Sonogashira synthesis aryl chlorides

Aryl iodides, bromides, and inflates are used for Sonogashira coupling. But so far few smooth reactions of aryl chlorides with alkynes have been reported. On the other hand, smooth coupling takes place with alkenyl chlorides. The Pd-catalyzed reaction of 1-alkynes with alkenyl chlorides, which are inert in many other Pd-catalyzed reactions, proceeds smoothly without special activation of the chlorides. For example, cw-l,2-dichloroethylene (31) can be coupled with 1-alkynes smoothly, and the coupling has wide synthetic applications, particularly for the synthesis of enediyne structures [30]. The reaction of 31 with two different 1-alkynes is extensively used for construction of highly strained enediyne structures present in naturally occurring anticancer antibiotics such as espermicin and calichemicin [31,32]. The asymmetric (Z)-enediyne 34 can be prepared by a one-pot reaction of 31 with two different 1-alkynes 32 and 33. Similarly the asymmetric ( )-enediyne 37 was obtained in a one-pot reaction of 1-alkynes 33 and 23 with 1,2-dichloroethylene 35. 

A similar strategy was applied in the synthesis of aryl-substituted 5-(3-indolyl)oxazoles 43. Here, propatgyl amides 5 were reacted with acid chlorides 4 in a modified Sonogashira cross-coupling I followed by the above described add-catalyzed cycloisomerization. The remaining methylene ketone was then transformed via Fischer indole synthesis with different aryl hydrazine hydrochlorides to form the indole ring (Scheme 24) (20110BC(9)8130). 

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