Repurposing Mander's reagent for the first direct carbonyl deoxycyanation: Synthesis of oxoalkenenitriles from 1,3-diketones

Abstract

The deoxycyanation of ketones is an uncommon reaction. Recently, we demonstrated that alkyl cyanoformates, such as methyl cyanoformate (Mander's reagent) or ethyl cyanoformate, can perform deoxycyanation on 1,3-diketones to deliver oxoalkenenitriles directly. This represents a significant departure from the typical reactivity of these reagents, which are predominantly used for the synthesis of β-ketoesters (α-acylation). By transitioning from lithium bases to amine-based bases, the selectivity of the acylation shifts from carbon to oxygen, yielding an enol carbonate intermediate. Density Functional Theory (DFT) investigations and in vitro experiments corroborate the synthetic outcome, namely, the synthesis of oxonitriles via deoxycyanation. The reaction mechanism was studied, revealing a series of sequential additions and eliminations consistent with the mechanistic proposal for the generation of a major byproduct, which poses one of the main drawbacks of this method. Although this approach was proven to be non-general, it represents the first direct synthesis of oxoalkenenitriles through a deoxycyanation process, thereby deviating from the conventional C-selective applications of alkyl cyanoformates.