Expedient Synthesis of Alkyl and Aryl Thioethers Using Xanthates as Thiol-Free Reagents

Thioethers are critical in the fields of pharmaceuticals and organic synthesis, but most of the methods for synthesis alkyl thioethers employ foul-smelling thiols as starting materials or generate them as by-products. Additionally, most thiols are air-sensitive and are easily oxidized to produce disulfides under atmospheric conditions; thus, a novel method for synthesizing thioethers is necessary. This paper reports a simple, effective, green method for synthesizing dialkyl or alkyl aryl thioether derivatives using odorless, stable, low-cost ROCS2K as a thiol surrogate. This transformation offers a broad substrate scope and good functional group tolerance with excellent selectivity. The reaction likely proceeds via xanthate intermediates, which can be readily generated via the nucleophilic substitution of alkyl halides or aryl halides with ROCS2K under transition-metal-free and base-free conditions.


Introduction
The development of efficient, sustainable methods for synthesizing thioethers has attracted increasing attention due to the importance of these compounds in the fields of fine chemicals, pharmaceuticals, functional materials, and organic synthesis.Among the most studied S-containing compounds, alkyl thioether derivatives have attracted considerable interest owing to their biological potential, and have been exploited in developing drugs, such as Griseoviridin [1], Viracept [2], Montelukast sodium [3], and Cilastatin [4].Therefore, the direct synthesis of alkyl thioethers is an active area of research.Most of the strategies used in synthesizing alkyl thioethers employ thiols as starting materials or involve the addition of an organometallic reagent to a disulfide [5,6].The disadvantage of these methods is the use of malodorous thiols as starting materials or the production of thiols as by-products.Most thiols are air-sensitive and readily oxidized to produce disulfides under aerobic atmospheric conditions.To overcome these limitations, the attractive alternative methods for the sulfuration of alkyl halides and aryl halides involve the use of other sulfurizing agents, e.g., S powder [7][8][9][10], bunte salts [11][12][13], dimethyl sulfoxide (DMSO) [14,15], carenesulfonyl cyanides [16], S-methylisothiourea [17], N-substituted sulfanylsuccinimides [18,19], disulfides [20][21][22], sulfonyl chlorides [23,24], sodium sulfinates [25][26][27], and sulfonyl hydrazides [28,29], because these off-the-shelf thiol-free sulfurizing agents generally release little to no odors.
Xanthates are attractive sulfurizing agents used in both transition-metal-catalyzed and transition-metal-free transformations because they are odorless and have low toxicities and can be readily prepared on large scales using low-cost alcohols and CS 2 [30][31][32][33].The addition of alkyl halides and aryl halides to xanthates may provide a general route for preparing thioethers without using odorous thiol starting materials.Baranov [34] and Kakulapati [35] reported the use of xanthates as thiol surrogates in nucleophilic substitution or cross-coupling with aryl halides in synthesizing aryl thioethers (Scheme 1a,b).Karchava et al. described the visible-light-driven S-arylation of EtOCS 2 K (Et = ethyl) using aryl halides in synthesizing aryl thioethers [36], followed by the reaction of diaryliodonium salts with xanthate salts to prepare the corresponding alkyl aryl thioether compounds (Scheme 1c) [37].Nevertheless, xanthates, which are generally used as thiol surrogates, react with aryl halides to generate aryl thioethers, but the synthesis of dialkyl thioethers using xanthates has rarely been reported.To the best of our knowledge, the sole attempt to directly transform xanthates into dialkyl thioethers was reported by Degani et al.They obtained only small amounts of the desired dialkyl thioethers via the sulfurization of alkyl halides using EtOCS 2 K as a sulfurizing agent [38].Based on our research on the development of xanthate chemistry (Scheme 1d-f) [39][40][41], we herein report a facile approach for use in generating various dialkyl thioethers and aryl thioethers.This approach involves the sulfuration of alkyl halides and aryl halides using ROCS 2 K as a thiol-free sulfurizing and alkylating reagent (Scheme 1g).
Molecules 2024, 29,2485 2 of 20 toxicities and can be readily prepared on large scales using low-cost alcohols and CS2 [30][31][32][33].The addition of alkyl halides and aryl halides to xanthates may provide a general route for preparing thioethers without using odorous thiol starting materials.Baranov [34] and Kakulapati [35] reported the use of xanthates as thiol surrogates in nucleophilic substitution or cross-coupling with aryl halides in synthesizing aryl thioethers (Scheme 1a,b).Karchava et al. described the visible-light-driven S-arylation of EtOCS2K (Et = ethyl) using aryl halides in synthesizing aryl thioethers [36], followed by the reaction of diaryliodonium salts with xanthate salts to prepare the corresponding alkyl aryl thioether compounds (Scheme 1c) [37].Nevertheless, xanthates, which are generally used as thiol surrogates, react with aryl halides to generate aryl thioethers, but the synthesis of dialkyl thioethers using xanthates has rarely been reported.To the best of our knowledge, the sole attempt to directly transform xanthates into dialkyl thioethers was reported by Degani et al.They obtained only small amounts of the desired dialkyl thioethers via the sulfurization of alkyl halides using EtOCS2K as a sulfurizing agent [38].Based on our research on the development of xanthate chemistry (Scheme 1d-f) [39][40][41], we herein report a facile approach for use in generating various dialkyl thioethers and aryl thioethers.This approach involves the sulfuration of alkyl halides and aryl halides using ROCS2K as a thiol-free sulfurizing and alkylating reagent (Scheme 1g).

