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• Aryl sulfides are important synthetic intermediates which can be used in biological or pharmaceutical industry.^[1] Catalytic cross-coupling of aryl halides with thiols proved to be one of very effective method for the construction of C—S bond, wherein palladium^[2] and copper^[3] salts or their complexes have been commonly used as effective catalysts under strong basic conditions. It is generally believed that the transition metal catalyzed coupling of aryl halides with thiols firstly undergoes the oxidative addition of M(0) with ArX, then the ligand exchanges of Ar—M—X with RSH, and finally the reductive elimination of Ar—M—SR to form the desired Ar—SR coupling product.^[4] Interestingly, it has been found that the reactivity for the coupling of electron rich or poor aryl halides are quite different. In the presence of a strong base, the coupling of electron-poor aryl halides can be facilitated even in the absence of a transition metal catalyst under a comparatively high temperature ( > 80 ℃).^[5] For these electron-poor aryl halides, the reaction is assumed to proceed via S_NAr mechanism. Despite significant efforts have been made in this transformation, it is surprising that so far most reported processes are mainly focused on the coupling of aryl halides and aryl thiols.^[6] However, the coupling of aryl halides with alkyl thiols is unfortunately still not well-established, even though alkyl aryl thioethers are also important synthetic intermediates. Based on this consideration, we were interested in investigating the C—S cross-coupling of aryl halides with alkyl thiols under transition metal-free conditions. Surprisingly, it was found that the reaction could be smoothly proceeded even at room temperature. It is known that the S_NAr reaction normally proceeds at high temperatures. Such a phenomenon motivated us to make further studies on the mechanism of this reaction. Therefore, we wish to report our recent findings on this work herein.

  1   Result and discussion

  The C—S cross-coupling of electron-poor 4-bromo-acetophenone (1a) and butanethiol (2a) was initially explored to examine the reactivity. Different solvents were firstly applied using 1.5 equiv. of KO^tBu at 100 ℃ under nitrogen protection. The reaction was not able to proceed in toluene, but moderate yield was achieved in tetrahydrofuran (THF) (Table 1, Entries 1 and 2). To our delight, excellent yield could be obtained when carrying out the reaction in pyridine, 1, 2-dimethoxyethane (DME), dimethyl sulfoxide (DMSO) and N, N-dimethylformamide (DMF) (Entries 3~6). To our surprise, further studies indicated that excellent yields of 3aa could also be maintained when decreasing the temperature from 100 ℃ to room temperature (Entries 6~9). To further determine the reactivity, various bases were studied at room temperature. The results indicated that the replacement of KO^tBu with NaO^tBu, KOH or NaOH also afforded excellent product yields at room temperature (Entries 10~12), while K₂CO₃ led to a loweryield (Entry 13) and Na₂CO₃ proved to be not quite effective (Entry 14). Decreasing of the amount of KO^tBu to 1.0 equiv., the product yield also decreased (Entry 15).

  Table 1.  C—S cross-coupling of 4-bromoacetophenone and bu-tanethiol^a

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  Based on the above studies, a condition A (1 mmol of 4-bromoacetophenone, 1.1 mmol of butanethiol, 1.5 equiv. of KO^tBu in 3 mL of DMF at room temperature for 1 h under N₂ protection was applied as a standard condition for further study on the substrate scope of this reaction (Table 2). It turned out that reactions between butanethiol and all examined electron-poor aryl bromides can be facilitated very well at room temperature, leading to the corresponding cross-coupling products in good yields. Excellent yields can be obtained for the coupling of 4-bromoacetophenone with heptanthiol, 2-methyl-2-propanethiol or cyclohexylthiol (3aa~3ad). A comparatively lower yield can be achieved when using bulkyl alkylthiols such as 3-methyl-2-bu-tanethiol (3ae). For the sake of comparison, the coupling of 4-bromoaceto-phenone with aryl thiol such as 4-methyl-benzenethiol and 4-chlorobenzenethiol was also conducted, and no obvious difference on activity was observed as compared to alkyl thiols (3af, 3ag). Additionally, excellent yields were also obtained for the coupling of various CF₃ or NO₂ substituted aryl bromide with butanethiol (3ba~3fa). However, this reaction did not occur when the substrates bearing with F, H or Me group (3ga~3ia). Obviously, the electronic effect of substituted aryl bromides had a significant impact on this transformation.

