Formic acid-formaldehyde methylation of amines

Abstract

The formic acid-formaldehyde methylation of benzylamines has been investigated relative to reaction parameters and competing reactions. The formation of tertiary amine is favored over secondary amine, even when less than stoichiometric amounts of formaldehyde are used. Excess formaldehyde gives only a small increase in the tertiary amine yield. Formation of benzaldehyde is markedly reduced by the addition of sodium formate, presumably through enhancement of the reduction step of the methylation sequence. The absence of acid or specific base catalysis of the aldehyde formation along with a substituent effect trend suggests that the carbonyl side product results from hydrolysis of a benzylideneamine formed in an oxidation-reduction sequence of primary amine and Schiff base.Although the formic acid-formaldehyde (Eschweiler-Clarke2•3) methylation of amines is a method of extensive synthetic utility,4 it has received only limited critical investigation.48"5 In contrast to the mixtures which are often obtained through the methylation of primary amines with methyl iodide, the formic acidformaldehyde method generally leads to good yields of the AjiV-dimethyl tertiary amines. In some cases the formation of a carbonyl product derived from the amine can markedly reduce the useful yield.6In the following, we have used benzylamines as our model and have approached the reaction from three aspects: ( 1) in what way do the reaction parameters affect the synthetic utility of the reaction, ( 2) what is the origin of the carbonyl side product, and (3) can the reaction mechanism be more clearly defined through the use of proposed intermediates and the detection of minor side products? Results and DiscussionThe formation of W,iV-dimethylbenzyIamine (5) from benzylamine (1) using formic acid-formaldehyde is expected to follow the sequence given in Scheme I.

A study of substituent effect on 1H and 13C nmr spectra of N‐ and C‐substituted carbazoles

“…The introduction of methyl groups into a primary or secondary amine by reductive alkylation with formaldehyde and formic acid derivatives, the Clarke-Eschweiler method [31], has proved to be a useful method for the preparation of tertiary methylated amines. In some cases, however, complex mixtures have resulted from the multiplicity of side reactions that can take place [32]. Borch et al [33] have introduced a novel method for the methylation of "reactive" and "unreactive" amines with aqueous formaldehyde and sodium cyanoborohydride.…”

RuO4-mediated oxidation of N-benzylated tertiary amines. 2. Regioselectivity for N,N-dimethyl- and N,N-diethylbenzylamine as substrates

“…This means that the secondary amines 8A-B, formed from 1A-B, were actually in the presence of all these aliphatic aldehydes and acids. It is known 5 that 8A…”

Hydrothermal Synthesis of Mesoporous Nanocrystalline Tetragonal ZrO2 Using Dehydroabietyltrimethyl Ammonium Bromine

“…1. N,N-dimethyl dehydroabietylamine starting from dehydroabietylamine was prepared through the formic acid-formaldehyde method (Pine and Sanchez 1971 …”