Oxidative trifluoromethylthiolation and thiocyanation of amines: a general approach to N–S bond formation

Abstract

Herein, we described a practical and efficient one-pot oxidative trifluoromethylthiolation of amines. A panel of primary and secondary amines was functionalized in good yields at room temperature. This general approach was further applied to the thiocyanation of anilines and the corresponding products can be readily used as SCN electrophilic sources.

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Over the last few years, the organofluorine research field has witnessed a rapid expansion¹ which could be explained by the number of pharmaceuticals and agrochemicals containing at least one fluorine atom.² Indeed, due to the unique features of the fluorine atom to modify the biological and physical properties of a molecule,³ its presence is often crucial for the discovery of biorelevant molecules. Consequently, a large panel of fluorinated groups is available and their introduction onto molecules can be realized by means of various transformations. In this blossoming field, the SCF₃ moiety is now considered as an emerging fluorinated group thanks to its interesting features such as its high lipophilicity and its strong electron-withdrawing character.⁴ In this context, several original and elegant transformations to introduce the SCF₃ group onto unsaturated and aliphatic derivatives have been reported.⁵ Very recently, special attention has been paid to the formation of the N–SCF₃ bond. Indeed, trifluoromethanesulfenamides and more generally sulfenamide-containing molecules are compounds of interest. These key molecules have already demonstrated interesting applications in the rubber industry, in agrochemistry and in pharmaceutical research for instance.⁶ This particular interest results from the good lipophilicity of the N–SCF₃ group (Hansch parameter, π_R = 1.50) compared to other fluorinated groups.⁷ In addition, molecules bearing a N–SCF₃ group appeared as versatile electrophilic sources of SCF₃.^5a,b As a consequence, several research groups reported elegant synthetic pathways to access these derivatives (Fig. 1). To avoid the use of toxic and volatile reagents (e.g. ClSCF₃, (SCF₃)₂),⁸ Langlois, Billard and co-workers^9a reported the synthesis of trifluoromethanesulfenamides using primary amines, diethylaminosulfur trifluoride (DAST™) and the Ruppert–Prakash reagent (TMSCF₃). Note that secondary amines were unreactive under these conditions. Later, Billard and co-workers overcame that limitation by designing a base-mediated transamination process involving reagent I.^9b In 2014, Rueping and co-workers reported the electrophilic trifluoromethylthiolation of aliphatic and benzylic amines using the Munavalli reagent II. However, in the case of anilines and secondary amines, the reaction required the additional use of a strong base (n-BuLi), limiting the scope of the process.^7a Shen and co-workers designed a new SCF₃ electrophilic reagent (N-trifluoromethylthiosaccharin III), which allowed the functionalization of amines within a panel of nucleophiles.^9c Moreover, in 2015, the group of Shibata depicted an alternative pathway to synthesize a broad range of trifluoromethanesulfenamides by means of a copper-catalyzed transformation with the electrophilic trifluoromethanesulfonyl hypervalent iodonium ylide IV.^7b In light of these considerations, we aimed at developing a general and straightforward access to trifluoromethanesulfenamides from amines. This approach avoids the employment of the commonly used electrophilic SCF₃ reagents, usually prepared from a nucleophilic SCF₃ source.

Fig. 1 State of the art.

To build up the N–SCF₃ bond, we envisioned an oxidative trifluoromethylthiolation of amine derivatives using a nucleophilic SCF₃ source (AgSCF₃) and an oxidant (Fig. 2).¹⁰ We hypothesized that a N-halo amine derivative could be in situ generated from the reaction between an amine and a suitable oxidant.¹¹ The latter would then undergo an anionic metathesis with AgSCF₃ to afford the expected product. To achieve this goal, we anticipated that the main synthetic issues to tackle would be: (1) the selective generation of the required N-halo (aryl)amine A prior to the formation of the unreactive electrophilic SCF₃ source, resulting from the in situ reaction between the oxidant and AgSCF₃ ¹² (Fig. 2); and (2) the possible competitive intramolecular halogenation of the aromatic ring¹³ over the desired anionic metathesis with the silver salt.

Fig. 2 Proposed strategy.