Results and Discussion
To evaluate this synthesis of dialkyl thioethers hypothesis, we screened the reaction conditions using 4-(chloromethyl)biphenyl (1a), EtOCS2K (2a), and dimethylformamide (DMF) as a model reaction.Gratifyingly, sulfidation proceeds at a reaction temperature of 150 °C to afford the dialkyl thioether 3a in 77% yield (Table 1, entry 1).The screening of various solvents reveals that the solvent is critical in the sulfidation reaction (Table 1, entries 1-5), and a trace amount of the thioether 3a is obtained when non-polar solvent o-xylene is used (Table 1, entry 2).The optimal results are obtained when the reaction is conducted in DMSO at 150 °C (Table 1, entry 3), whereas unsatisfactory results are Scheme 1. Methods of sulfide synthesis using xanthates (a-c) and xanthate chemistry in our laboratory (d-g).EWG, electron-withdrawing group; OTf, triflate.
Finally, the use of aromatic xanthates as substituents was investigated.Gratifyingly, benzyl and phenyl substituent xanthates were well tolerated under the optimized conditions, affording the corresponding thioethers in good yields (Scheme 2, 3ae-3af).
quinolone (3x), quinazoline (3y), pyrazole (3z), and tetrazole (3aa), can undergo the reaction to produce the desired products in moderate-to-good yields.Next, 1,4-bis(chloromethyl)benzene, 1-(chloromethyl)adamantane, and (chloromethylene)dibenzene successfully undergo the reaction, indicating that the sulfuration reaction is characterized by a good functional group tolerance (Scheme 2, 3ab-3ad).Finally, the use of aromatic xanthates as substituents was investigated.Gratifyingly, benzyl and phenyl substituent xanthates were well tolerated under the optimized conditions, affording the corresponding thioethers in good yields (Scheme 2, 3ae-3af).Scheme 2. Synthesis of thioethers using various alkyl chlorides a,b .a Reaction conditions: alkyl halide (0.5 mmol), ROCS2K (1.0 mmol) in DMSO (1.0 mL) at 100 °C in a sealed tube in an air atmosphere for 1 h b isolated yields.To evaluate this synthesis of aryl alkyl thioethers' hypothesis, we screened the reaction conditions using 3-iodopyridine (1ae), EtOCS 2 K (2a), additive, and DMF as a model reaction.Initially, sulfidation proceeds at a reaction temperature of 150 • C for 24 h to afford the 3-(ethylthio)pyridine 4a in 37% yield (Table 2, entry 1).The screening of various reaction times reveals that the reaction time is critical in the sulfidation reaction, and excellent results are obtained when the sulfidation reaction was carried out in 36 h (Table 2, entries 1-3).Notably, the yield decreases significantly when the dosage of EtOCS 2 K (2a) or I 2 is decreased (Table 2, entries 4-5).With EtOCS 2 K (2a) as the sulfur source, the examination of different additives showed that NH 4 I and HI was inefficient (Table 2, entries 6-7).Further optimum solvents showed that DMF was the best choice; the other solvents-DMSO, NMP, and DMAc-all decreased the yield of 4a (Table 2, entries 8-10).Furthermore, decreasing the reaction temperature led to a decrease in yield (Table 2, entry 11).Without the use of an iodine reagent, only a trace of the sulfidation reaction product was obtained; mostly the starting material was recovered (Table 2, entry 12).Based on these results, the optimized reaction conditions are halopyridine (0.5 mmol) and EtOCS 2 K (1.2 mmol) and I 2 (1.5 mmol) in 3.0 mL DMF at 150 • C for 36 h (Table 1, entry 3).To evaluate this synthesis of aryl alkyl thioethers' hypothesis, we screened the reaction conditions using 3-iodopyridine (1ae), EtOCS2K (2a), additive, and DMF as a model reaction.Initially, sulfidation proceeds at a reaction temperature of 150 °C for 24 h to afford the 3-(ethylthio)pyridine 4a in 37% yield (Table 2, entry 1).The screening of various reaction times reveals that the reaction time is critical in the sulfidation reaction, and excellent results are obtained when the sulfidation reaction was carried out in 36 h (Table 2, entries 1-3).Notably, the yield decreases significantly when the dosage of EtOCS2K (2a) or I2 is decreased (Table 2, entries 4-5).With EtOCS2K (2a) as the sulfur source, the examination of different additives showed that NH4I and HI was inefficient (Table 2, entries 6-7).Further optimum solvents showed