One-carbon ring expansion of pyrroles and indoles to 3-arylazinium salts Ben W. Joynson 1 , Graham R. Cumming 2 and Liam T. Ball 1 1 University of Nottingham, UK, 2 Eli Lilly and Co., Spain Aromatic heterocycles are ubiquitous in biologically and medicinally active compounds. Two particularly common classes of heterocycle are based on the five-membered pyrroles and their six-membered congeners, pyridines. Despite differing by only a single carbon atom, five-membered and six-membered heterocycles possess distinctly different chemical and physicochemical properties. The ability to achieve late-stage conversion of pyrroles or indoles directly to the corresponding pyridine or quinoline would therefore enable facile modulation of a molecule’s biological activity and would represent a powerful tool for significantly expanding chemical space. Despite its conceptual appeal, there are few examples of direct transformation of the heteroaromatic skeleton of five-membered heterocycles to their six-membered counterparts and the few reported examples are limited in scope. 1,2 We have developed a robust method for the one-carbon ring expansion of pyrroles and indoles that employs arylchlorodiazirines as carbene precursors. Diazirines are more stable than diazo compounds and therefore less electron-withdrawing groups, such as aryl groups, could be introduced. Unlike previous work, a range of substitution patterns, notably 2- and 3-unsubstituted indoles are tolerated. 3 By employing benzyl protected substrates, our methodology avoids unproductive side-reactions to deliver the corresponding azinium salts in good to excellent yields. Investigations of substrate scope reveal the impact of both steric and electronic factors on reaction efficiency and a comprehensive robustness screen with medicinally relevant functional groups illustrates the potential for application to complex drug-like molecules.
References 1. Ciamician, G.L., Dennstedt, M., Dtsch. Chem. Ges. , 1881, 14 , 1153-1163 2. Mortén, M., Hennum, M., Bonge-Hansen, T., Beilstein J. Org. Chem. , 2015, 11 , 1944-1949 3. Dherange, B. D. et al. , Am. Chem. Soc ., 2021, 143 , 11337-11344
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