Introduction
Organosulfur compounds are considered extremely relevant building blocks in organic synthesis since it is found in a wide variety of natural products,[1 ]
[2 ] pharmaceuticals,[3 ] catalysts,[4 ] as well as essential amino acids and peptides. Of note, Sulfur-containing compounds bearing C–S,[5 ] N–S,[6 ] and O–S bonds[7 ] often show different biological activities and serve important functions in the pharmaceutical industry ([Fig. 1 ]),[8 ] including various valence states of S (II, IV, and VI), which can be sulfur-containing heterocycles, aromatic or nonaromatic. In this review, we focused on the green synthesis of the C–S bond.
Fig. 1 Representative sulfur-containing scaffolds in natural products and pharmaceuticals.
Over the past decades, sustainable efforts have been devoted to the development of efficient methods for the formation of C–S bonds.[5 ]
[9 ] Transition metal-catalyzed cross-coupling reactions between aryl halides/triflates and thiols/thiolates are one of the most commonly used conventional pathways,[10 ]
[11 ] however, prone to over-oxidation under traditional harsh chemical oxidation conditions.[12 ]
[13 ]
[14 ] In addition, catalyst poisoning is inevitable, which leads to the deactivation of the metal catalyst.[15 ]
Organic electrosynthesis straightforwardly translates electrons as a “traceless” reagent in place of the generally used reactive oxidants/reductants to achieve the redox process, which has aroused much attention for its desirability to achieve sustainable synthesis.[16 ]
[17 ]
[18 ] Fine control for oxidative abilities, which is one of the most important characterizations of electrosynthesis, provides a good option for C–S bond establishment.[19 ] The past decade has witnessed the development of electrosynthesis of C–S bonds using a variety of substrates and sulfur surrogates under electrochemical conditions.[20 ]
[21 ] Our research group has been actively working in the area of green and sustainable chemistry.[22 ]
[23 ]
[24 ] In this perspective, herein, we reviewed the recent progress of electrosynthesis of the C–S bond, emphasizing their basic scopes and limitations, applications in the construction of pharmaceutical molecules, and the plausible reaction mechanisms.
Electrosynthesis of C–S Bond
In 2017, Xu's group reported a metal- and reagent-free method via 2,2,6,6-tetramethylpiperidine-N -oxyl radical (TEMPO)-catalyzed electrolytic C–H thiolation, furnishing the benzothiazoles and thiazolopyridines in good yields ([Fig. 2 ]).[25 ] This approach employs n -Bu4 NBF4 in MeCN/MeOH (1:1) as an electrolyte solution, in an undivided cell with a reticulated vitreous carbon (RVC) anode and Pt plate cathode under a constant current of 10 mA. Various substituents on the N -aryl group are well tolerated under standard conditions. Notably, this reaction provides an efficient method to access the thiazolo[4,5-c ]quinoline in three steps from commercially available 3-quinolinamine involving acylation, thiolation, and electrochemical cyclization, which is an intermediate for the preparation of CL075, a toll-like receptor (TRL8) agonist.[26 ] Mechanistic investigations revealed that the reaction of anode-generated TEMPO+ and a thioamidyl radical was involved.
Fig. 2 TEMPO-catalyzed electrolytic C–H thiolation. TEMPO, 2,2,6,6-tetramethylpiperidine-N -oxyl radical.
Later in 2019, Mei and coworkers accomplished novel nickel-catalyzed electrochemical thiolation reactions of aryl bromides and chlorides in the absence of an external base under room temperature, using undivided electrochemical cells with a Ni foam electrode and a magnesium sheet as a sacrificial anode ([Fig. 3 ]).[27 ] In Mei et al's work, a variety of aryl bromides and chlorides with diverse structures are successfully coupled with aryl thiols in high efficiency under constant-current electrolysis at 4.0 mA in the presence of 10 mol% NiBr2 •glyme and 4 equiv. of LiBr in N ,N -dimethylformamide.
