Visible-Light-Induced Direct Difluoroalkylation of Uracils, Pyridinones, and Coumarins

Abstract

An efficient and general method for the synthesis of difluoroalkylated uracils, pyridinones, and coumarins through visible-light-induced reaction with commercial materials is developed. The strategy proceeds with high efficiency under mild reaction conditions and shows excellent functional group compatibility, even toward bromide and hydroxyl group, thus demonstrates high potent application in a late-stage fluoroalkylation. Moreover, the difluoroalkylated products can be further transformed to a diverse variety of difluoroalkylated heterocycles, including molecules of potential biological activity.

Difluoromethylation Reactions of Organic Compounds

“…In recent years, radical fluoroalkylation reactions by visible‐light photoredox catalysis have attracted considerable attention due to mild reaction conditions and broad functional group tolerance, and many radical difluoroalkylation reagents including PhSO 2 CF 2 I, BrCF 2 COOEt, and fluoroalkanesulfonyl halides HCF 2 SO 2 Cl, have been used for this purpose. Chung‐Ya He and colleagues have very recently introduced a method for the difluoromethylation of uracils, pyrimidinones and coumarins employing BrCF 2 CO 2 Et and BrCF 2 CONEt 2 as difluoromethylating agents under photocatalysis . The photocatalyst employed is fac ‐Ir(ppy) 3 , K 2 HPO 4 as a base, in DMSO as solvent; irradiation source is a blue LED.…”

“…Irradiation of photocatalyst fac-[Ir(ppy) 3 ]w ith visible light will produce al ong-lived excited state (À1. 73 In summary,t he use of photocatalyst fac-[Ir(ppy) 3 ]e nables photoreduction of BrCF 2 CO 2 Et, BrCF 2 NEt 2 , [66] Ph 3 PCF 2 Br + Br À , [67] N-tosyl-S-difluoromethyl-S-phenylsulfoximine, [14] 2-((difluoromethyl)sulfonyl)benzo[d]thiazole, [74] and HCF 2 SO 2 Cl [76] to CF 2 Yr adicals that could add to double bonds.…”

“…Chung-YaH ea nd colleagues have very recently introduceda methodf or the difluoromethylation of uracils, pyrimidinones and coumarins employing BrCF 2 CO 2 Et and BrCF 2 CONEt 2 as difluoromethylating agents under photocatalysis. [66] Thep hotocatalyste mployed is fac-Ir(ppy) 3 ,K 2 HPO 4 as ab ase, in DMSO as solvent; irradiation sourcei sablue LED. The scope of the reaction is illustrated in Scheme 7.…”

“…The authors [66] supply ap lausible reaction mechanism showni nS cheme 8. Irradiationw ith visible light excites Ir(ppy) 3 converting it into as trong reductive species [i.e., *Ir(ppy) 3 ,( E 1/2 = À2.14 Vv s. FeCp 2 )] that suffers an ET process to generate CCF 2 Rf rom BrCF 2 R ( 47).…”

Nickel‐Catalyzed Regioselective C(2)−H Difluoroalkylation of Indoles with Difluoroalkyl Bromides

“…Particularly, the regioselective fluoroalkylation of indoles is compelling because of the biological significance of this important alkaloid. In that direction, trifluromethylation and trifluoroethylation of indoles have been effectively accomplished by both the noble metal and earth‐abundant metal catalysts. Similarly, difluoroalkylation of indoles has been reported by different transition‐metal catalysts.…”