AbstractThe (hetero)aryl sulfoximines are important structures for developing bioactive molecules, whose synthesis relies on oxidation of (hetero)aryl sulfilimines. However, asymmetric approaches for assembling (hetero)aryl sulfilimines are still rare. Here we show that combination of CuI and NOBIN-derived amide ligands offers an effective catalytic system for enantioselective coupling of (hetero)aryl iodides with sulfenamides. A large number of functional groups and heterocycles are tolerated under the coupling conditions, providing a powerful approach for diverse synthesis of enantioenriched (hetero)aryl sulfilimines. The efficiency of the coupling reaction is highly dependent on the electronic nature of (hetero)aryl iodides and sulfenamides. Both (hetero)aryl- and some bulky alkyl-substituted sulfenamides give excellent enantioselectivities, while sulfenamides with smaller alkyl substituents lead to the formation of the (hetero)aryl sulfilimines with moderate enantioselectivities. Density functional theory (DFT) calculations reveal that proper steric repulsions in the transition states of the intramolecular SNAr reaction are crucial for achieving desirable enantioselectivity.
IntroductionThe (hetero)aryl sulfone moiety has been recognized as one of the top five most frequently used structural units for pharmaceutical design1. Recent investigations have revealed that (hetero)aryl sulfoximines are very attractive bioisosteres of (hetero)aryl sulfones in medicinal chemistry because the formers have improved aqueous solubility and metabolic stability than latters2,3,4. Given this background, it is not surprising that (hetero)aryl sulfoximine-containing structures have received great attention from both medicinal chemists and agrochemical researchers during the past decades2,3,4,5,6,7,8, which has resulted in the discovery of a large number of structurally diverse compounds with interesting bioactivities, including some drug candidates for late-stage pharmaceutical development. For example, TNG260 (1) (Fig. 1a), a CoREST-selective deacetylase (CoreDAC) inhibitor, has entered phase I clinical trials to treat STK11 (serine/threonine kinase 11) mutant cancers through reversing anti-PD1 resistance5; roniciclib (2), a pan-CDK inhibitor, has entered phase II clinical trials for the treatment of advanced solid tumors6; trifluoromethyl substituted aryl sulfoximine 3 has been developed by Amgen as a potent GKRP disruptor that can significantly lowered fed blood glucose levels7; and biaryl sulfoximine 4 was reported as a kinase inhibitor by Schering8.Fig. 1: Bioactive aryl sulfoximines and their synthetic methods.a Structures of representative bioactive of aryl sulfoximines; b general methods for preparing aryl sulfoximines; c general approaches for asymmetric assembly of sulfilimines.Full size imageThe importance of sulfoximines moiety in the development of pharmaceuticals and agrochemicals has triggered intensive studies on asymmetric assembly of enantioenriched (hetero)aryl sulfoximines during the past 10 years9. While increasing kinetic resolution10,11 and desymmetric approaches12,13,14,15,16 for preparing structurally specific aryl sulfoximines were disclosed, three general strategies have appeared for diverse synthesis of enantioenriched (hetero)aryl sulfoximines (Fig. 1b). One is using enantioenriched sulfinamides as the building blocks, which underwent S-alkylation with alkyl halides17 or S-arylation with diaryliodonium salts18, providing the corresponding aryl sulfoximines stereospecifically. Another one is the condensation of some enantioenriched sulfonimidoyl halides (F, Cl) with Grignard reagents or organolithium reagents to deliver the corresponding (hetero)aryl sulfoximines stereospecifically19,20. Since both approaches required the preparation of enantioenriched sulfur reagents in multi-steps starting from enantiopure tert-butyl sulfinamide17,18,19 or desymmetrizing enantioselective hydrolysis20, more attention has been directed to the third strategy, that is, stereospecific imidation of enantioenriched sulfoxides and oxidation of enantioenriched sulfilimines9,21,22,23,24,25,26,27. This has elicited synthetic chemists to develop more powerful catalytic methods for asymmetric assembly of sulfilimines (Fig. 1c) and sulfoxides in recent years. Remarkable examples include Lebel’s Rh-catalyzed stereoselective amination of thioethers with N-mesyloxycarbamates21, Bach’s silver-catalyzed enantioselective