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

Kaj M. van Vliet, Lara H. Polak, Maxime A. Siegler, Jarl Ivar van der Vlugt, Célia Fonseca Guerra, Bas de Bruin

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)15240-15249
Number of pages10
JournalJournal of the American Chemical Society
Volume141
Issue number38
Early online date29 Aug 2019
DOIs
Publication statusPublished - 25 Sep 2019

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Amidines
Copper
Catalysts
Organometallic Compounds
Alkynes
Organometallics
Substrates
Acetylene
Amines
Byproducts
Air
Derivatives

Cite this

van Vliet, Kaj M. ; Polak, Lara H. ; Siegler, Maxime A. ; van der Vlugt, Jarl Ivar ; Guerra, Célia Fonseca ; de Bruin, Bas. / Efficient Copper-Catalyzed Multicomponent Synthesis of N-Acyl Amidines via Acyl Nitrenes. In: Journal of the American Chemical Society. 2019 ; Vol. 141, No. 38. pp. 15240-15249.
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abstract = "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.",
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Efficient Copper-Catalyzed Multicomponent Synthesis of N-Acyl Amidines via Acyl Nitrenes. / van Vliet, Kaj M.; Polak, Lara H.; Siegler, Maxime A.; van der Vlugt, Jarl Ivar; Guerra, Célia Fonseca; de Bruin, Bas.

In: Journal of the American Chemical Society, Vol. 141, No. 38, 25.09.2019, p. 15240-15249.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Efficient Copper-Catalyzed Multicomponent Synthesis of N-Acyl Amidines via Acyl Nitrenes

AU - van Vliet, Kaj M.

AU - Polak, Lara H.

AU - Siegler, Maxime A.

AU - van der Vlugt, Jarl Ivar

AU - Guerra, Célia Fonseca

AU - de Bruin, Bas

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AB - 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.

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