Late-Stage C(sp2)–C(sp3) Diversification via Nickel Oxidative Addition Complexes

Carlota Odena^1,3, María Lourdes Linares⁴, Nahury Castellanos-Blanco¹, Ryan T. McGuire¹, Jose Manuel Alonso⁴, Alejandro Diéguez⁵, Eric Tan⁵, Jesús Alcázar⁴, Peter Buijnsters⁵ Santiago Cañellas⁴ and Ruben Martin^1,2

• ¹Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology, Av. Països Catalans 16, 43007 Tarragona, Spain
• ²ICREA, Passeig Lluïs Companys 23, 08010 Barcelona, Spain
• ³Department de Química Analítica i Química Orgànica, Universitat Rovira i Virgili, c/ Marcel·lí Domingo 1, 43007 Tarragona, Spain
• ⁴Janssen Research and Development, Janssen-Cilag, S. A. c/ Rio Jarama 75, 45007 Toledo, Spain
• ⁵Medicinal Chemistry, Janssen Pharmaceutica, N. V. B-2340 Beerse, Belgium

Nickel catalysis has emerged as a powerful technique for streamlining the access to exceedingly complex organic molecules from simple precursors. However, nickel-catalyzed cross-couplings with advanced synthetic intermediates still remain a considerable challenge. Herein, we describe a technique based on the utilization of nickel oxidative addition complexes (Ni-OAC) of drug-like molecules as a platform to rapidly and reliably generate lead candidates with enhanced C(sp3) fraction. The potential of Ni-OACs to access new chemical space has been assessed in three different C(sp2)–C(sp3) bond-forming events without recourse to specialized ligand backbones. Reactions with Ni-OACs proceed under exceptionally mild conditions and with improved generality when compared to nickel-catalyzed reactions. The development of an automated process for forging C(sp2)–C(sp3) architectures further illustrates the robustness and generality of Ni-OACs, thus offering a new gateway to expedite the design-make-test-analyze (DMTA) cycle in drug discovery

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