Reductive amination methylation with formaldehyde

Pr)4, " borohydride-exchange resin,and formic acid. When the last is used, the process is called the Wallach reaction. Conjugated aldehydes are converted to alkenyl-amines with the amine/silica gel followed by reduction with zinc borohydride.In the particular case where primary or secondary amines are reductively methylated with formaldehyde and formic acid, the method is called the Esch-weiler-Clarke procedure. It is possible to use ammonium (or amine) salts of formic acid, " or formamides, as a substitute for the Wallach conditions. This method is called the Leuckart reaction,and in this case the products obtained are often the N-formyl derivatives of the amines instead of the free amines. Primary and secondary amines can be iV-ethylated (e.g., ArNHR ArNREt) by treatment with NaBH4 in acetic acid. Aldehydes react with aniline in the presence of Mont-morillonite KIO clay and microwaves to give the amine. Formaldehyde with formic acid converts secondary amines to the N-methyl derivative with microwave irradiation. 

The reductive alkylation of amines is called the Leuckart-Wallach reaction [112-115]. The primary or secondary amine reacts with the ketone or aldehyde. The formed imine is then reduced with formic acid as hydrogen donor (Scheme 20.27). When amines are reductively methylated with formaldehyde and formic acid, the process is termed the Eschweiler-Clarke procedure [116, 117]. 

This reaction specifically refers to the case when a primary or secondary amine is reductively methylated with formaldehyde and formic acid. 

The mechanism of the Eschweiler-Clarke reaction proceeds via the formation of an imine, followed by reduction by formic acid. That the methylation is attributable to the formaldehyde and the reduction to the formic acid has been confirmed using 14C-labeled isomers of each in a series of studies.5 Thus, the amine reacts with formaldehyde to produce an imine, and this is then reduced with the loss of carbon dioxide by formic acid. In the case of primary amines this process is then repeated to produce a tertiary N.iV-dimethyl amine. 

The yield of the more active RRR-a-tocopherol can be improved by selective methylation of the other tocopherol isomers or by hydrogenation of a-tocotrienol (25,26). Methylation can be accompHshed by several processes, such as simultaneous halo alkylation and reduction with an aldehyde and a hydrogen haUde in the presence of staimous chloride (27), amino alkylation with ammonia or amines and an aldehyde such as paraformaldehyde followed by catalytic reduction (28), or via formylation with formaldehyde followed by catalytic reduction (29). 

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-... 

The synthesis of a triptan with a chiral side chain begins by reduction of the carboxylic acid in chiral 4-nitrophenylalanine (15-1). The two-step procedure involves conversion of the acid to its ester by the acid chloride by successive reaction with thionyl chloride and then methanol. Treatment of the ester with sodium borohy-dride then afford the alanilol (15-2). Reaction of this last intermediate with phosgene closes the ring to afford the oxazolidone (15-3) the nitro group is then reduced to the aniline (15-4). The newly obtained amine is then converted to the hydrazine (15-5). Reaction of this product with the acetal from 3-chloropropionaldehyde followed by treatment of the hydrazone with acid affords the indole (15-6). The terminal halogen on the side chain is then replaced by an amine by successive displacement by means of sodium azide followed by catalytic reduction of the azide. The newly formed amine is then methylated by reductive alkylation with formaldehyde in the presence of sodium cyanoborohydride to afford zolmitriptan (15-7) [15]. 

As a further illustration of the reactivity of the 3 position toward electrophiles, the methoxyindole (25-1) readily undergoes Mannich reaction with formaldehyde and dimethylamine to afford the aminomethylated derivative (25-2). Treatment of that intermediate with potassium cyanide leads to the displacement of dimethylamine and the formation of the nitrile (25-3), possibly by an elimination-addition sequence involving a 3-exomethylene-indolenine intermediate. The protons on the methylene group adjacent to the nitrile are quite acidic and readily removed. Reaction of (25-3) with methyl carbonate in the presence of sodium methoxide gives the carbo-methoxylated derivative (25-4). Catalytic hydrogenation leads to reduction of the nitrile to a primary amine. There is thus obtained the antihypertensive agent indorenate (25-5) [26]. 

The amino groups of ovomucoid, lysozyme, and ovotransferrin were alkylated extensively (40-100%) with various carbonyl reagents in the presence of sodium borohydride. Monosubstitution was observed with acetone, cyclopentanone, cyclohexanone, and benzaldehyde, while 20-50% disubstitution was observed with 1-butanal and nearly 100% disubstitution was observed with formaldehyde. The methylated and isopropylated derivatives of all three proteins were soluble and retained almost full biochemical activities. Recently amine boranes have been shown to be possible alternative reducing agents for reductive alkylation... 

The reduction of enamine unit occurs much more rapidly than that of the carbonyl group. Therefore, this reagent can be used to perform reductive amination of aldehydes and ketones, by simply reacting the carbonyl compound with a fourfold excess of the amine. In a similar manner, reductive methylation of amines could be accomplished by addition of formaldehyde to the amine119. 

The reductive methylation of amines with formaldehyde in the presence of formic acid. See Lindeke, B., Anderson, B., and Jenden, D.J., Specific deuteromethylation by the Eschweiler-Clark reaction. Synthesis of differently labelled variants of trimethylamine and their use of the preparation of labelled choline and acetylcholine, Biomed. Mass Spectrom. 3, 257-259, 1976 Boldavalli, E, Bruno, O., Mariani, E. et al.. Esters of A-methyl-iV-(2-hydroxyethyl or... 

Table 1 demonstrates that NaBH4 may be used in the presence of heterocyclic rings (entries 8-10, 13-17), esters (entries 8-10, 17), amides (entries 1, 9), conjugated double bonds (entry 7), alkynes (entry 5) and acetals (entry 4). The process can also be used to methylate an amine with formaldehyde as the carbonyl (entry 13). With certain structures, further reactions may occur subsequent to reduction (e.g. entry 6). Entry 15 illustrates a synthetically useful amine alkylation reaction which may occur in acetic acid. This remarkable reaction is attributed to self-reduction of an acyloxyborohydride to an aldehyde... 

The usefulness of reductive amination is augmented by the facile methylation of amines with formaldehyde (usually in MeCN), which provides a convenient, mild alternative to Clark-Eschweiler and other methylation procedures. Table 8 presents a selection of successful methylation applications with various amines, and further illustrates the chemoselectivity and versatility of the process. 

Eschweiler-Clarke reaction. Reductive methylation of primary or secondary amines with formaldehyde and formic acid (special form of the Leuckart-Wallach reaction). 

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