Fig. 3 Nickel-catalyzed formation of C–S bond through electrochemistry.
Oxidation of thiolates to thiyl radicals occurred on the Mg anode, as revealed by cyclic voltammetry (CV) experiment and confirmed by trapping the thiyl radical with TEMPO in 30% yield. The catalytic cycle of Ni could be accomplished through the cathodic reduction and aryl Ni(II) complex reductive elimination.
In 2018, Yuan et al revealed the difunctionalization of alkenes from the C–S and C–O/N bonds together ([Fig. 4 ]).[28 ] To overcome the inherent limitation of sensitivity to oxidants under traditional essential oxidation conditions, Yuan et al applied electrolysis to achieve the oxysulfenylation and aminosulfenylation of alkenes. Such a judicial strategy enables the simultaneous generation of C–S and C–N bonds, in an undivided cell using a two-electrode system with the graphite rod as the anode, the platinum plate as the cathode, the solution-containing n -Bu4 NBF4 as the electrolyte, and CH3 CN as the solvent. Notably, this electrochemical oxidative synthetic strategy could also be applied to the hydroxysulfenylation and acyloxysulfenylation of alkenes.
Fig. 4 Difunctionalization of alkenes by electrochemical formation of both C–S and C–O/N bonds.
In 2019, Yang et al reported the first electrochemical decarboxylative coupling reaction between cinnamic acids and NH4 SCN to provide vinyl thiocyanates in good yields.[29 ] The reaction was conducted in the presence of CH3 COONH4 (3 equiv.) and NaHCO3 (1 equiv.), under constant current at 5 mA in an undivided cell ([Fig. 5 ]). It was worth noting that water was vital that no desired product was formed in the absence of water. Screening of solvent showed that mixed solvent CH3 CN/H2 O (7:1) gave the best result. While cinnamic acids bearing electron-donating or withdrawing groups were well tolerated, acrylic acid could not transform into the target products. A radical trapped experiment implied that the coupling reaction probably underwent a radical pathway and that the SCN radical intermediate might be involved in the transformation. The reaction failed to proceed when 2-methylstyrene was used instead of acrylic acid under the standard conditions, which suggested 2-methylstyrene was not the intermediate of this reaction. In addition, when the carboxyl group was replaced by ester, no desired product was formed, which indicated that the carboxyl group was necessary for the reaction. CV experiments showed that the oxidation of thiocyanate occurred preferentially during the reaction process, and bases could promote this reaction.
Fig. 5 Electrochemical decarboxylative coupling reactions.
Later in 2021, Lei's group reported an unpresented electrochemical oxidative one-carbon difunctionalization of isocyanides via the sequential addition of simple mercaptans and alcohols ([Fig. 6 ]).[30 ] In a simple system consisting of a C(+)|Pt(−) electrode, n -Bu4 BF4 electrolyte, MeCN solvent, and N2 atmosphere under an undivided cell with 10 mA constant current at room temperature, a series of multisubstituted imine ethers were facilely obtained under mild conditions, with S–C(sp2 )–O bond formation. The mechanistic study showed that the sulfur radical was formed by single electron transfer (SET) oxidation of the thiophenol at the anode, which attacked the isocyanide to generate the imine radical. Further, SET of the imine radical gave the carbon cation to be captured by nucleophile MeOH and forge the desired product with hydrogen evolution. It is worth noting that the potential application of this strategy was demonstrated by the synthesis of pharmaceutical relevance moiety probenecid and ciprofibrate.
Fig. 6 Difunctionalization of isocyanides.
As the thiols/thiophenols (RSH) are prone to bind with transition metals and poison transition-metal catalysts which deeply hampered the development of direct C–S cross-coupling, Lei and coworkers disclosed a transition-metal catalyst and oxidant-free electrocatalytic protocol for dehydrogenative C–H/S–H cross-coupling ([Fig. 7 ]).[19 ] Under undivided electrolysis conditions, various aryl/heteroaryl thiols and electron-rich arenes afforded the desired products in moderate to high yield. A preliminary mechanistic study indicated that aryl radical cations are the key intermediates.
