Trifluoromethylation of heteroarenes

SCHEME 7.8 Copp>er-catalyzed oxidative trifluoromethylation of heteroarenes and arenes with di-ferf-butyl peroxide. 

Recently, Blechert s group used a heterogeneous photocatalyst, mesoporous graphitic carbon nitride (mpg-CN), to achieve the trifluoromethylation of heteroarenes with CF3SO2CI under visible-light irradiation (Scheme 13.32) [67]. 

Scheme 13.32 Heterogeneous catalytic approaches for the C-H trifluoromethylation of heteroarenes.

Wiehn MS, Vinogradova EV, Togni A (2010) Electrophilic trifluoromethylation of arenes and V-heteroarenes using hypervalent iodine reagents. J Fluor Chem 131 951-957. doi 10.1016/j. jfluchem.2010.06.020... 

Mejia E, Togni A (2012) Rhcmium-catalyzed trifluoromethylation of arenes and heteroarenes by hypervalent iodine reagents. ACS Catal 2 521-527. doi 10.1021/cs300089y... 

Trifluoromethylated heteroarenes are widely applicable in the synthesis of pharmaceuticals. Using 10 mol% palladinm acetate as catalyst, TMSCF3 as trifluoro-methylating reagent, bidentate nitrogen-containing ligand L, and PhI(OAc)2 as oxidant, Liu and coworkers developed a novel palladium catalyzed oxidative trifluoromethylation of indoles at room temperatnre (Scheme 9.20). This reaction likely involves a palladium (II/IV) mechanism for the formation of the sp C—CF3 bond. 

A novel methyltrioxorhenium (MTO) catalyzed methodology for the direct trifluoromethylation of both activated and nonactivated arenes and heteroarenes using an easily accessible, shelf-stable hypervalent iodine trifluoromethylating reagent has been developed by Togni and coworkers (Scheme 9.21). This reagent system exhibited a broad substrate scope in direct aromatic trifluoromethylation. 

Photoredox catalysis with a redox-active ruthenium (11) catalyst and CF3SO2CI developed by MacMillan has been used to generate the electrophilic CF3 and leads to the formation of trifluoromethylated products of heteroarenes (Scheme... 

Mejfa et al. achieved trifluoromethylation of arenes and heteroarenes by h) ervalent iodine reagents with MTO as a catalyst (5-10 mol %) and yields up to 77% (eq 64). 

Nagib DA, MacMillan DWC (2011) Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis. Nature 480 224—227... 

Just before Cho s report, Nagib and MacMillan reported a high-impact work on direct C—H trifluoromethylation of arenes by photoredox catalysis [79]. The use of [Ru(phen)3]Cl2 as photocatalyst and CF3SO2CI (18a) as a CF3 source enables the reaction with the broad scope with respect to the arenes, i.e., electron-rich/electron-deficient heteroarenes and unactivated arenes, in the absence of sacrificial electron... 

Scheme 11 Trifluoromethylation of electron-rich heteroarenes by photoredox catalysis...

Around the same time, the photocatalytic trifluoromethylation of electron-rich heteroarenes such as indole, furan, pyrrole, and thiophene using CF3I as the tri-fluoromethane source was reported by Cho and coworkers (Eq. (13.24)) [66b]. 

Bucci, R. Laguzzi, G. Pompili, M.L. Speranza, M. Gas-phase heteroaromatic suhstitution. 12. Reaction of free trifluoromethyl cation with simple five-memhered heteroarenes in the gas phase. J. Am. Chem. Soc. 1991, 113, 4544-4550. 

Carbazoles 292 and azaindoles were trifluoromethylated selectively to 294 under copper catalysis with the Ruppert—Prakash reagent in the presence of trimethyl borate, 1,10-phenanthroline, and KF as a base. This reaction is also applicable to a variety of other arenes and heteroarenes (140L4268). 

The introduction of trifluoromethyl groups via copper-catalyzed oxidation under efficient conditions has been reported by Chu and Qing. Moderate-to-excellent yields were obtained and common functionalities such as ester, nitrile, and bromine, were well-tolerated. The reaction works well on heteroarenes and electron-deficient arenes such as 1,3-oxadiazoles and benzo[t/]imidazoles. Selected examples are shown here (Scheme 7.8). 

KobatakeT,YoshidaS,YorimitsuH,OshimaK(2010)Reactionof2-(2,2,2-trifluoroethylidene)-1,3-dithiane 1-oxide with ketones under pummerer conditions and its application to the synthesis of 3-trifluoromethyl-substituted five-membered heteroarenes. Angew Chem Int Ed 49 2340-2343... 

Heteroarene Functionalization One-pot Sequential Functionalization Chemistry. Zinc isopropylsuUinate can be considered as a radical with nucleophilic character. Zinc trifluoromethanesulfinate (TFMS), another zinc bis(alkanesulfinate) reagent, possesses a rather electrophilic character. By taking advantage of the electrophiUcity/ nucleophiUcity of the reactive radical species, a one-pot sequential functionalization reaction was developed. Dihydroquinine can undergo tandem trifluoromethylation and isopropylation without the need for secondary alcohol protection (eq 7). 

Introduction. Zinc trifluoromethanesulfinate (TFMS) is a commercially available reagent that appends trifluoromethyl units to heteroarenes under practical and mild conditions. Reaction temperatures range between room temperature (rt) and 50 °C, the reaction is tolerant of air and moisture, and the reaction solvent can be H2O or even unconventional media such as tea or cell lysate. Innately reactive positions of a heteroarene undergo the transformation of carbon-hydrogen to carbon-trifluoromethyl. C-H functionalization of innate positions and methods to override this inherent reactivity, as well as one-pot sequential functionalizations of two different positions of a heteroarene will be discussed herein. 

The authors have proposed a plausible mechanism for the trifluoromethylation reaction (Scheme 13.31). They assumed that a SET reduction ofCF3S02Cl224 by the photoexcited catalyst gives the oxidatively active catalyst and a CF3SO2CI radical anion 227, which rapidly collapses to generate the CF3 radical by the release of SO2 and chloride. The CFg radical then adds to a heteroarene to form the radical 228. Single-electron oxidation and subsequent deprotonation of the resulting cation 229 furnishes the trrfluoromethyl-substituted heteroarene products. 

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