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.

1. Introduction

Organic fluorine chemistry, as a prominent research area, has garnered significant attention for several decades and has also become essential to the evolution of many different but interconnected research fields [1]. The introduction of the fluorine group, especially the trifluoromethyl group, into organic compounds has become known as one of the most efficient methods for modulating molecular properties, for example, lipophilicity and metabolic stability [2]. Due to its potential utility, many methods have been studied extensively [3,4]. However, in contrast to the well-developed C-trifluoromethylations, the N-trifluoromethyl (N-CF₃) motif has rarely been investigated to date. Considering the widespread dissemination of nitrogen (especially nitrogen-containing heterocycles) in drug molecules [5,6,7], constructing the N-CF₃ motif in molecules is of great significance in pharmaceutical and agrochemical industries. Drug analogues and potential agents containing the N-CF₃ motif are partially shown in Figure 1 [8,9,10,11,12,13].

Despite the great potential of the N-CF₃ motif, the synthesis of this moiety and its relative chemistry have been rarely explored. The limited use of N-CF₃ compounds is primarily due to the absence of scalable methods for their preparation [14,15,16]. Recently, thanks to the new reagents and methods, this motif has increasingly been featured in the literature.

In terms of constructing the N-CF₃ motif in heterocycles, there are two main approaches. The first involves utilizing starting materials containing the N-CF₃ motif to generate heterocycles directly, while the second strategy entails introducing the CF₃ group via trifluoromethylation or fluorination of nitrogen-containing species. In this paper we review the construction of N-CF₃ heterocycles on the basis of the size of the cycles, involving three-, four-, five-, six- and larger-membered heterocycles. This article covers as much literature as possible, from the 1960s to early 2023. The structures mentioned in this paper are shown in Figure 2.

2. Three-Membered Heterocycles

In previous reports, the synthesis of three-membered N-CF₃ heterocycles mainly relied on starting materials containing the N-CF₃ motif. In 1964, Logothetis reported the aziridination of N-CF₃ imines 1a in the presence of diazomethane, which obtained aziridine 2a in the yield of 64% (Scheme 1a) [17]. Subsequently, Coe et al. investigated the substructure scope of imines [18]. Unfortunately, poor selectivity was exhibited when R was replaced with ⁱC₃F₇ (perfluoroisopropyl) or CF=CHCF₃. When R = ⁱC₃F₇, a mixture of three components in the ratio of 2b:2b″:2b′ = 6:9:1 was obtained and when R = CF=CHCF₃, a mixture of two products was obtained in the ratio of 2d:2d′ = 71:29 by F shift and further CH insertion into a C-F bond. Kaupp et al. synthesized some stable triaziridines 4 which could be purified by fractional distillation by the irradiation of azimines 3 at room temperature (Scheme 1b) [19]. However, not much attention has been paid to N-CF₃ triaziridine.

Compared to the structures mentioned above, diaziridine attracted more attention, and its synthesis could be divided into two strategies: Mitsch et al., while studying the reductive defluorination-cyclization of organic fluoronitrogens, found that diaziridine 6 could be generated from 1,1-bis(difluoramino)perfluoro-2-azapropan 5 in the presence of ferrocene (Scheme 1c) [20]. Later DesMarteau et al. obtained another diaziridine 6 by nucleophilic cyclization when studying perfluoroalkanamine ions (Scheme 1d) [21]. In the presence of CsF, CF₂=NX (when X = F) yielded perfluoroalkanamine ion (CF₃NF⁻), which underwent further reaction with another CF₂=NX to form perfluoro-1-methylformamidine 8. On the basis of previous work, DesMarteau group achieved synthesis of other diaziridines (when X = Br, Cl) through perfIuoroalkanamine ions [22,23]. Meanwhile, other electrophilic species, such as N-CF₃ imine 1a, could also be attacked by CF₃NF⁻, leading to 3,3-difluoro-1,2-bis(trifluoromethyl)diaziridine [24].

Furthermore, perfluorinated oxaziridine 9 has drawn wide attention and its structure, synthesis and applications have been studied. Petrov and Resnati have already summarized the synthesis and reactivity of perfluorinated oxaziridines, in which N-CF₃ oxaziridines are included [25]. In previous reports, the most common methods of synthesis were oxidative cyclization. In 1976, DesMarteau et al. reported that oxaziridine was obtained by the oxidation of a N-CF₃ imines 1a by CF₃OOH [26]. This reaction was performed in two steps: addition, and further cyclization mediated by NaF. Later, different metal fluorides were investigated by the authors of [27] and KHF₂ was found to be the most suitable reagent for the yield of oxaziridine 7 (the yield was up to 92%). This method was difficult and the starting materials were potentially explosive. In order to make the reaction safer and more convenient, different oxidants, such as hydrogen peroxide [28] and chlorine gas in the presence of metal carbonate [29], etc., have been developed, but these methods were still difficult. Finally, using meta-chloroperbenzoic acid (mCPBA) as the oxidant was determined to be a safer and more attractive choice (Scheme 2) [30,31].