Fig. 7 Electrocatalytic oxidant-free dehydrogenative C–H/S–H cross-coupling.
In the following year, the group achieved selective oxidative C–H sulfenylation of imidazopyridine heterocycles using hydrogen evolution as an undivided electrolytic cell ([Fig. 8 ]).[31 ] Neither transition metal catalysts nor external chemical oxidants were required to facilitate the C–S bond formation process. A broad substrate scope of thiols and imidazopyridines bearing various substituents is presented and shows good tolerance. Significantly, the scope of the thiols could be extended to aliphatic thiols. In addition, the scaled-up reactions in batches have also been successfully performed in 5 mmol. As disulfides were observed as side products in the reaction system, the control experiment was performed using disulfide as the starting material and the result confirmed the key intermediate role of disulfides.
Fig. 8 Electrochemical oxidative C–H sulfenylation of imidazopyridines.
Mitsudo et al realized the metal-free dehydrogenative C–H/S–H coupling for the formation of π-expanded heteroacene derivatives ([Fig. 9 ]).[32 ] While only the homo-coupling product was formed without additive, the desired π-expanded cyclized products were formed in the presence of electrogenerated [Br+ ] from n -Bu4 NBr. It is worth noting that the product distribution of cyclization and homo-coupling were strongly influenced by the amount of charge. Given that the amount of charge could be reduced by further stirring of the reaction mixture after electrolysis, a series of thienoacene derivatives are accommodated in good to excellent conversion yields under the standard condition of 15 minutes of additional stirring after electrolysis. Control experiments showed that the homo-coupling product is an important intermediate, CV experiments indicate that Br− of n -Bu4 NBr would be oxidized to afford [Br+ ], and 2-arylbenzene-1-thiol would be oxidized by [Br+ ] to give disulfide D and Br− , which would be oxidized to [Br+ ] again on the anode. D would react with [Br+ ] to give the cationic species A . Subsequent intramolecular cyclization would give the cyclized product.
Fig. 9 Electrochemical C–H/S–H coupling for the formation of π-expanded heteroacenes.
While arene activation has been well established toward the thiolation of aromatic C–H bonds over the past decades,[33 ]
[34 ]
[35 ]
[36 ]
[37 ]
[38 ]
[39 ] Wu and coworkers disclosed a thiol activation strategy for the construction of C–S bond ([Fig. 10 ]).[40 ] Mechanistic studies suggested that thiophenol was oxidized to the corresponding radical through SET on the anode. In this pathway, two platinum plates were used as electrodes, n -Bu4 NPF6 as electrolytes, and hexafluoroisopropanol as a solvent or a co-solvent for the stabilization of the radical cation intermediate.
Fig.10 The construction of the C–S bond via an electrochemical thiol activation strategy.
Besides the coupling between sp2 C–H of arenes and S–H, electrochemical oxidative C–H/S–H cross-coupling between sp2 C–H of enamines and thiophenols with H2 evolution was also developed,[41 ] and biologically important vinyl sulfides could be formed without external oxidant, transition-metal catalyst, and higher reaction temperature. The optimized conditions consist of the solvent (CH3 CN), the electrolyte (n -Bu4 NBF4 ), the electrodes (C(close)(+)|Fe(−)) and the atmosphere (N2 ), all of which are essential to achieve a smooth reaction with satisfactory yield ([Fig. 11 ]). This protocol is compatible with halogen-substituted substrates but does not tolerate 2-mercaptobenzothiazole due to poor solubility. In addition, when mercaptans were used as substrates, either no or a trace amount of products was detected.
Fig. 11 Electrochemical coupling between sp2 C–H of arenes and S–H.
