Reductive sulfinylation by nucleophilic chain isomerization of sulfonylpyridinium

Abstract

Sulfur-containing units are fundamental components widely found in bioactive compounds, prompting notable efforts toward developing synthetic methodologies for incorporating sulfur functionality into organic precursors. The synthesis of sulfinate esters and sulfinamides has garnered significant interest owing to their immense potential for applications, especially in drug development. However, most existing synthetic protocols suffer from some limitations. To address these challenges, we herein present a practical and efficient approach for the reductive sulfinylation of diverse nucleophiles with sulfonylpyridinium salts (SulPy) through the nucleophilic chain substitution, namely S_NC reaction, which involves S(VI) to S(IV) nucleophilic chain isomerization process. These versatile sulfinylation reagents can be readily accessed from diverse commercially available resourses. The late-stage modification of complex molecules and the ability to rapidly synthesize numerous sulfinyl bioisosteres of various drugs highlights the utility of this protocol.

The synthesis of sulfinate esters and sulfinamides has garnered significant interest owing to their potential for applications. Here, the authors report the reductive sulfinylation of diverse nucleophiles with sulfonylpyridinium salts through nucleophilic chain substitution, which involves S(VI) to S(IV) nucleophilic chain isomerization process.

Introduction

For recent decades, synthetic methodologies aiming to access organosulfur compounds have been extensively explored in various fields, including organic synthesis, pharmaceutics, agriculture, polymer science, and biochemistry^1–14. Among these sulfur compounds, sulfinyl derivatives have been found to be of remarkable utility in various applications, including pharmaceuticals^15,16, natural products¹⁷, fluorescent probes^18,19, and more (Fig. 1a)^20–29. In addition, their application in constructing bioactive compounds^30–32, especially as bioisosteres of carbonyl or sulfonyl groups^33,34, has also shown potential prospects of S(IV) centers. Compared to sulfone and sulfoxide compounds, the construction of tetravalent sulfur-centered species including sulfinate esters and sulfinamides is still under-developed and has several drawbacks (Fig. 1b). The partial oxidation of disulfides or thiols^35–39 and reductive conversion of sulfonyl chlorides^40,41 often suffered from uncontrollable disproportionation of the multi-valent sulfur centers^42,43, leading to over-oxidation/reduction during the process. Meanwhile, the substitution of sulfinyl halides, sulfoxides, and sulfinates to access sulfinyl compounds^44–49 involved the use of unstable precursors and harsh reaction conditions^50–53.

Fig. 1. Origin of the reaction design.

a Selected examples of bioactive molecules incorporating S(IV) and S(VI) moieties. b Current status of research on diverse S(VI) and S(IV) compounds. c Conceptual outline for the synthesis of sulfinyl compounds through nucleophilic chain substitution (S_NC). d This work: Late-stage sulfinylation of complex molecules via the nucleophilic chain isomerization process of sulfones (VI) to sulfinates (IV) utilizing abundant gas feedstocks and commercially available chemicals. SulPy sulfonylpyridinium salts, AG activating group, Nu nucleophiles.

Recently, a carbon-radical trapping strategy employing N-sulfinylamine (R-NSO) as radical receptors to deliver sulfinamides has been reported^54,55. Meanwhile, the in situ activation of sulfinates using highly active anhydrides or acyl chlorides to facilitate nucleophilic substitution has provided a different perspective on the organocatalytic asymmetric synthesis of sulfinyl derivatives^56–58. However, the competition between the nucleophiles and sulfinates during the activation step might interfere with the tetravalent sulfur center formation and limit the scope of sulfinate substrates. Consequently, there is a pressing need for the development of a more general and convenient method for synthesizing sulfinyl compounds from readily available precursors.

