Synthesis of N-trifluoromethylsulfilimines via trifluoromethyl nitrene and their synthetic potential

Abstract

Trifluoromethyl nitrene generated photocatalytically from azidotrifluoromethane was added to sulfides to afford new N-trifluoromethylsulfilimines. Their methylation yielded N-methyl-N trifluoromethyl sulfonium salts and oxidation provided N-trifluoromethyl sulfoximines.

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Introduction

Fluorinated compounds are essential across various disciplines, including materials science, agrochemistry, and pharmaceuticals. Notably, over 20% of approved drugs feature at least one fluorine atom,^1–7 underscoring the critical need for advanced synthetic strategies that enable the precise and selective incorporation of fluorine atoms and fluorine-containing moieties into molecular frameworks. Recent studies have shown that the substitution of an azole by the trifluoromethyl group might enhance its medicinal properties such as cell membrane permeability, lipophilicity, and metabolic stability.⁸ Regardless of their high demand, N-fluoroalkylated compounds are still much less explored in comparison to their O-, S-, and C-fluoroalkylated counterparts, which is partly due to their underdeveloped synthetic approaches. Despite the extensive literature on fluoroalkylation, direct fluoroalkylation is challenging due to the selectivity issues, particularly in the late-stage modification of complex substrates.^9,10 For instance, rather than introducing a fluoroalkyl group onto a heteroatom such as nitrogen, it may be more efficient to incorporate the heteroatom-fluoroalkyl unit into the molecule in a single step.

The incorporation of N–R into a molecular framework with R being alkyl, acyl, or aryl might be envisioned via nitrenes. Nitrenes have been utilized in synthetic organic chemistry for several decades for the modification of various structures.¹¹ Nowadays, there are numerous methods known for the generation of these highly reactive species in situ under mild and well-controlled conditions.¹² The most atom-economical way starts from the corresponding azides by photolysis, heating, or microwave-assisted methods, by which a molecule of nitrogen is eliminated to form the electrophilic nitrene.^13,14 The application of these uncharged species might be favoured as they can be utilized in the late-stage modification or skeletal editing of molecules.¹⁵

Previously, fluoroalkylated nitrenes were not known to partake in intermolecular reactions as they were formed under harsh conditions that promoted their quick rearrangement and decomposition.^16,17 Last year, we published a method that enabled the generation of triplet trifluoromethyl nitrene (CF₃N) by mild, photochemical conditions and showcased the utilization of the nitrene in alkene aziridination (Scheme 1).¹⁸

Scheme 1 Synthetic application of triplet trifluoromethyl nitrene. Our previous study and the present work.

Apart from aziridination and C–H amination reactions, nitrenes are known to transfer to electron-rich heteroatoms such as sulfur.^19,20 The resulting products are sulfilimines, featuring an S=N double bond, with electrophilic character at the sulfur atom and nucleophilic character at the nitrogen atom, which opens the possibility for further modifications.²¹ Different sulfilimines are known in the literature having various substituents on the nitrogen atom such as alkyl, aryl,²² or electron-acceptor moieties such as acyl²³ or tosyl.²⁴ Sulfilimines are good substrates for the preparation of biologically relevant sulfoximines by simple oxidation. The significance of these molecules is demonstrated by their diverse applications,^25,26 including their use as a pest control agent (sulfoxaflor)²⁷ and as an ATR inhibitor (ceralasertib).²⁸

In the present study, we aimed at harvesting further the reactivity of in situ generated triplet trifluoromethyl nitrene by the preparation of novel N-trifluoromethyl sulfilimines from sulfides. The synthetic application of these novel structures was shown through the preparation of their derivatives: N-methyl-N-trifluoromethyl sulfonium salts and N-trifluoromethyl sulfoximines (Scheme 1).

Results and discussion

Azidotrifluoromethane was prepared according to our previously published procedure.¹⁸ We described the generation of trifluoromethyl nitrene using Ir(ppy)₃ as a photocatalyst through energy transfer. Then we optimized the conditions for the formation of previously unknown N-trifluoromethyl sulfilimines 2 (Table 1). First, the catalyst load was examined by irradiating the reaction mixture for 30 min with different equivalents of the photocatalyst (entries 1–4). It showed that increasing the amount of Ir(ppy)₃ resulted in a higher ¹⁹F NMR yield. Next, the procedure was conducted separately, without a photocatalyst and light, which ensured that both were necessary for the reaction to occur (entries 5 and 6). Finally, the reaction time was optimized (entries 7–9). From the comparison of entries 8 and 9, it is evident that the reaction reached almost full conversion in 90 minutes, but to make sure that quantitative yield is achieved a two-hour irradiation was used.

