Practical and Efficient Synthesis of (E)-α,β-Unsaturated Amides Incorporating α-Aminophosphonates via the Horner-Wadsworth-Emmons Reaction

An efficient and practical procedure for the synthesis of (E)-α,β-unsaturated amides incorporating α-aminophosphonates, derived from readily accessible phosphonoacetamides, via the Horner-Wadsworth-Emmons (HWE) reaction was developed. The influence of reaction parameters, including base, solvent, and temperature, as well as the scope of the method with different aldehydes, was examined, affording the target compounds in good yields and with high (E)-selectivity. The required phosphonoacetamides were conveniently prepared through a Kabachnik-Fields reaction of aldehydes, benzylamine and dimethyl phosphite followed by hydrogenolytic cleavage of the N-Bn bond, acylation with bromoacetyl bromide, and a subsequent Arbuzov reaction. This HWE protocol provides straightforward access to a broad range of (E)-α,β-unsaturated amides incorporating α-aminophosphonates under mild conditions, offering valuable scaffolds with potential pharmacological relevance as anticancer agents.