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Efficient Copper Catalyzed Multi-component Synthesis of N-acyl amidines via Acyl Nitrenes

preprint
submitted on 11.07.2019 and posted on 12.07.2019 by K.M. van Vliet, Lara H. Polak, Maxime A. Siegler, J.I. van der Vlugt, Célia Fonseca Guerra, Bas de Bruin
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 3-component reaction of aryl acetylenes, amines and easily accessible 1,4,2-dioxazol-5-ones to N-acyl amidines, generating CO2 as the only by-product. 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 non-aromatic dioxazolones, [Cu(OAc)(Xantphos)] is a superior catalyst for this transformation, leading to full substrate conversion within 10 minutes. 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 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 does not only provide a new, practical and direct route to N-acyl amidines, but also represents a new type of
C-N bond formation.

Funding

Netherlands Organization for Scientific Research (NWO TOP Grant 716.015.001)

History

Email Address of Submitting Author

b.debruin@uva.nl

Institution

University of Amsterdam

Country

Netherlands

ORCID For Submitting Author

0000-0002-3482-7669

Declaration of Conflict of Interest

No conflicts of interest

Version Notes

First submission

Exports