Given that sulfone derivatives are readily procurable from a wide range of abundant sulfur feedstocks^59–62, we were motivated to develop a different method to facilitate the transformation of sulfone to synthetically versatile sulfinyl derivatives, such as sulfinate esters and amides. Typically, sulfonyl compounds require initial conversion to sulfinate intermediates under strong alkaline or high-temperature conditions^63–66, followed by isolation and further activation through a deoxygenation process to react with nucleophiles and produce the desired sulfinyl compounds^{45,46,56–58}. Establishing a modular synthesis platform of sulfinyl compounds from sulfones in a one-step procedure remains a significant challenge, especially for the late-stage selective sulfinylation of complex molecules and pharmaceuticals^67,68. Recently, Yan and co-workers⁶⁹ have reported an enantioselective deoxygenation process of sulfonyl cyanides for the synthesis of chiral sulfonate esters. Despite remarkable advancements in the direct transformation of sulfonyl compounds to sulfinyl derivatives, this approach remains constrained by the limited substrate scope of sulfonyl cyanides, especially alkyl-derived precursors, and by the challenges in achieving broad nucleophile compatibility.

Nucleophilic substitution (S_N), a fundamental reaction in organic chemistry, plays a pivotal role in organic synthesis, materials, pharmaceuticals, and biochemistry^70–75. Of note, exploring a different process based on the existing mechanism remains an important complement to this traditional approach. Inspired by the classic Mukaiyama esterification where N-heteroaryl cationic salts were employed to trigger the condensation of carboxylic acids and alcohols⁷⁶, we envisioned the N-methylpyridinium moiety could also activate sulfones for the construction of sulfinate esters and amides under mild conditions. We herein unlocked the nucleophilic chain substitution (S_NC) process^77–80 for the direct reductive sulfinylation of complex molecules, employing readily preparable and bench-stable sulfonylpyridinium salts (SulPy) as sulfinyl group transfer reagents. Mechanistic investigations revealed that the sulfinylation reaction achieved through nucleophilic chain substitution (S_NC) involved nucleophilic chain isomerization of the S(VI) center in the SulPy reagents to form an S(IV)-containing electrophilic sulfinate ester, which then underwent nucleophilic substitution to provide sulfinyl compounds (Fig. 1c; for details, see the mechanistic studies in Fig. 2). Compared to the precedented nucleophilic substitution sulfinylation methods, the current S_NC eliminates side reactions between nucleophiles and exogenous activating reagents, avoids the use of unstable sulfinyl halides, as well as addresses issues of product over-oxidation or over-reduction. This mild, modular, and practical S_NC strategy has been employed for the reductive sulfinylation of diverse nucleophiles utilizing SulPy salts to access a broad array of sulfinyl compounds. Meanwhile, the highly reactive and bench-stable SulPy reagents proved to be highly effective for late-stage applications in drug development and bio-relevant complex molecules (Fig. 1d).

Fig. 2. Mechanistic studies.

a Initial exploration of SulPy with different types of nucleophiles. b Computational mechanistic investigations. M06-2X/6-311 + G** (SMD, ε = 35.688 for acetonitrile) level of theory. c Detection of 2-alkoxypyrimidinium salt (II). d Control reaction using isolated 2-alkoxypyrimidinium salt II. e Scrambling experiment using SulPy 2a and sodium phenylsulfinate 5a. Bn, Benzyl.

Results

Mechanistic studies

Based on our working hypothesis, we initiated our study using alcohol or amine with the newly designed SulPy reagent. Under the optimized conditions (see Supplementary Tables 1–3 for detailed reaction optimization studies), when the nucleophiles were treated with 2-(difluoromethylphenyl)sulfonyl-N-methylpyridinium (SulPy 2a), sulfinate ester 1 and sulfinamide 2 were obtained with high yields in the presence of stoichiometric Na₃PO₄ (Fig. 2a). This result led us to consider a possibility interchanging the S(VI) center as well as repositioning the oxygen atom in the course of this transformation. With the promising demonstration of SulPy for sulfinylation, we first sought to elucidate its mechanistic underpinnings. To shed light on the mechanistic intricacies, density functional theory (DFT) calculations were performed (Fig. 2b, see Supplementary Figs. 6–9 for computational details). The benzyl alcohol 1b and SulPy 2a were selected as the model substrates in silico study due to their molecular simplicity and the ease with which they form the corresponding sulfinylation product.

