Synthesis of Perfluoroalkyl Pyrroles and Thiophenes from Cyclopropanes

Significance

Demonstrated is the synthesis of substituted pyrroles and thiophenes via the deprotonation of alkyl-2-silyloxycyclopropanecarboxylates and reaction of the resulting ester enolates with isothiocyanates and carbon disulfide. The reaction proceeds via a facile (occurring already at –78 °C) anionic [1,3]-sigmatropic rearrangement to provide the ring-enlarged heterocyclic products. The starting materials are available from silyl enol ethers by rhodium-catalyzed reaction with methyl diazoacetate. The pyrrole-forming reactions occur seemingly smoothly, affording the products in reasonable yields despite the many steps involved in the mechanism. The only exception was tert-butyl isothiocyanate, which failed to react, presumably because of steric bulk. On the other hand, the thiophenes were obtained in poor to mediocre yields. Some further transformations on the thiophenes and pyrroles synthesized were performed, namely dethiomethylation by oxidation and treatment with i-PrMgCl and Stille cross-coupling with PhSnBu₃.

Comment

It is well-established that having fluorine atoms in molecules leads to new and sometimes dramatic changes in molecules especially in bioactivity properties (see Review below). The present approach offers a one-pot methodology to thiophenes and pyrroles, starting with fluorinated materials, as opposed to a late-stage fluorine introduction. The presented scope is poor, but the method offers an interesting alternative to access such compounds. The paper is well-written, but at times confusing in terms of schemes and the variety of different reactions performed. Based on this report, large-scale applications appear not to be imminent; however, the paper is presented in the spirit of the joy of exploring new vistas, as opposed to the current widely seen publications with the ubiquitous table of 15+ examples composed of trivial variation of starting material structural type.

Review

J. Wang, M. Sánchez-Roselló, J. L. Aceña, C. del Pozo, A. E. Sorochinsky, S. Fustero, V. A. Soloshonok, H. Liu Chem. Rev. 2014, 114, 2432–2506.