C-H arylation of arenes without the use of directing groups is a challenge, even for simple molecules, such as benzene. We describe spatial anion control as a concept for the design of catalytic sites for C-H bond activation, thereby enabling nondirected C-H arylation of arenes at ambient temperature. The mild conditions enable late-stage structural diversification of biologically relevant small molecules, and site-selectivity complementary to that obtained with other methods of arene functionalization can be achieved. These results reveal the potential of spatial anion control in transition-metal catalysis for the functionalization of C-H bonds under mild conditions.
Catalytic systems for direct CÀ H activation of arenes commonly show preference for electronically activated and sterically exposed CÀ H sites. Here we show that a range of functionally rich and pharmaceutically relevant arene classes can undergo site-selective CÀ H arylation ortho to small alkyl substituents, preferably endocyclic methylene groups. The CÀ H activation is experimentally supported as being the selectivitydetermining step, while computational studies of the transition state models indicate the relevance of noncovalent interactions between the catalyst and the methylene group of the substrate. Our results suggest that preference for C(sp 2 )À H activation next to alkyl groups could be a general selectivity mode, distinct from common steric and electronic factors.
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