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Unsymmetric monothiooxalamides from S8, bromodifluoro reagents and anilines: Synthesis and applications

  • Author Footnotes
    1 These two authors are equally contributed to this work.
    Xingxing Ma
    Footnotes
    1 These two authors are equally contributed to this work.
    Affiliations
    Key Laboratory of Molecule Synthesis and Function Discovery, Fujian Province University, College of Chemistry and College of Materials Science at Fuzhou University Fuzhou, Fujian, 350108, China
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  • Author Footnotes
    1 These two authors are equally contributed to this work.
    Shuilin Deng
    Footnotes
    1 These two authors are equally contributed to this work.
    Affiliations
    Institute of Next Generation Matter Transformation, College of Materials Science Engineering at Huaqiao University 668 Jimei Boulevard, Xiamen, Fujian, 361021, China
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  • Jinchao Liang
    Affiliations
    Key Laboratory of Molecule Synthesis and Function Discovery, Fujian Province University, College of Chemistry and College of Materials Science at Fuzhou University Fuzhou, Fujian, 350108, China
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  • Jinglong Chen
    Affiliations
    Key Laboratory of Molecule Synthesis and Function Discovery, Fujian Province University, College of Chemistry and College of Materials Science at Fuzhou University Fuzhou, Fujian, 350108, China
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  • Jianke Su
    Affiliations
    Institute of Next Generation Matter Transformation, College of Materials Science Engineering at Huaqiao University 668 Jimei Boulevard, Xiamen, Fujian, 361021, China
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  • Hua Huang
    Affiliations
    Institute of Next Generation Matter Transformation, College of Materials Science Engineering at Huaqiao University 668 Jimei Boulevard, Xiamen, Fujian, 361021, China
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  • Qiuling Song
    Correspondence
    Corresponding author. Key Laboratory of Molecule Synthesis and Function Discovery, Fujian Province University, College of Chemistry and College of Materials Science at Fuzhou University Fuzhou, Fujian, 350108, China.,
    Affiliations
    Key Laboratory of Molecule Synthesis and Function Discovery, Fujian Province University, College of Chemistry and College of Materials Science at Fuzhou University Fuzhou, Fujian, 350108, China

    Institute of Next Generation Matter Transformation, College of Materials Science Engineering at Huaqiao University 668 Jimei Boulevard, Xiamen, Fujian, 361021, China

    School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan, 453007, China
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  • Author Footnotes
    1 These two authors are equally contributed to this work.
Open AccessPublished:August 26, 2022DOI:https://doi.org/10.1016/j.tchem.2022.100026

      Abstract

      Unsymmetric monothiooxamides as very special and important scaffolds have been widely existing in natural products and bioactive molecules. However, the efficient construction of such compounds are very rare. Herein, we report a simple and practical strategy to achieve unsymmetric monothiooxalamides via S8-mediated defluorination and vulcanization of amines with bromodifluoroalkylative reagents under mild conditions. And the potential applications of such compounds as ligands has been demonstrated in Cu-catalyzed cross coupling reactions. The fluorinated quinoxalinones, benzooxazinone, α-phenyliminoamides, as well as 2-amidobenzothiazoles are obtained in-situ from unsymmetric monothiooxalamides, in which bromodifluoroalkylative reagents undertake selective triple cleavage. Moreover, we also discover that N-aryl-2-amidobenzothiazoles have aggregation-induced luminescence (AIE) characteristics, which might have great potential in the fields of sensing, imaging, diagnosis and treatment.