To date, N-CF₃ aziridine, triaziridine and diaziridine have still gained less attention and their properties and applications are less-developed. On the other hand, there have been studies into the structure, properties, and applications of oxaziridine [25] (shown in Scheme 2), such as its reaction with nucleophiles [32,33] and its use as an oxidant [34] or as building blocks. These studies are included in Section 4.2 of this paper.

3. Four-Membered Heterocycles

Similarly, the synthesis of four-membered N-CF₃ heterocycles was based on starting materials containing the N-CF₃ motif.

The predominant approach to oxazetidine was [2+2] cycloaddition reaction. Trifluoronitrosomethane (CF₃NO) was the most common starting material. In the 1950s, Barr and Haszeldine reported that CF₃NO reacted with tetrafluoroethylene 10a to give two products: an oxazetidine 11a and a copolymer (consisting of two monomers in a 1:1 ratio) [35,36]. The oxazetidine predominated in this reaction at a high temperature (ca. 100 °C) and the copolymer at room temperature (Scheme 3a). Since then, several halogenated tetrafluoroethylenes (CF₂=CXY) have been investigated (Scheme 3b) [37,38]. It was found that the formation of an oxazetidine and the copolymer from CF₃NO occurred most readily with the olefins CF₂=CF₂, CF₂=CHF (adducts were a 99:1 mixture of 3,3,4-trifluoro-2-trifluoromethyl-1,2-oxazetidine and 3,4,4-trifluoro-2-trifluoromethyl-1,2-oxazetidine), CF₂=CFCl, and CF₂=CCl₂, and less readily with perfluoro-olefins containing more than two carbon atoms, or with ethylenes containing two or more vinylic hydrogens [38].

Meanwhile, it was reported that an attack on the substituted allene by CF₃NO led to another form of oxazetidine. Banks et al. found that tetrafluoroallene 12 reacted with CF₃NO to yield a complex mixture of oxazetidine 13 and 14 [39]. By adjusting the reaction conditions, the highest yields of oxazetidine 13 and 14 can reach 43% and 42%, respectively. They also found that compound 14 could be obtained (82% yield) when heating oxazetidine 13 with CF₃NO. Later, Haszeldine et al. synthesized a series of oxazedines 16 with limited regioselectivity and stereoselectivity through the reaction of N, N-bistrifluoromethylamino-substituted allenes 15 with CF₃NO (Scheme 3b) [40,41].

In addition to CF₃NO, there were other reagents used in [2+2] cycloaddition. For example, in 1986, Sundermeyer and co-workers found that CF₃N=S=O could react with ketene to generate thiazetidin 17 (Scheme 4a) [42]. Burger et al. reported that the reaction of CF₃N=C=O and boranamine led to diazaboretidin 18 (Scheme 4b) [43].

4. Five-Membered Heterocycles

The literature on three- and four-membered N-CF₃ heterocycles was more focused on their synthesis, with limited exploration of their properties and potential applications. However, in contrast, five- and six-membered heterocycles featuring the N-CF₃ motif have recently been receiving more and more attention [8,44,45,46]. Their synthesis methods, as well as biological activities and derivatization, are gradually being studied.

To evaluate the suitability of the N-CF₃ motif on amines and azoles in drug design, Schiesser et al. synthesized a series of N-CF₃ amines and azoles (shown in Figure 3), and determined their stability in aqueous media and other properties [45]. For example, the stability of N-CF₃ analogues of known bioactive compounds (sulfamethoxazole derivative 19a, tetracaine derivative 20a, inhibitors of hedgehog pathway 21a [47,48], inhibitors of methionine aminopeptidase 22a [49], inhibitors of interleukin-1 receptor associated kinase 4 (IRAK4) 23a [50], and sildenafil analogue 24a) were studied and are shown in Table 1.

