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Please login or sign up for a free trial to access the full content. Method 6: From Alkyl Isocyanides and S—C Synthons

DOI: 10.1055/sos-SD-011-00783

Kikelj, D.; Urleb, U.Science of Synthesis, (200211692.

2-Unsubstituted thiazoles 241 are available by cyclization of isocyanides 240, substituted with an α-acceptor group, with various SC synthons, e.g. carbon disulfide, isothiocyanates, thionoesters or dithioesters (Scheme 90). Thus, the reactions of 240 with carbon disulfide give intermediate thiazole-5-thiolates, which can be alkylated in situ to afford 5-(alkylsulfanyl)thiazoles 241 (R2=alkylsulfanyl).[‌503‌,‌504‌] A reaction of tosylmethyl isocyanide with carbon disulfide under phase-transfer conditions provides a simple, efficient and high yielding method for the preparation of the tetrabutylammonium salt of 5-sulfanyl-4-tosylthiazole.[‌505‌] Metal-coordinated α-deprotonated ethyl 2-isocyanoacetate [M(CO)5CNCH2CO2Et, M=Cr or W] reacts with carbon disulfide in a [3+2]-cycloaddition process to give pentacarbonyl[4-(ethoxycarbonyl)-5-(methylsulfanyl-2,3-dihydrothiazol-2-ylidene)chromium or -tungsten complexes in 5055% yield.[‌506‌] The reactions of α-substituted methyl isocyanides with various isothiocyanates analogously leads to the formation of N-substituted thiazol-5-amines.[‌507‌‌509‌] A variety of thiazoles is readily prepared by treatment of 2-metalated isocyanides with dithioesters[‌510‌] or thionoesters.[‌511‌] In all variations of this synthesis, the mechanism probably involves nucleophilic attack of the metalated isocyanide on the carbon of the SC synthon to give an intermediate which undergoes internal cyclization and aromatization.

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M8 M8 MM Meeeeee Meee Meeeeeeeee Meeee (%) ee (°M)/ee (°M)/Meee Mee
M MMe MM8 MeMe MMM, 88 ee 88°M, 8.88e 88e 8888/88 [‌888‌]
Me MMe MM8 e-MeMM MMM, 88 ee 88°M, 8.88e 88e 888/8.888 [‌888‌]
Me MMMe8+ MM8 MeMM MMMe8, ee, 8.8e 88 eee [‌888‌]
MM(MMe)8 MMe MM8 e-MeMM MM8Me8, 88°M, 8e 88e 888/8.88 [‌888‌]
MM8Me MMMe MeMMM e-MeMM MMM, ee, 8e 88 888888 [‌888‌]
MM8Me MMMe MeMMM MeM MMM, 8888°M 88 88.888.8 [‌888‌]
MM8Me MMMe MeMMM e-MeMM MMM, ee, 8e 88 888888 [‌888‌]
Me MMMM8MM=MM8 M8M=MMMM8MMM MeM MMM, 88°M, 8.8e 88 888888 [‌888‌]
MM M MMMMMe MeMM MeMM, ee, 88e 88 8888 [‌888‌]
MM8Me M MMMMMe MeMM MeMM, 88°M, 8.8e 88 8888 [‌888‌]

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Meeee Meeeeeee-8-eeeeeeeeeee (888; M8=MM8Me, M8=M):[‌888‌]

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