The Development of Csp3–Csp2 Coupling Methodology
Medicinal chemistry programs often suffer synthetic limitations when single-step attachment of non-aromatic heterocycles to aryl (or heteroaryl) substrates (Csp3–Csp2) is desirable in a structure–activity relationship (SAR). Often, lengthy synthetic sequences are required with the consequences that the totality of the SAR space is not completely investigated. One promising approach is to extend the well-known Suzuki or Negishi coupling processes (Csp2–Csp2) to non-aromatic heterocycles and other Csp3 nucleophiles. The challenges include the low reactivity of Csp3-boronates compared with less versatile but more reactive organometallics and the potential for protodeboronation. Coupling of other Csp3 organometallics is limited to highly reactive species that require custom synthesis using air and moisture sensitive chemistry or multiple steps that are not amenable to parallel protocols or complex functionality. Recent progress on issues with Csp3 coupling, such as avoiding β-hydride elimination and moderating nucleophile reactivity, have been achieved with specific substrates after optimisation of the metal–ligand complex and reaction conditions. This chapter discusses methodology that has begun to address the current limitations and extend the scope of single step coupling technology to Csp3 centres with valuable pharmacophore elements.