that DMF was the best choice; the other solvents-DMSO, NMP, and DMAc-all decreased the yield of 4a (Table 2, entries 8-10).Furthermore, decreasing the reaction temperature led to a decrease in yield (Table 2, entry 11).Without the use of an iodine reagent, only a trace of the sulfidation reaction product was obtained; mostly the starting material was recovered (Table 2, entry  12).Based on these results, the optimized reaction conditions are halopyridine (0.5 mmol) and EtOCS2K (1.2 mmol) and I2 (1.5 mmol) in 3.0 mL DMF at 150 °C for 36 h (Table 1, entry 3). a Reaction conditions: 3-Iodine pyridine (0.5 mmol), EtOCS2K, and additive in solvent (3.0 mL) at 150 °C in a sealed tube in an air atmosphere.b Isolated yields.c 140 °C.
The iodopyridine reactions with various substituted potassium xanthates also proceed with smooth conversions under the optimized conditions, furnishing the corresponding thioethers in moderate-to-good yields (Scheme 3).Notably, substituted potassium xanthates with ethyl (4a), n-propyl (4b), n-butyl (4c), and n-pentyl groups (4d) are tolerated well under mild reaction conditions.When sulfuration is conducted using 3-iodoquinoline and 4-iodoisoquinoline, the thioether products 4e-4f are obtained in yields of 94% and 85%, respectively.2-Fluoropyridines bearing various functional groups are completely converted in the presence of 2a to furnish the corresponding sulfides in good yields.2-Fluoropyridines, substituted with both electron-donating and electron-withdrawing groups, react with 2a to generate the corresponding sulfuration products 4g-4o in good yields.The reaction tolerates various substituents, including -Me, -Ph, -NH2, -OH, -I, -OCNMe2, and -CN groups, and whether the substituent is at The iodopyridine reactions with various substituted potassium xanthates also proceed with smooth conversions under the optimized conditions, furnishing the corresponding thioethers in moderate-to-good yields (Scheme 3).Notably, substituted potassium xanthates with ethyl (4a), n-propyl (4b), n-butyl (4c), and n-pentyl groups (4d) are tolerated well under mild reaction conditions.When sulfuration is conducted using 3-iodoquinoline and 4-iodoisoquinoline, the thioether products 4e-4f are obtained in yields of 94% and 85%, respectively.2-Fluoropyridines bearing various functional groups are completely converted in the presence of 2a to furnish the corresponding sulfides in good yields.2-Fluoropyridines, substituted with both electron-donating and electron-withdrawing groups, react with 2a to generate the corresponding sulfuration products 4g-4o in good yields.The reaction tolerates various substituents, including -Me, -Ph, -NH 2 , -OH, -I, -OCNMe 2 , and -CN groups, and whether the substituent is at the 3-, 4-, 5-, or 6-position of the pyridine ring does not affect the yield of the reaction.When 2-fluoro-3-iodopyridine is used as the starting material, the F atom at the 2-position of the pyridine ring exhibits a higher reactivity, and the reaction affords the 2-(ethylthio)-3-iodopyridine product (4p) in 90% yield.Remarkably, when 3,5-dibromopyridine is used, the disulfuration product 4r is obtained in 40% yield.The activities of the halogen atoms depend more on their positions when 2-chloro-5-iodopyrimidine is used as the starting material, affording product 4s in 92% yield.
Finally, in the presence of I2 and 2a, a novel, efficient protocol affords the substituted thiophene 5e in 78% yield via the sulfidation and sulfur cyclization of 4-(6-fluoropyridin-3-yl)-2-methylbut-3-yn-2-ol 5d with 2a (Equation ( 4)) [44].To enhance our understanding of the reaction mechanism, we designed control experiments, as shown in Scheme 5. First, the reaction of phenylmethanethiol with 2a furnishes thioether 3ag in trace amounts and 1,2-dibenzyldisulfane 5f in 87% yield, suggesting that thiol alone cannot undergo the sulfation reaction with 2a (Scheme 5a).When benzyl chloride and p-tolylmethanethiol are mixed as substrates, the results of gas chromatography-mass spectrometry reveal that the thioether products 3ag and 3b are obtained in yields of 36% and 33%, respectively.This suggests that xanthate 5g generated via the nucleophilic substitution of benzyl chloride with 2a may be the reaction intermediate (Scheme 