Direct fluorination of the pymole ring with electron-withdrawing gtmym, such as, -CHO, -COR, -COOR, -CON&, using xctm difluoride under mild conditions leads to the comsponding flwtopymAcs in 2544% yields. It was found that fluorination takes place only at the u-position of the pyrrole even when the @position h also free. In connection with our syntheses of fluorinated porphobilinogen (PBG) 1 and hydroxymethylbilane (HMB) 2 as potential inhibitors of the enzymes PBG deaminase and uro'gea III cosynthase respectiv~ly,~~~ we required an efficient method for preparing fluoropyrrole compounds. Although it has been known for some time that fluorine often has profound and unexpected effects on biological activity, general methods for the direct introduction of fluorine into pyrrole rings,3 which are frequently found in natural products, -are not available, due to the high reactivity of pyrroles towards electrophiles and the oxidizing power of electrophilic fluorinating reagents, nor can fluorine be introduced into the pyrrole ring by the classic Balx-Schiemann reaction.4 We report herein the first preparation of fluoropyrroles by direct fluorination of the pyrrole ring witbout N-H protection, using xenon difluoride as fluorinating reagent A P * PA PA p A=CH,COOH. P=CH&I-12CGGH As illustrated in Scheme 1. a series of a-free substituted pyrrole compounds 3a-3I were reacted with xenon difluoride to give the expected products 4a-41. In a typical experiment, the a-unsubstituted pyrrole was dissolved in degas& acetonitrile or dichlorometbane under a nitrogen atomospkre and xenon difbtoride (1.2 equiv) added with stirring at OยฐC. The resulting mixture was warmed gradually to room temperature. Slow Xe gas evolution was observed and the reaction was monitored for the disappearance of xenon difluoride using XI-starch paper. The mixture was poured into water and extracted with dichloromethane. The extract was dried with anhydrous sodium sulfate and the solvent evaporated to give the crude product which was purified by chromatography on silica gel. The results are listed in
Table 1.