Syntheses of Aryl Thioethers via Aromatic Substitution of Aryl Halides at 0 to 25 °C

Abstract

In this study, we developed mild conditions for the synthesis of an aryl thioether via aromatic substitution using aryl halides, which is a process that has rarely been studied. Aromatic substrates such as aryl fluorides activated with a halogen substituent are difficult to use for substitution reactions, but by using 18-crown-6-ether as an additive, these were successfully converted to their corresponding thioether products. Under the conditions we established, in addition to a wide variety of thiols, less-toxic and odorless disulfides could be used directly as nucleophiles at 0 to 25 °C.

Introduction

Since aryl thioethers are commonly found in natural products, in biologically active chemicals, in pharmaceuticals, and in agrochemicals, numerous effective methods to construct a C–S bond have been reported to date.¹⁾ For example, several Pd-, Cu-, and Ni-catalyzed cross-coupling reactions between aryl halides and thiols or disulfides have been widely employed for this objective.^2–12) These reactions, however, typically require relatively harsh reaction conditions in the presence of high levels of catalyst loading to overcome the strong coordination of thiolates to transition-metal catalysts. More recently, cross-coupling reactions using a cooperative metal and photoredox catalysts have been developed as alternatives, which can be conducted under much milder conditions than those involving traditional coupling reactions.^13–15)

Formations of the C–S bond without metal catalysts have also been actively studied because of their environmentally benign nature. To achieve such transformations, reactions through intermediates such as benzyne,^16–19) electron donor–acceptor (EDA) complexes,^20–22) aryl radical species²³⁾ (S_RN1 reaction) as well as Meisenheimer complexes^24–37) (S_NAr reaction) have been established (Fig. 1). Among these methods, the S_NAr reaction is arguably the simplest pathway because of its similarity to widely applied aryl ether formations via S_NAr processes between aryl halides and alkoxide. Recently, Zhang and colleagues applied arylammonium salts (Ar-N⁺Me₃·^–OTf)²⁴⁾ and arylsulfonium salts (Ar-S⁺Me₂·^–OTf)²⁵⁾ to aryl thioether formations via S_NAr reactions. In addition to these cationic substrates, some nitro arenes have also been successfully transformed to the corresponding aryl thioethers. In contrast to the aryl ether formations, somewhat unexpectedly, thioether formations through S_NAr processes using aryl halides have rarely been studied. Here, we report simple and mild reaction conditions for aryl thioether syntheses via aromatic substitution, which proceeds at 0 or 25 °C. Under the conditions we developed, the pre-formation of thiolate anion from thiols and a pyrophoric base such as sodium hydride (NaH) is not required. Additionally, disulfides, which are odorless, much less toxic than thiols, and more easily stored and handled than thiols, could also be used as nucleophiles under almost identical conditions.³⁷⁾

Fig. 1. Reported Methods for Aryl Thioether Synthesis and the Reaction Reported in This Study

Results and Discussion

Recently, we reported useful reaction conditions for aryl ether syntheses, which can be applied to a wide variety of aryl halides including relatively tough examples such as aryl fluorides activated with either a bromide or a chloride substituent.^38,39) During these investigations, we found that the choices of dimethylformamide (DMF) as a solvent, tert-potassium butoxide (t-BuOK) as a base, and a particular sequence for the addition of reagents are important steps to accomplishing etherification under mild conditions. Additionally, 18-crown-6 ether proved to be an effective additive for etherification of non-activated aromatic substrates such as 1,3-disubstituted arylhalides. We envisioned that user-friendly methods for thioether formations via aromatic substitution under mild conditions could be achieved when we optimized our methods. Modification of reaction conditions using a model reaction between 1-chloro-3-fluorobenzene 1L and 1-dodecanethiol 2a was accomplished by screening solvents and bases (Table 1). Initially, we used our original conditions for aryl ether formations: a solution of t-BuOK in tetrahydrofuran (THF) was added to a solution of 1-chloro-3-fluorobenzene 1L and 1-dodecanethiol 2a in DMF at 0 °C in the presence of 18-crown-6 ether (entry 1). With stirring at 25 °C for 24 h, the corresponding thioether, 1-chloro-3-(dodecylthio)-benzene 3La was obtained in a 91% yield. Polar aprotic solvents proved usable (entries 2 to 4), but the use of THF as a solvent resulted in a diminished yield of 1-chloro-3-(dodecylthio)-benzene 3La (entry 5). Similar to our previously developed conditions for aryl ether syntheses, 18-crown-6 proved to be critical for the transformation of this 1,3-disubstituted substrate (entry 6). When we tested t-butoxide bases with other alkali cations, the yields decreased even with the additions of crown ethers (entries 7 and 8). The use of Cs₂CO₃ and K₂CO₃, which was previously reported,^24,25) gave the product 3La in inferior yields (entries 9 and 10). The addition of a solution of the substrate 1L in DMF to a solution of thiol 2a and t-BuOK in THF gave the product 3La in the same yield as that achieved using the general conditions listed in Table 1, although this sequence is ineffective in aryl ether formations (see Supplementary Materials).

