Visible-light photocatalytic trifluoromethylthiolation of aryldiazonium salts: conversion of amino group into trifluoromethylthiol group

Xia Zhao*a, Xiancai Zhenga, Miaomiao Tiana, Yifan Tonga, Bo Yanga, Xianfu Weiab, Di Qiua and Kui Lub
aCollege of Chemistry, Tianjin Key Laboratory of Structure and Performance for Functional Molecules, Key laboratory of Inorganic–organic Hybrid Functional Material Chemistry, Ministry of Education, Tianjin Normal University, Tianjin 300387, China. E-mail: hxxyzhx@mail.tjnu.edu.cn
bCollege of Biotechnology, Tianjin University of Science & Technology, Tianjin 300457, China

Received 18th April 2018 , Accepted 26th May 2018

First published on 28th May 2018


A visible-light photocatalytic trifluoromethylthiolation of aryl amine through in situ generation of aryldiazonium salts as key intermediates was achieved with S-trifluoromethyl 4-methoxylbenzenesulfonothioate for the first time. The mild reaction conditions and readily accessible reagents provide a practical protocol to prepare aryl trifluoromethylthioether.


Introduction

The trifluoromethylthiol group (SCF3) has attracted great attention of both academia and industry because of its special physical and chemical properties.1 Its good lipophilicity helps tune the cell membrane permeability to improve bioavailability.2 Although a variety of efficient methods have been developed to form the C–SCF3 group,3 new methods to incorporate the SCF3 group under mild conditions are still highly desirable.

Arylamines are widely used in research laboratories and industry because of their ready accessibility, low cost, and diverse reactivity.4 Arene diazonium salts, easily prepared from aromatic amines, are important intermediates in organic transformation. Among the organic transformations, Sandmeyer-type reactions5 are employed for direct conversions of the aromatic amino group to boryl,6 phosphoryl,7 stannyl,8 and trifluoromethyl groups.9 Recently, the Wangelin group reported a visible-light photocatalytic trifluoromethylthiolation of arenediazonium salts with 1,2-bis(trifluoromethyl)disulfane (F3CS)2.10 However, (F3CS)2 is a toxic low boiling point (bp ≈ 34 °C) reagent, which limits its practical application.

As a part of our ongoing program to develop efficient methods to construct C–SCF3 bonds,11 we recently reported a silver-mediated radical aryltrifluoromethylthiolation of activated alkenes by S-trifluoromethyl 4-methylbenzenesulfonothioate,12 which was also used as a F3CS radical source by Shen and Xu's group.13,14 Herein, we report a visible-light photocatalytic trifluoromethylthiolation of arylamines with S-trifluoromethyl 4-methoxylbenzenesulfonothioate through aryldiazonium salts as key intermediates (Scheme 1).


image file: c8qo00401c-s1.tif
Scheme 1 Visible-light photocatalytic trifluoromethylthiolation of aryldiazonium salts.

Results and discussion

First, 4-(ethoxycarbonyl)benzenediazonium tetrafluoroborate (1a) was treated with S-(trifluoromethyl) 4-methoxybenzenesulfonothioate (2a) in the presence of Eosin Y under green light irradiation in dimethyl sulfoxide (DMSO) at room temperature. To our delight, the desired trifluoromethylthiolation product 3a was obtained in 61% yield. To optimize the reaction conditions, various photocatalysts such as Eosin Y-Na2, Rhodamine B, Methylene Blue, Rose Bengale, and Ru(bpy)3(PF6)2 (Table 1, entries 2–6) as well as different types of visible light were investigated (entries 7 and 8). We found that Ru(bpy)3(PF6)2 under white LED gave the best yield (Table 1, entry 7). Next, different solvents were examined; however, none of them gave superior results except for DMSO. Finally, the catalyst loading, substrate loading, and reaction concentration were examined. In the case of catalyst loading, 0.5% catalyst was enough for complete conversion of the substrate. Decreasing the concentration of 1a from 0.17 M to 0.125 M decreased the yield from 67% to 62%, while increasing the concentration of 1a from 0.17 M to 0.25 M increased the yield from 67% to 70%. Further increasing the concentration of 1a to 0.5 M diminished the yield (Table 1, entries 16 and 17). Moreover, decreasing the loading of the trifluoromethylthiolation reagent 2a to 1.2 eq. led to a diminished yield. Thus, the optimized reaction conditions for trifluoromethylthiolation of 1a were as follows: 1a (0.25 mmol), 2a (0.35 mmol), and Ru(bpy)3(PF6)2 (0.00125 mmol) under white LED in DMSO.
Table 1 Optimization of trifluoromethylthiolation of 4-(ethoxycarbonyl)benzenediazonium tetrafluoroborate (1a) by S-(trifluoromethyl) 4-methoxybenzenesulfonothioate (2a)a

