Abstract
Small, strained rings have rigid, defined conformations and unique electronic properties. For these reasons, many groups seek to use these subunits to form biologically active molecules. We report a generally applicable approach to attach small rings to a wide range of aromatic compounds by palladium-catalyzed α-arylation of cyclopropyl, cyclobutyl and azetidinyl esters. The direct α-arylation of cyclopropyl esters and cyclobutyl esters is achieved in high yield by ensuring that the rate of coupling exceeds the rate of Claisen condensation. The α-arylation of azetidines is achieved without ring opening of the strained saturated heterocycle by conducting the reactions with an azetidine derivative bearing a benzyl protecting group on nitrogen. Mechanistic studies show that the α-arylation of small rings is challenging because of the weak acidity of α C-H bond (cyclopropanes), strong sensitivity of the strained esters to Claisen condensation (cyclobutatanes), or facile decomposition of the enolates (azetidinyl esters).
Highlights
Small, strained rings have rigid, defined conformations and unique electronic properties
The lower acidity of cyclopropyl esters and the greater electrophilicity of cyclopropyl and cyclobutyl ester carbonyl groups, relative to those of unstrained esters, cause Claisen condensation to compete with coupling
Ester derivatives that form the enolates in high yield, conditions to generate the enolates without condensation, catalysts with high activity to outcompete competing processes, and azetidine derivatives that resist ring opening are needed
Summary
Small, strained rings have rigid, defined conformations and unique electronic properties For these reasons, many groups seek to use these subunits to form biologically active molecules. We report a generally applicable approach to attach small rings to a wide range of aromatic compounds by palladium-catalyzed α-arylation of cyclopropyl, cyclobutyl and azetidinyl esters. The propensity of azetidines protected with typical carbamate substituents makes the enolates of such azetidines unstable To overcome these challenges, ester derivatives that form the enolates in high yield, conditions to generate the enolates without condensation, catalysts with high activity to outcompete competing processes, and azetidine derivatives that resist ring opening are needed. The synthesis of three biologically relevant molecules containing small rings demonstrates the value of these valuable αarylations
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