      Graphical abstract

      1. Introduction

      Monothiooxamide fragments, which can be considered as one of carbonyl groups in oxalamides derivatized by thiocarbonyl, are very important in various fields owing to their wide existence in natural products and biologically active compounds [
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      ]. And they could also act as reaction synthons to assemble S,N-containing compounds in organic synthesis. Despite their high potentials in various fields and similarity to oxalamides, such compounds have been barely studied mainly attribute to the lack of efficient methods for their synthesis [
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      ]. In this context, so far only very few protocols for the construction of unsymmetric monothiooxalamides have been reported since 1989, however, there are significant drawbacks on such tactics: harsh the reaction conditions, limited substrates, requirment of toxic thiophosgene, multi-step reaction as well as low efficiency (mostly symmetrical) (Fig. 1A) [
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      ], commercially available halodifluoroalkylative reagents could serve as a C2 synthon via selective triple cleavage in this retrosynthetic analysis as well (Fig. 1B) [
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      ]. However, there are several challenges to achieve unsymmetric monothiooxalamides in our hypothesis: (1) How to selectively disassemble two stable C–F bonds of bromodifluoroalkyl compounds while retaining weak C-R bonds to form C2 synthon? (2) How to introduce the S atom of the octet S8 into the desired product? (3) Which substrates are suitable to capture S atoms and C2 sources to form new C–S and C–N bonds in one-pot protocol?
      Fig. 1
      Fig. 1Synthesis and transformations of unsymmetric monothiooxalamides. (A) Strategies, challenges as well as retrosynthetic analysis for the assembly of unsymmetric monothioxalamides; (B) Various roles of halodifluoroalkyl reagents; (C) One-pot synthesis of unsymmetric monothiooxalamides as well as preparation of various substituted quinoxalinone derivatives and acyclic related scaffolds, 2-amidobenzothiazoles from monothiooxalamides (This work).
      Herein, we present a general transition-metal free, facile and efficient route to streamline assembly of unsymmetric monothiooxalamides via a one-pot protocol, in which S8 acts as both substrate and sulfur source to construct thiocarbonyl group, bromodifluoroalkylative reagents is regarded as C2 synthon via triple cleavage (Fig. 1C). In order to explore the synthetic applications of such compounds, we also diclose the synthesis of various substituted quinoxalinones [
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      ] via a single-vessel reaction with monothiooxalamides as intermediates (Fig. 1C, right). This reaction portraits readily accessible starting materials, divergent synthesis to render versatile valuable products, transition-metal free, easy of execution and potential applications as ligands and luminescent materials.

