Amine Reductive methylation

Cyanoborohydride has been incorporated into Amberlyst A-26 and used in reductive aminations, reductive methylations, and for reducing pyridinium ions to their tetrahydro derivatives (Hutchins et al., 1978). 

Reductions of aldehydes and ketones to alcohols proceed at slower rates with AERs in BH4 form than with NaBH4 in ethanol.a,j8-Unsaturated carbonyl compounds are reduced by BH4 in a gel AER to the allylic alcohols. Cyanoborohydride ion in a macroporous AER effects reductive aminations of ketones and ammonia to primary amines, reductive methylations of primary amines to the N,iV-dimethyl tertiary amines with aqueous formaldehyde, reductions of N-alkyl- and AT-acyl-pyridinium ions to tetrahydropyridines, and reductions of primary alkyl halides to alkanes. Nitroarenes are reduced to amines, the bromide of a-bromocarbonyl compounds is replaced by hydride, and 1,2-dibromoalkanes give alkenes by treatment with HFe(CO)4 in a macroporous AER. 

Methylation of Primary and Secondary Fatty Amines. This is done by the Leuckait reaction (1,30) or reductive methylation (1,29,31,32). 

Alkyl dimethyl and dialkylmethyl tertiary amines are commercially available. These amines are prepared by reductive methylation of primary and secondary amines using formaldehyde and nickel catalysts (1,3,47,48). The asymmetrical tertiary amines are used as reactive intermediates for preparing many commercial products. 

ESCHWEILER CLARKE Amine methylation Reductive methylation of amines by a mixture of formaldehyde and formic acid... 

Amine oxides, prepared to protect tertiary amines during methylation and to prevent their protonation in diazotized aminopyridines, can be cleaved by reduction (e.g., SO2/H2O, 1 h, 22°, 63% yield H2/Pd-C, AcOH, AC2O, 7 h, 91% yield Zn/HCl, 30% yield). Photolytic reduction of an aromatic amine oxide has been reported [i.e., 4-nitropyridine A-oxide, 300 nm, (MeO)3PO/CH2Cl2, 15 min, 85-95% yieldl. ... 

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-... 

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]. 

N-Methylethylamine has been prepared by heating ethyl-amine with methyl iodide in alcohol at 100° 3 by the hydrolysis of N-methyl-N-ethylarenesulfonamides,4-5 -nitroso-N-methyl-N-ethylaniline,6 or methylethylbenzhydrylidene ammonium iodide 7 by catalytic hydrogenation of ethyl isocyanate or ethyl isocyanide 8 and by the reduction of ethyl isocyanate by lithium aluminum hydride,9 of N-methylacetisoaldoxime by sodium amalgam and acetic acid,10 or of a nitromethane/ethylmagnesium bromide adduct by zinc and hydrochloric acid.11... 

Reductive methylation of primary or secondary amines using formaldehyde and formic acid. Cf. Leuckart-Wallach reaction. 

Reductive methylation is achieved by the reaction of formaldehyde with ammonium chloride. It is carried out by heating the components at 100-120° and gives mono-, di- and trimethylamine in high yields (Eschweiler reaction) [312, 962]. No catalyst is needed part of the formaldehyde provides the necessary hydrogen while the other part is oxidized to formic acid. The same reaction can be applied to methylation of primary and secondary amines [962]. Reductive alkylation can also be accomplished by reducing mixtures of amines with acids which are first reduced to aldehydes (p. 171). 

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

N-Methylation of secondary amines is usually accomplished either with CH20/HC02H (Leuckart/Clarke-Eschweiler reaction) or with CH20 followed by NaBH4 reduction. Methyl iodide treatment of secondary or tertiary bisben-zylisoquinoline alkaloids leads ultimately to the bis quaternary salts, and, in the presence of base, phenolic alkaloids are also O-alkylated. For example, lin-doldhamine (165) on treatment with ethyl bromide in 0.5 N ethanolic KOH gave the N,N,0,0,0-pentaethy 1 derivative (108, Section II,C,56) daurisoline was similarly permethylated with Mel and base (68, Section II,C,19). 

Scheme 2 shows Rapoport s synthesis [15]. The cinnamic acid derivative 3 prepared from m-methoxy benzaldehyde [20] was ethylated by diethyl sulfate to give ethyl cinnamate derivative 4, followed by Michael addition with ethyl cyanoacetate to afford compound 5. Compound 5 was converted to lactam 6 by the reduction of the cyano group and subsequent cyclization. Selective reduction of the lactam moiety of 6 was achieved by treatment with trimethy-loxonium fluorob orate followed by sodium borohydride reduction. Amine 8 was obtained by the reductive methylation of amine 7. Amine 8 was converted to compound 9 by methylene lactam rearrangement [21], followed by selenium dioxide oxidation to provide compound 10. Allylic rearrangement of compound 10 and subsequent hydrolysis gave compound 12. The construction of the decahydroisoquinoline structure began with compound 12,... 

Deoxytazettine neomethide (31), a key degradation product of tazettine, has been prepared (Scheme 4).11 The biphenyl derivative (28), obtained in low yield by Ullman condensation, was converted into the cyano-oxepin (29) in two steps (34% overall yield). Reduction gave the amine (30), which upon resolution followed by reductive methylation provided a sample of (—)-deoxytazettine neomethide (31) that was identical (including optical rotation) with the degradation product of tazettine. 

Reductive amination of methyl ketoreserpate was studied in detail. The use of re-propylamine in the presence of a palladium-charcoal catalyst led not only to the expected mixture of a- and /3-amino derivatives (X), but also to a methyl 17-demethoxy-18-deoxy-l 8-re-propyl -aminoreserpate (XII). In the last case, no attempt was made to define the stereochemistry at C-16 and C-18. Similar eliminations of the C-17 methoxyl under basic conditions were also encountered with other ketone derivative. Reductive aminations were also effected with secondary amines. Piperidine yielded as the sole insolable product the... 

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 racemic acid can be resolved by crystallization of the salt of (+ )-l with cinchonine. The optically pure acids are useful for resolution of amines. Reduction of the corresponding methyl esters provides a particularly useful route to (S)-( -)- and (R)-( + )-binaphthol (9, 169-170). ... 

Primary and secondary amines also undergo reductive methylation in >80% yield on reaction with aqueous foimaldehyde and a salt of phosphorous acid (NaH.PO,) in dioxanc. ... 

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