Table 1 Optimization of photocatalytic sulfilimination^a

Entry	Ir(ppy)3 (mol%)	Time (min)	Yield of 2a ^b (%)
a 1a (0.1 mmol), CF3N3 (3 equiv.), Ir(ppy)3, 3 Å molecular sieves, DCE/DCM under Ar atmosphere, irradiated with visible light LED (λmax = 400 nm, 3 W). b ^19F NMR yields using PhCF3 as an internal standard. c No light.
1	1.0	30	37
2	2.0	30	55
3	3.5	30	62
4	5.0	30	71
5^c	5.0	30	0
6	—	30	0
7	5.0	60	88
8	5.0	90	98
9	5.0	120	>98

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The scope of the photochemical sulfilimination reaction, including the major limitations, is summarized in Scheme 2. The optimized conditions were applicable to a broad range of sulfides; however, electron-rich diaryl sulfides showed the highest reactivity. Compounds 2a–h formed in high yields and in most cases, quantitative ¹⁹F NMR yields were achieved. Scale-up from 0.1 mol to 1 mmol scale of 2a required the extension of reaction time from 2 hours to 6 hours. Compounds 2g and 2h were obtained in excellent yields and exhibited high stabilities. Additionally, the structure of 2g was confirmed by single-crystal X-ray diffraction analysis. Notably, in the case of 2h, only one of the sulfur atoms participated in the reaction, and no trace of a double sulfiliminated product was detected. Compounds 2i and 2j gave less favorable results: in the case of 2i, an unidentified side product formed, while the yield of 2j was lower due to possible C–H amination at the activated benzylic position. The electron-acceptor acyl group was tolerated on the aromatic ring of the sulfide; however, in the ortho position the steric hindrance further reduced product yield (2l). Generally, diaryl sulfimines showed sufficient stability for purification by crystallization. The unreacted substrate was washed off with an apolar solvent, and the product dissolved in diethyl ether which efficiently removed the residual catalyst and any decomposed material. Aryl–benzyl and aryl–alkyl sulfides took part in the sulfilimination reaction efficiently; however, product stabilities were reduced. Compounds 2m and 2n can be handled at room temperature, but during the lengthy process of crystallization, both slowly decomposed. Products 2o and 2p formed almost quantitatively, but 2o was unstable even at −20 °C in solution or neat. In product 2q the t-Bu group was partially cleaved with the applied irradiation conditions. The formation of products 2r and 2s showed that the reaction efficiently proceeds with dialkyl substrates. Together with 2n, they show that the procedure can be applied in late-stage introduction of the N-CF₃ moiety into complex sulfides. The major limitation of the scope were electron-deficient substrates. Thiophene derivatives and electron-poor sulfides afforded products only in low to moderate yields. Vinyl sulfide reacted partially on the alkene moiety in alkene aziridination fashion. Other electron-poor sulfides were mostly unreactive. Side reactions were not observed which showed that the process is generally selective to the electron-rich sulfur atom. Exceptions were compounds 1aa, which gave 3 in good yield by thiol elimination, and 1ab, which underwent a rearrangement after initial sulfimination at low temperature.

Scheme 2 Sulfilimination scope. Sulfide (0.1–0.2 mmol), Ir(ppy)₃ (5 mol%), CF₃N₃ (3 equiv.) and 3 Å molecular sieves sealed under argon at 0 °C irradiated for 2 h with LED light (400 nm, 3 W); isolated yields; ¹⁹F NMR yields using PhCF₃ as an internal standard in parentheses. ^a 1 mmol scale and 6 h reaction time.

Next, we explored the reactivity novel N-CF₃ sulfilimines 2. Some N-substituted sulfilimines were shown to undergo methylation on nitrogen to form sulfonium salts. This area has been relatively unresearched in recent decades as most of the relevant literature is from the 1970s and 1980s. Strong methylating reagents, such as FSO₃Me,²⁹ CF₃SO₃Me³⁰ and (Me₃O)BF₄³¹ were used for methylation of electron-poor sulfilimines. Several examples of the exotic N-methyl-N-trifluoromethyl sulfonium salts 5 were prepared and isolated as hexafluorophosphate salts by reacting sulfilimines 2 with the Meerwein salt, followed by ion exchange (Scheme 3).

Scheme 3 Preparation of N-methylated sulfonium salts 5 in one pot from 1.