      2. Results and discussion

      Reaction condition optimization. Originally, to validate our hypothesis, extensive research on the reaction conditions were studied with o-iodoaniline (1a) and 2-bromo-N-(tert-butyl)-2,2-difluoroacetamide (2a) as the model substrates with S8 (3) as the sulfur source. And a series of promising reaction conditions suggested that in the presence of PhONa (3 equiv.) in CH3CN (2 ​mL) under argon, 0.4 ​mmol of 1a reacted with 1.8 equiv. of 2a and 50 ​mol% of S8 (3) to lead to the desired unsymmetric monothiooxalamide 4a in 77% yield (Table 1, entry 1). When the model reaction was carried out under air atmosphere, a sluggish reaction was observed (Table 1, entry 2). Not surprisingly, no reaction proceeded without S8 (Table 1, entry 3). When the reaction temperature was reduced to 110 oC, only 50% yield of 4a was obtained (Table 1, entry 4). The attempt to shorten the reaction time led to the inferior result (Table 1, entry 5). When PhONa was replaced by NaOH, Na2CO3, K2CO3 or Cs2CO3, no improvements were achieved (Table 1, entries 6–9). Subsequently, we also screened the effect of different solvents. However, the utilization of THF, dioxane or DMF as reaction medium just diminished the yields of 4a (Table 1, entries 10–12). During the exploration process, we found that increasing the reaction concentration slightly changed the conversion of 1a to 4a (Table 1, entry 13). After studying the effect of the amount of 2a, it turned out that 1.8 equiv. of 2a was the best choice (Table 1, entries 14–15).
      Table 1Optimization of reaction conditions.a.
      Table thumbnail fx1
      Scope of substrates. With the optimal reaction conditions in hand, the scope of anilines was first investigated, as shown in Fig. 2. A sequence of anilines bearing different electronic properties and steric hindrance were well tolerable, enabling the generation of the desired products 4a-4s in moderate to good yields. Meanwhile, disubstituted anilines such 3, 4-dichloroaniline and 3,4-dimethylaniline also demonstrated good reactivity, affording the targeted products 4t and 4u in good yields. Heteroaromatic anilines such as pyridin-3-amine, 5-phenyl-1H-pyrazol-3-amine and 2-aminobenzothiazole could work smoothly under the identified conditions as well, rendering the target products 4v-4x in moderate to good yields. Subsequently, we turned our attention to inspect the applicability of aliphatic amines. Secondary aliphatic amines such as piperidine, morpholine and indoline were proved to be good candidates in this transformation, delivering the desired products 4y-4 ​ab in 71–88% yields. Other primary aliphatic amines could be commendably engaged in this reaction and the corresponding compounds 4ac-4ar were easily achieved in good yields except 4aq. Of note, the subject of tryptamine and dehydroabiethylamine to this S8-mediated defluorination sulfidation amination was also triumphant, furnishing the bioactive and complex molecule-derived thioamides 4as and 4 ​at in moderate yields.
      Fig. 2
      Fig. 2Substrate scope for the construction of unsymmetrically substituted monothiooxalamides. a Reaction conditions: amines (1, 0.4 ​mmol), bromodifluoroacetamide (2, 1.8 equiv), S8 (3, 50 ​mol%), PhONa (3.0 equiv), CH3CN (2.0 ​mL) at 120 oC for 24 ​h under argon, isolated yield.
      Next, we examined the scope of bromodifluoroacetamides for this transformation by utilizing PhNH2 as a benchmark substrate. As depicted in Fig. 2B, the identified reaction conditions proved to be suitable to multitudinous bromodifluoroacetamides and a strand of functionalized monothiooxalamides were obtained in moderate yields. Aromatic amine-derived bromodifluoroacetamides could be well converted to deliver 4au-4aw in decent yields. Compared with aromatic amines, the aliphatic amine-derived bromodifluoroacetamides presented better results, giving rise to the formation of 4ax-4bh in moderate to excellent yields. The bromodifluoroacetamide bearing sterically demanding adamantane moiety was also compatible in this reaction, offering the 4bh in 77% yield, whose structure was unambiguously confirmed by X-ray single crystal diffraction (Fig. 2). And the desired unsymmetric monothiooxalamides 4bi was also obtained in 72% yield under standard conditions. In addition, the symmetric monothiooxalamides 4bj was isolated as well in good yield by reaction of phenylmethanamine with N-benzyl-2-bromo-2,2-difluoroacetamide under the same reaction conditions.
