A Brief Review on the Synthesis of the N-CF3 Motif in Heterocycles

Abstract

The trifluoromethyl group is widely recognized for its significant role in the fields of medicinal chemistry and material science due to its unique electronic and steric properties that can alter various physiochemical properties of the parent molecule, such as lipophilicity, acidity, and hydrogen bonding capabilities. Compared to the well-established C-trifluoromethylation, N-trifluoromethylation has received lesser attention. Considering the extensive contribution of nitrogen to drug molecules, it is predicted that constructing N-trifluoromethyl (N-CF₃) motifs will be of great significance in pharmaceutical and agrochemical industries. This review is mainly concerned with the synthesis of heterocycles containing this motif. In three-membered heterocycles containing the N-CF₃ motif, the existing literature mostly demonstrated the synthetic strategy, as it does for four- and larger-membered heterocycles. Certain structures, such as oxaziridines, could serve as an oxidant or building blocks in organic synthesis. In five-membered heterocycles, it has been reported that N-CF₃ azoles showed a higher lipophilicity and a latent increased metabolic stability and Caco-2-permeability compared with their N-CH₃ counterparts, illustrating the potential of the N-CF₃ motif. Various N-CF₃ analogues of drugs or bioactive molecules, such as sildenafil analogue, have been obtained. In general, the N-CF₃ motif is developing and has great potential in bioactive molecules or materials. Give the recent development in this motif, it is foreseeable that its synthesis methods and applications will become more and more extensive. In this paper, we present an overview of the synthesis of N-CF₃ heterocycles, categorized on the basis of the number of rings (three-, four-, five-, six- and larger-membered heterocycles), and focus on the five-membered heterocycles containing the N-CF₃ group.

Keywords: N-trifluoromethyl group; heterocycles.

Figure 1

Drug analogues containing N-trifluoromethyl motif.

Figure 2

Variably sized N-heterocycles containing the N-trifluoromethyl motif.

Scheme 1

Synthesis of (a) aziridines, (b) triziridines and (c,d) diaziridines.

Scheme 2

Synthesis and applications of oxaziridines.

Scheme 3

Synthesis of oxazetidines through trifluoronitrosomethane.

Scheme 4

Synthesis of (a) thiazetidine and (b) diazaboretidin through [2+2] cycloaddition reaction.

Figure 3

Synthesis of N-trifluoromethyl compounds to determine their aqueous stability and additional key in vitro properties.

Scheme 5

Synthesis of N-trifluoromethyl benzotriazole or benzimidazole through fluorine/halogen exchange.

Scheme 6

Synthesis of N-trifluoromethyl amines from (a) methyl dithiocarbamate or (b) phenyl dithiocarbamate.

Scheme 7

Synthesis of thiocarbomoyl fluoride intermediate and further oxidative desulfurization and fluorination to access N-trifluoromethyl amines.

Scheme 8

Synthesis of N-trifluoromethyl compounds through cyclization of fluoro-olefins induced by fluoride ion.

Scheme 9

Synthesis of oxazolidines or dioxazolidines through [3+2] cycloaddition of perfluorinated oxaziridine.

Scheme 10

(a) Synthesis of perfluoroalkyl azides; (b) cycloaddition of trifluoromethyl azides with alkynes or ketones; (c) mechanism of the cycloaddition of trifluoromethyl azides with ketones.

Scheme 11

Synthesis of diverse N-trifluoromethyl heterocycles through transannulation catalyzed by rhodium.

Scheme 12

Mechanism of transannulation catalyzed by rhodium.

Scheme 13

Synthesis of N-trifluoromethyl heterocycles through 1,3-dipoles generated by hypervalent iodine reagent with nitriles.

Scheme 14

Synthesis of other N-trifluoromethyl heterocycles through cyclization of (a) trifluoromethyl isocyanate, (b) trifluoronitrosomethane, (c) trifluoromethyl isocyanide, and (d) N-trifluoromethyl hydrazides.

Scheme 15

Synthesis of diverse N-trifluoromethyl heterocycles through N-trifluoromethyl carbomoyl building blocks.

Scheme 16

(a) Synthesis of N-trifluoromethyl oxazolidinones through trifluoromethylamination/cyclization of styrenes or vinyl; (b) Proposed reaction mechanism; (c) estrone analogue 65a; (d) Synthesis of N-trifluoromethyl oxazolidinones through trifluoromethylamination of vinyl acetate 66 and further cyclization; (e) Synthesis of oxazolidinones through cyclization of allenes.

Scheme 17

(a) Togni’s reagents and trifluoromethylation of benzotriazole; (b) Synthesis of various five-membered N-trifluoromethyl heterocycles through Togni’s reagent; (c) Synthesis of trifluoromethyl amines through Umemoto’s reagents.

Scheme 18

(a) Synthesis of thiocarbomoyl fluoride intermediate through DAST and CS₂ and subsequently Oxidative desulfurization and fluorination; (b) examples of drug analogues obtained by Oxidative desulfurization and fluorination.

Scheme 19

Synthesis of six-membered N-trifluoromethyl heterocycles through [2+2] cycloaddition: (a) trifluoronitrosomethane with substituted diene; (b) N-trifluoromethyl imines with cyclopentadiene; (c) Trifluoromethyl-substituted N-sulfinylamine with diene and further oxidation.

Scheme 20

Synthesis of diverse six-membered heterocycles: (a) Dimerization or trimerization of N-trifluoromethyl carbodiimide; (b) Dimerization or trimerization of trifluoromethyl-substituted N-sulfinylamine; (c) direct fluorination of N, N-dimethyl piperidine.

Scheme 21

Synthesis of larger-membered N-trifluoromethyl heterocycles through addition reaction of dioxyl 80 or its mercurial 84.

Scheme 22

Synthesis of N-trifluoromethyl azepine and azepinone via rhodium-catalyzed annulation of 1,2,3-triazoles.

Scheme 23

Synthesis of perfluoro heterocycles through reaction of tetrafluoroformaldazine with oxalyl fluoride or carbonyl fluoride.

Scheme 24

Synthesis of diverse N-trifluoromethyl heterocycles: (a) pyrolysis of perfluoropiperidine, perfluoromorpholine or perfluorooxazinane; (b) fluorination of 4-methylpyridine in the presence of caesium tetrafluorocobaltate; (c) electrochemical fluorination of various nitrogen-containing materials.