Formic acid, Eschweiler-Clark reductive

Amine synthesis from reductive amination of a ketone and an amine in the presence of excess formic acid, which serves as the reducing reagent by delivering a hydride. When the ketone is replaced by formaldehyde, it becomes Eschweiler-Clarke reductive alkylation of amines. 

This reaction was initially reported by Eschweiler in 1905, and subsequently by Clarke and co-workers in 1933. It is the preparation of tertiary methylamines from primary or secondary amines by means of the treatment of those amines with an excess amount of aqueous formaldehyde and formic acid. Therefore, it is generally known as the Eschweiler-Clarke methylation. In addition, this reaction is also referred to as the Eschweiler-Clarke condition," Eschweiler-Clarke A -methylation, Eschweiler-Clarke procedure, -) Eschweiler-Clarke reaction, s.3j,7 Eschweiler-Clarke reductive methylation, Eschweiler-Clarke reductive -methylation, Clarke-Eschweiler methylation, Clarke-Eschweiler reaction,or Clarke-Eschweiler procedure. In this reaction, the formate anion donates its proton to reduce the imine or iminium salt, so that carbon dioxide is evolved. Thus the whole process is a reductive amination of formaldehyde. This reaction is very useful for the reductive amination, without the application of hydrogen gas, catalyst (e.g., Pd/C), and high-pressure apparatus and has been widely applied to alkaloid chemistry. A special case of such reductive amination that occurs on phenylethylamine and results in the formation of tetrahydroisoquinolines is also referred to as the Clarke-Eschweiler cyclization. In a few cases, the methylation also occurs on an aromatic ring during the reductive amination. J... 

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

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]. 

Eschweiler-Clarke modification org chem A modification of the Leuckart reaction, involving reductive alkylation of ammonia or amines (except tertiary amines) by formaldehyde and formic acid. esh,vTl-3r klark. mad-o-fo ka-shon ... 

For ammonia and primary amines there are two possible pathways, but when secondary amines are involved, only the hydrogenolysis pathway is possible. Other reducing agents167 can be used instead of hydrogen and a catalyst, among them zinc and HCI, sodium cyano-borohydride NaBHjCN,168 sodium triacetoxyborohydride,169 sodium borohydride,170 iron pentacarbonyl and alcoholic KOH,171 BH -pyridine,172 and formic acid. When the last is used, the process is called the Wallach reaction. In the particular case where primary or secondary amines are reductively methylated with formaldehyde and formic acid, the method is called the Eschweiler-Clarke procedure. It is possible to use ammonium (or amine) salts of formic acid,173 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 N-ethylated (e.g., ArNHR —< ArNREt) by treatment with NaBH4 in acetic acid.175... 

N,N-Dimethylcyclohexylmethylamine has been prepared by reduction of N,N-dimethylcyclohexanecarboxamide with lithium aluminum hydride 2 3 by the action of dimethylformamide on cyclohexanecarboxaldehyde 4 by methylation of cyclohexyl-methylamine3 6 and of N-methylcyclohexylmethylamine by the Clarke-Eschweiler method (treatment with formaldehyde and formic acid) and by the action of dimethylamine on cyclo-hexylmethyl bromide.6... 

A modified protocol of the Eschweiler-Clarke reaction, a reductive transamination, was also used for an efficient N-alkylation of hexahydroazepine and benzylamine in the presence of formic acid and aldehydes or ketones53. 

In preparation for the eventual removal of the undesired oxygen function at C-10 of 313 via a Birch reduction, the phenol 313 was phosphorylated with diethyl phosphorochloridate in the presence of triethylamine to give 314, which underwent stereoselective reduction with sodium borohydride with concomitant N-deacylation to deliver the amino alcohol 315. N-Methylation of 315 by the Eschweiler-Clarke protocol using formaldehyde and formic acid followed by ammonolysis of the ester group and acetylation of the C-2 hydroxyl function afforded 316. Dehydration of the amide moiety in 316 with phosphorus oxychloride and subsequent reaction of the resulting amino nitrile 317 with LiAlH4 furnished 318, which underwent reduction with sodium in liquid ammonia to provide unnatural (+)-galanthamine. 

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... 

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

The Eschweiler-Clarke reaction is the reductive methylation of amines 1, both primary and secondary, using formaldehyde (2) and formic acid (3).1 2 This represents a specific application of the Leuckart-Wallach reaction. 

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 Leuckart-Wallach reaction1,2 is the reductive animation of carbonyl compounds 1 in the presence of excess formic acid (3) as a reducing agent. The Eschweiler-Clarke reaction represents a specific example of this reaction, where the carbonyl compound is formaldehyde. 

Reductive amination with formaldehyde and sodium cyanoborohydride provides a convenient method for methylation of a secondary amine (or dimethylation of a primary amine). An alternative procedure uses formaldehyde together with formic acid (HCOOH) as the source of hydride in what is termed the Eschweiler-Clark reaction. Deprotonation of formic acid provides the formate anion, which delivers hydride to the iminium ion with concomitant formation of carbon dioxide. 

This useful way of adding two methyl groups to a primary amine by reductive amination is sometimes called the Eschweiler-Clarke reaction. For more on formic acid as a reducing agent, see Chapter 41,... 

The reductive methylation of primary or secondary amines employing formaldehyde and formic acid is known as the Eschweiler-Clarke reaction W. Eschweiler, Ber. 38, 880 (1905) H. T. Clarke, etal, J. Am. Chem. Soc. 55,4571 (1933). Synthetic applications E. Farkas, C. J. Sunman, J. Org. Chem. 50,1110 (1985) J. Casanova, P. Devi, Synth. Commun. 23,245 (1993). 

The related Clarke-Eschweiler reaction in whidi the reductive alkylation of an amine is carried out with formaldehyde and formic acid was used to prepare 3-dimethylamino-l-phenyl-1-(2-pyridyl)ptopane (IX-2S8) from 3-phenyl-3-(2-pyridyl)propylamine (IX-257). ... 

A useful application is the Clark-Eschweiler reductive alkylation of amines. Heating a primary or secondary amine with formaldehyde and formic acid results in complete methylation to the tertiary amine. The hydride acceptor is the iminium ion resulting from condensation of the amine with formaldehyde. 

For Petasis borono-Mannich reactions of formaldehyde, methylation of the amine reportedly occurs as a side-reaction, presumably by iminium ion reduction [19]. The hydride source under these conditions may be formic acid, as in the Eschweiler-Clarke methylation reaction. This problem was overcome by the use of potassium trifluoroborate salts and Lewis acids in toluene at 90 °C (the reaction in highly polar solvents such as acetonitrile, DMF and DM SO gives the reduction product). 

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