylbenzylamine by azeotropic water removal in refluxing benzene.
The resulting enamine was not isolated but was reduced directly at 50 psig
in a Parr shaker. Moderate yields were obtained. The hydrogenolysis step
proceeded in good yield in less than 36 hr. using 10% palladium/carbon
catalyst. The procedure is general and has been extended to a large number
of ring-methoxylated amphetamines. The route is represented below.

Diagram: phenylacetone + (S)-(-)-alpha-methylbenzylamine - H2O in the
presence of Raney Ni-H2 and HCl yields the N-(alpha-phenethyl)-
phenylisopropylamine HCl which is reduced in presence of 10% Pd/C-H2 to
give S-(+)-phenylisopropylamine HCl

Highest enantiomer purity was obtained by several recrystallizations of the
N-(alpha-phenethyl) precursors, indicating that final purity is dependent on the
purity of the diastereomeric intermediates. However, a single recrystallization
sufficed to give enantiomeric purities of final compounds in the range 96-97%.

The procedure as originally published utilized the (R)-(+)-alpha-methylbenzyl-
amine to produce the levo (-)-phenylisopropylamine in about 58% overall yield.
In the example below (S)-(-)-(-methylbenzylamine will yield the dextro
(+)-phenylisopropylamine. Use of racemic alpha- methylbenzylamine will give
the racemic (R)(S)-phenylisopropylamine.

(S,S)-(-)-N-(alpha-Phenethyl)phenylisopropylamine Hydrochloride:
6.7 g. (0.05 mole) phenyl-2-propanone and 6.1 g. (0.05 M) (S)-(-)-alpha-
methylbenzylamine were heated under reflux in 50 ml benzene for 24 hr with
continuous H2O removal (i.e., Dean-Stark trap). The benzene was removed, the
residue dissolved in 50 ml of absolute ethanol, and the resulting solution
shaken over 2g of ethanol-washed W-2 Raney nickel at 50 psig of H2 until the
calculated amount of H2 was absorbed, usually within 24 hr. The mixture was
filtered through sintered glass (fn.6); the filtrate was acidified with
anhydrous ethanol saturated with hydrogen chloride gas and concentrated to
small volume. The hydrochloride salt precipitated upon dilution with diethyl
ether and was recrystallized from acetone-water or acetone-isopropanol.
Yield 70.5%, m.p. 233.5-234.5.

(S)-(+)-Phenylisopropylamine Hydrochloride:
To a slurry of 0.35 g. of 10% palladium on carbon in several milliliters of
H2O was added 90 ml of methanol and 5 g. of the (S,S)-(-)-N-(alpha-phenethyl)-
phenylisopropylamine hydrochloride prepared above. The mixture was shaken at 50
psig of H2. The calculated uptake usually occurred within 48 hr (reduced amounts
of catalyst greatly prolonged this time). The mixture was filtered and
concentrated to dryness, and the residue was recrystallized from isopropanol-
diethyl ether. Yield 83%, m.p. 157-158, [alpha]25D (c 2, H2O) -27.2.

Monomethylation of Phenylisopropylamine with Formaldehyde via Platinum Oxide:

This is an adaptation of the procedure found in Freifelder, Catalytic
Hydrogenation in Organic Synthesis: Procedures and Commentary at page 98-101 for
the monomethylation of 2-phenylethylamine. As in any adaptation of published
procedures, an initial trial run should be conducted on a small scale.

