Direct Functionalization via C-H Activation of Heterocyclic Substrates

Synthetic protocols are now in place for a range of direct functionalizations with heterocyclic substrates, and the field is still expanding rapidly. This activity is matched by parallel computational studies, where in many cases the full catalytic cycle is considered. In the following, the discussion will focus on the computational understanding of the C-H activation step, but the importance of this step within the context of the overall catalytic cycle will also be discussed, where appropriate. 

The unusual C4-selective arylation of 2,3-disubstituted thiophenes reported by Itami and coworkers [43] has been the subject of two theoretical studies. 

Rate-limiting C—H activation Rate-limiting C—C coupling 

Gorelsky has modeled the C-H activation step in the direct arylation of both free and Cu(I)-bound azoles at a Pd(Ph)(K -OAc)(PMej) intermediate [37c]. These two reactions provide complementary regioselectivities, with reaction at C5 favored for the free azoles but C2-arylation favored in the presence of Cu(I) salts. With A-methylimidazole and oxazole, the formation of A-bound 

The Pd(OAc)2-catalyzed oxidative coupling of Af-methylimidazole (as a model for xanthines) with thiophene has been modeled by Hu, You, and coworkers 

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