Keeping these considerations in mind, we initially investigated the N-trifluoromethylthiolation of 4-fluoroaniline 1d in the presence of a stoichiometric amount of AgSCF₃ and N-bromophthalimide (N-Br-Phth) as an oxidant in CH₂Cl₂ at rt. Under these reaction conditions, we were pleased to observe traces of the expected product 2d (Table 1, entry 1). Gratifyingly, the replacement of N-Br-Phth by its chlorinated analogue provided a significant enhancement of the reaction yield since 2d was obtained in 79% NMR yield (Table 1, entry 2), whereas the use of the N-chlorosaccharin provided 2d in a poor yield (Table 1, entry 3). Finally, we found that NCS was the best oxidant giving 2d in 86% NMR yield (Table 1, entry 4). Then, a screening of solvents revealed that THF was highly beneficial for the desired transformation (Table 1, entries 4–7). Moreover, we observed that the transformation turned out to be quite robust since the reaction performed under an air atmosphere gave a similar NMR yield (98%) and 2d was isolated in 92% yield (Table 1, entry 8).

Table 1 Optimization of the reaction conditions^a

Entry	Oxidant	Solvent	Yield^b (%)
a Reaction conditions: 1 (0.2 mmol), oxidant (0.24 mmol, 1.2 equiv.), AgSCF3 (0.24 mmol, 1.2 equiv.), solvent (0.1 M), 25 °C, argon, 2 h. b NMR yield determined by ^19F NMR using α,α,α-trifluoroacetophenone as an internal standard. c Reaction run on a 0.1 mmol scale. d Reaction performed under an air atmosphere. e Isolated yield. Phth = phthalimide. Sacc = saccharin. NCS = N-chlorosuccinimide.
1	N-Br-Phth	CH2Cl2	7
2	N-Cl-Phth	CH2Cl2	79
3	N-Cl-Sacc	CH2Cl2	11
4	NCS	CH2Cl2	86
5^c	NCS	CH3CN	41
6^c	NCS	Toluene	83
7^c	NCS	THF	97
8^c^,^d	NCS	THF	98 (92)^e

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With the best conditions in hand, we investigated the scope of the reaction (Table 2). First, a wide range of primary aniline derivatives with different substitution patterns was evaluated. The reaction proceeded smoothly with aromatic rings bearing either an electron-donating (tBu and OMe, 2b and 2c) or an electron-withdrawing group (halogens or CF₃; 2d–g) showcasing the functional group tolerance of the process. The substitution pattern on the aromatic ring does not have an influence on the outcome of the reaction since meta-substituted anilines with various substituents (2h–2j) were obtained in good yields (up to 93%). Notably, the presence of halogens on the aryl group (2f, 2g, 2j and 2k) might allow further functionalizations through cross-coupling reactions, for instance. Di-and tri-substituted anilines (1k and 1l) provided the expected trifluoromethanesulfenamides 2k and 2l, albeit in lower yields. To further demonstrate the synthetic utility of such an approach, a reaction has been performed on a 3 mmol scale and the expected compound 2a was obtained in 88% yield. Interestingly, the secondary amine, N-methylaniline 1m, was converted into the expected compound 2m in a moderate yield. Importantly, this approach constitutes an alternative and straightforward access to the electrophilic Billard–Langlois reagents (2a and 2m). It is worth mentioning that heteroarylamines (2n and 2o) were also functionalized in decent yields. Moreover, primary and secondary aliphatic amines were suitable substrates giving the corresponding trifluoromethanesulfenamides in fairly good yields (2p–2u). The versatility of the method was further illustrated through the synthesis of the SCF₃-containing analogues of biorelevant molecules such as L-phenylalanine and tryptamine derivatives (2s and 2t) in 42% and 83% yields, respectively. Note that in the case of 2t, the selective functionalization of the primary amine over the aromatic ring was observed. Even the diamine 1u was functionalized demonstrating the possibility to use secondary amines albeit in lower yield.¹⁴

Table 2 Scope of the trifluoromethylthiolation reaction of amine derivatives^a

a Reaction conditions: 1 (0.2 mmol), NCS (0.24 mmol, 1.2 equiv.), AgSCF₃ (0.24 mmol, 1.2 equiv.), THF (0.1 M), 25 °C, air, 2 h. b The reaction was carried out on a 3 mmol scale. c 20 h. d 24 h. e 12 h. f 8 h. g The reaction was carried out on a 0.5 mmol scale. h 4 h. i 2.4 equiv. of AgSCF₃ were used. j 1 equiv. of Et₃N was added. k 2.4 equiv. of NCS were used.