A solution of 33.8 g. (0.25 mole) of phenylisopropylamine and 7.5 g. (0.25 mole)
of paraformaldehyde (fn.7) in 50 ml of 95% ethanol was allowed to stand for a
short period. (fn.8) Additional ethanol (100 ml), 15 g. (0.25 mole) of glacial
acetic acid, (fn.9) and 0.5 g. of platinum oxide (fn.10) were added, and
hydrogenation was carried out at room temperature and 3 atm. When hydrogen
absorption was complete, the catalyst was removed, and the filtrate and washings
concentrated to dryness. The residue was treated with sodium hydroxide solution,
(fn.11) extracted with ether, dried and distilled. (fn.12), (fn.13)

Reductive Alkylation of Methylamine with 1-Phenyl-2-Propanone via Palladium:

American Home Products Corp., Imines. British Pat. No. 702,985, Jan. 27,
1954; C.A. 49: 5515g (1955).
This reference offers a method for preparing and isolating imines, which may
then be reduced to the amine in the usual manner. Imines were prepared by
dehydrating hemiaminals, at a temperature below 100C and in the absence of
oxygen. Suitable dehydrating agents are those strongly alkaline compounds whose
cations fall within Groups IA or IIA of the periodic table, especially KOH,
K2CO3, CaO, and mixtures of NaOH and KOH. The hemiaminal compounds may be
obtained from the reaction between a ketone and a primary alkylamine, and need
not be isolated before the dehydration is carried out.

62 g. (2.0 mole) methylamine was added to a cooled mixture of 134 g. phenyl-
2-propanone and anhydrous potassium hydroxide (e.g., 75 g.) and the mixture
allowed to stand 5 days in a stoppered bottle to give the imine. 10 g. of 5%
palladium on carbon was added to a solution of 20.6 g. of the imine in 45 cc.
ethyl acetate, and hydrogen added to yield deoxyephedrine, b.p. 1.1mm. 58-61.5C.

Reductive Alkylation of Methylamine with 1-Phenyl-2-Propanone via Platinum:

Keil et al., beta-Arylalkylamines. German Pat. No. 767,263 (1952); C.A. 47:
2772c (1953).

Catalytic pressure-hydrogenation of ketones with primary amines in water-free
solvents in the presence of platinum catalysts gave beta-arylkylamines.

Hydrogenating phenyl-2-propanone 15 in diethyl ether 75 containing methylamine
5.6 in the presence of a supported platinum catalyst with hydrogen at 3.5 atm
and room temperature, extracting the mixture after separation of the catalyst
with 3 N hydrochloric acid and alkalinizing the acid extract gives
2-methylamino-1-phenylpropane (Chemical Abstracts gives the ethylamine example).

REDUCTIVE ALKYLATION VIA DISSOLVING METAL REDUCTIONS

Please see the Reductive Amination for a discussion of dissolving metal
reductions.

Reductive Alkylation of Methylamine with Phenyl-2-Propanone via Aluminum-Mercury
Amalgam:

Laboratoires Amido, Imine (Schiff Base from Phenyl-2-Propanone and Methylamine)
Reduced to Methamphetamine. French Pat. No. M2782, Oct. 5, 1964; C.A. 62: 5228g
(1965).

A mixture of 40 g. phenyl-2-propanone, 200 cc ethanol, 200 cc 25% aqueous
methylamine, 40 g. aluminum turnings and 0.30 g. mercuric chloride is allowed to
react, refluxed 2 hours, concentrated in vacuo, poured into ice-water,
alkalinized with 120 g. potassium hydroxide, and extracted with 750 cc diethyl
ether. The extract is treated with 160 cc 20% HCl, the acid solution mixed with
60 cc aqueous sodium hydroxide and extracted with 150 cc diethyl ether, and the
ethereal extract dried and evaporated. The residue was distilled in vacuo to
give 1-phenyl-2-methylaminopropane, b.p. 16mm. 94-6C in about 70% yield. (fn.14)

Reductive Alkylation of Methylamine with Phenyl-2-Propanone via Aluminum-Mercury
Amalgam and Hydrogen:

Temmler-Werke, Amines. French Pat. No. 844,288, July 20, 1939; C.A. 34: 75446
(1940).

In an unusual method, methamphetamine was prepared from phenyl-2-propanone and
a methanolic/aqueous methylamine solution in diethyl ether solvent utilizing
aluminum-mercury amalgam and hydrogen under 3 atm. pressure.

