N-Sulfenylsuccinimide/phthalimide: an alternative sulfenylating reagent in organic transformations

Introduction

Sulfur-containing compounds are of high importance in organic synthesis, medicinal chemistry, and materials science [1-5]. For example, they are used in the treatment of cancer [6-8], inflammation [9-11], human immunodeficiency virus [12,13], Alzheimer’s and Parkinson’s diseases [14,15]. Scheme 1 shows selected examples of sulfur-containing pharmaceutical molecules. Considering the synthetic applications of sulfur-based compounds, a large number of researchers have noted that these scaffolds have promising potential for the research and development of new biomedicines.

In the sulfenylation of organic compounds, the sulfenylating agents are important factors, and the commonly utilized chemicals include thiols [16-18], disulfides [19-22], sulfenyl halides [23-25], sulfonamides [26], sulfenate esters [27,28], and methyl(bismethylthio)sulfonium salts [29,30]. Among various organic molecules, aryl sulfides are recognized as functional materials and indispensable synthetic intermediates in drug discovery [31-33]. Because of their value, constructing C–S bonds has attracted significant attention via metal-catalyzed cross-coupling reactions and metal-free C–S bond formation [34-37]. Direct sulfenylation of the C–H bonds of unactivated aryls or aromatic sulfenylation by electrophilic aromatic substitution (S_EAr) has also recently received attention [38].

In recent years, N-(aryl/alkylsulfenyl)succinimides and N-(arylsulfenyl)phthalimides have been widely employed as new alternative sulfenylating reagents in the field of organic synthesis. These compounds are readily accessible, safe, and more stable than toxic, unstable, and foul-smelling thiols. These electrophilic sulfur sources have deserved particular interest for the C–S bond formation via the reaction with various nucleophiles. Their preparation is usually a two-step procedure, involving a treatment of the thiol with sulfuryl chloride in the presence of Et₃N and the addition of the resulting solution to a mixture of succinimide/phthalimide and Et₃N in the next step [39,40].

According to the irreplaceable role of sulfur-based frameworks in materials science and the pharmaceutical area, there is a force for researchers to identify sustainable methodologies for efficient C–S bond coupling under mild reaction conditions for achieving these distinguished compounds. Recently, several reviews about sulfenylating reagents have been reported [41-43]. To the best of our knowledge there are no review articles focusing on the application of N-(sulfenyl)succinimides/phthalimides in sulfenylation reactions. In this context, we describe various sulfenylation reactions, such as electrophilic aromatic substitution, ring-opening, dehydrogenative cross-coupling, and direct sulfenylation reactions, which are classified into three categories: sulfenylation catalyzed by i) transition metal catalysts, ii) organocompound catalysts, and iii) catalyst-free sulfenylation.

Review

Sulfenylation of organic compounds by N-(sulfenyl)succinimides/phthalimides

Metal-catalyzed sulfenylation by N-(sulfenyl)succinimides/phthalimides

In 2012, Chen and co-workers found that in the reaction of N-(organothio)succinimides 1 and sodium sulfinates 2 using a Lewis acid in ionic liquids (ILs) and water as a green solvent system leads to the formation of thiosulfonates 3 (Scheme 2) [44]. Among different Lewis acid catalysts, such as Cu(OTf)₂, Mg(OTf)₂, Zn(OTf)₂, Sc(OTf)₃, Eu(OTf)₃, and Yb(OTf)₃, it was found that Sc(OTf)₃ gave higher product yield. In addition, the combination of Sc(OTf)₃/ILs displayed good recyclability in this transformation.

In 2014, Anbarasan and Saravanan succeeded in synthesizing various diaryl(alkyl) sulfides 5 through the sulfenylation of unactivated arenes 4 with an electrophilic sulfur reagent in the presence of a palladium catalyst (Scheme 3) [45]. In the second phase, dibenzothiophene derivatives 6 were obtained via subsequent intramolecular arylation of aryl sulfides by using the catalyst and the base. A catalytic cycle is shown in Scheme 4. Firstly, electrophilic Pd(TFA)₂ generated from Pd(OAc)₂ and TFA, which (by C–H functionalization of arene 4) led to intermediate II. Oxidative insertion of intermediate II into the N–S bond of 1 afforded intermediate III. Reductive elimination of Pd from III gave product 5 and species IV. Finaly, Pd(II) species were reproduced by ligand exchange to restart the next cycle (Scheme 4).

In 2014, Fu and co-workers described a facile method for the C–H thiolation of phenols 7 with 1-(substituted phenylthio)pyrrolidine-2,5-diones 1 using FeCl₃ or BF₃·OEt₂ as a catalyst (Scheme 5) [46]. A wide variety of thiolated phenols 8 were produced under mild reaction conditions without using any base, ligand, or additive. For both substrates, 7 and 1 aryl rings containing electron-donating groups exhibited a higher reactivity than electron-withdrawing groups, and the thiolation occurred mainly at the para position to the hydroxy group in phenols.

