Amide synthesis from alcohols and amines by the extrusion of dihydrogen

The prevalence of amide functionality in organic chemistry has prompted the development of numerous protocols for amide synthesis. Nevertheless, amidation procedures reported to date require stoichiometric amounts of reagents and consequently generate equimolar amounts of by-products. In contrast, the direct amidation of amines with alcohol with concomitant liberation of 2 equiv of dihydrogen is an environmentally benign strategy to prepare molecular entities containing amide bonds (Scheme 1). During the course of this research, a new catalytic system that successfully promotes the direct synthesis of amides from alcohols and amines was discovered. (Chemical Equation Presented) The initial experiment involved 2-phenylethanol, benzylamine, and 5% catalyst generated in situ from Ru(PPh₃)₃Cl₂, imidazolium salt A, and potassium tert-butoxide (Fig. 1). The reaction produced N-benzyl 2-phenylacetamide in 15% yield as well as a substantial amount of unreacted alcohol and amine (Table 1, entry 1). Upon replacement of ruthenium precatalyst with Ru(COD)Cl₂ and without the phosphine ligand, amidation failed to occur (entry 2). However, the use of monodentate ligands having a larger cone angle slightly improved the yield of the amide (entries 3-6). (Table Presented) Alternatively, variation of carbene precursors has a remarkable influence on the amidation (entries 8-14), with precursor D providing the best result. Subsequently, precursor D was used to explore variation of phosphine ligands (entries 15-19). Although PCyp₃ gave the best yield (entry 18), the more stable and crystalline HBF₄ salt (entry 19) was used to examine the scope and limitation of the method. A variety of primary alcohols reacted with primary amines under optimized conditions to produce the corresponding secondary amides in very satisfactory yields (Table 2, entries 1-9). Noticeably, the unhindered alcohols and amines delivered the amide in excellent yield (entries 1 and 2). However, aniline and secondary amines were unreactive at 110°C, although raising the temperature to 163°C afforded amide, albeit in moderate yield (entries 10 and 11). Presumably, the amidation sequence does not involve an intermediate ester but proceeds through an aldehyde that is coordinated to the metal (Scheme 2). The hemiaminal generated upon introduction of amine also remained attached to the metal. The subsequent β-hydride elimination completes the catalytic cycle and delivers the amide without concomitant release of aldehyde or hemiaminal. (Chemical Equation Presented)