As an initiation step (Fig. 2b, top), the nucleophilic aromatic substitution of SulPy 2a at the 2-position with benzyl alcohol 1b and Na₃PO₄ was computed to be both kinetically and thermodynamically favorable, traversing TS-I and leading to the formation of the 2-alkoxy pyridinium byproduct II and sulfinate III ([II + III + Na₃HPO₄], ΔG^‡ = 2.7 kcal/mol, ΔG = –65.3 kcal/mol). It was supported by the experimental detection of II using high-resolution mass spectroscopy (HRMS) upon the reaction of 1b and 2a under standard reaction conditions, along with the corresponding product 3 in 84% yield (Fig. 2c). It is worth noting that direct nucleophilic attack of neutral benzyl alcohol (1b) without base was calculated to be kinetically inaccessible (ΔG^‡ = 38.3 kcal/mol). while the direct nucleophilic addition of Na₃PO₄ on SulPy 2a was computed to be also accessible, exhibiting a slightly higher barrier than TS-I (ΔG^‡ = 4.6 kcal/mol, this progress was also was also considered, see the Supplementary Figs. 6 for details). Notably, Na₃PO₄ is poorly soluble in MeCN, and thus we assume that only a small portion of the base additive actively participates in the reaction initiation step. Meanwhile, we applied the less-nucleophilic 2,2,6,6-Tetramethylpiperidine (HTMP) as base and it also worked well in this reaction, which also indicated the possibility of initiation by benzyl alcohol 1b along with the base (see Supplementary Page 30 for details). Moreover, the absence of sulfinylated product 3 formation when the reaction was conducted with sodium difluoromethylphenylsulfate 4a and separately prepared II excluded further possible mechanistic pathways involving direct formation of the sulfinylated product from 2-alkoxypyridinium II, implying an additional role of sulfinate III in yielding the corresponding sulfinylated product (Fig. 2d).

These results led us to propose a mechanism involving additional SulPy 2a to react with sulfinate III (Fig. 2b, bottom). Interestingly, sulfinate III was found to operate as a catalyst in transforming additional SulPy reagent (2a) into nucleophilie-susceptible sulfinyl ester intermediate IV, proceeding through another S_NAr transition state TS-II with a reasonable ΔG^‡ value of 15.7 kcal/mol (Fig. 2b, bottom-left, chain propagation). It should be noted that the regenerated sulfinate III can again participate in the isomerization of the SulPy reagent 2a to electrophilic intermediate IV, leading us to refer to this process as nucleophilic chain substitution (S_NC, vide supra). In fact, the reaction involving alcohol 1b, SulPy 2a, and different sodium alkyl sulfinate 5a resulted in the formation of mixed sulfinate esters (3 and 4) as observed by NMR analysis (Fig. 2e), thus indicating the presence of the nucleophilic aromatic substitution (S_NAr) of 2a and 5a to provide an active S(IV)-intermediate (e.g., IV) during the course of the reaction. Additionally, the reaction of 2a and 1b with catalytic amount of separately prepared sulfinate 4a also provided desired reactivity in the absence of base additive, again supporting sulfinate-catalyzed sulfinylation reaction mechanism (see the Supplementary Fig. 5). In this context, intermediate IV can be considered as an activated sulfinate, susceptible to nucleophilic substitution with neutral benzyl alcohol, facilitated by hydrogen bonding with the counter anion TfO^– (TS-III, ΔG^‡ = 15.4 kcal/mol), eventually forming desired sulfinylated product 3 along with pyridone byproduct V (Fig. 2b, bottom-right).

