Reductive alkylation with formaldehyde

Condensation of the anion obtained on reaction of acetonitrile with sodium amide, with o-chlorobenzophenone (36), affords the hydroxynitrile, 37. Catalytic reduction leads to the corresponding amino alcohol (note that the benzhydryl alcohol is not hydrogenolyzed). Reductive alkylation with formaldehyde and hydrogen in the presence of Raney nickel gives the antitussive a-gent, chlorphedianol (39). °... 

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]. 

Reductive amination of benzaldehyde with (R)-81 provided the corresponding benzyl amine, which was reductively alkylated with formaldehyde to give 82 (Scheme H) " Compound 82 was debenzylated by hydrogenation in the presence of Pearlman s catalyst to afford frovatriptan ((/J)-6). Alternatively, monomethylation of amine (/ )-81 was affected by treatment with carbon disulfide and dicyclohexylcarbodiimide in pyridine to provide isothiocyanate 83, which was reduced with sodium borohydride to give (l )-6. 

The synthesis of hydrastine (61) by Falck and Manna demonstrate that the amide product of the Passerini reaction could be used in a subsequent Bischler-Napieralski reaction as a method to produce isoquinolines. In their report, carboxybenzaldehyde derivative 62 was condensed with isonitrile 63 in 71% yield to provide amide 64. Cyclization (POCI3/CH3CN), reduction of the dihydroisoquinoline (Adam s catalyst/H2), and reductive alkylation with formaldehyde gave a diastereomeric mixture of a- and p-hydrastines in 58% overall yield from Passerini product 64. 

For preparation of A -methylaniline, an important commodity, industrial methods of reductive methylation by the mixture formaldehyde/formic acid, catalytic alkylation with methanol, reductive methylation of nitrobenezene or catalytic arylation of methylamine by phenol have been developed. Producers use various technologies depending on the range of the related products they offer to the market. 

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). 

Pyrrole has been condensed under alkaline conditions with formaldehyde to give products of either N- or C-hydroxymethylation (Scheme 22). Although acid-catalyzed hydroxy-methylation is not a practical possibility, by addition of a reducing agent to the reaction mixture overall reductive alkylation can be achieved (Scheme 23). 

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-... 

Dottavio-Martin, D., and Ravel, J.M. (1978) Radiolabeling of proteins by reductive alkylation with [14C]-formaldehyde and sodium cyanoborohydride. Anal. Biochem. 87, 562. 

An attractive feature of this route is that the macrobicyclic intermediate 40a can be readily N-alkylated without affecting the masked thiolate functions (209). Thus, reductive methylation of 40a with formaldehyde and formic acid under Eschweiler-Clarke conditions, followed by deprotection of 40b with Na/NH3 provides the otherwise inaccessible N6S2 ligand H2L19 in nearly quantitative yield (Scheme 1). Several other aza-thioethers 40c-p and their corresponding thiophenolate ligands were prepared by this route (see Fig. 30 and Table I) and some of them will be discussed further in later sections (210-215). 

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]. 

Indole 12b, prepared by Fischer indolization of 11b (Scheme 1), was also converted to sumatriptan (1) according to Scheme 3. The dimethylamino group was incorporated via a two-step procedure. First, aminolysis of 12b with ammonia provided the aminoethyl compound 17, albeit in low yield. Then reductive alkylation of 17 with formaldehyde in the presence of NaBHt gave sumitriptan (1). 

The procedure given above is an adaptation of the methylation method first used by Sommelet and Ferrand3 and developed more fully by Clarke, Gillespie, and Weisshaus.2 /3-Phenylethyldi-methylamine has been prepared from /9-phenylethylamine by alkylation with dimethyl sulfate 4 by the reaction of fi-phenyl-ethylamine and of N-methyl- S-phenylethylamine with formaldehyde 6 by catalytic reduction of phenylacetonitrile in the presence of dimethylamine 3 by the reaction of dimethylamine with /3-phenylethyl chloride 7 8 9 and with /3-phenylethyl bromide 9 and by the reaction of phenylacetaldehyde with dimethylamine.10... 

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... 

Similarly, (V-ethyl-l-naphthylamine was prepared in 88% yield, and (V-ethyl-, N-bu-tyl- and (V-benzyl-2-naphthylamine, and (V-ethyl- and (V-butyl-/ -toluidine were prepared in 50-64% yields.34 In the alkylation of / -toluidine and / -anisidine with butyraldehyde, N,N-dibutyl derivatives were also produced in 19 and 25% yields, respectively. The Emerson-Waters procedure was also applied to the reductive alkylation of 2-phenylpropylamines and 2-phenylisopropylamines with C1-C3 aldehydes (amine aldehyde ratio = 1 3).35 With higher aldehydes the monosubstituted products were isolated in good yields (in 48-94% yields with acetaldehyde), while with formaldehyde (V.N-dimethyl derivatives were obtained in 51-85% yields. 

The reductive alkylation with aldehydes to prepare Al-n-alkylarylamines generally leads to a mixture of /V,/V-dialkyl- and A-alkylarylamines, and the yields of alkylated amines are often poor with aldehydes other than formaldehyde (see eq. 6.12). 

The reductive alkylation of a primary amine to give tertiary amine is often successful with formaldehyde over nickel catalyst. Thus aralkylamines ArCH(CH3)CH2NH2 and ArCH2CH(CH3)NH2 were converted to /V,/V-dimclhyl derivatives in 51-85% yields with formaldehyde and hydrogen over Raney Ni in ethanol in the presence of sodium acetate (eq. 6.16).35... 

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