Two anilines 19a and 20a, as well as piperazine 24a, showed fast hydrolysis at all three pH values investigated, with half-lives of less than 1.5 days at 25 °C (Table 1). It should to be noted that for 20a, the corresponding carbamoyl fluoride 20b was the main product at pH 1.0, with a small amount of product where both the carbamoyl fluoride had been further hydrolyzed to the secondary amine and the ester bond had been cleaved. The latter compound was also the main product at pH 7.4 and pH 10.0. In contrast to the N-CF₃ anilines and piperazine, for all the N-CF₃ azoles they investigated no corresponding carbamoyl fluoride of free azole was detected in aqueous media at any of the three pH values studied.

Moreover, they then compared the key in vitro properties in medicinal chemistry (log D, experimentally determined polar surface area (ePSA) [51,52], permeability in human epithelial colorectal adenocarcinoma cells (Caco-2), and metabolic stability for the N-CF₃ compounds 19a–24a and their N-CH₃ counterparts (Table 2).

In the compounds investigated, the exchange of a methyl for trifluoromethyl led to the expected higher lipophilicity as proven by an increased log D_7.4 and chromlog D_7.4 and a decreased ePSA. Log D_7.4 increases by on average 1.1 log units and chromlog D_7.4 by 1.6 log units. However, the extent of this change can vary significantly and was dependent on both the individual compound and type of log D_7.4 analysis used. Changes in permeability and metabolic stability were less consistent.Stability to human liver microsomes (HLMs) can be significantly increased for the trifluoromethyl analogue as seen for 22a (p = 0.004) or decreased as for 21a. The decreased metabolic stability of the latter two compounds could be due to an increased lipophilicity, rendering the potential metabolic soft spots (benzylic methyl group in 21a) more susceptible to metabolism.

According to Schiesser’s research [45], N-CF₃ amines were prone to hydrolysis, whereas N-CF₃ azoles have excellent aqueous stability. Compared to N-CH₃ analogues, N-CF₃ azoles showed a higher lipophilicity and a latent increase in metabolic stability and Caco-2-permeability, which illustrated the value and potentiality of N-CF₃ diazole in medicinal chemistry.

In terms of synthesizing these five-membered N-CF₃ structures, both types of constructing N-CF₃ were included. In this section, the synthesis of five-membered heterocycles would be divided into the three parts: nucleophilic fluorination, cyclization based on N-CF₃ starting materials, and electrophilic trifluoromethylation.

4.1. Nucleophilic Fluorination

4.1.1. Fluorine/Halogen Exchange

Fluorine/halogen exchange was one of the first reactions to obtain the trifluoromethyl group on the nitrogen atom (Scheme 5) [16]. Yagupolskii et al. achieved fluorine/halogen exchange with N-trichloromethyl derivatives in the presence of HF or Me₄NF [53]. This strategy was also capable of generating N-CF₃ pyrazoles [54,55] and N-CF₃ 1,2,4-triazoles [55]. However, highly toxic or environmentally unfriendly reagents (such as CF₂Br₂, a known ozone-depleting reagent [56]) would be used in this method for fluorine/halogen exchange or in the preparation of the precursors (such as 26) for fluorine/halogen exchange, which limited its use.

4.1.2. Oxidative Desulfurization and Fluorination

Compared to fluorine/halogen exchange, this method has been much more thoroughly studied. This method allowed people to replace C-S bonds with C-F bods under extremely mild conditions compared to the fluorination of formamides [57] or fluorination induced by SF₄ [58].

Hiyama et al. reported conversion from methyl dithiocarbamates to trifluoromethylamines in the presence of readily available fluoride ions (Scheme 6a) [59]. The reaction conditions were applicable to a wide range of disubstituted nitrogen, with substituents including phenyl, heteroaromatic or alkyl. Recently, Schindler et al. applied chlorodithiophenylformiate as an electrophile and successfully obtained phenyl aminodithioate 30 [60]. Then trifluoromethylamines 31 were generated after the desulfurization and fluorination. Additionally, Hagooly et al. used BrF₃ for desulfurization and fluorination and obtained 2-(trifluoromethyl)isoindoline-1,3-dione and 1-(trifluoromethyl)azepan-2-one [61].

Furthermore, Schoenebeck et al. reported that amines and SCF₃^- source (Me₄N)SCF₃ could generate the highly electrophilic thiocarbomoyl fluoride 32 followed by a reaction with AgF to yield trifluoromethyl amines 31 [62]. Furthermore, there were other approaches to the intermediate 32. Lin and Xiao et al. [63] generated this intermediate from difluorocarbene and sulfur (S₈), while Jiang and Yi et al. [64] reported a method using CF₃SO₂Na (Scheme 7). These strategies have been used to synthesize interesting analogues of biologically active compounds (examples are shown in Section 5.1).