Sulfilimines are known to be oxidized to sulfoximines by various oxidants. Several conditions were tested: KO₂³² or KMnO₄³³ in the presence of crown ether, Davis reagent, mCPBA with K₂CO₃,³⁴ TPAP with NMO³⁵ and RuCl₃ in the presence of periodate for the in situ formation of ruthenium tetroxide.³⁶ In the case of sulfilimines 2, the modified methods utilizing mCPBA or the RuCl₃/NaIO₄ systems resulted in oxidation. However, with mCPBA only a maximum of 30% conversion could be reached. Reaction optimization with Ru(III) was conducted on compound 2a (Table 2). The process gave a mixture of products; apart from the anticipated sulfoximine (6a), diphenyl sulfone (7a) was formed.

Table 2 Optimization of the sulfoximination process to 6a

Entry	Oxidant	MeCN/DCE/H2O	6a/7a
a RuCl3·H2O (20 mol%). b Under N2 atmosphere.
1^a^,^b	NaIO4	1 : 1 : 2	48 : 52
2^a	NaIO4	1 : 1 : 2	82 : 18
3	NaIO4	1 : 1 : 2	83 : 17
4	n-Bu4NIO4	1 : 1 : 1	31 : 69
5	n-Bu4NIO4	2 : 0 : 1	10 : 90
6	n-Bu4NIO4	10 : 10 : 1	1 : 99
7	n-Bu4NIO4	1 : 1 : 0	1 : 99
8	n-Bu4NIO4	1 : 1 : 2	86 : 14
9	n-Bu4NIO4	0 : 1 : 1	91 : 9
10	NaIO4	0 : 1 : 2	58 : 42
11	n-Bu4NIO4	0 : 1 : 2	75 : 25
12	NaIO4	0 : 1 : 1	73 : 27

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First, NaIO₄ was tested with a higher Ru(III) load under an inert and oxygenated atmosphere (entries 1 and 2). In both cases, full conversion was achieved within the two-hour reaction time; however, the absence of oxygen negatively impacted the 6a/7a ratio. The catalyst load was reduced to 5 mol% which resulted in approximately the same product ratio (entry 3). Periodate with a lipophilic tetrabutylammonium cation was tested in different solvents (entries 4–9) revealing that this oxidant was superior to NaIO₄. The reaction was best conducted in DCE/water mixture as in the absence of water only sulfone 7a was formed.

Applying the optimized conditions (entry 9), a range of N-trifluoromethyl sulfoximines 6 was prepared and isolated successfully in moderate to good yields (Scheme 4). The oxidative procedure worked efficiently with various substrates including diaryl, aryl–alkyl and even dialkyl substituted sulfilimines. Good yields were obtained mainly with the diaryl-substituted sulfilimines. In the case of 6h the free sulfur atom was also oxidized during the reaction upon using a higher excess of the oxidant. Additionally, structures 6a, 6g and 6h were confirmed by single-crystal X-ray analysis. Moderate yields of sulfoximines 6m, 6p and 6r were obtained from rather unstable, non-isolable sulfilimines. In the case of 6r a mixture of diastereomers in 1 : 1 ratio was isolated. The procedure was extended to more complex structures such as 6n and 6r. The scope clearly demonstrated that even poorly stable N-CF₃-sulfilimines can be oxidized using this procedure, yielding products stable in aqueous media. This paves the way for further exploration of the properties of these rare trifluoromethyl-containing sulfoximine moieties.

Scheme 4 Scope of the sulfoximines 6 prepared in two steps from sulfides 1. ^a n-Bu₄NIO₄ (5 equiv.).

Conclusions

In conclusion, we demonstrated a new reactivity of the in situ formed trifluoromethyl nitrene under mild photocatalytic conditions. This highly reactive nitrene species selectively added to electron-rich sulfides, leading to previously unreported N-CF₃ sulfilimines. They were further functionalized through nitrogen methylation and sulfur oxidation giving N-methyl-N-trifluoromethyl sulfonium salts and N-trifluoromethyl sulfoximines, respectively. Access to these structures significantly enhances the diversity of N-CF₃-containing molecular library, offering promising opportunities for applications in synthetic and medicinal chemistry.

Author contributions

N. B. conceived the idea, performed experiments, and partially wrote the manuscript, M. D. performed NMR experiments, L. J. T. synthesized and characterized 1n, B. K. performed X-ray crystallography. P. B. conceived the idea, acquired funding, administered and supervised the project, and partially wrote the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the ESI.† Crystallographic data has been deposited at the CCDC under the following accession numbers: 2g (2457295), 5b (2457296), 5g (2457297), 6a (2457298), 6g (2457299), 6h (2457300).†

Acknowledgements

This research was financially supported by the Czech Academy of Science (Research Plan RVO: 61388963) and Czech Science Foundation (Project 23-04659S). We thank the following researchers from IOCB Prague: Dr Eszter Szánti-Pintér for providing steroid substrates and Dr Lucie Bednářová for IR measurements.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2457295–2457300. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d5qo00873e

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