  Table 2.  C—S cross-coupling of aryl bromides with thiols^{a, b}

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  2   Mechanistic considerations

  As mentioned previously, the S_NAr reaction normally occurs at high temperatures. In our case, the coupling reaction could be smoothly facilitated at room temperature.^[5] Additionally, Liu et al.^[5d] also found that the coupling of 1-chloro-4-nitrobenzene with 1-octanethiol in the presence of 3 equiv. of KOH in PEG-600 (solvent) could proceed at room temperature, in which 90% of octyl p-nitrobenzyl thioether was obtained. Nevertheless, the mechanism was not discussed in this work. The main concern is whether C—S coupling of electron-poor aryl halides with thiols can proceed via a S_NAr mechanism at room temperature. Therefore, the mechanism needs to be carefully examined. First, if the reaction proceeds via an aryne mecha nism, two isomers (para and meta-substituted thioethers) should be observed in a roughly 1:1 molar ratio when using para-substituted aryl halides as substrates.^{[5b, 7]} However, only one isomer could be detected for all examined electron-poor aryl bromides. Therefore, the aryne mechanism can be ruled out. A mechanism proceeding via a benzene radical intermediate induced by the KO^tBu/DMF super-base system should not be ignored. KO^tBu or NaO^tBu has been found to be able to promote the direct C—H arylation of unactivated benzene with aryl halides, which has been independently described by the group of Shi, Kong/Lei, and Shirakawa/Hayashi.^[8~10] Moreover, Yan et al.^[11] have also reported a series of KO^tBu/DMF promoted radical coupling reactions. To further explore the mechanism, radical trapping experiments were carried out using 1~3 equiv. of tetra-methylpiperidine N-oxide (TEMPO) or 2, 6-di-tert-butyl-4-methylphenol (BHT) as the radical scavengers in the presence of 1.5 equiv. of KO^tBu in DMF at room temperature. However, the reaction could not be significantly hindered by both scavengers. Thus, a benzene radical based mechanism appears unlikely. Therefore, the C—S coupling using electron-poor aryl halides might proceed via a S_NAr mechanism, even at room temperature, which is in accordance to the reported mechanism.^[5b]

  3   Conclusions

  C—S cross-coupling of aryl bromides with alkyl thiols under transition metal-free conditions is described. The examined coupling of electron-poor aryl halides with alkyl-thiols proved to be highly effective at room temperature under transition metal-free conditions. The reaction is applicable for aryl bromides bearing various electron-with-drawing groups. The reaction is also applicable for various linear, bulkyl and cyclic alkyl thiols. Reaction mechanism studies indicate that the reaction likely undergoes a S_NAr mechanism, even at room temperature. This reaction protocol provides an efficient and cost-effective method for the synthesis of alkyl aryl thioethers under mild conditions.

  4   Experimental

  4.1   General method

  All reactions were carried out under a nitrogen atmosphere with standard Schlenk techniques. All solvents were purified and dried according to standard methods prior to use. The GC-MS spectra were determined by a Thermo Fisher ISQ GC-MS; NMR spectra were recorded on a Bruker Ascend HD 500 spectrometer; IR spectra were recorded on a Nicolet 6700 FT-IR spectrometer; The melting points of compounds were obtained on a Shang Hai Shen Guang WRS-3 melting point instrument; HRMS (ESI) determinations were carried out on a Bruker Daltonics McriOTOF Ⅱ spectrometer.