      Synthetic applications of unsymmetric monothiooxalamides. To explore the applications of the obtained unsymmetric monothiooxalamides, we firstly studied the transformations with our desired products as ligands, given the structure similarity of such compounds with oxalamides, and the latter have been widely used as ligands to achieve very nice Cu-catalyzed Ullman coupling reactions.[14-15] When the substrate 4-iodo-1,1′-biphenyl (5) reacted with phenol (6) in MeCN or THF under argon atmosphere, only the trace amount of target product 7 was detected in the absence of ligand (Fig. 3a). Of note, when the monothiooxalamide 4a (L1), 4bi (L2), 4bj, (L3), featuring facile synthesis and good stability, were added into this reaction system respectively, the coupling product 7 was obtained in 45%, 54%, or 27% yields correspondingly [
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      ]. As a contrast, when the reaction was performed in the presence of other N or P ligands, no reaction occurred at all (Fig. 3a). The above experiments suggested that monothiooxalamides could be a potential ligand in the formation of C–O and C–N bonds in Cu-catalyzed cross coupling reactions (Fig. 3a). Moreover, quinoxalinones, as well as their derivatives and 2-amidobenzothiazoles have been considered as important and promising bioactive skeletons due to their intriguing physicochemical properties, and their prominent biological and pharmacological activities [
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      • Ma B.
      • Zhu C.
      An efficient synthesis of quinoxalinone derivatives as potent inhibitors of aldose reductase.
      ,
      • Wang Y.
      • Mu S.
      • Li X.
      • Song Q.
      [4+1] cyclization of benzohydrazide and ClCF2COONa enables 1,3,4-oxadiazoles and 1,3,4-Oxadiazoles-d5.
      ,
      • Xu J.
      • Yang H.
      • Cai H.
      • Bao H.
      • Li W.
      • Zhang P.
      Transition-metal and solvent-free oxidative C−H fluoroalkoxylation of quinoxalinones with fluoroalkyl alcohols.
      ]. Meanwhile, they are widely involved in various fields as well, such as in organic synthesis, medicinal chemistry, agro-chemistry and materials science. Therefore, we speculated whether unsymmetric monothiooxalamides could be utilized to construct aforementioned compounds in-situ. Intriguingly, after we evaluated a large number of reaction conditions, the various viable reaction conditions were obtained (See Supporting Information for details). Subsequently, we examined the substrate scope using various benzene-1,2-diamines to synthesize fluorinated quinoxalinones and their derivatives via monothiooxalamides (Fig. 3b). The desired product 10a was obtained under conditions A, and its structure was unambiguously characterized by X-ray crystallographic diffraction analysis (see SI for details). Next, various substituted substrates were investigated under reaction conditions A to provide the corresponding products 10b-10k in moderate yields (Fig. 3b). Of note, the anticipated α-phenyliminoamides 11 and 12 were obtained in 73% and 67% yields (Fig. 3c), when the reactions were carried out using amines and two different bromodifluoroalkylative reagents as reactants via one-pot means [
      • Cunico R.F.
      • Pandey R.K.
      Palladium-catalyzed synthesis of α-iminoamides from imidoyl chlorides and a carbamoylsilane.
      ,
      • Chen J.
      • Cunico R.F.
      α-Aminoamides from a carbamoylsilane and aldehyde imines.
      ,
      • Chen J.
      • Cunico R.F.
      α-(Dimethylamino)amides from a carbamoylsilane and iminium salts.
      ]. Meanwhile, various 2-amidobenzothiazoles were also assembled in-situ via monothiooxalamides from a broad range of o-iodoanilines and bromofluoroamides under conditions B (See SI for details). o-Iodoanilines bearing different substituents could react smoothly with difluoroacetamides as C2 sources to afford the corresponding products 13a-13j in up to 99% yields (Fig. 3d). The structure of 13h was characterized by X-ray crystal diffraction (See SI for details). Subsequently, we turned to explore the substrates scope with respect to bromodifluoroamides. Various lactam compounds were good candidates, delivering the expected products 13k-13v in moderate to good yields. The structure of 13n was also confirmed by X-ray single crystal diffraction (Fig. 3d). Given that 1,2-dicarbonyls are life-related structure which are ubiquitously existing in biomolecules, especially natural products and pharmaceuticals [
      • Jin S.
      • Dang H.T.
      • Haug G.C.
      • Nguyen V.D.
      • Arman H.D.
      • Larionov O.V.
      Deoxygenative α-alkylation and α-arylation of 1,2-dicarbonyls.
      ,
      • Dubovtsev A.Y.
      • Shcherbakov N.V.
      • Dar’in D.V.
      • Kukushkin V.Y.
      Nature of the nucleophilic oxygenation reagent is key to acid-free gold-catalyzed conversion of terminal and internal alkynes to 1,2-dicarbonyls.
      ], the desired product 14 was isolated in 31% yield via ethyl 2-((4-(methylthio)phenyl)amino)-2-thioxoacetate under oxidation and its structure was determined by X-ray analysis as well (see SI for details) (Fig. 3e).
      Fig. 3
