Sonogashira coupling reaction heterocycle synthesis

The Sonogashira reaction is of considerable value in heterocyclic synthesis. Heteroaryl halides like bromooxazoles are viable substrates for the Pd-catalyzed cross-coupling reactions with terminal acetylene in the presence of Pd/Cu catalyst. In 1987, Yamanaka s group described the Pd-catalyzed reactions of halothiazoles with terminal acetylenes [50]. Submission of 4-bromo- (72) and 5-bromo-4-methyloxazoles (73) to the Sonogashira reaction conditions with phenylacetylene led to the expected acetylenes (74 and 75). 

Many cascade reactions, including the reaction between X—H and alkyne, have been reported. A Sonogashira coupling-cyclization cascade (e.g.. Scheme 19.66) is an especially good combination for heterocycle synthesis from haloarenes bearing a nucleophilic functionality at the 2-position. In this section, a quite limited number of useful cascade reactions, especially those including the latest frontiers of modern organic chemistry, are presented. 

Also exploiting an intramolecular C—S bond formation, Bryan et al. extended their investigation of gem-dihalovinylarene substrates in the synthesis of heterocycles to encompass a thiol analogue (Scheme 34.38, disconnection D-2). The combination of an unusual palladium-catalyzed S-alkenylation with a second cross-coupling process, such as a Suzuki, Heck, or Sonogashira reaction led to diversely functionalized benzothiophenes such as 67, produced in excellent yield (Scheme 24.40) [132], Routes incorporating a tandem carbonylation step [133] and a direct arylation [117] process have subsequently been reported. 

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