5b-d).However, when directly using S-benzyl O-ethyl carbonodithioate 5g to complete the reaction in the absence of 2a, the expected thioether 3ae is not produced, and a small amount of the 1,2-dibenzyldisulfane 5f is generated instead (Scheme 5c).Unexpectedly, when 5g and n BuOCS2K ( n Bu = n-butyl) are used concurrently, sulfation proceeds smoothly to produce a mixture of thioethers 3ag and 3ah, indicating that ROCS2K is indispensable in the reaction (Scheme 5d).To enhance our understanding of the reaction mechanism, we designed control experiments, as shown in Scheme 5. First, the reaction of phenylmethanethiol with 2a furnishes thioether 3ag in trace amounts and 1,2-dibenzyldisulfane 5f in 87% yield, suggesting that thiol alone cannot undergo the sulfation reaction with 2a (Scheme 5a).When benzyl chloride and p-tolylmethanethiol are mixed as substrates, the results of gas chromatography-mass spectrometry reveal that the thioether products 3ag and 3b are obtained in yields of 36% and 33%, respectively.This suggests that xanthate 5g generated via the nucleophilic substitution of benzyl chloride with 2a may be the reaction intermediate (Scheme 5b-d).However, when directly using S-benzyl O-ethyl carbonodithioate 5g to complete the reaction in the absence of 2a, the expected thioether 3ae is not produced, and a small amount of the 1,2-dibenzyldisulfane 5f is generated instead (Scheme 5c).Unexpectedly, when 5g and n BuOCS 2 K ( n Bu = n-butyl) are used concurrently, sulfation proceeds smoothly to produce a mixture of thioethers 3ag and 3ah, indicating that ROCS 2 K is indispensable in the reaction (Scheme 5d).
The reaction mechanism of the synthesis of pyridine thioether was then explored.First, pyridine molecules without halogen substituents do not undergo sulfation under the standard reaction conditions, indicating the necessity of halogen substituents or suitable leaving groups (Scheme 6a).When 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) or butylated hydroxytoluene (BHT) is added as a radical scavenger, the sulfuration of 3-iodopyridine is heavily inhibited (Scheme 6b), and thus, the sulfuration reaction may proceed via a radical pathway.When radical initiator lauroyl peroxide was used instead of I 2 , we were pleased to find that the sulfation reaction could still be completed and give 4a in 86% yields (Scheme 6c).When using 3-fluoropyridine, 3-chloropyridine, 3-bromopyridine, and 3-iodopyridine mixed with 2a (1.2 mmol), the reactivities of the halogens follow the order F > Cl ≈ Br > I (Scheme 6d) [45].When 3-iodopyridine and 2-iodopyridine are involved in the reaction, the halogen at the 2-position of pyridine exhibits a higher reactivity (Scheme 6e).The reaction mechanism of the synthesis of pyridine thioether was then explored.First, pyridine molecules without halogen substituents do not undergo sulfation under the standard reaction conditions, indicating the necessity of halogen substituents or suitable leaving groups (Scheme 6a).When 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) or butylated hydroxytoluene (BHT) is added as a radical scavenger, the sulfuration of 3-iodopyridine is heavily inhibited (Scheme 6b), and thus, the sulfuration reaction may proceed via a radical pathway.When radical initiator lauroyl peroxide was used instead of I2, we were pleased to find that the sulfation reaction could still be completed and give 4a in 86% yields (Scheme 6c).When using 3-fluoropyridine, 3-chloropyridine, 3-bromopyridine, and 3-iodopyridine mixed with 2a (1.2 mmol), the reactivities of the halogens follow the order F > Cl ≈ Br > I (Scheme 6d) [45].When 3-iodopyridine and 2-iodopyridine are involved in the reaction, the halogen at the 2-position of pyridine exhibits a higher reactivity (Scheme 6e).
Based on these results, a plausible mechanism for the sulfuration reaction is proposed, as shown in Scheme 7. Initially, I2 liberates an iodine radical (I•), which activates 2a to afford EtOCSS•, with the concomitant release of electrons [46,47]   Based on these results, a plausible mechanism for the sulfuration reaction is proposed, as shown in Scheme 7. Initially, I 2 liberates an iodine radical (I•), which activates 2a to afford EtOCSS•, with the concomitant release of electrons [46,47]

