There is growing interest in the preparation of drug candidates that possess an increasing percentage of sp3 (alkyl) content. A series of new N-heterocyclic carbene (NHC) based Pd complexes has been created and evaluated in the Negishi cross-coupling of aryl- and heteroaryl chlorides and bromides with a variety of secondary alkylzinc reagents. With the optimized catalyst, Pd-PEPPPSI-IPent-Chloro the coupling proceeds with very minor isomerization of the position of the zinc centre (i.e., migratory insertion) in the final coupled product. Rationale is presented for how substituents on the NHC ring have such a profound impact on the selectivity of this useful chemical transformation. Finally, the scope of the reaction will be demonstrated in the preparation of alkyl-substituted 5- and 6-membered ring heterocycles of interest in drug discovery.

Selective Negishi coupling of secondary alkylzinc reagents: Strategy and catalyst design

248th National Meeting (2014)

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