Inhibition of Kornblum Reaction with Lithium Salts in S_N2 Reactions of Sulfonates and a Nucleophile Containing a Pyridine <i>N</i>-Oxide Moiety: Convergent and Selective Synthesis of an MRGPRX2 Antagonist

A critical step in the development of a convergent synthesis of an MRGPRX2 antagonist (<b>1</b>) was the S_N2 reaction with a highly functionalized lactamide electrophile and a unique difluoropiperidine nucleophile containing a pyridine <i>N</i>-oxide moiety. Initial reactions with sulfonate leaving groups exhibited superb stereoselectivity, but yields were very low due to side reactions originated from competitive Kornblum reactions of the pyridine <i>N</i>-oxide and the sulfonates. Markedly improved reaction profiles were achieved by including stoichiometric lithium triflate. NMR data provided insights into how the lithium cation impacted the pyridine <i>N</i>-oxide through coordination and attenuating its nucleophilicity, leading to the inhibition of the undesired Kornblum reactions. Our approach is highly relevant to preservation of the <i>N</i>-oxide, a structural motif known to several marketed products and emerging as an important class in drug discovery in nucleophilic substitutions. Application of this method enabled the production of the target (<b>1</b> and its HCl salt <b>1a</b>) up to multikilogram scale with high selectivity and in much improved yield.