4.1.3. Cyclization Induced by Fluoride Ion

Fluoro-olefins containing terminal double bonds have been shown to isomerize in the presence of fluoride ion (Scheme 8) [65]. There is a considerable amount of literature on the transformation of perfluoro-2,5-diazahexa-2,4-diene (CF₂=NCF₂CF₂N=CF_2, 36a) and its precursor CCl₂=NCCl₂CCl₂N=CCl₂, 35. In 1967, Ogden and Mitsch reported that isomerization of perfluoro-, -diazomethines with CsF could form a cyclic five-membered N-CF₃ heterocycle as a minor product (34, 30% yield) [66].

Scholl et al. synthesized 36a from 35 via two steps, and found that 36a could cyclize to form two isomers (37a and 37b) in the presence of fluoride ion [67]. Both isomers could form nitrogen anion 37c in the presence of fluoride ion. 37c could also react with 37b to generate substituted N-CF₃ imidazolidine 38. Subsequently, the same group found another transformation of 35 and obtained 39 in two steps [68]. In the presence of fluoride ion, another nitrogen anion 40 could be generated, which subsequently reacted with another 39 to obtain imidazolidine 41.

Later in 1984, Banks et al. [69] investigated in some detail the effect of temperature and metal fluoride on the systems used by Scholl. The product composition depends on the reactivity of the fluoride source and the reaction conditions, i.e., the product may be under kinetic or equilibrium control. In addition to the substances reported earlier by Scholl, they detected others. Later, Chambers et al. [70,71] reacted the nitrogen anion 37c with different trapping agents including haloalkane, perfluoro azaarene, perfluoro cyclobutene, etc., and obtained diverse heterocycles 38.

Meanwhile, Pawelke et al. [72] investigated the transformation of 35 or its derivative in the presence of fluoride source. Cyclization of compound 35 led to the perfluorinated 1H-imidazole 42, whose chlorine atom could be further substituted by OPh or NEt₂.

4.2. Cyclization Based on N-CF₃ Starting Materials

4.2.1. [3+2] Cycloaddition

Utilization of starting materials containing the N-CF₃ motif is a commonly employed strategy for achieving the target heterocyclic compounds. As mentioned in Section 2, perfluorinated oxaziridine 9a could serve as building blocks in organic chemistry. DesMarteau et al. reported that some cycloaddition of oxaziridine 9a with electron-rich alkenes and ketones resulted in oxazolidines or dioxazolidines (Scheme 9) [73,74]. However, perfluorinated oxaziridine 9a also had certain limitations as a building block: attempts to achieve the cycloaddition of 9a with CH₂=CH₂, CFCl=CFCl, perfluorocyclopentene, acrylonitrile, and acetylene have failed. Additionally, the reaction could not occur with fluorinated ketones such as hexafluoroacetone.

In recent decades [3+2] cycloaddition between azide and alkyne has attracted significant attention, and copper-catalyzed azide-alkyne cycloaddition is one of the most widely used forms of this technique [75]. In 2017, Beier et al. reported the synthesis of azidoperfluoroalkanes 43 which could be synthesized from perfluoroalkyl trimethylsilane (TMSR_F) with p-toluenesulfonyl azide (TsN₃) in the presence of CsF, or synthesized from (perfluoroethyl)lithium (R_F = C₂F₅) with TsN₃ [76]. These azidoperfluoroalkanes could undergo [3+2] cycloaddition with alkynes catalyzed by copper to access diverse N-perfluoroalkyl 1,2,3-triazoles 44 (Scheme 10). Later in 2018, Beier et al. reported a mild and efficient and synthesis of highly functionalized 1-perfluoroalkyl-1H-1,2,3-triazoles 45 via in situ generated enamines in azide-ketone [3+2] cycloaddition (Scheme 10) [77].

In the same year, the Beier group developed a highly efficient method for the synthesis of a broad range of previously unreported N-fluoroalkyl-substituted five-membered heterocycles with microwave heating-assisted rhodium-catalyzed transannulation of N-fluoroalkyl-substituted 1,2,3-triazoles 44 [78]. Subsequently, the same group expanded this approach to acetylene substrates and successfully generated N-fluoroalkyl pyrrole (Scheme 11) [79]. The mechanism proposed by authors is shown in Scheme 12.

