jo025661o_si_001.pdf (871.08 kB)
Synthesis of 2‘-Substituted 4-Bromo-2,4‘-bithiazoles by Regioselective Cross-Coupling Reactions
journal contributionposted on 2002-07-11, 00:00 authored by Thorsten Bach, Stefan Heuser
The synthesis of the title compounds (1) was achieved in two steps starting from readily available 2,4-dibromothiazole (2). In a regioselective Pd(0)-catalyzed cross-coupling step, compound 2 was converted into a variety of 2-substituted 4-bromothiazoles 3 (10 examples, 65−85% yield). Alkyl and aryl zinc halides were employed as nucleophiles to introduce an alkyl or aryl substituent. The Sonogashira protocol was followed to achieve an alkynyl-debromination. Bromo−lithium exchange at carbon atom C-4 and subsequent transmetalation to zinc or tin converted the 4-bromothiazoles 3 into carbon nucleophiles which underwent a second regioselective cross-coupling with another equivalent of 2,4-dibromothiazole (2). The Negishi cross-coupling gave high yields of the 2‘-alkyl-4-bromo-2,4‘-bithiazoles 1a−g (88−97%). The synthesis of the 2‘-phenyl- and 2‘-alkynyl-4-bromo-2,4‘-bithiazoles 1h−j required a Stille cross-coupling that did not proceed as smoothly as the Negishi cross-coupling (58−62% yield). The title compounds which were accessible in total yields of 38−82% are versatile building blocks for the synthesis of 2,4‘-bithiazoles.