DABCO-catalyzed esterification of N-pivaloyl-activated amides

Abstract

A previously elusive organocatalytic protocol for the esterification of amides is disclosed. DABCO (10 mol%) is identified as an effective catalyst for the esterification of N-pivaloyl amides. Although N-pivaloyl amides are nearly planar (amide bond twist (τ) = 4.54° and pyramidalization (χ_N = 6.39°)) and resonance stabilized, esterification is achieved with high efficiency. The developed protocol is generic, phenols, thiophenols, aliphatic alcohols, and thiols were identified as effective substrates. Furthermore, the reaction features a broad substrate scope and excellent functional group tolerance. To exemplify the practical applicability of the developed protocol, the esterification of bioactive natural products, pterostilbene and menthol, is demonstrated. In addition, a series of competitive experiments were conducted to establish the reactivity pattern of alcohols, thiols, and phenols, which could serve as selectivity principles for future synthetic design. Our findings signify a notable advancement in utilizing amides as versatile synthetic building blocks in organic synthesis under metal-free conditions.