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Besides, organic thiocyanates are an important and versatile class of compounds with large potential for applications in several research fields.¹⁵ The intrinsic ability of the SCN moiety to be converted into other functional groups makes this functional group very appealing from a synthetic point of view. As a consequence, the development of new and efficient methodologies to synthesize these key thiocyanate building blocks has been depicted. In this context, we have been interested in extending our strategy to the N–SCN bond formation. To our delight, the above-described strategy was successfully applied to the thiocyanation of aniline derivatives showcasing the generality of this approach. Several anilines bearing different substitution patterns were functionalized in good yields (71–87%) on a large scale (2 or 3 mmol) offering an efficient synthetic access to such derivatives (Table 3). The aniline derivative 3a was synthesized in 76% yield, and even the sterically hindered substrate 3b was functionalized in good yield despite a longer reaction time. Halogen atoms like fluorine and chlorine were tolerated (3c and 3d) showcasing the functional group tolerance of the process. Interestingly, the inexpensive NaSCN can be used as a nucleophilic SCN source furnishing 3c in a similar yield (75%), a real asset for the reaction on a larger scale.¹⁶

Table 3 Scope of the thiocyanation reaction of aniline derivatives^a

a Reaction conditions: 1 (2 mmol), NCS (2.4 mmol, 1.2 equiv.), AgSCN (2.4 mmol, 1.2 equiv.), THF (0.1 M), 25 °C, air, 2 h. b The reaction was carried out on a 3 mmol scale. c 18 h instead of 2 h. d The reaction was carried out on a 0.2 mmol scale and NaSCN was used instead of AgSCN.

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As an alternative to the unstable thiocyanogen (SCN)₂, N-thiocyanatosuccinimide (NTS)^16,17 and in analogy with the Billard–Langlois reagent, these N-(cyanosulfanyl)aniline derivatives 3 might be considered as SCN electrophilic sources. To further demonstrate their synthetic utility, reactions with nucleophiles were carried out. Pleasingly, Friedel Crafts-type reactions with a non-protected indole and 1,3,5-trimethoxybenzene furnished the desired thiocyanates 4 and 5 in high yields. This represents a straightforward method for the introduction of the thiocyanate group onto aromatic and heteroaromatic compounds (Scheme 1).

Scheme 1 Application of 3c as an electrophilic SCN source.

From a mechanistic point of view, two plausible pathways might be envisioned for the trifluoromethylthiolation transformation: (1) the chlorination of the amine followed by an anionic metathesis with AgSCF₃ or (2) the in situ formation of the SCF₃ electrophilic source followed by the nucleophilic attack of the amine.¹⁸ To ascertain that there is no reaction with the electrophilic SCF₃ source that might be in situ generated from NCS and AgSCF₃,¹⁹ we carried out reactions of 1d and 1m in the presence of 1-(trifluoromethylthio)pyrrolidine-2,5-dione in THF (Scheme 2). Interestingly, both reactions did not provide any trace of products 2d and 2m after 2 h by ¹⁹F NMR. In light of these results, the following mechanism might be proposed: first, the chlorination of the amine 1 by NCS would lead to a plausible N-chloroamine as an intermediate. This latter might undergo an anionic metathesis in the presence of AgSCF₃ to afford the expected product 2.

Scheme 2 Control experiments and the proposed mechanism.

In conclusion, we have developed an oxidative trifluoromethylthiolation of amine derivatives using AgSCF₃ as the nucleophilic source under mild conditions. This methodology offers an easy, safe and practical access to the valuable trifluoromethanesulfenamides. The developed strategy avoids the use of electrophilic sources, which require extra synthesis steps. The preliminary results regarding the mechanism indicate a two-step and one-pot process. Moreover, this strategy was successfully applied to the synthesis of original N-(cyanosulfanyl)aniline derivatives and their features to act as electrophilic SCN sources were demonstrated. Beyond doubt, these results would significantly broaden the toolbox for the synthesis of trifluoromethanesulfenamides and organic thiocyanate derivatives.

This work has been partially supported by INSA de Rouen, Université de Rouen, CNRS, LABEX SynOrg (ANR-11-LABX-0029), EFRD and Région Haute-Normandie (CRUNCh network). H.-Y. X. thanks the CSC for a doctoral fellowship.

Notes and references

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14. Note that in the case of sulfonamide derivatives, our standard procedure did not work and a sequential two-step process was required to obtain the expected compound. The use of TCCA (trichloroisocyanuric acid) instead of NCS was necessary and the reaction with AgSCF₃ led to the corresponding trifluoromethylthiolated sulfonamide in only 31% yield (see the ESI,† compound 2v).
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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6qo00064a

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