Zinc Binding Enhances the S _{<i> <b>N</b> </i>} Ar Route to GSK332

The route and process for the penultimate intermediate toward an mTOR inhibitor GSK332 in GSK’s respiratory portfolio is described. It relies on a heterocycle formation from a crystalline sodium ketoester enolate and an amidine derived from Pd-catalyzed cyanation of an azaindole. The final step involves an S N Ar reaction through selective activation by a hindered sulfonyl chloride and Lewis acid activation to accelerate the rate.