Fluoromethyl-substituted compounds and their preparation

摘要

Monofluoromethyl and difluoromethyl substituted organic compounds are prepared by reacting fluorocarbene or difluorocarbene with a carbanion or an anion derived from nitrogen. The anion and the carbene may be prepared in situ by reaction of a protonated carbanion or nitrogen anion precursor and a fluorocarbene precursor (e.g. chlorodifluoromethane or chlorofluoromethane) with a base. A proton donor, e.g. t.-butyl alcohol, is preferably present. Typical carbanions and anions derived from nitrogen are of the types. where at least one of R1, R2 and R3 or of X1 and Y1 provides an electron-withdrawing group enabling the anion to form, e.g. carboxy, carboalkoxy, carbonyl, dialkylaminocarbonyl, cyano, phenyl, nitro, sulphonyl, vinyl, substituted vinyl, acetylenic or halomethyl. Many examples are given. Any two of R1, R2 and R3 may be joined together to form a single group which may or may not be electron-withdrawing, e.g. vinylidene, or all three may be joined in a single electron-withdrawing group, e.g. phenyl in the phenyl-lithium carbanion. X1 and Y1 may be joined in a single electron-withdrawing group. The invention also comprises as novel compounds those of formula where X is hydrogen or fluorine, R1 is an electron-withdrawing group and R2 is either an electron-withdrawing group or an aliphatic, cycloaliphatic, aromatic or heterocyclic group. (N, R1 and R2 may be combined in a ring system), and also the specific compounds: diethyl a - difluoromethyl - a - acetonylmalonate ethylene ketal; a - difluoromethyldiphenylacetonitrile; N - difluoromethyl - 2 - carbethoxyindole; dimethyl a - difluoromethyl 1 - naphthylmalonate; and methyl N - difluoromethyl - N - benzoyloxycarbonyl 3,4,6 - tribenzoyl - D - glucosaminide. Examples also prepare: diethyl a -difluoromethyl-a -acetonyl -malonate ethylene ketal; diethyl and dibenzyl a -difluoromethyl-a -phenylmalonate; ethyl a - difluoromethyl - a - ethylacetoacetate; N - difluoromethyl - a - quinoline; methyl o - (N - difluoromethylacetamido) cinnamate; 2 - nitro - 2 - difluoromethyl propane; triphenyldifluoromethylmethane; difluoromethylbenzene; a ,a -dibenzenesulphonyl - a - difluoromethylethane; N,N-dimethyl - 3,3 - difluoro - 2,2 - diphenylpropionamide; a - phenyl - b - difluoromethylacetylene; N - difluoromethyl - N - methylacetamide; N - difluoromethyl - N - propionylpropionamide; ethyl N - difluoromethyl - N - propionylcarbamate; N - difluoromethyl diphenylamine; N - difluoromethylindole; N - difluoromethyl - N - methylbenzenesulphonamide; N - difluoromethyl saccharin; N - difluoromethyl phthalimidine and N - difluoromethyl phthalimide. N - difluoromethylindole - 2 - acetic acid and a - difluoromethyl diphenylacetic acid are obtained by base hydrolysis of the corresponding ethyl ester and nitrile respectively. 5 - Phenyl - 5 - difluoromethyl barbituric acid is obtained by condensing diethyl a -difluoromethyl -a -phenylmalonate with urea. 2-Difluoromethoxyquinoline is obtained as a byproduct in Example 6. Dimethyl a - naphthylmalonate is prepared by heating methyl a -methoxyoxalyl-naphthalene-1-acetate obtained by treating methyl a -naphthylacetate with dimethyl oxalate in the presence of sodium hydride or methoxide (Example 10).