1 Introduction

Organosulfur chemistry is one of the important areas of research in organic synthesis. Numerous pharmacological compounds and bioactive natural products contain ‘S’ atom and such moieties serve as the building block for synthesizing many biologically active compounds.1 Reduction reaction is one of the most fundamental reactions in organic chemistry, which generally involves relatively spotless reagents like molecular hydrogen with extremely heavy metal salts or different phosphines.2 The deoxygenation strategies of diverse sulfoxides have been summarized in a few reviews.3 Significant progress has been achieved during the last two decades in the field of thioether synthesis through the reduction of sulfoxides using various deoxygenation reagents such as metal complexes, oxo and phosphines containing metal complexes, cyanuric chlorides, triflic anhydride, phosphines, electrophilic chlorine, and strong acids with additives, etc.4,5,6 Among various reducing agents, acids have gained profound attention in reducing sulfoxides in combination with different additives. It was extracted from the literature that various acids, such as 3-mercaptopropionic, thioacetic, ascorbic, sulfuric, hydrochloric, and Lewis acid (anhyd AlCl3), etc., have been utilized as a deoxygenating agent in combination with different additives such as I2, NBS, TMCS, NaI, H2O2, etc., for the reduction of various sulfoxides.7,8,9,10,11,12 However, these reactions are generally conducted under harsh conditions utilizing toxic and expensive reagents where chemoselective conversion can’t be carried out always due to the reduction of a few functional groups (C=O, NO2, C≡N, C=C) during the course of reactions. In addition, using phosphine-based ligands affords phosphonium oxide as the side product, which creates difficulties in the purification of the products. To address the above hurdles, herein, we report a novel and chemoselective deoxygenation strategy of diverse sulfoxides using common organic reagent D-camphorsulfonic acid (D-CSA) as the reducing agent without any additive. This reagent is well known as a promising organocatalyst with low sensitivity to air and moisture.13

2 Experimental procedure

2.1 General procedure for deoxygenation of sulfoxides

A mixture of corresponding sulfoxide derivative (1) (0.72 mmol) and D-Camphorsulfonic acid (1.8 mmol) in dry acetonitrile (2 mL) was stirred at 90°C for 12 h. After completion of the reaction (monitored by TLC), the solvent was removed under reduced pressure, and the residue was extracted with EtOAc (2 × 40 mL) and washed with H2O (2 × 20 mL). The combined organic layer was washed with brine (2 × 15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to obtain the desired sulfide (3).

3 Results and discussion

Initially, 1-methoxy-4-[(phenylsulfinyl)methyl]benzene (1a) was considered as the model substrate, and it was treated with 1 equiv. of various acids such as benzoic acid, trifluoromethane sulfonic acids, trifluoro acetic acid, pivalic acid, and D-camphorsulfonic acid (D-CSA) in dichloroethane at 90°C for 24 h (Table 1, Entries 1–5). It was found that D-camphorsulfonic acid afforded the best result to obtain the deoxygenated product (3a) in 41% yield (Table 1, Entry 5). On increasing the loading of D-CSA up to 2 equiv. and subsequently, up to 2.5 equiv., enhanced yield of the corresponding sulfide (3a) could be attained (53% and 62%, respectively) (Table 1, Entries 6 and 7). Further enhancement of D-CSA loading up to 3 equiv. did not increase the yield of the product. Sequentially, the reaction was optimized by screening various solvents such as DMF, DMSO, ethanol, toluene, and acetonitrile (Table 1, Entries 8–12). It was observed that CH3CN afforded the best yield (85%) within 12 h, probably due to the lowering of the activation energy through coordination with the polar sulfoxide (Table 1, Entry 12). The product yields decreased when the deoxygenations were carried out at 50°C and 60°C instead of 90°C (Table 1, Entries 13 and 14). Subsequently, the conduction of the reaction at room temperature afforded the deoxygenation product (3a) in only 22% yield (Table 1, Entry 15). Thus, the optimal reaction conditions were established as follows: 2.5 equiv. of D-CSA in CH3CN (2 mL) at 90°C for 12 h. With the optimized conditions in hand, we attempted the deoxygenation reaction of several other benzylphenyl sulfoxides under the standardized reaction conditions (Scheme 1). Different electron-donating and -withdrawing substituents (OMe, Me, OPh, CO2Me, CN, NO2, F, Br, Cl) on the benzyl ring of benzylphenyl sulfoxides were well tolerated under the optimized reaction conditions and provided moderate to good yields of corresponding sulfides (66–85%). Benzylphenyl sulfoxide (1e) without substituents afforded the desired product (3e) in 64% yield. Notably, the presence of ortho-substituents (F, Cl, Br, Me, CN, CO2Me) on the benzyl ring did not hamper the reaction yields (3h-3m). Meta-substituted sulfoxides (1n-1p) also afforded good yields of corresponding thioethers (69–74%, 3n-3p). In addition, chloro and methyl groups at the para-position on the phenyl ring of benzylphenyl sulfoxides also produced target thioethers (3q-3s) in good yields (Scheme 1).