Inspired by Lei and coworker's work, Li et al explored the disulfide arylation of terminal olefins for the synthesis of gem-bisarylthio enamines from vinyl azides and thiophenols under electrochemical conditions ([Fig. 12 ]).[42 ] An undivided cell with two platinum plates as electrodes, KI (1 equiv.) as the electrolyte, and MeCN as the solvent was used in the reaction. When the reaction is conducted at room temperature with a constant current of 10 mA, the target product was obtained in up to 97% yield. It is worth noting that a nitrogen atmosphere is not required as the reaction can proceed in the air. A series of mechanistic control experiments showed that I2 was not directly involved in the reaction, but the iodine atom was responsible for the oxidative coupling. Different from the common mechanism in C–S bond formation which involves disulfanes, the replacement of thiophenol with disulfane failed to obtain the desired product, indicating that disulfanes were not the key intermediate in this transformation. Additionally, an electrochemical study was conducted at the glassy carbon electrode, and the results showed that thiophenol readily reacts with iodine radicals, and vinyl azides can further help the overall electrochemical cross-coupling reaction.
Fig. 12 Electrochemical oxidative cross-coupling between vinyl azides and thiophenols.
Besides, vinyl azides can be coupled with sodium azide and benzenesulfonyl hydrazides for environmentally benign electrochemical synthesis of phenanthridines and β-ketosulfones. Exogenous oxidants, metal catalysts, or expensive photoredox are considered to be indispensable for the preparation of phenanthridine and its derivatives via tandem radical addition/cyclization. In 2020, Li et al reported an efficient metal-free oxidative cyclization of biaryl vinyl azide with readily available sodium azide and benzenesulfonyl hydrazide as radical precursors. In this method, diverse phenanthridines and β-ketosulfones were prepared at room temperature in moderate to high yield ([Fig. 13 ]).[43 ] The optimized reaction condition was obtained in MeCN:H2 O (10:1) using LiClO4 (0.1 mol/L) as the supporting electrolyte and C(+)/Pt(−) as the electrodes at a constant potential of 2.3 V for 2 hours. Control experiments indicated that the reaction proceeds through a radical process, and sulfonyl radicals come from electro-oxidation of sulfonyl hydrazide. Cyclic voltammogram studies showed that the oxidation of sulfonyl hydrazide undergoes a coupling reaction with biaryl vinyl azide.
Fig. 13 Electrochemical coupling of vinyl azides.
Benzothiazole is one of the most important frameworks in the field of pharmaceuticals due to its bioactivities including antiviral, antitumor, and antiseptic agents as well as tracers for β-amyloid plaques in Alzheimer's disease.[44 ]
[45 ] While the traditional intramolecular dehydrogenative C–S cross-coupling of N -aryl thioureas or N -aryl thioamides using external chemical oxidants are prone to over-oxidation to afford ureas or amides, electrosynthesis avoids the over-oxidation by controlling the operating voltage and current. Wang et al developed external oxidant-free intramolecular dehydrogenative C–S cross-coupling reactions under undivided electrolytic conditions ([Fig. 14 ]).[46 ] Thiourea E was generated during the reaction and the intramolecular dehydrogenative C–S cross-coupling could be performed in the presence of sodium benzoate (2 equiv.) as a base. Mechanistic experiments showed that SET was preferred with a sulfur anion intermediate generated in situ from the acid–base equilibrium rather than with N -phenylbenzothioamide F . Notably, this reaction could be conducted on a gram scale in 5 mmol, which is important for further application.
Fig. 14 Electrochemical intramolecular dehydrogenative C–S cross-coupling reactions.
As the collaborative analysis of continuous-flow and electrochemistry, flow electrochemistry provides advantages over traditional batch reactors including a large ratio of electrode surface to reactor volume, a shorter reaction time, a more efficient mass transfer enabled by the shorter distance between electrodes, lower concentrations or even obviate of supporting electrolyte.[47 ]
[48 ]
[49 ]
[50 ] In 2018, Xu's group and Wirth collaborated to achieve a novel catalyst- and supporting electrolyte-free method for the electrosynthesis of benzothiazoles and thiazolopyridines in continuous flow ([Fig. 15 ]).[51 ] Especially, thiazolo[4,5-c ]quinolone G , an important intermediate in the synthesis of TLR8 receptor agonist CL075, could be obtained in 97% isolated yield, by employing platinum as the cathode and graphite as the anode.
