Telescoped Two-Step Deaminative Ni-Catalyzed C(sp 2 )–C(sp 3 ) Cross-Electrophile Coupling for Late-Stage Parallel Library Synthesis

Abstract A two-step deaminative C(sp2)–C(sp3) cross-electrophile coupling (XEC) protocol to enable late-stage parallel library diversification of medicinally relevant aryl halides is reported. In the first step, sodium pivalate facilitates the condensation of primary amines with pyryliums to enable the parallel synthesis of 2,4,6-triaryl-N-alkylpyridinium salts. In the second step, robust XEC conditions were developed to enable the use of telescoped N-alkylpyridinium salts. The utility of our two-step deaminative C(sp2)–C(sp3) XEC protocol for medicinal chemistry is demonstrated through the late-stage library diversification of the anticancer drug, trametinib, which proceeded with an 85% success rate. Several alkyl substrates that are challenging in deaminative C(sp2)–C(sp3) XEC, such as α-ester and β-quaternary substrates, were successfully coupled, exemplifying the generality of the reaction conditions. The utility of our XEC conditions is further showcased through the coupling of a diverse set of medicinally relevant aryl halides. Given the value of primary amines as a substrate pool and the importance of C(sp2)–C(sp3) bond-forming reactions in drug discovery, our two-step deaminative Ni-catalyzed C(sp2)–C(sp3) XEC protocol could find utility within the medicinal chemistry community. Furthermore, the conditions reported herein for parallel N-alkylpyridinium salt synthesis could enable the development of parallel synthesis-compatible protocols for new and existing deaminative transformations.