Eschweiler-Clarke

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

Many of the modifications of the pyrazolone antiinflammatory agents are intended to increase the limited hydrophilicity of the parent molecules. Reaction of aminopyrine (157) with formaldehyde and sodium hydrogen sulfite affords dipyrone (158). The first step can be rationalized as an Eschweiler-Clark type N-methylation reaction, with bisulfite acting as the reducing agent. The resulting mono N-methyl analogue of 157 then apparently forms the sulfite adduct of the carbinolamine of formaldehyde. 

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]. 

The five-membered ring can also be formed by intramolecular nucleophilic attack of an alkoxide on a carbamate such as for the formation of 196 from 195 <1997T9553>, by dehydration of fV-carbamate-pipecolic acid derivatives <2002EJO3936>, by treatment of amino-amides under Eschweiler-Clarke conditions <1999TA3371>, or by treatment of hydroxyl aminonitriles with silver trifluoroacetate <2002JA2951> (Scheme 57). 

Phenylphosphinic acid and dialkyl sulphoxides are alternatives for, respectively, the reducing agent (formic acid) and the alkylating agent (an aldehyde) used for the TV-alkylation of secondary aliphatic amines (the Eschweiler-Clarke procedure) (equation 55b)166. 

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 ... 

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. 

Elantrine, 418 Elucaine, 44 Encyprate, 27 Endorphins, 317 Endrysone, 200 Enkephalins, 316 Ephedrine, 39 Epimestrol, 13 Epinephrine, 38, 105 Eprozinol, 44 Eryonovine, 475 Ergotism, 475 Eritadenine, 467 Eschweiler-Clark methyla-tion, 29, 162, 210, 28( Esproquin, 373 Estradiol, 136 Estrazinol, 142 Estriols, 138 Estrofurate, 137 Estrogenic activity, 9 Estrogens, 137 Estrone, 137 Estrus synchronization,... 

Eggert 298 Elling 376, 381-383 Enders 1, 38, 45, 392 Engels 383, 384 Eppendorf 303 Eschweiler-Clark 158 Eurogentec 303 Eustache 62... 

---