Fig. 15 Flow electrochemical synthesis of benzothiazoles and thiazolopyridines.
After these findings, in 2019, Xu's group further extended the modular flow electrolysis cell to the synthesis of benzofused six-membered S -heterocycles by intramolecular dehydrogenative C–S coupling ([Fig. 16 ]).[52 ] The reaction was equipped with a Pt cathode and a carbon-filled polyvinylidene fluoride (C/PVDF) anode. Given the ease of oxidative desulfurization of thioamides, the addition of trifluoroacetic acid and Sc(OTf)3 was important for the success of this reaction, which helped avoid overoxidation of the heterocyclic product and promoted the oxidation of the thioamide substrate. It is worth mentioning that in contrast to the reaction in flow, electrolysis of H in a batch reactor afforded a mixture of I and J , indicating the great importance of the flow cell.
Fig. 16 Flow electrochemical synthesis of benzofused six-membered S -heterocycles.
In 2022, de Souza et al developed an electrochemical sulfenylation protocol for the synthesis of α- sulfenylated ketones in both batch and continuous-flow regimes, involving thiophenols/thiols and enol-acetates ([Fig. 17 ]).[53 ] In the batch conditions, α-sulfenylated ketones were obtained in high yields in the absence of additional oxidant and metallic catalysts. Notably, the Boc-cysteine proved to be extremely tolerant, which opened up the possibilities of synthesizing new building blocks from amino acids and peptides or functionalizing them at a later stage. Although n -Bu4 NBF4 was screened as the ideal electrolyte in batch conditions with an undivided cell using ACN:H2 O as the solvent, the translation of batch protocol to continuous flow is an obstacle because the reaction mixture can clog up in the microchip regardless of monophasic reaction for pumping or use two different channels for pumping each of the reagents. To address this limitation, HBF4 •Py was used as an electrolyte which is completely miscible in ACN:H2 O. After the screening of reaction conditions, the optimal continuous-flow conditions were established as two different channels for pumping (substrates K and L and ACN were pumped in channel 1 , and the mixture of HBF4 •Py and H2 O was pumped in channel 2 ), resulting the desired product in 83% yield in a 7.5-minute residence time.
Fig. 17 Electrochemical synthesis of α- sulfenylated ketones.
He et al developed a C–S and C–O bond construction protocol via an electrochemical carbenoid insertion reaction of diazo compounds ([Fig. 18 ]).[54 ] The S–H insertion reaction was performed at room temperature under 5 mA constant current in an undivided electrolytic cell equipped with a graphite anode and a graphite cathode using TBAB as the electrolyte and DCE as the solvent. A variety of thiols underwent S–H insertion reactions with diazo esters, giving the desired product in moderate to high yields. The robustness of this transformation was further demonstrated by the O–H insertion reaction. In contrast to S–H insertion reactions, O–H insertion results in poor efficiency besides the synthesis of analgesic drug salicylic acid; however, the substituents in the phenyl were tolerated well in the process. When TBAI was used as the electrolyte for the optimization of reaction conditions, various C–O bond products were obtained in a yield of 22 to 73%.
Fig. 18 Electrochemical carbenoid insertion reaction of diazo compounds.
