Cross-coupling in a flow microreactor: space integration of lithiation and Murahashi coupling.

Cross-coupling reactions of aryl metals with organic halides serve as a powerful method for carbon–carbon bond formation in the synthesis of a variety of functional materials and biologically active compounds. Aryl–boron, aryl–silane, aryl–tin, aryl–zinc, and aryl–magnesium compounds are often used for these cross-coupling reactions because these organometallic compounds are relatively stable. In contrast, the use of less stable but more reactive aryllithium compounds in cross-coupling has been rather limited, 3] although many aryl metals including arylboron compounds are often prepared from aryllithium compounds. In 1979 Murahashi et al. reported pioneering work on the palladium-catalyzed cross-coupling of organolithium compounds with organic halides. Since then, to the best of our knowledge, additional studies have not been reported, one of the major reasons being that X–Li exchange of ArX with BuLi, which is one of the most powerful methods for generating ArLi, leads to the formation of BuX. However, ArLi reacts with BuX if the subsequent coupling is slow. This is indeed the case. Usually, cross-coupling reactions take hours to reach completion at room temperature or higher temperatures, whereas reactions of ArLi with alkyl halides such as BuX are complete within minutes at 0 8C. If this problem is solved, the combination of X–Li exchange and Murahashi coupling will then enable the cross-coupling of two aryl halides, hence providing a powerful method in organic synthesis [Eq. (1)]. 6] Though tBuLi does not suffer from this problem, the use of two equivalents of highly reactive tBuLi is not suitable for large-scale laboratory synthesis and industrial production.