sulfimidation mediated by hydrogen bonding interactions22, Feng’s iron-catalyzed asymmetric imidation of sulfides via sterically biased nitrene transfer23, Ellman’s Rh-catalyzed enantioselective sulfur alkylation of sulfenamides with diazo compounds24 and cinchona alkaloid derived phase-transfer catalyst (PTC) mediated enantioselective alkylation of sulfenamides with alkyl iodides25, Zhang’s transition metal-free pentanidium-catalyzed sulfur alkylation of sulfenamides with alkyl halides26, List’s chiral confined Brønsted acids-catalyzed enantioselective sulfoxidation27, Tan’s asymmetric oxidation of thioethers with ion-pair catalysts generated from a chiral dicationic bisguanidinium and tungstste28 (or molybdate29), as well as Míšek’s kinetic resolution via enzyme-catalyzed reduction of chiral sulfoxides30.Obviously, metal-catalyzed cross-coupling reactions between aromatic electrophiles and suitable sulfenamides is a straightforward approach for diverse synthesis of enantioenriched sulfilimines because both coupling partners are abundant and readily accessible. However, this is a nearly unexplored aspect and only few attempts have been disclosed until quite recently. In 2023, Jia31 and Ellman32 independently reported that copper-catalyzed S-arylation of sulfenamides with boronic acids produced sulfilimines in a racemic manner. Soon after that, Ellman group disclosed the copper-catalyzed coupling reaction of (hetero)aryl iodides with sulfenamides (20 mol% CuI, Na2CO3, DMSO, 110 oC)33. Interestingly, they found that introduction of bidentate ligands such as 1,10-phenanthroline led to decreased yields33. During the preparation and submission of this manuscript, Zhang group disclosed the asymmetric arylation of sulfenamides with aryldiazonium salts as the electrophiles, in which 10 mol% Pd(OAc)2 and 18 mol% P,S-ligand were required to ensure successful formation of enantioenriched sulfilimines with 80-92% ee34. While Kozlowski and Jia groups collaboratively reported the enantioselective Chan-Lam S-arylation of sulfenamides, in which the application of a well-designed chiral bidentate ligand, 2-pyridyl N-phenyl dihydroimidazole, was crucial for suppressing the background racemic transformation and enabling high enantioselectivity (up to 94% ee)35.Based on the development of more reactive oxalamide ligands for Cu-catalyzed arylation of nucleophiles36,37,38,39,40, we recently discovered Cu-catalyzed formation of α-(heteroaryl)-α-alkyl cyanoacetates from (hetero)aryl iodides and α-alkyl-substituted cyanoacetates in good to excellent enantioselectivities under the assistance of (S)-nobin-embodied picolinamides and L-hydroxyproline-derived amides41. In this work, we report that a simple NOBIN-derived amide ligand made CuI-catalyzed arylation of sulfenamides with (hetero)aryl iodides proceed smoothly to afford (hetero)aryl sulfilimines with up to 97% ee.ResultsCondition screening for Cu-catalyzed coupling of sulfenamides with (hetero)aryl iodidesWe commenced our studies by screening suitable conditions for coupling of 4-phenyl-1-iodobenzene (5a) with sulfenamide (6a), and the results are summarized in Table 1. We were pleased that picolinamide L1 derived from (S)-nobin was an effective ligand for promoting CuI-catalyzed coupling of 5a and 6a, making the reaction proceed at 30 oC in DMSO using NaOH as the base to deliver sulfilimine 7a in 75% yield with 93% ee. It is notable that for a similar Cu-catalyzed reaction, Ellmann group has noticed that addition of bidentate ligand 1,10-phenanthroline had inhibition action33. The different ligand effect displayed in our hand further illustrated that dianionic ligands are more robust and powerful for promoting Cu-catalyzed arylation with different nucleophiles, which has caused a new wave in the Cu-catalyzed coupling reactions of (hetero)aryl halides with nucleophiles36,37,38,39,40,41,42,43,44,45,46,47,48. Introducing an electron-donating group to the pyridine ring could improve the yield and enantioselectivity, which led to the discovery of 4-methoxy substituted picolinamide L3 as the optimal ligand (entry 3). Contrarily, poorer conversions and asymmetric induction were observed in the case of two more electron-deficient ligands, 4-trifluoromethyl substituted picolinamide L4 and pyrazine-embodied amide L5. Additionally, some results suggested that a tridentate dianionic ligand is indispensable for the present success, as demonstrated by several control