General Methods (Chemistry)
General methods are described in the Supplementary Materials.

General Procedures for the Preparation of Compounds 3a-3af
A mixture of 4-(chloromethyl)-1,1′-biphenyl 1a (101 mg, 0.5 mmol), EtOCS2K (160 mg, 1.0 mmol) and DMSO (1 mL) was added successively in a 15 mL Schlenk tube.The Schlenk tube was then immersed in an oil bath at 100 °C in a sealed tube in an air atmosphere stirring for 1 h.After cooling down to room temperature, the solution was filtered through a small amount of silica gel.Then the residue was concentrated in vacuo and the crude was purified by flash chromatography with n-hexane/ethyl acetate (50/1, v/v).

General Methods (Chemistry)
General methods are described in the Supplementary Materials.

General Procedures for the Preparation of Compounds 3a-3af
A mixture of 4-(chloromethyl)-1,1 ′ -biphenyl 1a (101 mg, 0.5 mmol), EtOCS 2 K (160 mg, 1.0 mmol) and DMSO (1 mL) was added successively in a 15 mL Schlenk tube.The Schlenk tube was then immersed in an oil bath at 100 • C in a sealed tube in an air atmosphere stirring for 1 h.After cooling down to room temperature, the solution was filtered through a small amount of silica gel.Then the residue was concentrated in vacuo and the crude was purified by flash chromatography with n-hexane/ethyl acetate (50/1, v/v).

General Procedures for the Preparation of Compounds 4a-4s
A mixture of 3-Iodine pyridine (103 mg, 0.5 mmol), EtOCS 2 K (192 mg, 1.2 mmol), I 2 (381 mg, 1.5 mmol), and DMF (3 mL) was added successively in a 15 mL Schlenk tube.The Schlenk tube was then immersed in an oil bath at 150 • C in a sealed tube in an air atmosphere stirring for 36 h.After cooling down to room temperature, the solution was filtered through a small amount of silica gel.Then the residue was concentrated in vacuo and the crude was purified by flash chromatography with n-hexane/ethyl acetate (3/1, v/v).

Scheme 2 .
Scheme 2. Synthesis of thioethers using various alkyl chlorides a,b .a Reaction conditions: alkyl halide (0.5 mmol), ROCS 2 K (1.0 mmol) in DMSO (1.0 mL) at 100 • C in a sealed tube in an air atmosphere for 1 h b isolated yields.
. The addition of the EtOCSS• radical to 3-iodopyridine then produces radical cation A [48,49], which then releases iodine radicals to generate the intermediate xanthate C. Subsequently, xanthate C undergoes a hydrolysis reaction to produce pyridineethoxycarbothioylsulfanylmethanethioate E, which decomposes to generate ethyl(thioxomethylidene)oxonium F and xanthate anions.Finally, the nucleophilic substitution reaction of the pyridine-3-thiolate D with oxonium F furnishes 3-(ethylthio)pyridine 4a and releases COS.Alternatively, the intermediate xanthate C may be formed through a further single-electron oxidation of intermediate A by DMSO or O2 to afford the intermediate xanthate carbocation B and then releases iodine positive ions [50,51].

Scheme 7 .
Scheme 7. Proposed reaction mechanism.As shown in Scheme 7b, the sulfidation reaction of benzyl halides with 2a proceeds via a similar process.The difference is that benzyl halides react more easily with 2a via nucleophilic substitution to afford a similar intermediate, i.e., xanthate G, without free radical process.The reaction under a nucleophilic attack of EtOCS 2 K on the thiocarbonyl group form xanthate intermediate G and subsequently undergoes an intramolecular elimination reaction forming intermediate thiol anion I and O-ethyl ethoxycarbothioylsulfanylmethanethioate E. Finally, the nucleophilic substitution reaction of the thiol anion I with oxonium F furnishes dialkyl thioether 3 and releases COS.

Table 1 .
Optimization of the reaction conditions a,b .

Table 1 .
Optimization of the reaction conditions a,b .

Table 2 .
Optimization of reaction condition a,b .

Table 2 .
Optimization of reaction condition a,b .