Cross-coupling methods have revolutionized organic synthesis over the last decades. However, one of the key challenges is the incorporation of C(sp³)-rich fragments. Selective C(sp³)–H chlorination has emerged as an alternative yet complementary strategy to traditional cross-coupling methods for the construction of C(sp³)–C(sp²), C(sp³)–C(sp³), C(sp³)–X bonds from reactive chloride synthons. Our current research utilizes chemoinformatic tools to discover the best C(sp³)–H chlorination methods amenable to the selective functionalization of medicinal building blocks for downstream derivatization. The goal is to leverage the ubiquity of heterobenzylic C(sp³)–H in pharmaceutical feedstocks to significantly increase the three-dimensional character and chemical space coverage of cross-coupled products. Several C(sp³)–H chlorination methods have been reported in the literature targeting aliphatic and benzylic C–H bonds, and to a lesser extent heterobenzylic C–H bonds. Rather than developing unique procedures targeting nitrogen heterocycles, a library of alkylated heteroarenes was subjected to published chlorination chemistries to uncover substrate scope gaps and reactivity trends. After validating the best chlorination approaches for model substrates, pharmaceutical building blocks were subsequently subjected to a subset of known chlorination methods to generate intermediates with at least two distinct reactivity vectors: the preexisting aryl functional handles (e.g. C–B(OH)₂, C–Cl, C–Br, C–COOH etc.) for conventional cross-couplings and the newly formed heterobenzylic C(sp³)–Cl bond for reductive cross-electrophile couplings or nucleophilic displacement. All possible cross-coupling products from each of the reactivity vectors present on the building blocks were enumerated and data science techniques were employed to assess the extent of new chemical space coverage. Robustness screens also revealed that several published C–H chlorination methodologies were compatible with functional groups relevant to medicinal chemistry. Future work involves leveraging preliminary results to generate a heterobenzylic C–H chlorination roadmap for predicting the most selective chlorination condition of heteroarenes as well as factors governing benzylic selectivity, e.g. functional group compatibility, steric and/or electronic effects.

Dr. Shane W Krska

Distinguished Scientist, Merck & Co Inc

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