experiments (entry 6-8). When the free hydroxyl group on nobin part was substituted with a free amino group or methoxy group, as in the case of ligands L6 and L7, the reaction was completely suppressed, underscoring the necessity of a dianionic ligand with stronger coordinating ability. Moreover, when the pyridine ring is replaced with a benzene ring, as seen with ligand L8, no conversion was encountered, indicating that the copper and the ligand should be tridentate coordination in the active catalytic species.Table 1 Condition screening for Cu-catalyzed coupling reaction of 5a and 6aFull size tableDuring replicating this reaction, we found that the size of NaOH also influenced the conversion significantly. With the decrease in size, the yields dropped gradually (entries 9–11). The similar trend was observed when using KOH as the base (entries 12–14), but the influence of the size on yield was much less significant. Since using 18–100 mesh KOH gave the best result, we attempted to reduce the catalytic loading to 5 mol% of CuI and ligand when 24–30 mesh KOH was used, and observed the reaction still worked well, affording 7a with 97% ee in 86% (0.5 mmol scale) and 80% (4 mmol scale, 1.26 g obtained) isolated yields (entry 15), respectively.Further investigations by changing bases (K3PO4 and K2CO3) and solvents (DMAc, dioxane and MeCN) all failed to give any improved results (entries 16–20). Thus, we concluded that the optimal conditions were using 5 mol% CuI and L3 as the catalytic system, DMSO as solvent and 24–30 mesh KOH as the base.Reaction scope of Cu-catalyzed coupling of sulfenamides with (hetero)aryl iodidesThe established optimal conditions were then examined by varying (hetero)aryl iodides and sulfenamides. As indicated in Fig. 2, for para-substituted aryl iodides, electron-rich substrates gave the desired products in good yields (7b-7d), while electron-deficient ones led to decreased yields (7e–7g) owing to sluggish reaction even at an increased catalytic loading (10 mol%). However, in both cases excellent enantioselectivities (91-97% ee) were observed. When an electron-neutral meta-substituted aryl iodide was used, coupling with aryl sulfenamide possessing an electron-donating group provided 7h in 92% yield and 97% ee, but switching the coupling partner to an electron-deficient aryl sulfenamide (7i) caused slow conversion. In the latter case, an improved result was gained by changing ligand to L5. The ortho-NHCOMe substituted aryl iodide can also be converted into the corresponding sulfilimines (7j), albeit with lower ee value due to adjacent steric hindrance and background reaction (for more examples with no or low conversions and detailed discussion, see Section 6 of the SI). Pleasingly, some challenging sulfenamides with electron-withdrawing groups, such as 4-CF3 and 4-COOMe, still yield the desired sulfilimines (7k and 7l) with excellent enantioselectivity, despite unsatisfactory yields (for more examples with no or low conversions and detailed discussion, see Section 6 of the SI). These results demonstrated that electron-deficient partners from both sides were less favored for this reaction. The similar trend was also seen when heteroaryl coupling partners were employed (7m-7u), although all coupling reactions afforded the corresponding heteroaryl sulfilimines in moderate to good yields with 89-97% ee. Remarkably, through this coupling a vast variety of heterocycle-containing products, including pyridine- (7m and 7u), quinoline- (7n and 7o), benzofuran- (7p), indole- (7q), benzothiophene- (7r), 1H-pyrrolo[2,3-b]pyridine- (7s) and carbazole-embodied sulfilimines (7t) were accessed effectively. This fact, together with that a number of functional groups such as chloro, bromo, amino, ketone, hydroxy and ether substituents were well-tolerated under these conditions, render the present coupling very attractive for diverse synthesis of (hetero)aryl sulfilimines.Fig. 2: Reaction scope of Cu-catalyzed coupling between (hetero)aryl iodides and sulfenamides.aReaction conditions: (hetero)aryl iodides 5 (0.55 mmol), sulfenamide 6 (0.5 mmol), CuI (0.025 mmol), L3 (0.025 mmol), KOH (24–30 mesh, 0.75 mmol), DMSO (1.0 mL), 30 °C, 24 h. bCuI (0.05 mmol), L3 (0.05 mmol). c50 °C. dCuI (0.05 mmol), L5 (0.05 mmol).Full size imageWe next tested alkyl-substituted sulfenamides and surprisingly found that 7v was obtained with only 43% ee, although complete conversion was observed. With the increase in size