Fluorination of pyrroles

Wang, J. Scott, A.I. Fluorination of pyrrolic compounds with xenon difluoride. Tetrahedron Lett. 1994, 35, 3679-3682. 

Direct fluorination of pyrroles 5 without NH-protection can be performed with substrates bearing electron-withdrawing substituents, using xenon difluoride. The transformation gives substituted 2-fluoropyrroles 6 in moderate yields [7],... 

Direct fluorination of five-membered heterocyles gave products that were dependent on the heterocycle. For example, pyrrole yielded tar, whereas there was predominantly syn 1,4- addition of fluorine to furan (90G749). 

Unlike the nitrogen of pyrroles and the oxygen of furans, the sulfur of thiophenes does not significantly affect fluorine chemical shifts either inductively or as an electron donor. Thus, the fluorine chemical... 

Enantiopure fluorinated analogues of hematopoiphyrins have also been prepared through total syntheses. These preparations involve cyclocondensations with chiral derivatives of pyrroles (Figure 4.32). ... 

The fluorination of heterocyclic compounds with xenon difluoride has received much less attention. Pyridine reacts readily with xenon difluoridc in dichloromethane without a catalyst to form 2-fluoropyridine (35 %), 3-fluoropyridine (20 %) and 2,6-difluoropyridine (11 %).80 8-Hydroxyquinoline treated with xenon difluoride forms 5-fluoro-8-hydroxyquinoline at room temperature in 35% yield.80 Uracil reacts with xenon difluoride to give 5-fluorouracil in 10% yield.81 Only one example exists of a highly substituted pyrrole fluorinated with xenon difluoride in acetonitrile in 35% yield.82... 

A mixture of silver(I) fluoride and 2,2 -bipyridine replaces chlorine with fluorine in 1-chloro-octane in 86% yield after 45 minutes at 130°C.28 Some heterocyclic polychloro derivatives are also fluorinatcd by silver(I) fluoride. Thus, perfluoro(2,3,4,5-tetrahydropyridine) (1) and per-fluoro(3,4-dihydro-2//-pyrrole) are prepared from 2,2,6-trichloro-3,3,4,4,5,5-hexafluoro-2,3.4,5-tetrahydropyridine and 2,2,5-trichloro-3,3,4.4-tetrafluoro-3,4-dihydro-2//-pyrrole by reaction with silver(l) fluoride at room temperature.31 Since the fluorination of 2,2,5-trichloro-3,3,4,4-tetrafluoro-3,4-dihydro-2//-pyrrole with silver(l) fluoride is slow, recycling is necessary.31... 

Double substitution of fluorine with a primary amine has been used for the preparation of pyrrole derivative 5.8fi... 

Unlike the nitrogen of pyrroles and the oxygen of furans, the sulfur of thiophenes does not significantly affect fluorine chemical shifts either inductively or as an electron donor. Thus, the fluorine chemical shifts of fluorothiophenes are generally in the region of electron-rich fluo-robenzenes (Scheme 3.92). Moreover, in this heterocycle, fluorines at the 2-position are slightly shielded compared to those at the 3-position. 

The next stage of synthesis was the replacement of pyrrole hydrogen atoms by fluorine atoms. The zinc complex was fluorinated by cobalt fluoride according to the appropriate technique [44, 46], The target product was extracted from reaction products by chromatographic separation in a column filled with neutral aluminum oxide. 

The direct fluorination of thiophene, 1-methylpyrrole, pyrrole, and furan with dilute elemental fluorine (5%) at low conversion (ca. 5%) has been reported.1-Methyldihydropyrrole and thiophene give mixtures of products substituted by fluorine at positions 2 and 3 for thiophene the 2-position and for 1-methylpyrrole the 3-position are favored. Furan undergoes addition reactions and pyrrole produces only tars, even at — 65 C. 

An indole 9 and antipyrine (11) were fluorinated to give the respective fluoro derivatives 10 and 12. Attempts to fluorinate furan, pyrrole, N-benzylpyrrole, ethyl 2-thienylacetate, and methyl 2-thiophenecarboxylate with various salts were all unsuccessful owing to excessive tar formation (90JA8563). Porphyrins are efficiently fluorinated at meso positions, and tetrasubstituted derivatives, such as meso-tetraphenylporphyrin, are inert. The preparation of a mixture of fluorinated derivatives 14-18 from 13 and monofluorination of 19 to give 20 are instructive. Interestingly, the products 14-18 were separated into pure components by simple silica gel chromatography (92TL1069). 

Fluorination of aromatic compounds. Phenols and pyrrole derivatives afford fluorinated products on reaction with XeFi. 

Condensation of pyrroles with carbonyl compounds under Lewis acid catalysis followed by oxidation provides an efficient route to the porphyrin ring system. This has been effectively used to prepare polyfluorinated porphyrins from 3-fluoro and 3,4-difluoropyrroles, as well as pyrroles substituted with fluorinated side chains in these positions. For example, DiMagno and coworkers extended their studies of highly electron-deficient porphyrins to a series of 2,3,7,8,12,13,17,18-octafluoro-5,10,15,20-tetraarylporphyrins 96, including the perfluorinated compound, by BFs-catalyzed condensation of 3,4-difiuoropyrrole with benzaldehydes followed by dichloro dicyano quinone (DDQ) oxidation (Fig. 3.46). A similar approach was used by Leroy and coworkers. ... 

Reaction with Organolithium Reagents. The fluorination of vinyl lithium derivatives with NFSi has been demonstrated in good yields with complete retention of configuration about the double bond. Phenyl lithium reacts rather poorly with 7V-fluorobenzenesulfonlmlde, but more complex phenyl lithium derivatives have been fluorinated to prepare fluoro- and polyfluoro-veratraldehydes as well as complex fluorinated polyaromatic compounds. Organolithium derivatives of heterocycles have been fluorinated by reaction with NFSi at low temperature. In this manner, fluoro-pyrroles and 2-fluoro-5-methylthleno[3,2-b]pyrldlne are prepared from their corresponding llthlo-parent compounds (eq 16). ... 

Buchwald reported an improved catalyst system for the palladium-catalyzed fluorination of aryl and heteroaryl triflates a pyrrole substrate similar to 98 was converted to the corresponding fluoride in 71% yield. Although a side-chain reaction for pyrrole, the fluorination was used... 

Fluorination of N-substituted pyrroles 7,9 with xenon difluoride was also performed to give substituted products at a-position 8,10 in moderate yields [8]. 

Direct anodic fluorination of 1,2-disubstituted pyrroles 14 gives 5-fluoropyrroles 16 and/or fluorinated adducts 15,17, pyrroUn-2-ones 18. The transformation is performed with platinum plate electrode in acetonitrile containing supporting fluoride salts EtsN-nHF [12]. The structure of product depends on supporting fluoride salts. 

Another possibility for the synthesis of fluorinated pyrroles is the use of their nonaromatic precursors. Thus, 3,3-difluoro-l-pyrrolines 30 were prepared via electrophilic fluorination of the corresponding 1-pyrrolines 29 by Selectfluor. Reaction of the difluoropyrrolines 30 with sodium aUcoxides yielded fluorinated 5-(alkoxymethyl) pyrroles 31 in good yields [18],... 

The use of carbonyl function is classic approach in heterocyclic synthesis. In case of fluorinated pyrroles this approach was frequently used. Convenient method for synthesis of pyrroles 221 is based on the reaction of fluorinated 5-keto acid esters or amides 220 with ammonia. In case of methyl and ethyl esters amidolysis was... 

---