Efficient Copper-Catalyzed Multicomponent Synthesis of N-Acyl Amidines via Acyl Nitrenes

Direct synthetic routes to amidines are desired, as they are widely present in many biologically active compounds and organometallic complexes. N-Acyl amidines in particular can be used as a starting material for the synthesis of heterocycles and have several other applications. Here, we describe a...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2019-09, Vol.141 (38), p.15240-15249
Main Authors: van Vliet, Kaj M, Polak, Lara H, Siegler, Maxime A, van der Vlugt, Jarl Ivar, Guerra, Célia Fonseca, de Bruin, Bas
Format: Article
Language:English
Subjects:
alkynes
amidines
amines
aromatic compounds
bioactive compounds
byproducts
carbon dioxide
catalysts
catalytic activity
chemical bonding
copper
heterocyclic compounds
organometallic compounds
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Summary:Direct synthetic routes to amidines are desired, as they are widely present in many biologically active compounds and organometallic complexes. N-Acyl amidines in particular can be used as a starting material for the synthesis of heterocycles and have several other applications. Here, we describe a fast and practical copper-catalyzed three-component reaction of aryl acetylenes, amines, and easily accessible 1,4,2-dioxazol-5-ones to N-acyl amidines, generating CO2 as the only byproduct. Transformation of the dioxazolones on the Cu catalyst generates acyl nitrenes that rapidly insert into the copper acetylide Cu–C bond rather than undergoing an undesired Curtius rearrangement. For nonaromatic dioxazolones, [Cu­(OAc)­(Xantphos)] is a superior catalyst for this transformation, leading to full substrate conversion within 10 min. For the direct synthesis of N-benzoyl amidine derivatives from aromatic dioxazolones, [Cu­(OAc)­(Xantphos)] proved to be inactive, but moderate to good yields were obtained when using simple copper­(I) iodide (CuI) as the catalyst. Mechanistic studies revealed the aerobic instability of one of the intermediates at low catalyst loadings, but the reaction could still be performed in air for most substrates when using catalyst loadings of 5 mol %. The herein reported procedure not only provides a new, practical, and direct route to N-acyl amidines but also represents a new type of C–N bond formation.
ISSN:0002-7863
1520-5126
1520-5126
DOI:10.1021/jacs.9b07140