of alkyl groups, enantioselectivity generally turned better (compare 7v–7aa), with the exception of 7x. When bulky Boc-protected azetidinyl substituted sulfenamide was applied, the coupling product 7aa was produced in 90% yield with 95% ee. Changing the coupling partners of this sulfenamide to a disubstituted aryl iodide and two heteroaryl iodides still gave satisfactory results (7ab–7ad). Similarly, the Boc-protected piperidinyl-substituted sulfenamide also achieved excellent yield and a good ee value (7ae). Compared to the cyclohexyl-substituted sulfenamide, the presence of the N-Boc group significantly enhanced the enantioselectivity of the reaction (compare 7y and 7ae). In order to investigate the role of the N-Boc group on controlling the enantioselectivity of the reaction, DFT calculations were performed and the calculations shown that the N-Boc group hinders the better dispersion of the substrate and ligand around the copper center in the enantiodetermining transition state of the minor product, thereby enhancing enantioselectivity of the reaction (for details, see Section 8 of the SI). Interestingly, cyclopentenyl- and cyclohexenyl-substituted sulfenamides led to the formation of the desired sulfilimines with 95% ee and 91% ee respectively (7af and 7ag). The dramatic difference in stereochemical outcome between the formation of 7af and 7x, and 7ag and 7y, implied that the planar structure in substituents of sulfenamides is favored for asymmetric induction of the present chiral ligands, which might guide further ligand design to expand the reaction scope. DFT calculations indicated that the planar structures of such substitutions increase the steric repulsion between the substrates in the enantiodetermining transition state of the minor product, hence better enantioselectivity is obtained (for details, see Section 8 of the SI).The present method also provided a powerful tool for late-stage modification of complex (hetero)aryl iodides. For instance, coupling reactions of several sulfenamides with (hetero)aryl iodides generated from estrone, glucofuranose, antidepressive drugs Sertraline and Duloxetine, and synthetic intermediate of antidiabetic drug Canagliflozin proceeded smoothly to deliver 7ah–7al in 63–95% yields with excellent stereoselectivity, while coupling of 4-iodo-dibenzo[b,d]furan with sulfenamide prepared from a synthetic intermediate of antidiabetic drug Empagliflozin furnished sulfilimines 7am in 76% yield and >20:1 diastereomeric ratio.Synthetic applications of the present coupling products and calculated models for understanding the enantioselectivityTo further demonstrate the synthetic utility of our coupling reaction, we conducted the conversion of the coupling product to known kinase inhibitor 4. As depicted in Fig. 3a, Cu-catalyzed arylation of 6b with iodobenzenes gave rise to 8 in 65% yield with 93% ee, which was oxidized with m-CPBA and then underwent Piv deprotection via LAH-reduction to generate sulfoximine 9 without loss of enantiopurity. After alkylation of 9 with n-propyl iodide, the resultant aryl chloride 10 was subjected to a Cu-catalyzed amination with the assistance of BPMPO ligand to form aniline 1149, which has been reported as the key intermediate as the racemate form for preparing 4.Fig. 3: Further conversions of the coupling products and possible pathway for asymmetric induction.a, b Synthetic application of the coupling products. c Calculated models for understanding the enantioselectivity.Full size imageThe oxidation/deprotection approach was also applied for conversion of 7p to sulfoximine 13 (Fig. 3b), whose X-ray structural analysis clearly indicated that 13 has a (S)-form configuration which is in agreement with the stereochemical assignment resulted from the X-ray structural analysis of sulfoximine 7o. DFT calculations were further performed on possible enantiodetermining transition state structures to explain the observed enantioselectivity (Fig. 3c). TS-S, which leads to the observed S enantiomer, is 1.9 kcal/mol more stable than TS-R, consistent with the experimentally observed level and sense of enantioselectivity (97% ee). The enantioselectivity likely arises from stronger steric repulsion between the ligand and substrates 5a and 6a in TS-R, where the shortest H-H distance between 5a and 6a is 2.12 Å (Fig. 3c). However, such significant steric repulsion is not observed in the structure of TS-S, as the ligand and substrate are better