Substrate scope with respect to nucleophiles

Having the optimized conditions and mechanistic insights of the present sulfinylation protocol, we first examined the reactivity of amine nucleophiles (Fig. 3). Pleasingly, this reaction with a series of bio-relevant primary amines proceeded smoothly at room temperature with SulPy 2a, providing facile access to the corresponding sulfinamides in good to excellent yields (5–16). In fact, the present synthetic repertoire turned out to offer a convenient synthetic toolbox for amino acid modification (5–8). The convenient sulfinylation of bioactive primary amine molecules (9–16) underscores the utility of the current sulfinylation protocol for late-stage functionalization. It is noteworthy that recently reported sulfinylation methods, employing acyl halides as an activating reagent of sulfinates, exhibited good reactivity only for simple aniline and alkylamine derivatives^56–58. Furthermore, a wide range of potentially biorelevant cycloamines, encompassing tertiary (17), bicyclopentane (BCP, 18), and adamantane (19), were all facile in reaction with SulPy 2a to afford the corresponding sulfinamides in high yields. Additionally, not only primary amines, but also a series of secondary amines, including bioactive and drug-related molecules, were also readily amenable under the same reaction conditions to deliver sulfinylated products (20–29). Furthermore, the spiro (23) and bridged (26 and 27) secondary amines, which are deemed crucial molecular skeletons⁸¹, can be smoothly converted into corresponding products. Interestingly, the sulfinylation reaction remained productive even when an inorganic ammonium chloride salt was employed as the nucleophile, yielding unprotected sulfinylamide product 30 in excellent yield.

Fig. 3. Substrate scope of the amines.

Conditions: amines (0.2 mmol), SulPy 2a (0.4 mmol, 2.0 equiv.), and Na₃PO₄ (0.3 mmol, 1.5 equiv.) in CH₃CN (2 mL) under argon atmosphere at r.t. for 3 h. ^a2.5 Equivalents of Na₃PO₄. ^b3.5 Equivalents of Na₃PO₄. ^cDiastereomeric ratio (d.r.) was determined by ¹H NMR.

Subsequently, our sulfinylation protocol, employing 2-(difluoromethylphenyl)sulfonyl-N- methylpyridinium triflate (2a) as a linchpin motif, was found to be adaptable for incorporation of alcohol nucleophiles, resulting sulfinate ester products (Fig. 4). Remarkably, all classes of alcohols, including primary (31–44), secondary (45–54), tertiary variants (55–58), as well as phenols (59–61) could be effectively sulfinylated under mild conditions. Meanwhile, the sulfinylation protocol exhibited extraordinary compatibility with a diverse array of sensitive functional groups, including olefin (31), amide (32), acetal (36), ester (37), ether (38), azide (40), nitro (48), sulfone (50), and alkyne (58). Heteroaromatics, broadly present in bio-relevant compounds, such as imidazole (34), pyrimidine (39), purine (43), thiophene (50), and indole (51), were also well tolerated. Furthermore, the present sulfinylation reaction employing the SulPy reagent showed a notable preference toward primary alcohols, likely attributed to their higher nucleophilicity (42–44), suggesting the promising prospect of utilization of the reaction method for regio- and/or chemoselective sulfinylation.

Fig. 4. Substrate scope of alcohols and phenols.

Conditions: alcohols (or phenols) (0.2 mmol), SulPy 2a (0.4 mmol, 2.0 equiv.), and Na₃PO₄ (0.3 mmol, 1.5 equiv.) in CH₃CN (2 mL) under argon atmosphere at r.t. for 3 h. ^a2.5 Equivalents of Na₃PO₄ were used. ^b1.5 Equivalents of SulPy 2a were used. ^cDiastereomeric ratio (d.r.) was determined by ¹H NMR.

