DMSO as oxidant and sulfenylating agent for metal-free oxidation and methylthiolation of alcohol-containing indoles

Abstract

A simple and efficient methylthiolation protocol was successfully established for the synthesis of ketone-substituted indoles bearing 3-methylthioether moiety. The new synthetic approach featured metal-free oxidation and methylthiolation of alcohol-containing indoles, in which new C–S bond and C=O bond were formed simultaneously using dimethyl sulfoxide as the sulfur source under the Swern oxidation conditions. The methylthiolation reaction provides a simple and facile procedure to methylthiolated indoles from readily available starting materials in good yields.

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Sulfenylindoles represent a class of unique and synthetically useful heterocycles due to their biological activity.¹ Both the sulfenyl group and substituted indole functionality play a significant role in medicinal chemistry and drug development.² Especially for 3-sulfenylindole, they are potential drug molecules or precursors in the treatment of HIV, cancer, cardiovascular, obesity, allergies, heart disease, or as potent poxvirus inhibitor.^1,2 Notably, sulfenylindoles are found in a wide range of biologically active compounds (Fig. 1).³ As a result, the development of facile methods for direct sulfenylation of indoles has been attracted much attention as a long-standing interest.^4,5 Especially in the past decades, a number of synthetic routes to 3-sulfenylindoles or related sulfenylation of heterocycles have been reported by various organosulfur compounds,⁵ including disulfides,^5a–e thiols,^5f–h arylsulfonyl chlorides,⁵ⁱ sulfonyl hydrazides,^5j S-alkylor arylthiolphthalimides,^5k and other S-containing reagents. However, these sulfenylating agents often required harsh condition, and impractical on large scale due to the accessibility, odorous, and stability of these organosulfur reagents.

Fig. 1 Various sulfur-containing indole derivatives with biological activity.

Even though the importance of methylthiolation was also well-recognized and carbon–sulfur bond-forming transformation that promoted by metal or organic catalysts with different sulfenylating agents has recently gained significant development, the synthesis of 3-sulfenylindoles by direct methylthiolation of indoles with DMSO still remains a challenge. In this context, Qing and coworkers⁶ have reported firstly that DMSO could be used as an organosulfur source in the Cu(II)-mediated methylthiolation of heteroarenes via C–H activation.⁷ Subsequently, Cheng et al. also reported the copper(II)-mediated methylthiolation of aryl halides in high temperature with DMSO with the aid of ZnF₂ (Scheme 1).⁸

Scheme 1 Previous works on the utilization of DMSO as an organosulfur agent for copper-catalyzed methylthiolation on the aromatic rings.

Very recently, the DMSO was successfully served as organosulfur reagent in methylthiolation of imidazo[1,2-α]pyridines and other imidazo-fused heterocycles⁹ as well as in the methylthiolation-involving three-component coupling reactions triggered by insertion of arynes into the S=O bond of DMSO.¹⁰ Despite previous and impressive advances on the application of DMSO in the synthesis of sulfur-containing molecules,^6–11 to the best of our knowledge, there is no report on the use of DMSO in methylthiolation of indoles for the extensive synthesis of ketone-substituted indoles bearing 3-methylthioether moiety. Herein, we described an unexpected and unprecedented methylthiolation of substituted indoles using DMSO as a methylthiolation source without aid of metal catalyst, in which the direct synthesis of ketone-containing 3-sulfenylindoles via metal-free oxidation and methylthiolation was to be established firstly in this work.

As shown in Scheme 2, the methylthiolation reaction was accidently found during the course of our investigation on the Swern oxidation of alcohol-containing indole (1a). It is well known that the classic Swern oxidation by the combination of dimethyl sulfoxide (DMSO) with oxalyl dichloride has been proved to be highly effective in the mild oxidation of alcohols to carbonyls (aldehydes or ketones).¹² Thus in the initial studies, DMSO and oxalyl dichloride were used in the oxidation of 1a. Interestingly, upon treatment of 2-(1H-indol-1-yl)-1-phenylethanol (1a) that obtained from ring-opening reaction of 2-phenyloxirane with indole with DMSO and oxalyl dichloride in DCM at −78 °C, it was found that the 2-(3-(methylthio)-1H-indol-1-yl)-1-phenylethanone (2a) was formed in good yields (63% isolated yield). The designed product 3a was not detected in this reaction, which showed that the methylthiolation and oxidation of substituted indole 1a was occurred simultaneously. Intrigued by this exciting observation, we decided to optimize the metal-free oxidation and methylthiolation for the synthesis of ketone-containing 3-sulfenylindoles. Unfortunately, the modification of Swern oxidation condition by changing the amount of DMSO and oxalyl dichloride or other activator, such as CH₃SiCl₃,¹³ were not successfully because of low yields or the formation of unidentified side-products (Table S1 of ESI†).

Scheme 2 The Swern oxidation of indole 1a: an unexpected synthesis of ketone-containing 3-sulfenylindole 2a.

Having identified the optimized reaction conditions, this Swern oxidation approach was then applied to the oxidation and methylthiolation of alcohol-containing indoles. The starting indole derivatives 1 are readily prepared by the ring-opening reaction of epoxides with indoles.¹⁴ The results of this ring-opening reaction are summarized in the ESI.† Then the metal-free oxidation and methylthiolation of alcohol-substituted indoles were carried out under the classic Swern oxidation conditions. As shown in Scheme 3, the metal-free oxidation and methylthiolation was proved to be a very general route to the synthesis of a variety of 3-sulfenylindoles bearing N-substituted ketones. In this reaction, DMSO has been successfully employed as methylthiolation source and oxidant in the presence of oxalyl dichloride. The substituted indoles with various groups on aromatic rings, such as methyoxyl and halide, were suitable substrates for the metal-free oxidation and methylthiolation. For most of substituted indoles 1, the desired products 2 were obtained in good isolated yields. As expected, when 3-position of substituted indole was replaced by functional group, the methylthiolation did not proceed in this case, which, further suggested the methylthiolation was underlying occurred at 3-position of indole ring. In addition, when the 2-position of N-alkylindole was blocked, the methylthiolation and oxidation of such type of substrate, for example, substituted indole 1j, was also performed smoothly to the synthesis of the desired product 2j in promising yield (Scheme 4).