image file: c8qo00401c-u1.tif

Entry Solvent Solvent volume (mL) Catalyst Catalyst loading (%) LEDs Yieldb (%)
a Reaction conditions: 1a (0.25 mmol), 2 (0.35 mmol), and catalyst (0–0.02 mmol) in an appropriate solvent system (0.5–2 mL) for 12 h at room temperature.b Yield of isolated product after silica gel chromatography.c 2 (0.30 mmol) was used.
1 DMSO 1.5 Eosin Y 8 Green 61
2 DMSO 1.5 Eosin Y-Na2 8 Green 48
3 DMSO 1.5 Rhodamine B 8 Green 21
4 DMSO 1.5 Methylene blue 8 Green 43
5 DMSO 1.5 Rose Bengale 8 Green 48
6 DMSO 1.5 Ru(bpy)3(PF6)2 8 Green 64
7 DMSO 1.5 Ru(bpy)3(PF6)2 8 White 67
8 DMSO 1.5 Ru(bpy)3(PF6)2 8 Blue 64
9 DCE 1.5 Ru(bpy)3(PF6)2 8 White 28
10 MeCN 1.5 Ru(bpy)3(PF6)2 8 White 17
11 DMF 1.5 Ru(bpy)3(PF6)2 8 White 57
12 DMA 1.5 Ru(bpy)3(PF6)2 8 White 61
13 NMP 1.5 Ru(bpy)3(PF6)2 8 White 50
14 DMSO 1.5 Ru(bpy)3(PF6)2 3 White 66
15 DMSO 1.5 Ru(bpy)3(PF6)2 1 White 66
16 DMSO 1.5 Ru(bpy)3(PF6)2 0.5 White 67
17 DMSO 2.0 Ru(bpy)3(PF6)2 0.5 White 62
18 DMSO 1.0 Ru(bpy)3(PF6)2 0.5 White 70
19 DMSO 0.5 Ru(bpy)3(PF6)2 0.5 White 67
20 DMSO 1.0 Ru(bpy)3(PF6)2 0.5 White 65c


With the optimized reaction condition in hand, the substrate scope was investigated with a series of aryldiazonium tetrafluoroborate (Scheme 2). In general, the diazonium derivatives bearing either an electron-donating or electron-withdrawing group react smoothly to afford the corresponding trifluoromethylthiolation products in moderate to good yields. Moreover, more complex molecules (1l and 1m) could be transformed into trifluoromethylthiolation products 3l and 3m in 52% and 28% yields, respectively.


image file: c8qo00401c-s2.tif
Scheme 2 Trifluoromethylthiolation of diazonium derivatives.

Encouraged by these results, the transformation of arylamine to aryl trifluoromethylthioether through the in situ generation of diazonium was investigated by using ethyl 4-aminobenzoate (4a) as a substrate. To our delight, when 4a was treated with 2a, tert-butyl nitrite (t-BuONO), p-toluenesulfonic acid, and Eosin Y under green light irradiation in DMSO, the desired product was obtained in 62% yield (Table 2, entry 1). After screening the photocatalyst, catalyst loading, type of visible light, and solvent (Table 2, entries 2–15) as well as the trifluoromethylthiolation reagents (Table 2, entries 16–19), the optimized reaction conditions for trifluoromethylthiolation of 4a were identified as follows: 4a (0.25 mmol), 2a (0.35 mmol), t-BuONO (0.30 mmol), and Rose Bengale (0.02 mmol) under white LED in DMSO.

Table 2 Optimization of trifluoromethylthiolation of 4-aminobenzoate (4a)a

image file: c8qo00401c-u2.tif

Entry Solvent Trifluoromethylthiolation reagent X= Catalyst Catalyst loading (%) LED Yieldb (%)
a Reaction conditions: 1a (0.25 mmol), p-TsOH (0.30 mmol), t-BuONO (0.30 mmol), 2 (0.35 mmol), and catalyst (0.0125–0.025 mmol) in an appropriate solvent system (1 mL) for 12 h at room temperature.b Yield of isolated product after silica gel chromatography.
1 DMSO OMe Eosin Y 8 Green 62
2 DMSO OMe Eosin Y-Na2 8 Green 63
3 DMSO OMe Rhodamine B 8 Green 30
4 DMSO OMe Methylene blue 8 Green 39
5 DMSO OMe Rose Bengale 8 Green 67
6 DMSO OMe Ru(bpy)3(PF6)2 8 Green 64
7 DMSO OMe Rose Bengale 8 White 72
8 DMSO OMe Rose Bengale 8 Blue 55
9 DCE OMe Rose Bengale 8 White 20
10 MeCN OMe Rose Bengale 8 White 26
11 DMF OMe Rose Bengale 8 White 59
12 DMA OMe Rose Bengale 8 White 41
13 NMP OMe Rose Bengale 8 White 46
14 DMSO OMe Rose Bengale 10 White 61
15 DMSO OMe Rose Bengale 5 White 50
16 DMSO H Rose Bengale 8 White 47
17 DMSO Me Rose Bengale 8 White 62
18 DMSO CN Rose Bengale 8 White 37
19 DMSO F Ru(bpy)3(PF6)2 8 White 49


