On the synthesis of 4- and 5-pyrimidinyl-diphenyl-(1-imidazolyl)methanes and their antifungal activity

Abstract

On reaction of phenylmagnesium bromide with ethyl ester of 5-chloro-2-methyl-, 5-chloro-2-methylthio-, 5-bromo-2-methylthio-4-pyrimidinecarboxylic acid and 2,4-dimethyl-5-pyrimidinecarboxylic acid (IIa, IIb, IIc, V) corresponding 4-pyrimidinyl- or 5-pyrimidinyl-diphenylmethanols (IIIa, IIIb, IIIc, VI) were obtained. On reaction of thionyl-bis-imidazole with these methanols (4- or 5-pyrimidinyl)-diphenyl-(1-imidazolyl)-methanes IVa, IVb, IVc and VII were prepared. Phenylmagnesium bromide reacted with ethyl 4-methyl-2-methylthio-5-pyrimidinecarboxylate (VIII) under formation of dihydro derivative IX. We were unable to prepare Grignard's reagent from 5-bromo-2-methylthiopyrimidine and magnesium; it reacted with ethylmagnesium bromide under formation of dihydro derivative I. 5-Chloro-2-methylthio-4-pyrimidinecarboxylic acid when heated with NaOH in dimethyl sulfoxide gave 5-hydroxy-2-methylsulfinyl-4-pyrimidinecarboxylic acid. Compounds IVb and IVc prevented the growth of Candida albicans in vitro at almost the same concentrations as clotrimazole.

Electrochemical Synthesis of Hindered Primary and Secondary Amines via Proton-Coupled Electron Transfer

“…Functional groups such as primary amides (15) and esters (16) were tolerated, while the reactivity of the ketone functionality on the pyridine (e.g., 2acetyl group) was complicated by reduction of the carbonyl moiety concomitant with C−C bond formation. Protecting groups for primary alcohols (17) or terminal alkynes (18) are not necessary, as these functional groups can be successfully carried through the reaction and incorporated into the product. Higher yields of product are observed with pyridines substituted with electron-withdrawing groups such as chloro (19) and trifluoromethyl (20) groups compared to those bearing electron-donating groups such as methoxy (25), thiomethyl (24), or aliphatic groups such as Me or t-Bu substituents (21, 23).…”

“…These include structure 2a 2 related to melanin-concentrating hormone receptor (MCHR) 3 antagonists, structure 2b 4 related to neuropeptide Y 5 antagonists, structure 2c 6 related to human plasma kallikrein inhibitors, 7 structure 2d 8 related to betasecretase 1 (BACE1) 9 inhibitors, structures 2e 10 and 2f 11 related to transient receptor potential cation channel subfamily M member 8 (TRPM8) 12 inhibitors, structure 2g 13 related to cholesteryl ester transfer protein (CETP) 14 inhibitors, structure 2h 15 related to cell division cycle 7 kinase (CDC7) 16 inhibitors, herbicide 2i, 17 and fungicide 2j. 18,19 The heterocycle moiety of the α,α-diaryl alkylamine substructure 1 found in examples from Figure 1 includes pyridines, pyrimidines, and pyrazines. Nitrogen-containing heterocycles are quite prevalent in drugs, with pyridine and its saturated analog, piperidine, being the second and third most abundant ring structures found in FDA-approved drugs in a recent survey of the FDA Orange Book, 20 with only benzene rings appearing more often.…”