Preparation of Amines by Reductive Alkylation

Organic Syntheses contains detailed descriptions of the preparation of methylamine993 (50 % yield) and trimethylamine994 (89 % yield) from ammonium chloride and formaldehyde. 

Reductive alkylation does not differ in principle from hydrogenation of a Schiff base but has the advantage that preparation and hydrogenation take place in one operation (cf. page 554). 

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Alkyl groups may be introduced into ammonia, a primary amine, or a secondary amine by means of an aldehyde or ketone in the presence of a reducing agent, such as molecular hydrogen and a catalyst, active metals and acids, or formic acid or one of its derivatives. When the reducing agent is formic acid or a derivative, the reaction is known as the Leuckart reaction and is discussed elsewhere (method 432). An excellent review of the preparation of amines by reductive alkylation has been presented. This article includes a discussion of the scope and utility of the reaction, a selection of experimental conditions, illustrative preparations, and a tabulation of primary, secondary, and tertiary amines prepared thereby. ... 

The Preparation of Amines by Reductive Alkylation William S. Emerson... 

Attempts to prepare tertiary amines by reductive alkylation have in general proved unsatisfactory the only significant reactions are the methylation of secondary and the dimethylation of primary amines by formaldehyde. Bowman and Stroud1008 described the preparation of a series of aliphatic dimethyl-amino acids by hydrogenation of mixtures of amino acids and formaldehyde in the presence of palladium-charcoal at atmospheric pressure. In most cases results are improved if the aldehyde is added gradually to the reaction mixture. In the methylation of aromatic amines special precautions are necessary to prevent condensation of the formaldehyde with the aromatic ring.1009... 

For a review of the preparation of tertiary amines by reductive alkylation, see Spialter, L. ... 

The preparation of tertiary amines by reductive alkylation of ammonia appears to find only limited application. Triethylamine and tripropylamine were prepared by hydrogenation of acetaldehyde and propionaldehyde, respectively, in the presence of ammonia over platinum catalyst.38 A high yield (84.1% by GC) of trinonylamine was... 

Malz, Jr. and Greenfield studied the preparation of tertiary amines by reductive alkylation of aliphatic secondary amines with ketones, using platinum metals and their sulfides as catalysts.40 Excellent yields of tertiary amines were obtained with unhindered ketones, such as cyclohexanone and acetone, and relatively unhindered secondary amines. In this study, 5% Pd-C and various transition metal sulfides were compared in the reductive alkylation of dibutylamine with cyclohexanone. By using the reaction conditions suitable to each catalyst, excellent yields of tertiary amines were obtained, as shown in Table 6.5. Approximately 5-15% of the excess cyclohex-... 

Preparation of secondary amines by reductive alkylation of ammonia is not such a general reaction as that of primary amines. In the aliphatic series treating ammonia with 2 moles of a carbonyl compound usually affords a mixture of mono-, di-, and tri-alkylamines. However, 80-90% yields of the corresponding dibenzylamine are obtained from benzaldehyde or its o-chloro or o-methyl derivative.996... 

The N,]S -dialkyl-/)-PDAs are manufactured by reductively alkylating -PDA with ketones. Alternatively, these compounds can be prepared from the ketone and -lutroaruline with catalytic hydrogenation. The /V-alkyl-/V-aryl- -PDAs are made by reductively alkylating -nitro-, -nitroso-, or /)-aminodipheny1 amine with ketones. The AijAT-dialkyl- PDAs are made by condensing various anilines with hydroquinone in the presence of an acid catalyst (see Amines-aromatic,phenylenediamines). 

Notable examples of general synthetic procedures in Volume 47 include the synthesis of aromatic aldehydes (from dichloro-methyl methyl ether), aliphatic aldehydes (from alkyl halides and trimethylamine oxide and by oxidation of alcohols using dimethyl sulfoxide, dicyclohexylcarbodiimide, and pyridinum trifluoro-acetate the latter method is particularly useful since the conditions are so mild), carbethoxycycloalkanones (from sodium hydride, diethyl carbonate, and the cycloalkanone), m-dialkylbenzenes (from the />-isomer by isomerization with hydrogen fluoride and boron trifluoride), and the deamination of amines (by conversion to the nitrosoamide and thermolysis to the ester). Other general methods are represented by the synthesis of 1 J-difluoroolefins (from sodium chlorodifluoroacetate, triphenyl phosphine, and an aldehyde or ketone), the nitration of aromatic rings (with ni-tronium tetrafluoroborate), the reductive methylation of aromatic nitro compounds (with formaldehyde and hydrogen), the synthesis of dialkyl ketones (from carboxylic acids and iron powder), and the preparation of 1-substituted cyclopropanols (from the condensation of a 1,3-dichloro-2-propanol derivative and ethyl-... 

Benzhydrylamines are better suited than benzylamines as acid-labile linkers for amines. The MBHA linker ( methylbenzhydrylamine ), which is usually used to prepare peptide amides (see Section 3.3), can also be used as a linker for amines (Entry 1, Table 3.21). Hydrogen fluoride is, however, required as the cleavage reagent. Easier to cleave are alkoxy-substituted benzhydrylamines (Entries 2-5, Table 3.21), which can be prepared from the corresponding benzhydryl chlorides [263] or by reductive alkylation [410] or solvolysis [411] of the Rink amide linker. In the case of benzhydrylamines linked to polystyrene as benzyl ethers, treatment with TFA can lead to the release of the linker into solution (acidolysis of the benzylic C-O bond, see Figure 3.18). 

TERTIARY AMINE PREPARATION BY REDUCTIVE ALKYLATION OF ALIPHATIC SECONDARY AMINES WITH KETONES... 

Table 2 Selected anthranilic acid derivatives prepared by reductive alkylation of the Step 2 amine intermediate using 4-pyridinecarboxaldehyde and their corresponding melting points. 111-NMR data supplied by author...

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