separated around the Cu(III) center in TS-S. This stereocontrolling model also reproduces the enantioselectivity for the formation of 7ae–7ag (see supplementary information, section 8).In conclusion, we have described Cu-catalyzed asymmetric coupling reaction of (hetero)aryl iodides with sulfenamides, a class of very challenging nucleophiles with poor nucleophilicity, great steric hindrance, and sulfur-containing properties. This successful application further underlined the robustness of nobin-embodied-picolinamides as asymmetric catalysts. This brand-new asymmetric coupling provides a very attractive approach for assembling (hetero)aryl sulfilimines featuring a broad reaction scope, a simple operational procedure, and convenient availability of the starting materials. Given that (hetero)aryl sulfilimines can be easily transformed into (hetero)aryl sulfoximines, important structural motifs in the development of pharmaceutical agents and agrochemicals, this method is promised to provide widespread synthetic applications.MethodsGeneral procedure for the Cu-catalyzed enantioselective S-arylation of sulfenamides with (hetero)aryl halidesTo an oven-dried 4 mL reaction vial equipped with a stir bar were added CuI (0.025–0.05 mmol), L3/L5 (0.025–0.05 mmol), sulfenamide (0.5 mmol) and (hetero)aryl iodide (0.55 mmol), then the equipment was put into a glove box filled with nitrogen. After KOH (0.75 mmol) and anhydrous DMSO (1.0 mL) were added, the reaction vessel was capped with a septa screw cap and stirred at 30 °C for 24 h. The reaction mixture was diluted with dichloromethane and washed with water, the aqueous layer was extracted with dichloromethane three times. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Purification by silica gel flash chromatography afforded the corresponding sulfilimine.
Data availability
All experimental data supporting the findings of the study are available within the article and its Supplementary Information. Crystallographic data for the structure reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition number CCDC 2369064 (7o) and CCDC 2372439 (13). Copies of the data can be obtained free of charge via http://www.ccdc.cam.ac.uk/data_request/cif. Source data are provided with this paper.
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Download referencesAcknowledgementsThe authors are grateful to National Key Research Development Program China (grant 2022YFA1503700 M.D.) and the National Natural Science Foundation of China (grant 21991110 M.D., 22431011 M.D. and 22101292 X.X.) and the Strategic Priority Research Program of the Chinese Academy of Sciences (grant XDB0610000 M.D., XDB1060000 M.D.) for their financial support.Author informationAuthors and AffiliationsChang-Kung Chuang Institute, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, ChinaMingchuang HeShenzhen Key Laboratory of Cross-Coupling Reactions & Department of Chemistry, Southern University of Science and Technology (SUSTech), Shenzhen, ChinaRongxing Zhang & Dawei MaKey Laboratory of Fluorine and Nitrogen Chemistry and Advanced Materials, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Science, Shanghai, ChinaTongkun Wang & Xiao-Song XueState Key Laboratory of Chemical Biology, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Science, Shanghai, ChinaDawei MaAuthorsMingchuang HeView author publicationsYou can also search for this author in
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PubMed Google ScholarContributionsH.M. performed the majority of the experiments and prepared the supporting information. Z.R. performed a portion of the experiments. W.T. performed the computational studies. X.X. provided guidance for the computational studies. M.D. supervised the experimental research and wrote the manuscript.Corresponding authorsCorrespondence to
Xiao-Song Xue or Dawei Ma.Ethics declarations
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Reprints and permissionsAbout this articleCite this articleHe, M., Zhang, R., Wang, T. et al. Assembly of (hetero)aryl sulfilimines via copper-catalyzed enantioselective S-arylation of sulfenamides with (hetero)aryl Iodides.
Nat Commun 16, 2310 (2025). https://doi.org/10.1038/s41467-025-57474-6Download citationReceived: 11 November 2024Accepted: 24 February 2025Published: 08 March 2025DOI: https://doi.org/10.1038/s41467-025-57474-6Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard
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