  4.2   General procedure for the coupling reaction of aryl bromides with thiols

  In a typical procedure, aryl bromide (1.0 mmol), thiols (1.1 mmol) and KO^tBu (168 mg, 1.5 mmol) were added to a Schlenk tube under an atmosphere of nitrogen. DMF (3 mL) was then injected under vigorous stirring 1 h. After the reaction, the mixture was quenched by addition of distilled water. The organic phase was then separated, and the aqueous phase was extracted with ethyl acetate for three times. The combined organic layers were dried with MgSO₄, and the sample was conducted for GC or GC-MS analysis. The sample solution was further evaporated under vacuum to remove the solvent. The obtained crude product was purified by column chromatography (eluent, petroleum) on silica gel to afford the desired thioethers.

  1-(4-(Butylthio)phenyl)ethanone (3aa):^[12] Colorless liquid, 198 mg, 95% yield. ¹H NMR (500 MHz, CDCl₃) δ: 7.85 (d, J＝8.5 Hz, 2H), 7.29 (d, J＝8.5 Hz, 2H), 2.98 (t, J＝7.0 Hz, 2H), 2.55 (s, 3H) 1.71~1.65 (m, 2H), 1.51~1.44 (m, 2H), 0.94 (t, J＝7.0 Hz, 3 H).

  1-(4-(Heptylthio)phenyl)ethanone (3ab):^[13] Colorless liquid, 207 mg, 94% yield. ¹H NMR (500 MHz, CDCl₃) δ: 7.86 (d, J＝8.5 Hz, 2H), 7.30 (d, J＝9.0 Hz, 2H), 2.99 (t, J＝7.5 Hz, 2H), 2.57 (s, 3H), 1.73~1.66 (m, 2H), 1.46~1.43 (m, 2H), 1.34~1.26 (m, 6H), 0.89 (t, J＝7.0 Hz, 3H).

  1-(4-((3-Methylbutan-2-yl)thio)phenyl)ethanone (3ac): Colorless liquid, 162 mg, 84% yield. ¹H NMR (500 MHz, CDCl₃) δ: 7.85 (d, J＝8.5 Hz, 2H), 7.35 (d, J＝8.5 Hz, 2H), 3.39~3.34 (m, 1H), 2.55 (s, 3H), 1.98~1.92 (m, 1H), 1.30 (d, J＝7.0 Hz, 3H), 1.04~1.00 (m, 6H); ¹³C NMR (125 MHz, CDCl₃) δ: 196.9, 144.3, 134.0, 128.6, 128.1, 48.1, 32.5, 26.3, 19.9, 18.4, 16.9; IR (neat) ν: 2966, 2940, 2874, 1680, 1589, 1552, 1394, 1350, 1262, 1181, 1097, 957, 817, 762, 601 cm^－1; HRMS (EI) calcd for C₁₃H₁₈SO: 222.1078, found 222.1080.

  1-(4-(Cyclohexylthio)phenyl)ethanone (3ad):^{[4e, 14]} White solid, 161 mg, 78% yield. m.p. 67.4~67.6 ℃ (lit.^[14] 66~68 ℃); ¹H NMR (500 MHz, CDCl₃) δ: 7.85 (d, J＝8.5 Hz, 2H), 7.35 (d, J＝8.5 Hz, 2H), 3.33~3.30 (m, 1H), 2.56 (s, 3H), 2.09~1.95 (m, 4H), 1.80~1.77 (m, 4H), 1.66~1.59 (m, 2H).

  1-(4-(tert-Butylthio)phenyl)ethanone (3ae):^[15] Colorless liquid, 124 mg, 69% yield. ¹H NMR (500 MHz, CDCl₃) δ: 7.91 (d, J＝8.5 Hz, 2H), 7.62 (d, J＝8.5 Hz, 2H), 2.60 (s, 3H), 1.32 (s, 9H).

  1-(4-(p-Tolylthio)phenyl)ethanone (3af):^[6b] Yellow solid, 197 mg, 92% yield. m.p. 94.1~94.2 ℃ (lit.^[6b] 89~92 ℃); ¹H NMR (500 MHz, CDCl₃) δ: 7.83~7.79 (m, 2H), 7.42 (d, J＝8.5 Hz, 2H), 7.23 (d, J＝8.0 Hz, 2H), 7.16 (d, J＝8.0 Hz, 2H), 2.54 (s, 3H), 2.39 (s, 3H).