Table 1. Optimization of Reaction Conditions

Entry	Base	Crown ether	Solvent	Yield (%)
1	t-BuOK	18-Crown-6	DMF	91
2	t-BuOK	18-Crown-6	DMSO	46
3	t-BuOK	18-Crown-6	DMI	53
4	t-BuOK	18-Crown-6	DMAc	88
5	t-BuOK	18-Crown-6	THF	29
6	t-BuOK	—	DMF	0
7	t-BuONa	15-Crown-5	DMF	51
8	t-BuOLi	12-Crown-4	DMF	14
9	Cs2CO3	—	DMF	15
10	K2CO3	—	DMF	0

Yields were calculated based on NMR.

With the optimal conditions in hand, we investigated the scope of the aromatic components (Fig. 2). In the cases of electronically activated aromatic substrates such as chlorobenzene derivatives with an EWG at the para- or ortho-positions and some N-heterocycles, the reaction smoothly proceeded even without the addition of 18-crown-6 ether (Fig. 2, Condition A). Nitro- and cyano-substituted aryl chlorides showed excellent reactivity at 0 °C, and the desired products 3Aa–Ca were obtained in 89–98% yields. The reaction with benzaldehyde 1D showed less reactivity due to the formation of side products, and the corresponding thioether 3Da was produced in a somewhat lower yield (49%). When 4-chlorobenzophenone 1E was reacted at 0 °C, thioether 3Ea was produced in a quantitative yield. We additionally tested some N-heterocycles such as 2-chloroquinoline 1F, 2-chloropyrimidine 1G, 2-bromothiazole 1H, and 4,7-dichloro-1,10-phenanthroline 1I. These N-heterocycles worked well in this reaction, and thioether products 3Fa to 3Ia were isolated in good to excellent yields. Next, we tested the scope of a thiol using the reaction with 4-nitrochlorobenzene 1A. In addition to primary thiol 2, secondary and tertiary alkyl thiols reacted smoothly (3Ac and 3Ad), while the reaction with benzylmercaptane 2b produced side products, but the product 3Ab was isolated in a 57% yield. Thiophenol 2e was also applicable at 0 °C, and the reaction with 4-hydroxybenzenethiol 2f indicated that the reactivity of a thiophenol functionality was higher than that of a phenol. Although the reactivity was reduced, 2-mercaptpyridine 2g produced thioether 3Ag in a moderate yield (66%). For the electronically more challenging aromatic substrates shown in Table 1, the addition of 18-crown-6 ether proved effective (Fig. 2, Condition B). The substitution on 3-fluoronitrobenzene 1J caused side reactions that were selective for the ipso-position of the fluoro group. Dodecyl(3-nitrophenyl) sulfane 3Ja was isolated in a 78% yield, but the formation of dodecyl(3-fluorophenyl)sulfane was not observed even in the ¹H-NMR spectra of a crude mixture. In contrast to this observation, 3-fluorobromobenzene 1K and 3-fluorochlorobenzene 1L resulted in clean substitutions to afford fluoro-substituted thioether products in good yields. Additionally, the scalability of this reaction proved to be good via a 10 mmol scale reaction between 3-fluorochlorobenzene 1L and 1-dodecanethiol 2a, which resulted in the formation of the thioether 3La in a 99% yield (3.11 g). The weak electron-withdrawing nature of the bromo groups in 4-bromo- and 2-bromo-substituted fluorobenzene substrates did not prevent good reactivity in the presence of 18-crown-6 ether. And with the addition of 18-crown-6 ether, 2-chloropyridine 1O produced thioether 3Oa in a good yield. It should be noted that these reactions did not proceed without 18-crown-6 ether.

