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Tetrahedron Lett. 2016 Jun 1;57(22):2347-2350. Epub 2016 Apr 28.

Rapid cycloaddition of a diazo group with an unstrained dipolarophile.

Author information

1
Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
2
Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.

Abstract

The cycloaddition of a diazoacetamide with ethyl 4,4,4-trifluorocrotonate proceeds with k = 0.1 M-1s-1. This second-order rate constant rivals those of optimized strain-promoted azide- alkyne cycloadditions, even though the reaction does not release strain. The regioselectivity and a computational distortion/interaction analysis of the reaction energetics are consistent with the formation of an N-H…F-C hydrogen bond in the transition state and the electronic character of the trifluorocrotonate. Analogous reactions with an azidoacetamide dipole or with an acrylate or crotonate dipolarophile were much slower. These findings suggest a new strategy for the design of diazo-selective reagents for chemical biology.

KEYWORDS:

(E)-Ethyl 4,4,4-trifluorobut-2-enoate; 1,3-Dipolar cycloaddition; Diazo group; Hydrogen bond; Hyperconjugation

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