      Fig. 3Synthetic applications of unsymmetric monothiooxalamides. (a) Potential applications of substituted monothiooxalamides as ligands; (b) and (c) Transformations of monothiooxalamides in-situ; Condition A: amines (0.1 ​mmol), BrCF2COOEt (3 equiv.), S8 (40 ​mol%), Cu (5 ​mg), 1,10-phen (20 ​mol%), Na3PO4 (3 equiv), MeCN (2 ​mL), under argon at 80 oC for 18 ​h, isolated yields. b amines (0.1 ​mmol), BrCF2COOEt (3 equiv.), S8 (40 ​mol%), Cu(OTf)2 (10 ​mol%), 1,10-phen (10 ​mol%), Na3PO4 (3 equiv), MeCN (2 ​mL), under Ar atmosphere at 80 oC for 18 ​h, isolated yields; Conditions B: Reaction conditions: amines (0.2 ​mmol), bromofluoroamides (1.8 equiv), S8 (50 ​mol%), PhOH (2 equiv) Na2CO3 (3 equiv), MeCN (1 ​mL) at 120 oC for 24 ​h under argon.
      Emission and AIE effect of benzothiazoles. Simple benzothiazoles can only emit light in a low-concentration solution. Once it is in a solid state, molecular aggregation will make the luminescence weakened or even disappear (ACQ, aggregation leads to luminescence quenching). However, we unintentionally discovered that some N-phenyl-2-amidobenzothiazoles such as 13w hardly emits light in the dispersed state, but emits strong fluorescence in the solid state, so we set out to study this abnormal phenomenon. First, we collected the ultraviolet absorption spectra of target molecules and homologs (Fig. 4A). In the ultraviolet absorption spectrum (Fig. 4B), the maximum absorption peaks of compounds such as 2 (13x), 3 (13y), 4 (13z), 5 (13aa) and 6 (13a) are between 275 and 300 ​nm, and the maximum absorption peak of 13w is between 300 and 350 ​nm, in Fig. 4B we can see that 13w has almost no fluorescence in the liquid state, and the other molecules all emit blue fluorescence. We tested the quantum yield of several products, and we found that the quantum yield of the solid was higher than that of the same product in the solution. For example, the quantum yield of compound 13w in the solid state was 17.07%, but the quantum yield in the solution was dropped to 15.12%. We envisioned that the N-aryl-2-amidobenzothiazole synthesized by our strategy possess photophysical properties with aggregation induced emission (AIE) phenomenon. We collected 13w fluorescence emission spectra (Fig. 4C), The maximum excitation wavelength of 13w is 475–500 ​nm. We also did follow-up experiments to prove our hypothesis: Product 13w completely dissolved in THF showed very weak fluorescence under ultraviolet light (365 ​nm), as the proportion of water was increased to 95%, the fluorescence intensity increased significantly (Fig. 4D). These experimental results and phenomena indicate that N-aryl-2-amidobenzothiazole may be a new type of fluorescent organic material with AIE phenomenon.
      Fig. 4
      Fig. 4Emission and AIE effect of benzothiazoles. A. emission spectra of some 2-amidobenzothiazole products in DCM; B. picture of some 2-amidobenzothiazole products under irradiation with UV light (365 ​nm); C. emission spectra of 13w in H2O/THF; D. picture of 13w in H2O/THF mixtures under irradiation with UV light (365 ​nm).
      Possible reaction pathways. Based on our previous work [
      • Ma X.
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      Synthesis of thiazoles and isothiazoles via three-component reaction of enaminoesters, sulfur, and bromodifluoroacetamides/esters.
      ,
      • Deng S.
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      S8-Catalyzed triple cleavage of bromodifluoro compounds for the assembly of N-containing heterocycles.
      ,
      • Ma X.
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      Recent progress on selective deconstructive modes of halodifluoromethyl and trifluoromethyl-containing reagents.
      ,
      • Sheng H.
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      Deconstrutive difunctionalizations of cyclic ethers enabled by difluorocarbene to access difluoromethyl ethers.
      ,
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      Atom recombination of difluorocarbene enables 3-fluorinated oxindoles from 2-aminoarylketones.
      ,
      • Ai H.-J.
      • Ma X.
      • Song Q.
      • Wu X.-F.
      C-F bond activation under transition-metal-free conditions.
      ], a plausible mechanism for the assembly of unsymmetric monothiooxalamides was depicted in Fig. 5. Initially, amines react with bromodifluoroalkylative reagent rendering intermediate A in the presence of base, which further generates intermediate B by defluorination due to the lone electron pair of nitrogen. Then, the Sn originating from S8 in basic conditions attacks the complex B affording intermediate C, once again, defluorination occurs with the lone electron pair of nitrogen to lead to intermediate D, which undergoes the rearrangement to deliver E. Finally, the target product 4 is yielded along with the release of Sn-1-. Sn is regenerated by reaction of S8 with Sn-1- for next reaction.