Expanding the scope of alkylsulfonylpyridinium salts

Following the above successful sulfinylation of alcohols and amines in reaction with sulfonylpyridinium triflate salt 2a, we further investigated an additional scope of sulfonyl reagents bearing varied alkyl groups (Fig. 5). As noted, a range of alkyl sulfonylpyridinium derivatives was readily synthesized from commercially available resources with mercapto pyridine and alkyl sources, such as halides, alcohols, and carboxylic acids (see the General Procedures A-H in the Supplementary Information for detailed synthetic methods). Significantly, in this preparative route, fluorinated gases such as HCFC-22 (HCF₂Cl), CFC-31 (H₂CFCl), and HFC-23 (HCF₃) proved effective in generating the corresponding fluoroalkyl sulfonylpyridinium salts, which were then applied to the current sulfinylation procedure (62–65). Moreover, difluoroalkyl and fluoroalkenyl groups were viable for efficient transfer into the sulfinyl products (66, 67, and 68, respectively). Additionally, several alkyl sulfonylpyridinium salts were also reacted with various external nucleophiles with high efficiency (69–88). Different functional groups showed good compatibility with this approach, such as olefin (70), acetal (71), halogen (72), alkyne (73), ether (74), cyanide (77), protected amino (82), and carbonyl (88). And, sterically congested tertiary alkyl sulfonylpyridinium salts could also react with nucleophiles to deliver the desired products (87, 88). Additionally, aryl sulfonylpyridinium salt was compatible with sulfinylation with amine nucleophiles (89).

Fig. 5. Substrate scope of the SulPy reagents.

Conditions: nucleophiles (0.2 mmol), SulPy (0.4 mmol, 2.0 equiv.), and Na₃PO₄ (0.3 mmol, 1.5 equiv.) in CH₃CN (2 mL) under argon at r.t. for 3 h. ^a2.5 Equivalents of Na₃PO₄. ^b3.5 Equivalents of Na₃PO₄. ^cOn a 5.0 mmol scale. ^dIn CH₃CN (0.5 mL) for 6 h. ^eAt 60 °C for 6 h. ^fAn activating group (AG) was used. ^gAn activating group (AG¹) was used (See Supplementary General Procedure J for details). ^hDiastereomeric ratio (d.r.) was determined by ¹H NMR.

Synthetic applications towards bio-relevant molecules

Next, we sought to further investigate applications of the current sulfinylation approach in the context of medicinal chemistry. Given that sulfinyl would be considered as a bioisoster of carbonyl³³, synthesis of sulfinyl analogues of carbonyl-containing bioactive molecules is of special interest (Fig. 6). Indeed, synthesis of sulfinylamide variants starting from amide-bearing drugs, such as Linezolid, Trocimine, Moclobemide, Ramelteon, and Olaparib, was successfully demonstrated in satisfactory yields by employing our practical procedure (90–94). The efficient sulfinylation method was also fruitfully applied to the construction of sulfinate ester analogues of Abiraterone acetate (CYP17 inhibitor, 95) and Tropacocaine (local anesthetic, 96). Moreover, disulfination of butanediol took place efficiently to afford an analogue of antileukemic Busulfan (97). In addition, sulfinamide analogue of the antiarrhythmic sulfonamide drug (Dronedarone) was synthesized in high yield (98).

Fig. 6. Concise synthesis of sulfinyl drug analogues by coupling the corresponding SulPy and nucleophiles.

^aDiastereomeric ratio (d.r.) was determined by ¹H NMR.

As a more advanced, incorporating two bio-relevant ingredients into a sulfinyl bridge was successfully demonstrated (Fig. 7a). For instance, Corey lactone was effectively installed to give sulfonylpyridinium sulfonates, which were subsequently converted to sulfinamide 99 and sulfinate ester 100, respectively. Likewise, Ibuprofen and aryl iodide were also transformed into their corresponding sulfinamides and esters (101–104), thereby underscoring the potent applications for late-stage functionalization of the current protocol.