Xu, Guan, and Wang et al. [80] reported an alternative and scalable cyclization strategy based on N-CF₃-containing synthons for constructing diverse N-CF₃ azoles, including N-CF₃ tetrazoles, N-CF₃ imidazoles, and N-CF₃ 1,2,3-triazoles (Scheme 13). This method involved using a hypervalent iodine reagent for trifluoromethylation in combination with a base to efficiently carry out the reaction. Furthermore, estrone analogue 54 could be generated in two steps in a total of 74% yield. Subsequently, the authors’ group developed the reaction of the N-CF₃ nitrilium ions 51 with N-, O-, and S-nucleophiles, resulting in various N-CF₃ amidines, imidates, and Thioimidates [81]. Very recently, they utilized hypervalent iodine reagent for the trifluoromethylation of 4-alkylamino-pyridine to generate N-CF₃ pyridinium salt which could be further translated to 2-functionlized nicotinaldehydes [82].

4.2.2. Other Cyclization

In addition to [3+2] cycloaddition, other cyclization pathways have been explored for the synthesis of N-CF₃-containing five-membered heterocycles. For instance, Sundermeyer and co-workers reported access to the preparation of imidazolidinedione 55 through the reaction of trifluoromethyl isocyanate with trimethylsilyl cyanide, followed by hydrolysis [83]. In 1977, Rudiger Mews synthesized dioxazolidine 56 from CF₃NO and bis(trifluoromethyl)diazomethane [84]. Lentz reported that trifluoromethyl isocyanide reacted with hexafluoroacetone to yield compound 57 [85]. Later, the same group reacted trifluoromethyl isocyanide with diphosphene, leading to the formation of azaphospholidine 58 [86]. In addition, Crousse et al. developed a direct approach to obtaining N-CF₃ hydrazines from CF₃SO₂Na. Among the family of N-CF₃ hydrazines, hydrazides 59 showed hydrolysis in the presence of HCl and reacted further with diketone, leading to N-CF₃-1H-pyrazoles 60 in 44% yield totally (Scheme 14d) [87].

In 2019, Schoenebeck et al. reported straight access to N-CF₃ amides, carbamates, thiocarbamates or ureas via N-CF₃ carbomoyl building blocks 61 [88]. After that, the same group developed the transformation of the building blocks and generated non-cyclic or heterocyclic N-CF₃ compounds as shown in Scheme 15 [89,90,91,92]. Additionally, antihistamine derivative oxatomide analogue 64a could be generated in 62% in two steps by N-H functionalization of 64.

Meanwhile, Huang and Xu et al. reported the design and synthesis of novel N-CF₃ hydroxylamine reagents 66 as well as their applications in preparation of N-CF₃ compounds [93]. Some oxazolidinones 67 and 67′ could be generated from trifluoromethylamination/cyclization of styrenes or vinyl ether (Scheme 16a). For example, estrone analogue 67a, could be generated in 71% yield. Furthermore, ynamide 68 could be generated from reagent 66, which could further form heterocycles 69 via Pd-catalyzed cyclization (Scheme 16d). Subsequently, the same group employed reagent 66′ and trimethylsilyl cyanide to convert 1,3-enynes to trifluoromethylaminated allenes under a photoredox/copper-catalyzed 1,4-difunctionalization, in which allenes 70 could further yield oxazolidinones 71 in the presence of N-bromosuccinimide (NBS) or N-iodosuccinimide (NIS) (Scheme 16e) [94].

4.3. Electrophilic Trifluoromethylation

In 2006, Togni et al. developed two new trifluoromethylation reagents (72 and 73) based on hypervalent iodine [95,96]. Subsequently, in 2011, the same group reported a Ritter-type direct electrophilic trifluoromethylation at nitrogen atoms using hypervalent iodine reagent 72 and obtained N-CF₃ benzotriazole 74 as a side product (Scheme 17a) [97]. Subsequently, they further refined the method and successfully conducted the trifluoromethylation of a variety of heterocycles (Scheme 17b) [98].

Meanwhile, Umemoto developed diverse derivatives of (trifluoromethyl)dibenzofuranylium that could generate CF₃⁺ anion at a low temperature, which facilitated the electrophilic trifluoromethylation of primary, secondary, or aromatic amines (Scheme 17c) [99]. For example, 1-(trifluoromethyl)indoline could be generated in 68% yield.

5. Six-Membered Heterocycles

From the existing literature, the synthetic methodologies of six-membered heterocycles were similar to the five-membered heterocycles containing the N-CF₃ motif. Therefore, in this section, some examples are shown briefly.

