2.1 Fluorine/halogen exchange

One of the first reactions that led to the presence of the CF₃ group on the nitrogen is the fluorine/halogen exchange. The first main building block of the fluorine chemistry was hydrogen fluoride (HF) (or anhydrous hydrofluoric acid). From the dichloroimine in the presence of hydrofluoric acid in ether the N-CF₃ aniline was isolated (Scheme 1) [5]. Yagupolskii et al.[6] performed the fluorine/chlorine exchange starting with N-trichloromethyl derivatives in the presence of antimony trifluoride or HF.

2.2 Oxidative desulfurization–fluorination of dithiocarbamoyl disulfides

Another much more thoroughly studied reaction consists in oxidative desulfurization–fluorination of dithiocarbamoyl disulfides. In organic synthesis, sulfur tetrafluoride (SF₄) was mainly used to convert hydroxyl and carbonyl groups into CF and CF₂ groups, respectively. Harder and Smith [7] similarly reported on the synthesis of the N-CF₃ diethyl amine and piperidine in 58% and 70% yield from thiocarbamoyl disulfides in the presence of SF₄ (Scheme 2). Interestingly, Dmowski and Kamiński proposed to use the N-dialkyl formamides as precursors to form the N-CF₃ derivatives. Using 2.5 equiv of SF₄ and 1.5 equiv of potassium fluoride (KF) for 48 h at 150 °C, the N-trifluoromethyl amines were obtained in excellent yields from 89% to 94% [8]. These conditions are applicable to disubstituted, symmetrical, or not amines, as well as cyclic amines. The authors have demonstrated that the R₂N-CF₂H was the intermediate reaction, resulting from the fluorination of the carbonyl and not the formation of the R₂N-COF (Scheme 2).

Other fluorinated agents then appeared, being less constraining to handle, and elaborated from SF₄ and amines [9]. The most popular reagents are the diethylaminosulfur trifluoride (DAST) and the bis-(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor). In 1973, Markovski et al. [10] developed milder conditions using some dialkylaminosulfur trifluoride (R₁R₂N-SF₃) (see Scheme 3).

Tyrra [11] studied the transformation of bis(dialkylthiocarbamoyl) disulfides into N-CF₃ in the presence of various amounts of silver fluoride. At room temperature in the stoichiometric ratio of 1:1, the corresponding N,N-diorganothiocarbamoyl fluorides (R₂NC(S)₂F), AgSC(S)NR₂, and elemental sulfur were obtained. Under comparable conditions in a ratio >3:1 both reactants selectively yield diorgano(trifluoromethyl)amines, R₂NCF₃, AgSC(S)NR₂, Ag₂S, and elemental sulfur. At stoichiometry 6:1, R₂NCF₃, Ag₂S besides elemental sulfur were formed. By analogy, thiocarbamoyl fluorides and silver dithiocarbamates react with AgF yielding selectively the corresponding trifluoromethyl amines (Scheme 4).

Carbonyl fluoride [12] has also been found to cleave disulfide links and to replace thiono-sulfur by fluorine. Thus, the reaction led to both N,N-dimethylthiocarbamoyl fluoride and N-trifluorotrimethyl dimethyl amine. In a separate synthesis, Ν-trifluorotrimethyl amine was obtained in 55% conversion from N,N-dimethylthiocarbamoyl fluoride and carbonyl fluoride (Scheme 5).

However, given the toxicity of such reagents (SbF₃, SF₄, and so forth) and the need to use specific equipment for HF, such reactions are not widely used in laboratories. In addition, rather stringent conditions (high acidity and high temperatures) make these syntheses not applicable to functionalized molecules.

2.3 Oxidative desulfurization–fluorination of dithiocarbamates

After the oxidative desulfurization–fluorination reaction, the transformation of dithiocarbamates has been examined. Previous reagents such as DAST, Deoxofluor, and other derivatives have been used. Here some examples are commented on. The Deoxofluor with SbCl₃ as catalyst led to the N-CF₃ product (Scheme 6) [13].

In 2012, Umemoto and Singh [14] described the use of the phenylsulfur chlorotetrafluoride and phenylsulfur trifluoride to synthesize N-methyl-N-CF₃-aminopyridine from the pyridine-methyl-dithiocarbamate (Scheme 7).