Lactones are significant subunits in numerous natural products, bioactive molecules, and pharmaceuticals. However, the general procedures of synthesizing such compounds involve the use of toxic and expensive transition metal catalysts, as well as photocatalysts with exogenous oxidants, high temperatures, and long reaction times. To address those issues, Yang et al developed the first electrochemical cascade sulfonylation and lactonization process of alkenes using sulfonyl hydrazines as an arylsulfonylation reagent ([Fig. 19 ]).[6 ] The reaction was conducted in a N2 atmosphere using C (+)/Pt (−) as electrodes, CH3 CN/H2 O (10/1) as a solvent, LiClO4 as an electrolyte, and AcOH as an additive, and γ-sulfonylated phthalides with broad and excellent substrate tolerance were achieved. The CVs of substrates indicated that sulfonyl hydrazines were more susceptible to being electrochemically oxidized and forming the benzenesulfonyl radical.
Fig. 19 Electrochemical sulfonylation-induced lactonization of alkenes.
Electrochemical reactors play an important role in achieving satisfactory reaction results. Most electrochemical reactors used to establish C–S bonds consist of easily available setups including undivided cells and common electrodes like RVC, Pt, Fe, and carbon rods. In recent years, with the popularity of flow electrochemistry, researchers have begun to design flow electrochemistry reactors independently to improve the efficiency of the reaction. Huang et al designed an easy-to-machine flow electrolysis cell assembled from two aluminum bodies with a groove ([Fig. 20A ]).[52 ] The two aluminum bodies (① and ⑤) and the cathode (④) which consists of a piece of platinum foil were fixed on a stainless steel base for the avoidance of deformation. The anode (②) is made of carbon-filled polyvinylidene fluoride and insulated from the aluminum body by PTFE or silicone film. The anode and cathode are held apart by a fluorinated ethylene propylene (FEP) foil (③) of 125 μm thickness. A rectangular reaction channel with a total length of 313 mm and a width of 3.2 mm is cut in the FEP foil to give an overall channel volume of 125 μL. The whole device is held together by steel screws and wing nuts. The reaction mixture flows in and out through the inlet and outlet (⑥ and ⑦). Wirth et al designed the micro-flow electrochemical reactor made out of two bodies ([Fig. 20B ])[51 ] with two parts of the reactor held apart by one FEP foil, into which a reaction channel is cut, giving different reaction volumes depending on the design of the flow path ([Fig. 20C ]). The electrodes were placed in the square center of the body and connected by a copper plate attached to a wire and connected to the power supply.
Fig. 20 (A ) Design of flow electrolysis cell. ① and ⑤, aluminum bodies; ②, anode; ③, a fluorinated ethylene propylene foil; ④, cathode; ⑥ and ⑦, the inlet and outlet, respectively. (B ) Design of micro-flow electrochemical reactor. (C ) Flow path. (Reproduced with permission from Huang C, Qian XY, Xu HC. Continuous-flow electrosynthesis of benzofused S-heterocycles by dehydrogenative C–S cross-coupling. Angew Chem Int Ed 2019;58:6650–6653.[52 ])
Summary
The ubiquity of sulfur-containing molecules in biologically active natural products and pharmaceuticals has long attracted synthetic chemists to develop efficient strategies for their synthesis. Traditional methods usually require the use of chemical oxidants like carbon tetrabromide (CBr4 ), di-tert -butyl peroxide (DTBP), potassium persulfate (K2 S2 O8 ), etc., which were prone to over-oxidation; however, compared with the conventional methods, electrosynthesis, employing the electron as a potent, controllable, yet traceless redox reagent, has emerged as a mild and eco-friendly method for chemical transformation. Herein, we summarized the recent important developments in C–S bond formation in terms of various electrosynthesis ways, especially, for the synthesis of pharmaceutical molecules. In addition, the scope, limitations, and mechanisms are described and discussed, detailing the fundamental aspects and benefits of electrochemistry for the construction of the C–S bond.
The content of this review demonstrates that it is possible to provide new synthetic routes and to improve the existing methodologies, to obtain processes more in line with current environmental protection aims. However, the electrosynthesis construction of C–S bonds involving enantioselectivities is still challenging, and more attention from the electrochemical community is anticipated to focus on the development of more efficient, sustainable, and practical electro-strategies to address the current challenges in chemical selectivity and enantioselectivity.
