Late-Stage Sequential Functionalization of Arenes and Drug Molecules to Access Biaryls and Azahelicenes

Late-stage functionalization of complex substrates represents an important strategy for creating a diverse molecule library without the need for <i>de novo</i> synthesis. Although conventional cross-couplings have developed as a practical access to many (hetero)biaryls, late-stage directed arylation provides a more appealing and cost-effective platform to make these scaffolds. Given the economic and environmental benefits associated with sequential metal catalysis, the selective construction of polyfunctional (hetero)biaryl analogues by complementary multicatalytic sequential C-H halogenation/arylation/cross-coupling sequences is described, which starts from readily accessible (hetero)arenes and takes advantage of inherently present functional groups to guide the multiple late-stage functionalizations. The approach is compatible with sensitive polar and delicate functionalities to produce a diverse range of products that would be difficult to access by traditional methods. In particular, the application of this method has been demonstrated in the late-stage functionalization of many structurally complex natural products and drug/druglike molecules, including the bioactive compounds vismodegib, PH089, and diazepam, as well as in the streamlined synthesis of challenging azahelicenes.