Milder conditions were developed by Hiyama and colleagues [15], in particular, from dithiocarbamates, N-halo amides, and readily available fluoride ions, such as nBu₄NH₂F₃, HF_x-pyridine, and HF_x-Et₃N. These are the most common methods for generating trifluoromethyl amines, which allows for the use of very mild conditions. Different conditions have been tested, in particular, by varying the nature of the fluoride ion donor and the halonium ions “X⁺”. The best results were obtained with N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), or 1,3-dibromo-5,5-dimethylhydantoin. These conditions are applicable to various types of nitrogen, although it still needs to be disubstituted, and it includes substituted phenyl, heteroaromatics, or alkyl groups (Scheme 8).

The mechanism proposed by the authors is the following: the reaction is initiated by an attack of the dithiocarbamate on the halonium ion X⁺, followed by a nucleophilic attack of a fluoride ion to give the intermediate A. Two successive similar reactions then take place to give the N-trifluoromethyl amine (Scheme 9).

Other reactions have been experimented from dithiocarbamates with different fluoride and halogenated reagents [16]. Furthermore, the conditions involving pyridinium poly(hydrogen fluoride) and NBS have been used to introduce the CF₃ group on 4-quinolone-3-carboxylic acids, which exhibited antibacterial activity (Scheme 10) [17].

2.4 Fluorination by bromine trifluoride

Other fluoride reagents have been used for the oxidative desulfurization–fluorination of dithiocarbamates. Rozen et al. exploited commercially available bromine trifluoride (BrF₃). The reaction proceeded under mild conditions with amides to afford N-CF₃ amides. The mechanism of this reaction is the same as the one described in Scheme 9. Excellent yields of N-CF₃ amides were obtained from alkyl amides. In the case of aryl/alkyl amides a mixture of N-CF₃ and RCF₂-N-CF₃ compounds was formed in 30%–40% and 55%–75% yields, respectively. However, the difluoro/N-CF₃ products were successfully transformed into the N-CF₃ amides after hydrolysis (Scheme 11) [18].

The difference in stability to hydrolysis of the CF₂ group between aliphatic and aromatic series can be explained by fluorine hyperconjugation. In the aliphatic series, this phenomenon is exacerbated by both the lone pair of nitrogen and the donor-inductive effect of alkyl groups, which makes the difluoromethylene group susceptible to nucleophilic attack by the oxygen in the water. The aromatic series, containing ring electron acceptor, decrease the fluorine hyperconjugation required for the hydrolysis of difluoromethylene (Scheme 12).

The same group reported on the use of the Py·BrF₃ complex in the field of aromatic fluorinations. The authors observed that the use of the complex reduced the electrophilic bromination generally observed with most other reagents. In the case of the N-diphenyl xanthate, the complex Py·BrF₃ afforded only to the N-phenyl N-(trifluoromethyl)aniline whereas the BrF₃ led to unidentified brominated and fluorinated compounds (Scheme 13) [19].

2.5 From Me₄NSCF₃

Schoenebeck et al. [20] reported on a simple, fast, and selective one-pot synthesis of N-CF₃ compounds. From the stable Me₄NSCF₃ and secondary amines, the thiocarbamoyl fluoride intermediates were obtained in a few minutes at room temperature and then reacted with AgF to be transformed into N-CF₃. These mild conditions allowed the introduction of the CF₃ group on the nitrogen of certain pharmaceutical molecules, such as sildenafil or terbinafine (Scheme 14).

3.1 From Prakash–Ruppert reagent

The first examples of the addition of the CF₃ radical on nitrogen have been described for the detection of radical pathway by electron spin resonance (ESR) studies for the determination of mechanisms. The compound most often detected by ESR is the tert-butyl nitroxide trifluoromethyl, which comes from the attack of the radical “CF₃^·” on the tBuNO [21–23]. We will not discuss these articles here and will focus only on the articles that described a pathway to the synthesis of N-CF₃ compounds.

In 2015, Bolm et al. [24] released the first trifluoromethylation on sulfoximines in the presence of the Ruppert–Prakash reagent (CF₃TMS) catalyzed by silver carbonate in the presence of 1,10-phenanthroline. After 12 h at 60 °C, symmetrical or unsymmetrical sulfoximines substituted by various aliphatic and/or aromatic series were isolated in moderate to good yields (Scheme 15).

To indicate the pathway to the CF₃ radical, radical traps such as TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxyl) have been added in the media, and the corresponding TEMPO–CF₃ adduct was present. The proposed mechanism is shown in Scheme 16.

