Trifluoromethylation of heterocycles

Figure 7.21 Trifluoromethylation of heterocycles using CF3X/CU system.

In 2011, Baran developed a new method for innate C—H trifluoromethylation of heterocycles (Scheme 9.24). Using a bench-top stable trifluoromethyl radical source, the Langlois reagent (CF3SO2 Na+), reacts broadly on a variety of electron deficient and rich heteroaromatic systems. It demonstrates high functional group tolerance. This C—H trifluoromethylation protocol is operationally simple, scalable, proceeds at ambient temperature, and can be used directly on unprotected molecules. Finally, the regioselectivity of C—H trifluoromethylation can be fine-tuned simply by judicious solvent choice. 

In 2012, Baran reported a new reagent TFMS (Zn(S02CF3)2) for direct trifluoromethylation of heterocycles (Scheme 9.26). This transformation has several... 

Methods for the synthesis of trifluoromethyl-substituted furans and benzofurans can be divided into several groups direct trifluoromethylation of heterocycle, transformation of functional groups of hetarene into trifluoromethyl substituent, Diels-Alder/retro-Diels-Alder sequence, and various methods for the furan ring formation from precursors bearing trifluoromethyl moiety. 

Iqbak N, Choi S, Ko E, Cho EJ (2012) Trifluoromethylation of heterocycles via visible light photoredox catalysis. Tetrahedron Lett 53 2005-2008... 

Ji Y, Bmeckl T, Baxter RD, Fujiwara Y, Seiple IB, Su S, Blackmond DG, Baran PS (2011) Innate C-H trifluoromethylation of heterocycles. Proc Natl Acad Sci USA 108 14411-14415... 

Qing reported a Cu-mediated trifluoromethylation of terminal allq nes using Ruppert s reagent as the CF3 source. Similar conditions were also used for the trifluoromethylation of heterocycles, such as oxadiazoles, benzimidazoles, benzoxazoles, benzothiazoles and indoles. Sodeoka reported trifluoromethylation of the indole C2 position using copper catalysis in conjunction with Togni s reagent. ... 

Heteroaromatic esters such as 493 and amides are produced by the carbo-nylation of heterocyclic bromides[347,348]. Even dichloropyrazine (494) and chloropyridine are carbonylated under somewhat severe conditions (120 C, 40 atm)[349]. The carbonylation of trifluoroacetimidoyl iodide (495) proceeds under mild conditions, and can be used for the synthesis of the trifluoromethyl-glycine derivatives 496 and 497(350]. 

Methods for synthesis of a,(3-unsaturated trifluoromethyl ketones and their use in the synthesis of trifluoromethyl-substituted heterocycles 99UK483. 

Bis(trifluoromethyl)-substituted 1,3-heterodienes are a rich source of heterocycles through cycloadditions, for example, with ketenes (86CZ83) and azirines [89JFC(42)51] to give dioxazines and triazepines, respectively. 

Reaction of the thia-amino acid 392 with trifluoroacetic anhydride gave the 2,2,2-trifluoro-l-[7-(trifluoromethyl)-l//-pyrrolo[l,2-c]-[l,3]thiazol-6-yl] ethanone pyrrole 395. The formation of the pyrrole can be rationalized by a sequence involving trifluoroacetylation of the enamine 392 affording dione 393 followed by loss of water and carbon dioxide to give the aromatic product 395. These decarboxylations afford fluorinated derivatives of heterocyclic skeletons known to exhibit interesting biological activity (Scheme 58) <2000T7267>. 

Much care has been taken in the selection of work to be included but, necessarily, the choice is subjective and the review is in no way comprehensive. P-Lactam chemistry dominates the field in terms of the number of publications. In contrast, studies of heterocycles containing two different heteroatoms appear to be neglected. In general, reviews are mentioned in the appropriate section but mention of a survey of heterocycles bearing fluorine or trifluoromethyl substituents <98MI3SS> is more appropriate here. 

Semicarbazide hydrochloride [705] and amidrazones [106] react with trifluoropyruvates to give six-membered heterocycles A variety of trifluoromethyl substituted heterocyclic systems is available, starting from the hydrate of trifluoropy-ruvicacid, a versatile 1,2-bielectrophilic building block (reaction type 2, equation 10) [107] (equation 24). 

Syntheses of trifluoromethyl-substituted heterocycles from open-chain compounds 91YGK612. 

Song JJ, Tan Z, Reeves JT, Gallou F, Yee NK, Senanayake CH (2005) A-Heterocyclic carbene catalyzed trifluoromethylation of carbonyl compounds. Org Lett 7 2193-2196... 

The target compounds (33) were obtained in good yields from a variety of aliphatic, aromatic, and heteroaromatic aldehydes. Owing to mild reaction conditions, other functionalities such as ethers, trifluoromethyl, and heterocycles can be... 

Since the criss-cross cycloaddition reaction is a sequence of two [3 + 2] cycloaddition steps, the reaction of hexafluoroacetone azine with a,a>-diolefins offers access to a new class of trifluoromethyl-substituted heterocyclic macromolecules. Polymers with interesting structures and properties become available by criss-cross polymerization (88MI3 89MI2 90MI2). 

Efficient rontes to Q -trifluoromethylated nitrogen heterocycles of various sizes for applications in synthesis of CF3 tagged bioactive molecules were achieved in two steps from Q -(trifluoromethyl)homoallylamines via ene-ene or ene-yne metathesis catalyzed by (2a) and with better conversions by (4a) (equation 4)3 ... 

After a brief survey of the history of valence-bond isomers of aromatic compounds, new syntheses and the reactions of these isomers reported in the last decade are reviewed. In the second chapter, the valence-bond isomers of homoaromatic compounds, especially benzene derivatives, are described and in the third chapter those of heterocyclic compounds. Photoreactions of perfluoroalkylated aromatic compounds afford valence-bond isomers in high yields. These isomers are very stable and useful for the synthesis of highly strained compounds. Therefore, the emphasis is put on the chemistry of trifluoromethylated benzvalenes, Dewar thiophenes, and Dewar pyrroles. 

Since a review on Dewar heterocyclic compounds has been published recently102), in this chapter only some typical reactions of valence-bond isomers of heteroaromatic compounds will be discussed. The emphasis will be placed on the chemistry of trifluoromethylated Dewar thiophene and pyrroles, both of which are rare examples of stable valence-bond isomers of heterocyclic compounds. Since the isolation of valence-bond isomers of heteroaromatic compounds is mostly limited to the per-fluoroalkylated isomers, those postulated as intermediates are also included. 

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