A method for the preparation of amines from ketones and NH3 or its derivatives
consists of reducing the ketones in the presence of NH3 or its derivatives,
preferably under pressure, by means of activated aluminum and water. Among
examples, beta-phenyl-N-methylisopropylamine, b.p. 30mm. 105C, was obtained by
dissolving 1-phenyl-2-propanone 14 in diethyl ether 50 parts, adding 15 parts of
an alcoholic solution containing 20% methylamine, water 5 and activated aluminum
2 parts, agitating the mixture under a hydrogen pressure of 3 atm., eliminating
the formed Al(OH)3 by filtration, extracting the base by means of aqueous
hydrochloric acid and precipitating by means of an alkali.

Reductive Alkylation of Phenylisopropylamine with Formaldehyde via
Aluminum-Mercury Amalgam:

Keil et al., N-Monomethyl-beta-phenylethylamines, German Pat. No.
871,155, Mar. 19, 1953; C.A. 52: 20055e.
A procedure for converting amphetamine into methamphetamine.
N-Monomethyl-beta-phenylethylamines were prepared by the reaction of the
corresponding primary amine with formaldehyde and reduction in the absence of
acid. Thus, a mixture of d,l-phenylisopropylamine 136, alcohol 350 parts, 1 mole
formaldehyde solution, and an excess of activated aluminum was reduced for
several hours, water added, aluminum hydroxide filtered off, the solution
acidified and evaporated, and the free base separated by means of alkali
yielding phenyl-N-methylisopropylamine, converted to the hydrochloride, m.p.
140C. Similarly, d-phenylisopropylamine 70 in alcohol with aluminum and 1 mole
formaldehyde gave d-N-methyl-phenylisopropylamine, converted to the phosphate
salt. 1-Phenyl-2- aminopropanol yielded ephedrine, converted to the
hydrochloride salt.

REDUCTIVE ALKYLATION VIA CYANOBOROHYDRIDE

The use of sodium cyanoborohydride in methanol is considered by many to be the
easiest and most "foolproof" method of reductive amination. Control of the pH
allows excellent selective control of competing reactions. The use of sodium
cyanoborohydride (sodium cyanohydridoborate, NaBH3CN) was pioneered by Borch et
al. (see below). The reduction of ketones is pH dependent, the reaction
proceeding readily at pH 3-4, while negligible reduction of aldehydes or ketones
was observed under neutral conditions in water or methanol. The reaction of a
ketone with a primary amine at pH ~7 in the presence of BH3CN- leads to the
secondary amine via reductive amination of the carbonyl group. The reaction is
usually run using a fivefold excess of the amine; although this improves the
initial equilibrium in favor of the hemiaminal, the main purpose is to prevent
the product amine from undergoing further reaction with the ketone. Borch et al.
found that sodium cyanoborohydride and lithium cyanoborohydride (LiBH3CN) may be
used interchangeably; no differences in reactivity were observed.

Reductive Alkylation of Methylamine with Phenyl-2-Propanone via
Cyanohydridoborate Anion:

Borch et al., The Cyanohydridoborate Anion as a Selective Reducing Agent.
J. Am. Chem. Soc., 93 (1971) 2897-2904.
Purification of NaBH3CN:
The purity of the commercially available material is usually adequate. If
desired, the material may be further purified by recrystallization of its
dioxane complex. The dioxane complex is a poor reducing agent in organic
solvents as a result of its incomplete dissociation in all but aqueous systems.
Therefore, NaBH3CN is liberated from the complex by heating in vacuo, affording
a hygroscopic powder.