The authors assume the silver(I) cation is oxidized by dioxygen to a silver(II) species (A). At the same time, the trifluoromethyl radical is generated in situ from the chelate-stabilized silver AgCF₃ complex. Then the Ag(0) species is oxidized to Ag(I) reentering the catalytic cycle. The CF₃ radical reacts with A to give Ag(III) intermediate B. Reductive elimination of B provides the desired product N-CF₃ sulfoximine and regenerates the silver(I) cation, which starts the catalytic cycle again.

3.2 From Langlois reagents

Selander et al. [25], in their 2017 study, reported on the radical addition of the trifluoromethyl group from the reagent of Langlois (CF₃SO₂Na) on aryl nitroso derivatives. The CF₃ radical was generated in combination of copper (II) (Cu(ClO₄)₂) and t-butyl hydroperoxide. Once the radical was added to the nitrosoarenes, the hydroquinone transferred a proton and released the N-CF₃ hydroxylamines. The reaction that was performed in mild conditions was totally chemoselective (Scheme 17).

It was possible to convert N-trifluoromethylated hydroxylamine into N-CF₃ acetylated aniline and into N-CF₃ aniline by reduction of the N–O bond (Scheme 18).

4.1 From CF₂Br₂

The electrophilic trifluoromethylation involves the nucleophilic attack of nitrogen on an electrophilic fluorinated group. Several types of precursors of “CF₃⁺” have been developed to achieve these transformations. In 1991, Pawelke [26a] reported on the N-trifluoromethylation of secondary amines from the dibromodifluoromethane and the tetrakis(dimethylamino)ethylene (TMAE) in a polar solvent (CH₂)₄SO₄. The TMAE reduced the CBr₂F₂ into “F₂BrC⁻” that deprotonated the amine. The amide was then combined with the dibromodifluoromethane, resulting in the formation of intermediate N-(bromodifluoromethyl) amine. In the polar solvent, this type is in equilibrium with the ionic form that reacts very easily with fluoride to afford the desired N-CF₃ products in moderate yields (Scheme 19).

In 2000, Yaguposlkii et al [6b] performed the addition of 2-methyl benzimidazole on CF₂Br₂ by treatment with NaH in acetonitrile. The 1-bromo-difluoromethyl benzimidazole was converted into the 1-trifluoromethyl benzimidazole by refluxing with tetramethyl ammonium fluoride (Me₄NF) in monoglyme at reflux. The reaction resulted in a mixture of the N-CF₃ (40%) and N-CF₂H (35%) derivatives, which were separated by fractional distillation (Scheme 20).

In 2001, Kolomeitsev et al. [26b] reported on the deprotonation of the imidazole with potassium tert-butylate (t-BuOK) followed by the addition of CF₂Br₂ to afford the N-bromodifluoromethyl imidazole. The latter was converted into the N-CF₃ imidazole with antimony trifluoride in 30% yield (Scheme 21). In the same way, Sokolenko et al. [26c] in 2009 presented a method for synthesizing the N-CF₃ imidazole and N-CF₃ pyrazole (Scheme 21). First imidazole and pyrazole were deprotonated with NaH in DMF after the addition of CF₂Br₂ in the presence of tetrabutyl ammonium bromide (n-Bu₄NBr) as catalyst to afford in high yield the 1-bromodifluoromethyl imidazole and the 1-bromodifluoromethyl pyrazole. The substitution of the bromide by the fluorine was performed with Me₄NF in sulfolane at 170–180 °C. The 1-trifluoromethyl imidazole was obtained in 36% yield after distillation. In the case of the 1-trifluoromethyl pyrazole, which was obtained in 39% yield, the 1-difluoromethyl pyrazole was additionally formed (20%).

4.2 From trifluoromethyl oxonium

More recently, new reagents have been developed to generate trifluoromethylated carbocations. In 2007, Umemoto developed O-(trifluoromethyl)dibenzofuranylium derivatives (Fig. 1).

These CF₃ oxonium were able to generate the CF₃⁺ at low temperature and proved to be very good trifluoromethylation agents of primary, secondary, or aromatic amines such as pyridines, anilines, and indolines (Scheme 22) [27].

In 2006, Togni et al. [28] developed a new generation of trifluoromethylation reagents based upon hypervalent iodine (Fig. 2), which reacted with a number of C-, S-, P-, and O-centered nucleophiles.