Fig. 7. Synthetic applications.

a Elaboration of two bio-relevant ingredients into a sulfinyl bridge. b Building sulfomimidates via sulfinyl compounds. c Tandem process for the synthesis of diverse sulfonimidoyl derivatives. ^aDiastereomeric ratio (d.r.) was determined by ¹H NMR.

Subsequently, the post-modification of obtained sulfinyl amides or esters was also examined (Fig. 7b). Oxidative conversion of sulfimamide (94) or ester (103) was highly efficient by the action of PhI(OAc)₂ to afford the corresponding sulfomimidates 105 and 106, respectively. A one-pot procedure to convert sulfoximide (e.g., 104) to sulfonimidoyl derivatives was successfully applied, presumably proceeding via sulfonimidoyl chloride intermediate. According to this tandem process recipe, sulfonimidoyl fluoride (107), amide (108), and imidate ester (109) could also be obtained in good yields (Fig. 7c). Through this method, pharmacologically relevant molecules could be progressively stitched to the sulfur center, providing a new course for subsequent drug design.

Discussion

In summary, we have disclosed the nucleophilic chain substitution (S_NC) reaction for the reductive sulfinylation of readily available sulfonylpyridinium salts with external nucleophiles such as amines, alcohols, and phenols, encompassing S(VI) to S(IV) center nucleophilic chain isomerization pathway. This general protocol demonstrated broad substrate scope in the preparation of sulfinyl derivatives including valuable bio-relevant motifs. Furthermore, this approach utilizes sulfinyl functionality as a scaffold to install pharmacologically relevant structures under mild conditions for late-stage applications.

Methods

General procedure for the synthesis of sulfinyl compounds 1–104

If not specifically mentioned, all products were obtained through the following methods.

General procedure I

A flame-dried and argon-flushed test tube was charged with nucleophiles (0.2 mmol, 1.0 equiv.), Na₃PO₄ (0.3 mmol, 1.5 equiv.) and SulPy (0.4 mmol, 2.0 equiv.). Dried CH₃CN (2 mL, 1.0 M) was added, and the mixture was stirred at room temperature for 3 h. The reaction mixture was evaporated in vacuo. The mixture was extracted with EA (5 mL × 3). The combined organic layer was dried by Na₂SO₄. The crude products were purified by flash chromatography on silica gel to give the desired products.

General Procedure J. A flame-dried and argon-flushed test tube was charged with nucleophiles (0.2 mmol, 1.0 equiv.), Na₃PO₄ (0.3 mmol, 1.5 equiv.) and SulPy (0.4 mmol, 2.0 equiv.). CH₃CN (0.5 mL, 4.0 M) was added, and the mixture was stirred at room temperature under air for 6 h. The reaction mixture was evaporated in vacuo. The mixture was extracted with EA (5 mL × 3). The combined organic layer was dried by Na₂SO₄. The crude products were purified by flash chromatography on silica gel to give the desired products.

Author contributions

W.Z., Y.L., and Y.W. designed this project and analyzed the experiments. Y.L. and W.Z. carried out the experiments. S.C., J.K., and Q.W. conducted the computational studies. Y.L., J.K., W.Z., Y.W., and S.C. wrote the manuscript. Y. P. and Y.W. directed the whole project.

Peer review

Peer review information

Nature Communications thanks Fumito Saito and the other anonymous reviewer(s) for their contribution to the peer review of this work. A peer review file is available.

Data availability

The authors declare that the main data supporting the findings of this study, including experimental procedures and compound characterization, are available within the article and its Supplementary Information files, or from the corresponding author upon request. The X-ray structural data of Sulpy 2y, sulfinate ester 63, and sulfinamide 69 are deposited in CCDC (Nos. 2333870, 2333868, and 2333869, see Supplementary Tables 5-7 for details). These data can be obtained free of charge from The Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif. Cartesian coordinates of computationally optimized geometries are available in Supplementary Data 1.

Competing interests

The authors declare no competing interests.

Supplementary information

The online version contains supplementary material available at 10.1038/s41467-024-55786-7.