Sodium cyanoborohydride (10 g.) was dissolved in 80 ml. of tetrahydrofuran, and
1 M HCl-methanol was added until a drop of the solution showed pH ~9 on pH
paper. The solution was then poured with stirring into 250 ml. of dioxane. The
precipitate was filtered, and the wet solid was stirred for 2 hours in 250 ml.
of ethyl acetate. This solution was then filtered in vacuo through Hy-Flo and
heated to reflux on the steam bath; then 150 ml. of dioxane was added in
portions with swirling. This solution was slowly cooled to room temperature,
then chilled and filtered. The crystalline dioxane complex was dried in vacuo
for 4 hours at room temperature, then for 4 hours at 80C, resulting in 6.74 g.
of amorphous hygroscopic powder, >98% pure NaBH3CN.

Reductive Alkylation of Primary Amines:
To a solution of 1.9 g. of anhydrous methylamine in 25 ml. of absolute methanol
was added 4 ml. (20 mmol) of 5 N HCl-methanol, followed by 10 mmol of ketone
(e.g., 1.34 g. phenyl-2-propanone) and 300 mg. (6 mmol) of LiBH3CN. The solution
was stirred at 25C for 72 hours. Concentrated hydrochloric acid was added until
pH <2, and the methanol was removed in vacuo. The residue was taken up in 20 ml.
water and extracted with three 20 ml. portions of diethyl ether. The combined
extracts were dried and evaporated in vacuo to give the amine.

In the landmark PiHKAL: Phenethylamines I Have Known and Loved (Transform Press,
1991) 720-721, Shulgin et al. state that this synthetic procedure, utilizing the
hydrochloride salt of the amine and sodium cyanoborohydride in methanol, seems
to be quite general for ketone compounds related to 3,4-methylenedioxyphenyl-
acetone, including phenyl-2- propanone. 26.8 g. (.2 mole) Phenyl-2-propanone
with methylamine hydrochloride gave 24.6 g. (.16 mole) N-methylamphetamine,
yield 80% of theoretical. The reaction with simple ammonia (as ammonium acetate)
gave consistently poor yields.

REDUCTIVE ALKYLATION VIA CATALYTIC HYDROGENATION

Reductive Alkylation of Methylamine with Phenyl-2-Propanone via Catalytic
Hydrogenation over Cupric Oxide and Calcium or Barium Sulfate:

Tindall, Process for the Production of Secondary Amines. U.S. Pat. No.
2,828,343, Mar. 25, 1958; C.A. 52: 13775f (1958).
Secondary amines are produced by treating a ketone with ammonia or an alkylamine
and hydrogen over a catalyst composed of CuO and CaSO4 or BaSO4. Thus, a
solution containing 30 g.. CuSO4-5H2O in 150 ml. water was heated to 90C with
steam, and 1170 ml. of 0.23N Ba(OH)2 was added. The mixture was heated 3 hours
at 90 with steam, and the precipitate filtered off, washed with water, air
dried, and ground yielding 54 g. catalyst.

Skinner, Methamphetamine Synthesis Via Reductive Alkylation
Hydrogenolysis of Phenyl-2-Propanone with N-Benzylmethylamine. Forensic
Sci. International, 60(3) (1993) 155-62.

REDUCTIVE ALKYLATION VIA SODIUM BOROHYDRIDE

Reductive Alkylation of Methylamine with Phenyl-2-Propanone via Sodium
Borohydride:
Weichet et al., Reductive Amination of Phenylacetylcarbinols by Sodium
Borohydride. Coll. Czech. Chem. Commun., 26 (1961) 2040-4; C.A. 56: 5864c
(1962).