The study of the trifluoromethylation of heteroarenes resulted in the discovery of a Ritter-type reaction of an azole, as corresponding reactions were conducted with a hypervalent iodine trifluoromethylated reagent in acetonitrile. Optimized reaction conditions allowed this first N-trifluoromethylation to proceed in up to 63% isolated yield (Scheme 23) [29].

The authors proposed a mechanism that involved the protonated form of the reagent I (A) and also the formation of the N-trifluoromethyl nitrilium ion (B) as intermediates (Scheme 24).

In 2012, the same group [30] developed a selective way to obtain the direct trifluoromethylation of substituted electron-rich heterocycles such as indoles and pyrroles. The heteroarenes were first silylated in situ before being treated with the trifluoromethylated reagent (Scheme 25).

More recently, Wang et al. [31] published a 2015 study on trifluoromethylation of NH-aromatic ketimines by the in situ generation of a hypervalent iodine intermediate as donor of CF₃⁺. The intermediate was formed by using the Ruppert–Prakash reagent and the iodosobenzene diacetate in the presence of a fluoride ion donor (KF) or by using Togni's reagent II with copper salt as catalyst in acetonitrile. The trifluoromethylation of primary ketimines occurs with yields ranging from 40% to 88% (Scheme 26). They proposed the following mechanism: the trifluoromethyl anion “CF₃⁻”, generated in situ by the attack of KF on the Ruppert–Prakash reagent, reacted with the iodosobenzene diacetate to form the active species [PhICF₃]⁺[OAc]⁻. The ketimine was added onto this derivative resulting in the N-CF₃ ketimine after deprotonation and reductive elimination. In the case of Togni's reagent, the copper catalyst increased the electrophilic character of the hypervalent iodine reagent by chelation on the oxygen of the carbonyl [28].

4.3 Nucleophilic trifluoromethylation

In this section, the principal investigation was carried out with the addition of the Ruppert–Prakash reagent on various electrophilic nitrogen derivatives.

In 2012, the nucleophilic trifluoromethylation of nitrosoarenes using TMSCF₃ and CsF in 1.2-dimethoxyethane has been disclosed by Inoue and Handa [32]. After treatment with Ac₂O, the O-acetylated, N-trifluoromethylated hydroxylamines were obtained and were hydrogenated using Pd/C in THF to afford the PhNHCF₃. The N-CF₃ aniline was also treated with Ac₂O and CF₃SO₃SiMe₃ at 40° for 6 h to lead PhNAcCF₃ in 78% yield (Scheme 27).

Our group performed the nucleophilic addition of another electrophilic nitrogen, the azodicarboxylate derivatives. After exploring various conditions, it was determined that the best one consisted in the use of CF₃TMS and the t-butyl azodicarboxylate in the presence of AcONa as catalyst in DMF at 0 °C. The corresponding N-CF₃ hydrazide was isolated in 30% yield. From other azodicarboxylate derivatives such as Cbz, Et, and iPr, the trifluoromethylation addition occurred exclusively on the carbonyl of the ester group (Scheme 28) [33].

Under basic conditions, the N-CF₃ hydrazide was very stable and reacted with different nucleophiles such as allyl bromide, propargyl bromide, and ethyl iodoacetate, without decomposition and loss of fluorine. Furthermore, the azide methylester reacted easily with propargyl derivative, resulting in triazole in excellent yield (Scheme 29).

More recently, the addition of the Ruppert–Prakash reagent has been investigated on the p-toluenesulfonyl azide (TsN₃) to afford azidotrifluoromethane (CF₃N₃) for the first time. The reaction was performed at −60 °C in DMF with cesium fluoride (CsF, eq 1.2). The CF₃N₃ was isolated by distillation with THF in 70%–80% (Scheme 30) [34].

The reactivity of the solution of trifluoromethyl azide in THF has then been tested in CuAAC with alkynes and a catalytic amount of copper (I) 3-methylsalicylate in THF at room temperature for 18 h. The corresponding N-CF₃ triazoles were isolated in good yields with exclusive formation of 1,4-disubstituted triazoles (Scheme 31) [31].

Because of the high volatility of the CF₃N₃ (bp −28.5 °C), the authors attempted the direct one-pot, two-step synthesis of N-CF₃ triazoles. After the reaction of CF₃TMS with CsF and TsN₃ at −60 °C in DMF, alkyne, an aqueous solution of CuSO₄, and sodium ascorbate were added. These conditions allowed for the access of N-CF₃ triazoles in reasonable yields comparable with the two-step procedure, although with a slightly lower regioselectivity (Scheme 32).