  1-(4-((4-Chlorophenyl)thio)phenyl)ethanone (3ag):^[16] White solid, 212 mg, 91% yield. m.p. 56.0~56.7 ℃ (lit.^[16] 40~42 ℃); ¹H NMR (500 MHz, CDCl₃) δ: 7.84 (d, J＝9.0 Hz, 2H), 7.41~7.35 (m, 4H), 7.22 (d, J＝8.5 Hz, 2H), 2.55 (s, 3H).

  Butyl(2-(trifluoromethyl)phenyl)sulfane (3ba): Colorless liquid, 217 mg, 93% yield. ¹H NMR (500 MHz, CDCl₃) δ: 7.63 (d, J＝7.5 Hz, 1H), 7.46~7.44 (m, 2H), 7.25~7.23 (m, 1H), 2.97 (t, J＝7.5 Hz, 2H), 1.69~1.63 (m, 2H), 1.49~1.41 (m, 2H), 0.93 (t, J＝9.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ: 137.1, 131.8, 129.9, 126.7, 125.2, 33.6, 30.8, 21.9, 13.5; IR (neat) ν: 2959, 2931, 2869, 1596, 1568, 1471, 1433, 1310, 1255, 1171, 1126, 1023, 760 cm^－1; HRMS (EI) calcd for C₁₁H₁₃F₃S: 234.0690, found 234.0683.

  Butyl(3-(trifluoromethyl)phenyl)sulfane (3ca):^[17] Colorless liquid, 223 mg, 95% yield. ¹H NMR (500 MHz, CDCl₃) δ: 7.52 (s, 1H), 7.47~7.45 (m, 1H), 7.39~7.37 (m, 2H), 2.96 (t, J＝9.5 Hz, 2H), 1.69~1.60 (m, 2H), 1.49~1.41 (m, 2H), 0.94 (t, J＝9.5 Hz, 3H).

  Butyl(4-(trifluoromethyl)phenyl)sulfane (3da):^[18] Colorless liquid, 223 mg, 95% yield. ¹H NMR (500 MHz, CDCl₃) δ: 7.50 (d, J＝8.5 Hz, 2H), 7.34 (d, J＝8.5 Hz, 2H), 2.96 (t, J＝7.0 Hz, 2H), 1.69~1.63 (m, 2H), 1.51~1.45 (m, 2H), 0.94 (t, J＝7.5 Hz, 3H).

  Butyl(2-nitrophenyl)sulfane (3ea):^[12] Colorless liquid, 192 mg, 91% yield. ¹H NMR (500 MHz, CDCl₃) δ: 8.17~8.15 (m, 1H), 7.54~7.51 (m, 1H), 7.41 (d, J＝8.0 Hz, 1H), 7.22~7.19 (m, 1H), 2.94 (t, J＝7.5 Hz, 2H), 1.72~1.67 (m, 2H), 1.53~1.47 (m, 2H), 0.95 (t, J＝7.5 Hz, 3H).

  Butyl(4-nitrophenyl)sulfane (3fa):^[12] Colorless liquid, 194 mg, 92% yield. ¹H NMR (500 MHz, CDCl₃) δ: 8.11 (d, J＝9.0 Hz, 2H), 7.31 (d, J＝9.0 Hz, 2H), 3.01 (t, J＝8.0 Hz, 2H), 1.73~1.66 (m, 2H), 1.53~1.47 (m, 2H), 0.96 (t, J＝7.5 Hz, 3H).

  Supporting Information  ¹H NMR and ¹³C NMR spectra. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn/.

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• Table 1.  C—S cross-coupling of 4-bromoacetophenone and bu-tanethiol^a

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  Table 2.  C—S cross-coupling of aryl bromides with thiols^{a, b}

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•