REDUCTIVE ALKYLATION VIA SODIUM/ALCOHOL

Ogata, Constitution of ephedrine. Desoxyephedrine. J. Pharm. Soc. Jpn.,
451 (1919) 751-64; C.A. 14: 745 (1920).
To 100 g. of anhydrous alcoholic methylamine, 40 g. of phenyl-2-propanone was
added and left at room temperature for 4 weeks in a stoppered bottle. Then 150
g. of anhydrous alcohol was added, and 30 g. of sodium (caution!--some water
will have formed in the reaction) was used for reduction, collecting the large
amount of methylamine in hydrochloric acid. After the reduction, water was
added, the excess of alcohol was evaporated off, and steam distillation was
conducted till the distillate was no longer alkaline. Hydrochloric acid was used
for neutralization. The insoluble portion was extracted with ether and the
extract concentrated and precipitated with mercuric chloride. The mercury salt
was decomposed with hydrogen sulfide, giving 15 g. of the hydrochloride salt.
After purification with alcohol, plate-shaped crystals were obtained, m.p.
134-5C. The liquid free base had an amine odor and b.p. 760mm. 209-10C, b.p.
15mm 93C. In all respects the product was very similar to the amine obtained by
reducing ephedrine. Separation of the d- from the l-form was easily accomplished
by the tartaric acid method, the dextro isomer having a m.p. 170-5C as compared
to reported m.p. of 170-1C and 173C for deoxyephedrine prepared from ephedrine.


FOOTNOTES:
(1) 15.5 g. anhydrous methylamine as a solution in alcohol may be substituted.
(2) In general, the best procedure to alkylate low boiling amines is to dissolve
    the ketone in alcohol and add a solution of amine in alcohol to the ketone in
    portions to prevent loss of amine from the exothermic reaction. If there is
    no exothermic reaction, the solution may be allowed to stand before reduction.
(3) Immediate hydrogenation under 2 atm. pressure was also successful. Elsewhere
    Freifelder notes that, in general, at a fixed temperature there is little
    significant difference between a reaction run at 1 or 4 atm. pressure.
(4) It is possible to substitute 20 g of 5% platinum on carbon. Of interest was
    the poor reducibility with 5% palladium on carbon. Hydrogenation of a
    mixture of ketone and amine in alcohol with 15% by weight of 5% palladium on
    carbon was very slow, 60% uptake in 24 hours, even when pure redistilled
    phenyl-2-propanone was employed.
(5) Uptake of hydrogen was reasonably rapid even when the ketone and methylamine
    were hydrogenated in the absence of solvent.
(6) The catalyst is extremely pyrophoric.
(7) Originally about 20 ml of 37% formaldehyde solution was added (0.25 mole).
    In view of the reported danger of dimethylation of primary amines when
    formaldehyde is used, Freifelder believed it appeared safer to use
    paraformaldehyde, since an exact amount could be weighed.
(8) When the aldehyde and base were mixed, the solution became warm. The
    solution was allowed to stand for 0.25-0.5 hr. for complete reaction. In
    some cases the mixture was allowed to stand overnight, but this gave no
    improvement in yield after reduction. When no heat developed in the reaction
    of aldehyde and amine, the mixture was warmed slightly and allowed to stand
    before reduction. When low boiling components are to be mixed, it is best to
    cool the solution of amine while the aldehyde is added to prevent loss of
    amine or aldehyde from the exothermic reaction. After standing, the mixture
    can then be hydrogenated. Hydrogen uptake was usually complete within 2 hr
    or less.
(9) The reaction rate in this reduction was slower in the absence of acetic
    acid. Many reductive alkylations were carried out successfully with platinum
    or palladium in the absence of acid. When reduction was too slow,
    interruption for addition of the required amount of acid did speed hydrogen
    uptake.
(10) Palladium on carbon was not used in this experiment, but 5 g of 5% rhodium
     on carbon did prove satisfactory. Freifelder states there is little doubt
     that 5 g of 5% palladium on carbon or an equal amount of 5% platinum on
     carbon would work as they had in other reductive alkylations.
(11) When acid is not used, addition of alkali and extraction of base are
     unnecessary.
(12) In the monomethylation of 2-phenylethylamine, an 80-90% yield of N-methyl
     2-phenethylamine was obtained.
(13) A reaction such as this is actually a reduction of the imine in situ, a
     very useful procedure that may be used in alkylations with other aldehydes.
(14) The yield was stated to be 70% in Wassink et al., A synthesis of
     Amphetamine, J. Chem. Ed., 51, 671 (1974) (see Reductive Amination).

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