5.1. Nucleophilic Trifluoromethylation

Similarly, oxidative desulfurization and subsequent fluorination was also an efficient way to achieve six-membered heterocycles containing the N-CF₃ motif, such as piperazines and piperidines. For example, Tlili et al. [100] used carbon disulfide and (diethylamino)sulfur trifluoride (DAST) to generate thiocarbomoyl fluoride intermediate 32, and then synthesized a series of N-CF₃ piperazines. Borbas et al. employed DAST and NBS to generate N-CF₃ morpholine while studying N-fluoroalkylated nucleoside analogues [101]. In addition to AgF, pyridinium poly(hydrogen fluoride [8] could also be employed for oxidative desulfurization and fluorination to give the product 31c which exhibited antibacterial activity. These methods allowed the introduction of the CF₃ group into the nitrogen of pharmaceuticals or their analogues, demonstrating the potential of bioactive molecule modification (Scheme 18) [8,62,64].

5.2. [4+2] Cycloaddition

As described in Section 3, CF₃NO could serve as building blocks in cycloaddition. The application of CF₃NO in [4+2] cycloaddition has been investigated [39,102,103,104,105,106,107], yielding various adducts 75 (Scheme 19a). Carson et al. have studied the nucleophilic displacements of fluorine atoms in perfluoro-1,2-oxazines, in particular amino-defluorination reactions [107]. It was established that perfluoro-(3,6-dihydro-2-methyl-2H-1,2-oxazine) reacted with ammonia at room temperature to give a mixture of 4- and 5-amino derivatives, while when reacted with disubstituted amines in diethyl ester at −78 °C it only gave 5-amino compounds. Furthermore, other starting materials featuring N-CF₃ were utilized in [4+2] cycloaddition, as shown in Scheme 19b,c [108,109].

5.3. Other Approaches

In 1976, Haszeldine et al. reported the formation of triazine via unsymmetrical carbodiimide intermediate, which was subsequently dimerized, trimerized or intramolecular cyclized (Scheme 20a) [110]. Similarly, Mews et al. reported that R_FN=S=O reacted with SO₃, leading to the formation of sulfonimide [111]. The degree of oligomer depended on the size of the substituent, and at what time R_F = CF₃, dimer and trimer were formed in the ratio of 3:1 (Scheme 20b).

Direct fluorination of hydrocarbons by fluorine gas was indeed also a method used to synthesize the corresponding fluorous compounds. Lagow et al. reported the synthesis of perfluoro highly-branched heterocyclic fluorine compounds by direct fluorination, and also reported that 1,4-bis(trifluoromethyl)piperazine 79 was highly generated in 85% yield (Scheme 20c) [112].

6. Seven- and Larger-Membered Heterocycles

Perfluoro-2,5-diazahexane-2,5-dioxyl 80 could readily attack nitric oxide and hydrogen-atom donors, giving adducts, such as its monofunctional analogue, bis-trifluoromethyl nitroxide ((CF₃)₂NO) [113,114], which could readily react with fluoro-olefins. In some cases, the reaction of bis-trifluoromethyl nitroxide with a variable valence element compound led to an increase in the oxidation state of that element.

Banks et al. reported that an attack by dioxyl 80 on tetrafluoroethylene or hexafluoropropene led mainly to the formation of copolymers in, and also to a smaller number of adducts (81a, 81b) [115]. It should be noted that the yield of 81b could rise to 63% if the reactants were mixed at room temperature and at ca. 25 mmHg pressure. In addition, Banks et al. pointed out that the formation of adducts would require a gas-phase reaction [113]. Subsequently, Tipping et al. investigated the scope of the cycloadduct formation by using fluoroalkenes and a wide variety of hydrogen-containing alkenes [116]. Their report clearly illustrated the limitations of gas-phase reaction. Such reactions must be restricted to simple ethenes or halogenated propenes due to the possibility of hydrogen abstraction occurring.

Later, Tipping et al. synthesized mercurial 84 from dioxyl 80 and investigated the reaction of mercurial 84 with halogenated alkanes, acid chlorides, and dichlorosilanes [117]. The reaction of mercurial 84 with dichlorodimethylsilane resulted in the formation of silicon-containing heterocycle in 93% yield, while with l,l-dichlorosilacyclobutane, the spiro compound was isolated in 64% yield. On the other hand, Booth et al. reported that the dioxyl 80 could react readily by oxidative addition to [Pt(PPh₃)₄] or [IrCl(CO)L₂] (L = PPh₃, AsPh₃, PMePh₂) to afford the corresponding metal–nitroso complex containing a seven-membered chelate ring [118]. The resulting complexes were stable in air for several days or in N₂ atmosphere for several months.

