The Clauson-Kaas pyrrole synthesis under microwave irradiation
Kelsey C. Miles, Sunshine M. Mays, Benjamin K. Southerland, Tyler J. Auvil,
and Daniel M. Ketcha*
Department of Chemistry, Wright State University, Colonel Glenn Hwy,
Dayton OH 45435, USA
E-mail: daniel.ketcha@wright.edu
Dedicated to the memory of Professor R.O. Hutchins
Abstract
The Clauson-Kaas pyrrole synthesis involving the reaction of primary amines with 2,5- dialkoxytetrahydrofurans is traditionally carried out in refluxing acetic acid (AcOH), whereas extension to less activated nitrogen nucleophiles often necessitates the use of acidic promoters. It is now reported that the preparation of N-substituted pyrroles can be effected under microwave conditions (10 min – 30 min) using acetic acid or water without additional catalysts.
Keywords: Clauson-Kaas, microwave-assisted, N-substituted pyrroles, green
Introduction
The reaction of primary amines with 2,5-dialkoxytetrahydrofurans in refluxing acetic acid (AcOH) to afford N-substituted pyrroles was first introduced by Clauson-Kaas in 1952.1 The extension of this process to less nucleophilic nitrogen inputs such as amides2,3 and sulfonamides4 demonstrated the wide scope of this method, however longer reaction times were often required due to reduced reactivity. To overcome this impediment, a variety of acidic promoters such as phosphorus pentoxide,5 thionyl chloride,6 and 4-chloropyridinium hydrochloride7 have been employed. Moreover, the successful application of microwave heating to the mechanistically related Paal-Knorr cyclizations of hexane-2,5-dione (neat,9 in AcOH10 or on MK1011) prompted examinations of the use of microwaves to expedite the Clauson-Kaas reaction.
Török12 initially described the microwave assisted synthesis of pyrroles using montmori- llonite K-10 under solvent-free conditions (2-6 min, 100 oC). However, while aromatic and primary aliphatic amines afforded practically quantitative yields of the expected pyrroles with no by-product formation, in the case of amides successive cyclocondensation processes were found to predominate affording the corresponding N-acylindoles and -carbazoles in addition to the desired pyrroles. These authors later reported that by lowering the reaction temperature to 80 oC
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