This file is a part of the Rhodium site archive. This Aug 2004 static snapshot is hosted by Erowid
as of May 2005 and is not being updated. > > Back to Rhodium Archive Index > >

Reductive Alkylation Review

by Station

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-methylbenzylamine 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 Metals Reduction

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 Sodium 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-methylenedioxyphenylacetone, 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 90C 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).