Meanwhile, Smith et al. reported the reaction of SO₂ and SF₄ with dioxyl 80 and obtained two heterocycles 82a and 82b (Scheme 21) [119]. In neither case was a copolymer formed, something which differed from the results from the reaction of dioxyl 80 with tetrafluoroethene and hexafluoropropene in a previous report [113]. Compound 82a slowly reacted with PPh₃ at room temperature giving deoxidation products 83 and 83′.

Moreover, in 2018, Beier et al. reported another strategy based on N-perfluoroalkyl 1,2,3-triazoles (Scheme 22) [120]. A series of then-unknown N-perfluoroalkyl azepine derivatives were obtained via the aza-[4+3]-annulation of triazoles 44 with both (E)-1-subtituted and 2-substituted dienes. When silyloxy-substituted butadiene was employed, N-CF₃ azepinone 86′ could be prepared.

7. Other Methods

In addition to the methods mentioned above, various other synthetic routes have been explored for the generation of heterocycles containing the N-CF₃ motif. However, considering the involvement of multiple cyclic structures in these methods, their classification is challenging. Therefore, these approaches are described in this section.

In 1971, Ogden [121] reported a route to some perfluoroheterocyclic compounds via fluoride ion. In his work, tetrafluoroformaldazine 87 reacted with oxalyl fluoride and other carbonyl fluorides and obtained the heterocycles 88, which could be further photolysis to smaller heterocycles 89 (Scheme 23).

In early organic chemistry, pyrolysis was an effective tool used to study the composition and properties of substances. For example, Banks et al. found that pyrolysis of perfluoropiperidine or perfluoromorpholine led to the generation of N-CF₃ pyrrolidine 90a or N-CF₃ oxazolidine 90b, respectively [102,122,123,124]. The pyrolysis of perfluorooxazinane in platinum at 480 °C led to the formation of perfluoro-(1-methylazetidine) 91 in 73% yield and trace perfluoro-(1-methyl-2-pyrrolidone) 92, while at 580 °C/19 mm, the yield of 91 and 92 changed to 48% and 24%, respectively (Scheme 24a).

Tatlow et al. investigated the fluorination of 4-methylpyridine in the presence of caesium tetrafluorocobaltate (CsCoF₄) and obtained perfluoro-(1,3dimethylpyrrolidine) 93 and its analogue, together with a range of (per)fluoro-pyridine bearing CF₃, CHF_2, and CH₂F groups (Scheme 24b) [125]. Similar to CsCoF₄, CoF₃ was a useful reagent for the preparation of a wide array of highly fluorinated organic molecules including open chain/cyclic aliphatics and aromatics. However, the high reactivity of CoF₃ meant that most of these reactions were relatively unselective with poor functional compatibility [126].

In addition, electrochemical fluorination (ECF) was one of the most commonly used methods for the fluorination of nitrogen-containing materials [127]. In the past few decades, many different nitrogen-containing materials [128,129,130,131,132,133] have been used in the ECF (Scheme 24c), but the yield was generally unsatisfactory (mostly < 20%) and side products were inevitable, which limited the scope.

8. Conclusions

Over the last decades, the chemistry of the N-CF₃ motif has been weakly developed because of the limited approaches and an incompatibility with functionalized molecules. Very recently, some new simpler, safer, and powerful methods of obtaining this motif have been explored. In general, the existing literature mainly focuses on synthesis, with limited properties or applications. In three-membered heterocycles containing the N-CF₃ motif, cycloaddition, reductive defluorination-cyclization, nucleophilic cyclization, and oxidative cyclization can reach the motif. Among them, properties and applications of oxaziridine were reported (oxidant or building blocks [25,34,73,74]), while other three-membered heterocycles were not reported. In four-membered heterocycles, cycloaddition was the predominant approach, while trifluoronitrosomethane was the most common starting material. Similarly, there were limited reports on the applications of four-membered heterocycles containing the N-CF₃ motif. In five-membered heterocycles, Scheiesser et al. [45] studied, for example, the stability in aqueous media, lipophilicity and metabolic stability of various N-CF₃ amines or azoles, illustrating the potential of the N-CF₃ motif in medicinal chemistry. Generally, five-membered heterocycles containing this motif can be synthesized from nucleophilic fluorination, cyclization, and electrophilic trifluoromethylation. Furthermore, N-fluoroalkyl 1,2,3-triazoles could serve as the building blocks to access some other N-fluoroalkyl heterocycles [78,79,120]. In six-membered heterocycles, the synthetic approaches were similar. In larger-membered heterocycles, the perfluoro-2,5-diazahexane-2,5-dioxyl showed its potential in coordination chemistry. The dioxyl could react readily with [Pt(PPh₃)₄] or [IrCl(CO)L₂} to form the corresponding metal–nitroso complex containing a seven-membered chelate ring which was stable in air for several days or in N₂ atmosphere for several months [118].

