Abstract
Imidazole N-oxides are attractive starting materials for the preparation of complex molecules containing an imidazole ring. Dipolar cycloaddition between 1,1-difluoroalkenes and imidazole N-oxides bearing a chiral auxiliary performed in the presence of oxygen or nitrogen nucleophiles was found to provide access to esters and amides bearing a 2-azaheteroaryl substituent at the α position of the imidazole ring as mixtures of diastereomers that, in most cases, are readily separable. This three-component reaction introduces a new tertiary or quaternary all-carbon stereocenter into the heterocyclic ring at a position originally occupied by hydrogen. Importantly, products containing a trifluoromethyl group attached to this stereocenter are readily available as well.
Highlights
An imidazole ring is present in the structure of a large number of natural products and biologically active substances [1,2,3,4]
Several classical methods of preparation of imidazole derivatives based upon five-membered ring construction have been and are still being actively developed [7,8,9,10,11,12,13]
Functionalization of a carbon–hydrogen bond in a preformed imidazole ring is a much less common approach, but it is an emerging synthetic strategy that relies upon either transition-metal-catalyzed processes or metal-free reactions [3,14,15,16]
Summary
An imidazole ring is present in the structure of a large number of natural products and biologically active substances [1,2,3,4]. Diastereoselective Formation of Quaternary Stereocenters in Imidazole N-Oxide Cycloaddition with Fluoroalkenes. We have developed a method for the functionalization of azines and azoles via cycloaddition of the respective N-oxides to 1,1-difluoroalkenes in the presence of nucleophiles, which allows for the preparation of structurally diverse esters and amides of acetic acids bearing a 2-azaheteroaryl substituent at the α position, that is, derivatives of bis(aryl)methanes [34,35].
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