Scheme 3 Metal-free oxidation and methylthiolation of alcohol-containing indoles 1 under Swern oxidation reaction conditions. Reaction conditions: oxalyl chloride (2 mmol), DMSO (2 mmol), indole (2 mmol), DCM (20 mL), Et₃N (10 mmol), at −78 °C-rt for totally 6 h.

Scheme 4 Metal-free oxidation and methylthiolation of 2-substituted N-alkylindole 1j. Reaction conditions: oxalyl chloride (2 mmol), DMSO (2 mmol), indole 1j (2 mmol), DCM (20 mL), Et₃N (10 mmol), at −78 °C-rt for totally 6 h.

Inspired by these exciting results in the metal-free oxidation and methylthiolation of alcohol-containing indoles, the scope of this methylthiolation method is further expanded to substituted indoles without reactive alcohol moieties. As shown in Scheme 5, a variety of potential indoles 4 were tested to determine scope and limitations of this method. Except the Boc-protected indole and non-substituted indole (summarized as a representative structure 5a when R₂ = H or Boc), results presented in Scheme 5 demonstrate that the N-protected indoles underwent methylthiolation smoothly to give the structurally diverse 3-sulfenylindoles 5 in good to excellent yields (56–93% yields). Beside high yields, the advantages of this procedure include metal-free, mild conditions as well as easy work-up and practical use for organic synthesis. This technique also avoids the use of thiols as electrophilic organosulfur sources that have unpleasant odors.

Scheme 5 Methylthiolation of substituted indoles under Swern oxidation reaction conditions. Reaction conditions: oxalyl chloride (2 mmol), DMSO (2 mmol), indole (2 mmol), DCM (20 mL), Et₃N (10 mmol), at −78 °C-rt for totally 6 h.

Although the methylthiolation happened at 3-position of substituted indoles, the construction of 2-substituted indoles bearing methylthioether moiety could be successfully achieved by acid-catalyzed rearrangement of indol-3-yl sulphides to indol-2-yl sulphides.¹⁵ As shown in Scheme 6, the rearrangement of 3-methylthioether-substituted indoles 2 promoted by trifluoroacetic acid led to the facile synthesis of the corresponding 2-indolyl sulfides 6. All the desired indole products bearing 2-methylthioether moiety were isolated in moderate to good yields (40–68% yields). Notably, the ketone moiety was proved to stable under the reaction conditions, thus the general methylthiolation under Swern reaction conditions and subsequent rearrangement reaction provide a chemoselective and cascade procedure to indol-3-yl sulphides and indol-2-yl sulphides respectively.

Scheme 6 The rearrangement of 3-methylthioether-substituted indoles (2) to 2-indolyl sulphides (6). Reaction conditions: indole derivative (0.5 mmol), TFA (5 mL), at room temperature for overnight (15 h).

Furthermore, the isotope labeling experiment was conducted to evaluate the origin of methyl hydrogen atom in this methylthiolation. The oxidation and methylthiolation of substituted indole 1a with deuterated DMSO under the standard reaction conditions generated deuterium-labeled product 2a in good yield (Fig. S1 of ESI†). This result illustrated that DMSO took part in both oxidation and methylthiolation of such alcohol-containing indoles. On the basis of these experimental results and previous reports on Swern oxidation reaction,^12,16 a plausible mechanistic procedure is proposed for the methylthiolation and oxidation of substituted indoles (Scheme 7): (1) the initial formation of dimethylsulfonium chloride by the reaction of DMSO with oxalyl dichloride is well documented in the Swern oxidation of alcohols.¹⁶ And electrophilic attack of dimethylsulfonium chloride at the 3-position of indole to give the 3-indolylsulfonium salt.¹⁷ (2) Subsequently, similarly to the Swern oxidation of alcohols, the deprotonation of CH that linked with oxygen (CH–O) led to the formation of ketone moiety. At the same time, the formation of dimethylsulfonium intermediate occurred smoothly under the reaction conditions. Similarly to previous report,¹⁸ the demethylation of sulfonium intermediate as well as dehydrogenation of alcohol-linked C–H bond can be happened very easily in the presence of base (Et₃N). Thus the desired product 2 was obtained smoothly.

Scheme 7 A proposed mechanism for the metal-free oxidation and methylthiolation of N-alkylated indoles.

Conclusions

In summary, we have firstly determined an efficient and unexpected methylthiolation as well as metal-free oxidation firstly for the synthesis of ketone-substituted indoles bearing 3-methylthioether moiety. The new synthetic approach also features with metal-free oxidation of alcohol during methylthiolation of substituted indoles, in which new C–S bond and C=O bond were formed simultaneously using DMSO as the reactive substrate under mild conditions. Notably, because of its practical and environmental friendly conditions, the novel and general methylthiolation of substituted indoles might be very valuable and attractive protocol in organosulfur chemistry and medicinal chemistry.

Acknowledgements

This Project was supported by the National Natural Science Founder of China (no. 21173064 and 21472031) and Zhejiang Provincial Natural Science Foundation of China (LR14B030001).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra03606b

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