Nickel-mediated alkyl-, acyl-, and sulfonylcyanation of [1.1.1]propellane

The replacement of traditional functional groups with polycyclic scaffolds has been increasingly rewarding in medicinal chemistry programs. Over the decades, 1,3-disubstituted bicyclo[1.1.1]pentanes (BCPs) have demonstrated potential for being competent bioisosteres for aryl, alkyl, and alkynyl substructures. Although highly desired, mild and versatile synthetic methods to access synthetically valuable BCP-containing building blocks remain limited. Herein, a versatile way to access bridgehead substituted BCP nitriles, a useful BCP building block, is described, enabled by the unexpected selectivity of nickel in the multi-component radical cyanation. Commodity materials, including carboxylic acids, amines, sulfonyl chlorides, and alkyl chlorides, are engaged to provide a broad spectrum of substituted BCP nitriles in a single-step, multi-component fashion. [Display omitted] •A general single-step protocol to various substituted bicyclo[1.1.1]pentyl nitriles•Radicals of disparate steric and electronic characters can be engaged•Widely available starting materials are used to ensure broad applicability•Excellent selectivity of the nickel catalyst enables selective cyanation of BCP radicals The ever-increasing interest in “Escape from Flatland” has prompted people to seek bioisosteres to replace the ubiquitous phenyl rings in pharmaceuticals. Bicyclo[1.1.1]pentane (BCP), a rigid three-dimensional core, has stood out as a promising candidate. However, limited availability of BCP building blocks and lengthy synthetic routes required to incorporate BCP are hampering early discovery efforts. In this study, we developed a multi-component approach to synthesizing a wide variety of BCP nitriles from the most accessible BCP precursor, [1.1.1]propellane, enabled by nickel/photoredox dual catalysis. Due to the superior selectivity of the nickel catalyst in radical cyanation, alkyl-, acyl-, and sulfonylcyanation were successfully performed on [1.1.1]propellane using commercially available materials. We believe that the broad scope of this transformation, together with the synthetically versatile cyano handle, could facilitate the involvement of BCP in drug discovery research. The challenge of accessing useful building blocks for bicyclo[1.1.1]pentane has hindered its use as a promising bioisostere for para-disubstituted phenyl, alkynyl, and tert-butyl groups in drug discovery research. A simple and general method has now been developed for synthesizing versatile bicyclo[1.1