Overall, the literature has concentrated on the synthesis of this motif in recent years, and research investigating its properties or applications is becoming more frequent. We believe that the chemistry of the motif will become more and more clear, thereby extending its fields of application. We expect that this review will help to inspire the development of new synthetic strategies or the application of certain structures.

Author Contributions

Conceptualization, Z.Z.; writing—original draft preparation, Z.L. and H.G.; writing—review and editing, W.C. and J.F.; visualization, Z.L. and J.F.; supervision, Z.Z. and J.F.; project administration, Z.Z. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

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Figures, Schemes and Tables

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.

Table 1

Half-life of N-CF₃ compounds 19a–24a ^[a].

Structure	pH 1.0 [d]	pH 7.4 [d]	pH 10.0 [d]
19a	0.2	0.4	0.3
20a	<0.6	<0.6	<0.6
21a	>72	>72	>72
22a	>72	>72	>72
23a	>72	>72	71
24a	<1.3	<0.8	<0.5

^[a] The experiment was carried out at 25 °C in 0.1 M HCl solution (pH 1.0), 20 mM sodium phosphate buffer (pH 7.4), and 20 mM carbonate buffer (pH 10.0).

Table 2

Overview of the change in key in vitro properties when exchanging N-CH₃ and N-CF₃ ^[f].

Structure	Number	Log D7.4 [a]	Chrom-log D7.4 [a]	ePSA [b][Å2]	Caco-2 Papp [c][10−6 cm/s]	HLM [d][L/min/mg]
[Image omitted. Please see PDF.]	19aR = CF3	1.6 (0.1)	1.5 (0.1)	82 (1)	nd [e]	nd [e]
	19bR = CH3	0.6 (0.1)	1.3 (0.1)	81 (1)	nd [e]	nd [e]
[Image omitted. Please see PDF.]	20aR = CF3	>4.0	4.9 (0.2)	38 (2)	nd [e]	nd [e]
	20cR = CH3	2.8 (0.1)	3.3 (0.1)	50 (1)	nd [e]	nd [e]
[Image omitted. Please see PDF.]	21aR = CF3	3.7 (0.1)	3.3 (0.0)	73 (1)	61 (27)	47 (11)
	21bR = CH3	2.7 (0.1)	2.2 (0.1)	92 (1)	72 (1)	4.8 (1.9)
[Image omitted. Please see PDF.]	22aR = CF3	3.0 (0.1)	3.3 (0.0)	39 (2)	58 (18)	39 (18)
	22bR = CH3	2.3 (0.0)	1.5 (0.1)	56 (1)	72 (20)	172 (41)
[Image omitted. Please see PDF.]	23aR = CF3	2.2 (0.1)	2.2 (0.0)	92 (1)	12 (8)	<3.0
	23bR = CH3	0.6 (0.1)	<0.0	98 (0)	2.4 (0.9)	<3.0
[Image omitted. Please see PDF.]	24aR = CF3	>4.0	>5.3	67 (1)	nd [e]	nd [e]
	24bR = CH3	2.7 (0.1)	3.3 (0.1)	73 (0)	nd [e]	nd [e]

^[a] Due to limitations in the determination of log D_7.4 using the shake-flask method, exact values for measured log D_7.4 > 4 are given as >4.0. ^[b] Experimentally determined polar surface area. ^[c] Apical to basolateral passive permeability across the Caco-2 cell monolayer in the presence of inhibitors against the three major efflux transporters: P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug-associated protein 2 (MRP2). ^[d] Metabolic stability of the compound measured as the disappearance of the parent compound over time when incubated with human liver microsomes. ^[e] Due to the low stability of compounds 19a, 20a, and 24a in an aqueous environment, which would interfere with the proper determination of their metabolic stability or Caco-2 permeability, no metabolic stability or Caco-2 permeability was determined for these compounds or for their N-methyl analogues. ^[f] Each experimental value is the mean of at least three independent replicates. The standard deviation is given in brackets.

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