      3. Conclusion

      In summary, we report an efficient and practical methods for the assembly of a series of valuable unsymmetric monothiooxalamides, the current protocol exhibits high efficiency and excellent functional-group tolerance and readily accessible starting materials. Meanwhile, we also disclosed that such compounds could be potential ligands in Cu-catalyzed cross coupling reactions to construct C–O and C–N bonds. In addition, the fluorinated quinoxalinones, benzooxazinone, α-phenyliminoamides as well as 2-amidobenzothiazole compounds could be obtained in-situ with unsymmetric monothiooxalamides as intermediates, in which bromodifluoroalkyl reagents undertake selective triple cleavage under mild conditions. Moreover, we also discovered that N-aryl-2-amidobenzothiazoles have aggregation-induced luminescence (AIE) characteristics, which might have great potential in the fields of sensing, imaging, diagnosis and treatment.

      4. Experimental procedure

      4.1 Resource availability

      4.1.1 Lead contact

      Further information and requests for resources should be directed to and will be fulfilled by the lead contact, Qiuling Song ([email protected]).

      4.1.2 Materials availability

      All materials generated in this study are available from the lead contact without restriction.

      4.1.3 Data and code availability

      The data generated in this study are provided in the Supplementary Information file. The experimental procedures, data of NMR, HRMS have been deposited in Supplementary Information file. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC: 2054358, 2023496, 2023498, 1950764, 2018299, 2018304, and 1943044). These data could be obtained free of charge from The Cambridge Crystallographic Data Centre (https://www. ccdc.cam.ac.uk/data_request/cif).

      4.2 Methods

      4.2.1 General information

      All chemicals were purchased from Adamas Reagent, energy chemical company, J&K Scientific Ltd, Bide Pharmatech Ltd and Tansoole and used without further purification. Unless stated otherwise, reactions were performed in oven-dried or flame-dried glassware using a schlenk under a nitrogen or argon atmosphere. Reactions were monitored by TLC or GC-MS analysis. Flash column chromatography was performed over silica gel (200–300 mesh). 1H NMR spectra were recorded on a Bruker Avance III 500 ​MHz NMR spectrometer and chemical shifts (in ppm) were referred to CDCl3 (δ ​= ​7.26 ​ppm), as an internal standard. 13C NMR spectra were obtained by using the same NMR spectrometer and were calibrated with CDCl3 (δ ​= ​77.0 ​ppm). 19F NMR spectrometers were operated on the same NMR spectrometer with CDCl3. The following abbreviations were used to illuminate the diversities: δ ​= ​chemical shifts, J ​= ​coupling constant, s ​= ​singlet, d ​= ​doublet, t ​= ​triplet, q ​= ​quartet, m ​= ​multiplet. HRMS (ESI) were measured with a quadrupole and TOF mass spectrometers. All reagents and solvents were obtained from commercial suppliers and used without further purification. Reactions were monitored by thin-layer chromatography (TLC). UV/vis absorption spectra were recorded on a SHIMADZU UV-2500 UV–vis spectrophotometer. The products were purified by column chromatography on silica gel using petroleum ether and ethyl acetate as the eluent.

      4.2.2 General process for the synthesis of unsymmetrically substituted monothiooxalamides

      To a mixture of amine 1 (0.3 ​mmol, 1.0 equiv), BrCF2COR [2]R [3] 2 (1.2 equiv), S8 3 (38.4 ​mg, 50 ​mol %), PhONa (104.48 ​mg, 3 equiv) with was added MeCN (2 ​mL). The resulting mixture was heated to 120 ​°C under Ar. After 18 ​h, the mixture was cooled to room temperature. Upon completion of the reaction, the solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography to give the desired product 4.

      Author contributions

      Q.S. conceived and directed the project. X.M. & S.D. performed experiments and prepared the supplementary information. J.L., J.C., J.S. & H.H. helped collecting some new compounds analyzing the data. Q.S., X.M. & S.D. wrote the paper. All authors discussed the results and commented on the manuscript.

      Declaration of competing interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgements

      Financial support from the National Natural Science Foundation of China (21931013) (to Q.S.), Natural Science Foundation of Fujian Province (No. 2022J02009) (to Q.S.) and Open Research Open Research Fund of School of Chemistry and Chemical Engineering, Henan Normal University (to Q.S.) is gratefully acknowledged.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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