Table 1 Optimization of the reaction conditions.
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Scheme 1
scheme 1

Substrates scope.a

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Next, we explored the substrate scopes for aryl–ethyl (1t–1v), aryl–alkyl (1w, 1x), aryl–allyl (1y) sulfoxides under optimal conditions. Notably, 1-chloro-4-(methylsulfinyl)benzene (1w), 1-methoxy-3-(methylsulfinyl)benzene (1x), and 1-(allylsulfinyl)-4-methylbenzene (1y), afforded the related thioethers (3w, 3x, 3y) in 62%, 42%, and 73% yields, respectively (Scheme 1). Whereas, in the case of (phenethylsulfinyl)benzenes (1t–1v), the reduction reactions were found to be very sluggish and provided the corresponding sulphides (3t–3v) in 31%, 16%, and 28% yields under standard conditions even after treatment for 24 h. In all cases, starting materials remained, which were recovered. Surprisingly, these reactions almost proceeded to completion (58–80%) within just 5 h upon the addition of a catalytic amount of NBS under the standardized conditions (Scheme 1, compounds 3t–3v). The remaining starting materials were recovered without any side product in all cases. The presence of NBS in this reaction was examined in a few cases. The addition of a catalytic amount of NBS under standard conditions enhanced the reaction rate to complete within 4 h with a slight increase in the yields of the products along with remaining starting materials (3a, 3e, and 3f). Unfortunately, the established protocol did not work with diaryl sulfoxides (1z and 1za).

The scalability of this protocol was verified by a gram-scale reaction where 84% yield of the target product (3a) was obtained (Scheme 2).

Scheme 2
scheme 2

Gram scale reaction of 1a.

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A competition experiment was carried out to determine the electronic preference of this transformation. The reaction between equimolar mixtures of 1-methoxy-4-[(phenylsulfinyl)methyl]benzene (1a) and methyl 4-[(phenylsulfinyl)methyl]benzoate (1f) favored both the electron-rich (1a) and electron-deficient (1f) sulfoxides in an equal (1:1) ratio under optimal conditions (Scheme 3).

Scheme 3
scheme 3

Electronic effect on the reaction.

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A mechanism for this deoxygenation reaction is proposed in Scheme 4. Benzylphenyl sulfoxide (1e) reacts with D-CSA to form intermediate A, which, after intramolecular rearrangement followed by S–O bond cleavage, generates benzylphenyl sulfide (3e) along with dioxirane species (B).

Scheme 4
scheme 4

Proposed pathway of deoxygenation.

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4 Conclusions

In conclusion, we have successfully developed a strategy for the deoxygenation reaction of diverse sulfoxides under mild reaction conditions. This strategy using D-camphorsulfonic acid is an efficient reducing agent for deoxygenating diverse sulfoxides under metal and additive-free conditions. This protocol might have broad synthetic applications in organic synthesis because of the mild reaction conditions, high chemoselectivity, simplicity in operation, and broad substrate scope for synthesizing drug intermediates and biologically active products.