Fig. 2. The Scope of the Aromatic Components

^a 3.0 equivalents (equiv.) of 1-dodecanethiol and 3.0 equiv. of t-BuOK were used. ^b Yields were calculated based on NMR. ^c See Experimental for the reaction conditions. ^d The reaction was conducted on a 10 mmol scale.

For further investigations, we attempted to use disulfides as a nucleophile, because thiols are not easily handled due to odor, toxicity, and air-sensitivity. The generation of nucleophilic species from disulfides in the presence of a base had been previously reported, but there are only a few examples. In a rare case, Xu and colleagues reported an efficient S_NAr reaction of heteroaryl halides using disulfides as a nucleophile.³⁷⁾ In that report, a reaction solution in dimethyl sulfoxide (DMSO) was heated at 120 °C in the presence of NaOH for a smooth transformation. Gratifyingly, thioetherification using a disulfide proceeded under conditions that were almost identical to those listed in Fig. 2. The only difference from the conditions shown in Fig. 2 was the amount of t-BuOK—a 2.0 equiv. with respect to a disulfide (Fig. 3, Condition A). With the standard conditions established, we investigated the scope of the aryl substrates using didodecyl disulfide 5a as a sulfur source. Although the thioether from 3-chloronitorobenze 1A was obtained in a somewhat decreased yield (65%), a substitution of 2-chloroquinoline 1F gave the corresponding thioether product in a good yield at 0 °C. Similar to the reaction using thiols, 3-substituted aryl fluorides required the addition of 18-crown-6 ether with a slightly increased amount of didodecyl disulfide 5a (Condition B). Regardless of the requirement of a longer reaction time at 25 °C, 3-chlorofluorobenzene 1L produced 3La in a good yield (80%), whereas 3-bromofluorobenzene 1K resulted in only a moderate yield. During these experiments, no regioisomeric products were observed under these conditions, which suggests that this reaction does not include a benzyne intermediate.¹⁹⁾ Next, we tested the scope of various disulfides via reaction with 2-chloroquinoline 1F. Dibenzyl disulfide 5b and dicyclohexyl disulfide 5c reacted smoothly and produced good yields. Even in the case of dipheny disulfide 5e, thioether product 3Fe was successfully isolated in an acceptable yield (40%), whereas the pre-treatment of the disulfide 5e with t-BuOK for 2 h prior to the addition of 2-chloro quinoline 1F was needed.⁴⁰⁾ At this point, the mechanisms for the transformation of disulfides into the corresponding RS⁻ anions via t-BuOK remain unclear,⁴¹⁾ but 1-dodecylthiol was isolated when we treated didodecyl disulfide with t-BuOK in DMF (see Supplementary Materials for the details).

Fig. 3. Aromatic Substitution with a Disulfide

^a Yields were calculated based on NMR.

Conclusion

we developed thioether formations using aryl halides, which is a process that has rarely been studied. The use of DMF as a solvent and t-BuOK in THF as a base enabled thioether formations with the use of a wide variety of thiols at 0 to 25 °C. This process is also applicable to aryl fluorides activated via halogen substitution when a weak electron-withdrawing substituent is offset by the addition of 18-crown-6-ether. With the present method, the preformation of either potassium or sodium thiolate, which generally requires highly exothermic and moisture-sensitive processes, was unnecessary. Additionally, under almost identical conditions, the usually odorless, readily available, low-toxic, and easily stored and handled disulfides can also be used as nucleophiles. Investigations to develop widely applicable and effective thioether formation reactions using disulfides are under way in our laboratory, and this includes the pursuit of useful alternatives that could serve as sulfur-based nucleophiles to form C–S bonds.

Acknowledgments

This research was financially supported in part by by JSPS KAKENHI Grant Number 21K06456.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

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