Synthesis of N,N-Diethylbenzamides via a Nonclassical Mitsunobu Reaction

Abstract

The use of the Mitsunobu reaction for the synthesis of N,N-diethylbenzamides affords ortho-, meta-, and para-substituted benzamides containing both electron-donating and electron-withdrawing groups. While the preparation of numerous functional groups has been efficiently demonstrated employing the Mitsunobu reaction, our methodology represents the first application of the Mitsunobu reaction for the construction of benzamides using benzoic acid and amine starting materials. Moreover, this synthetic transformation is believed to proceed via a nonclassical mechanism involving the existence of an acyloxyphosphonium ion.

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GRAPHICAL ABSTRACT

Keywords:

• Acylation
• amides
• Mitsunobu reaction

ACKNOWLEDGMENTS

We gratefully acknowledge financial support from the National Institute of Allergy and Infectious Diseases (R15, AI084075-02) and the donors of the American Chemical Society Petroleum Research Fund (PRF 52168-UR1). Additionally, we thank the National Science Foundation, as part of its Major Research Instrumentation (MRI) Program (CHE-1126231), for the acquisition of a JEOL ECS-400 nuclear magnetic resonance spectrometer. Accurate mass measurements were performed by Dr. William Boggess of the Mass Spectrometry and Proteomics Facility at the University of Notre Dame.

Notes

^a Products obtained were >95% pure by ¹H and ¹³C NMR.