Nickel-catalyzed cross-electrophile coupling reactions represent a mild method for the formation of C(sp2)–C(sp3) bonds, which are commonly found in active pharmaceutical ingredients. Mn or Zn are the typical reductants of choice for these reactions, as their low cost and air tolerance offer practical advantages. However, the heterogeneous nature of Mn and Zn can pose mass-transfer challenges for large-scale batch manufacturing processes. Their heterogeneity can also impede flow chemistry, automated chemical synthesis that proceeds via solution dosing, and nanomole-scale high-throughput screening used in the discovery chemistry space. Furthermore, yield disparities are often observed between Mn and Zn, which suggests that the availability of additional reductants across a range of redox potentials would be beneficial. TDAE (tetrakis(dimethylamino)ethylene) is a homogeneous reductant that has been demonstrated for specific reductive coupling processes, albeit its performance in general Ni-catalyzed C(sp2)–C(sp3) cross-electrophile coupling has been poor compared to Mn and Zn. Herein, we first present a method that utilizes TDAE in conjunction with a cobalt co-catalyst to enable homogeneous Ni-catalyzed C(sp2)–C(sp3) cross-electrophile coupling. We then go on to prepare a series of redox-tuned homogeneous reductants based on the tetraaminoethylene scaffold. These reductants span 0.5V and offer practical advantages to TDAE in that they are easily isolable solids with greater to indefinite air stability. The reductants can be used in place of TDAE for C(sp2)–C(sp3) couplings between alkyl halide and aryl halide reaction partners. They are also demonstrated in C(sp2)–C(sp3) couplings between alkyl Katritzky salts and aryl halide reaction partners, wherein choice of redox-tuned reductant is matched with the electronic identity of the alkyl Katritzky salt (e.g. benzylic, primary, secondary) for optimal results. These reductants are now commercially available from MilliporeSigma.

New homogeneous reductant systems for nickel-catalyzed cross-electrophile coupling

ACS Spring 2022

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