title: Efficient transamidation of primary carboxamides by in situ activation with N,N-dialkylformamide dimethyl acetals.
abstract: Two protocols for the transamidation of primary amides with primary and secondary amines, forming secondary and tertiary amides, respectively, are described. Both processes employ N,N-dialkylformamide dimethyl acetals for primary amide activation, producing N'-acyl-N,N-dialkylformamidines as intermediates, as widely documented in the literature. Although the latter intermediates react irreversibly with amines by amidinyl transfer, we show that in the presence of certain Lewis acid additives efficient acyl transfer occurs, providing new and useful methods for amide exchange. In one protocol for transamidation, the N'-acyl-N,N-dialkylformamidine intermediates are purified by flash-column chromatography and the purified intermediates are then treated with an amine (typically, 2.5 equiv) in the presence of scandium triflate (10 mol %) in ether to form in high yields the products of transamidation. In a second procedure, N'-acyl-N,N-dialkylformamidines are generated in situ and, without isolation, are subjected to transamidation in the presence of zirconium chloride (0.5 equiv) and an amine (typically 2 equiv). A variety of different primary amides and amines are found to undergo efficient transamidation using the methods described.
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Dineen
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Zajac
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Myers
mesh_terms: D000080:Acetals / Q000737:chemistry*; D000577:Amides / Q000737:chemistry*; D002712:Chlorides / Q000737:chemistry; D008745:Methylation; D015394:Molecular Structure; D015040:Zirconium / Q000737:chemistry
chemical_list: D000080:Acetals; D000577:Amides; D002712:Chlorides; D015040:Zirconium; C429984:zirconium chloride