After optimizing the reaction condition, the generality of this transformation was examined with a series of arylamine (Scheme 3). Aniline with either an electron-donating or electron-withdrawing group could transform into the corresponding trifluoromethylthiolation products in moderate to good yields. Notably, 5-aminoisoindoline-1,3-dione (4l), and 6-amino-2-phenyl-4H-chromen-4-one (4o) could be transformed into trifluoromethylthiolation products 3l, and 3o in 41 and 31% yields, respectively.


image file: c8qo00401c-s3.tif
Scheme 3 Trifluoromethylthiolation of arylamine derivatives.

To illustrate the practical application of this transformation, the reaction was scaled up using 1.32 g of the substrate 4a. As shown in Scheme 4, the desired product 3a was obtained in 53% yield.


image file: c8qo00401c-s4.tif
Scheme 4 Scale up of the trifluoromethylthiolation reaction.

Based on the results reported in literature,13,14 a plausible mechanism for the trifluoromethylthiolation reaction is proposed (Scheme 5). Initially, the arylamine 4 reacts with t-BuONO and p-TsOH to form an arenediazonium salt 5. Single electron transfer (SET) between 5 and the excited photocatalyst (EYH2*) affords an aryl radical 6 that reacts with the trifluoromethylthiolation reagent 2 to give the corresponding aryl trifluoromethylthioether 3 and sulfone radical 7, which then undergoes a single electron transfer with the radical cation of the photocatalyst (EYH2˙+) to give a sulfonyl cation 8 and regenerate the photocatalyst (EYH2).


image file: c8qo00401c-s5.tif
Scheme 5 Proposed mechanism for visible-light photocatalytic trifluoromethylthiolation.

Experimental

General procedure for trifluoromethylthiolation of aryl diazonium tetrafluoroborate (Scheme 2)

To a sealed tube was added diazonium tetrafluoroborate (0.25 mmol), 4-methoxybenzenesulfonothioate (2a) (95 mg, 0.35 mmol) and Ru(bpy)3(PF6)2 (1 mg, 0.00125 mmol) and dry DMSO (1.0 mL). The mixture was irradiated with white light LED (5 w) for 12 h. After the irradiation, water (5 mL) was added to give an emulsion which was extracted with ethyl acetate (3 × 5 mL). The combined organic phase was washed with brine (5 mL) and dried over anhydrous Na2SO4. Solvent was removed in vacuo, and the residue which was purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate from 50[thin space (1/6-em)]:[thin space (1/6-em)]0 to 50[thin space (1/6-em)]:[thin space (1/6-em)]1).

General procedure for trifluoromethylthiolation of aryl amine (Scheme 2)

To a sealed tube was added amine (0.25 mmol), p-TsOH (52 mg, 0.30 mmol) and Rose Bengale (20 mg, 0.02 mmol) and dry DMSO (1.0 mL). The reaction mixture was stirred for 5 minutes, then t-BuONO (31 mg, 0.30 mmol) was added. After stirring for another 5 minutes, 4-methoxybenzenesulfonothioate (2a) (95 mg, 0.35 mmol) was added, and the mixture was irradiated with white light LED (5 w) for 12 h. After the irradiation, water (5 mL) was added to give an emulsion which was extracted with ethyl acetate (3 × 5 mL). The combined organic phase was washed with brine (5 mL) and dried over anhydrous Na2SO4. Solvent was removed in vacuo, and the residue which was purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate from 50[thin space (1/6-em)]:[thin space (1/6-em)]0 to 50[thin space (1/6-em)]:[thin space (1/6-em)]1).

Conclusions

In summary, we have developed a visible-light photocatalytic trifluoromethylthiolation of arylamine with S-trifluoromethyl 4-methoxylbenzenesulfonothioate through the in situ generation of aryldiazonium salts as key intermediates for the first time. The mild reaction conditions and the readily accessible reagents provide a practical protocol to prepare aryl trifluoromethylthioether. Trifluoromethylthiolation of other organic molecules by S-trifluoromethyl 4-methoxylbenzenesulfonothioate is currently underway in our lab.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The authors sincerely thank the financial support from National Science Foundation of China (Grants 21572158).

Notes and references

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Footnotes

Electronic supplementary information (ESI) available. See DOI: 10.1039/c8qo00401c
These two authors contributed equally to this work.

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