S. Gronowitz, A. Hörnfeldt
2004
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Abstract
The reaction of thiophene in chloroform with a dilute solution of elemental fluorine in helium at 63° C gives a mixture of 2-fluorothiophene (663%) and 3-fluorothiophene (343%) and is thus the least selective of the electrophilic halogenation reactions. The best method for the preparation of fluorothiophenes consists in the reaction of thienyllithium derivatives prepared by metalation of thiophenes or halogen–metal exchange with perchloryl fluoride. During recent years other electrophilic fluorinating reagents are developed. 2-Fluorothiophene is obtained in low yield through reaction with N-fluoroquinuclidinium fluoride. Nitration of 2-fluorothiophene and 3-fluorothiophene with nitric acid in acetic anhydride are good methods for the preparation of 2-fluoro-5-nitrothiophene and 3-fluoro-2-nitrothiophene. Since fluorine does not interfere in the metalation or in the halogen–metal exchange reactions, an alternative route to prepare substituted 2- and 3-fluorothiophenes is possible. The substituents so introduced can be modified. Also thiophenes with more complicated side chains can be chlorinated by elemental chlorine in chloroform at room temperature, as is demonstrated by the recent preparation of 3-trifluoroacetylamino-3-(2,5-dichlorothien-3-yl) propionic acid from the parent trifluoroacetylaminothienylpropionic acid.