In contrast to the considerable progress in the development of methodologies for amide bond formation in amines (i.e., primary amines, secondary amines, anilines), the development of direct N-acylation of less nucleophilic N-heterocycles and amides with carboxylic acids is still challenging. In this article, we describe the direct N-acylation of less nucleophilic heterocycles and amides with carboxylic acids promoted by the 4-(N,N-dimethylamino)pyridine N-oxide (DMAPO)/di-tert-butyl dicarbonate (Boc2O) system. The new one-pot method, which does not involve pre-activation of substrates, enables the direct N-acylation of a wide variety of nitrogen nucleophiles such as indole, carbazole, pyrrole, pyrazole, lactam, and anilide with carboxylic acids in high yield. This method also enables one-pot direct synthesis of bulky N-acyl heterocycles starting from a wide variety of less nucleophilic N-heterocycles and sterically hindered α-fully substituted carboxylic acids. Recently, we have also successfully developed a direct and selective N1-acylation of indazole by utilizing this method. In addition, a new synthesis of N1-functionalized alkyl indazoles utilizing N1-acyl indazoles as starting materials was achieved. The new protocol is useful for the selective synthesis of structurally diverse N1-functionalized alkyl indazoles, which are difficult to synthesize by other methods such as the Mitsunobu reaction and classical SN2 alkylation of indazole. Our protocol is also amenable to one-pot direct N-acylation of sulfoximines and can be carried out under mild reaction conditions. Furthermore, we demonstrated a simple and practical synthesis of N-acyl oxazolidinones which can then be used in various asymmetric transformations. The new method exhibits excellent functional group tolerance and broad substrate scope. As the present method is practical, operationally simple, and scalable, it should find wide applications in both academic and industrial laboratories.
Atsushi Umehara (Wed,) studied this question.