Abstract
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).
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Reference48 articles.
1. de Meijere, A., et al. Topics in Current Chemistry Vol. 207. p. 3 (Springer-Verlag, Berlin, 2010).
2. Talete, T. T. The “cyclopropyl fragment” is a versatile player that frequently appears in preclinical/clinical drug molecules. J. Med. Chem. 59, 8712–8756 (2016).
3. Seiser, T., Saget, T., Tran, D. N. & Cramer, N. Cyclobutanes in catalysis. Angew. Chem. Int. Ed. 50, 7740–7752 (2010).
4. Antermite, D., Degennaro, L. & Luisi, R. Recent advances in the chemistry of metallated azetidines. Org. Biomol. Chem. 15, 34 (2017).
5. Richard, D. T., MacCoss, M. & Lawson, A. D. G. Rings in drugs. J. Med. Chem. 57, 5845–5859 (2014).
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