In 2016, the azidoarylthiation of various alkenes 9 by trimethylsilyl azide (10) and N-(organothio)succinimide 1 to the corresponding products containing ortho-sited azide and sulfide moieties 11 was performed by Fu et al. (Scheme 6) [47]. Iron(III) chloride was used as a catalyst for this coupling reaction without the need of any ligand and additive. Screening for other metal salts, such as Cu(OAc)₂, Pd(OAc)₂, AgOAc or CuI was not successful, although FeS·7H₂O, FeS, Fe₂(SO₄)₃·H₂O, FeSO₄, and Fe(acac)₃ resulted in inferior chemical yields. Employment of 2,2,6,6-tetramethylpiperidinyl-1-oxyl (TEMPO) as a radical trapper inhibited the reaction, which proved that a radical process was involved. The reaction was initiated by a single electron transfer (SET) process from the sulfur atom to Fe³⁺ to generate Fe²⁺ and radical cation I. Subsequent cleavage of the N–S bond led to cation II and radical III. Interaction of III with Fe²⁺ regenerated the Fe³⁺ species and IV. At the same time, electrophilic addition of II to alkene 9 yielded intermediate V, which was subjected to the nucleophilic attack of TMSN₃ to deliver product 11 (Scheme 7).

Tian and Chang et al. could synthesize 3‑sulfenylated coumarin compounds 13 by using N-sulfanylsuccinimides 1 under a Lewis acid catalysis system (Scheme 8) [48]. Additionally, oxidation of 3-sulfenylated coumarins utilizing (diacetoxyiodo)benzene (PIDA) and meta-chloroperbenzoic acid (m-CPBA) toward 3-sulfinylated and 3-sulfonylated product, respectively, were performed in this work. A plausible mechanism involves the treatment of 1 with BF₃·Et₂O toward cation I, which reacted with the C–C triple bond in 12 to give sulfonium intermediate II. Intramolecular nucleophilic addition of the phenoxy ring of 12 to the activated C–C triple bond afforded intermediate III, followed by deprotonation to deliver product 13 (Scheme 9). When substrate 12 had an OMe group on the phenoxy ring, ipso sulfenylcyclization, or sulfenylation of the phenoxy ring occurred according to the different positions of the OMe group. The preparation of α,α-bisthiofunctionalized butenolides through a bis-sulfenylation methodology was reported by Zhou and Yuan et al. [49]. For this purpose, they applied N-(alkyl(aryl)sulfanyl)succinimides or N-(phenylsulfanyl)phthalimides using a catalytic amount of Et₃N. Moreover, mono-sulfenylation of α-methyl-γ-phenyl-substituted butenolide at α-position was carried out in the presence of Et₃N as well as quinine organocatalyst and products were obtained in high yields.

In addition to the use of N-(alkyl/arylthio)succinimides in the sulfenylation of organic compounds, N-(alkyl/arylthio)phthalimides are also considered good candidates for this purpose. In 2017, Sahoo and co-workers established a method for intramolecular annulation of N-(arylthio)phthalimides 14 and N-(arylthio)succinimides 1 with alkynes 15 in the presence of AlCl₃ as an efficient Lewis acid catalyst (Scheme 10) [50]. In the procedure, oxidative cleavage of one S–N bond and 1,2-sulfur migration afforded π-conjugated 6-substituted 2,3-diarylbenzo[b]thiophenes 16. A plausible mechanism is shown in Scheme 11. The coordination of AlCl₃ with the phthalimide/succinimide unit of 1 or 14, caused polarization of the S–N bond and produced an electrophilic intermediate I. Through the nucleophilic attack of the alkyne on I, cation II was generated, leaving Al-coordinated phthalimide/succinimide III. Finally, 4-endo-trig spirocyclization of II rendered the unstable intermediate IV, which underwent a ring expansion and 1,2-sulfur migration and subsequent deprotonation/aromatization to deliver product 16. Another work in the use of AlCl₃ for cyclization of N‑arylpropynamides 17 with N‑sulfanylsuccinimides 1 was described by Gao and Zhou et al. (Scheme 12) [51]. Annulation in the presence of AlCl₃ led to 3‑sulfenylquinolin-2-ones 18, while the addition of methanol into the reaction mixture gave 3-sulfenylazaspiro[4,5]trienones 19 as the target products. On the other hand, when free N–H alkynamides 20 were treated with N-sulfanylsuccinimides 1 in the presence of AlCl₃, the coupling chlorinated product 21 was detected, which with POCl₃ gave the cyclized product 22. Also, the synthesis of benzo[b]thieno[2,3-c]quinolone 24 as an anticancer molecule was demonstrated in this approach (Scheme 13).

An intermolecular sulfenoamination of alkenes 9 with sulfonamides 25 as the nitrogen source and N-thiosuccinimides 1 as the sulfur source was reported by Gao and Liu et al. (Scheme 14) [52]. Highly regio- and diastereoselective β-sulfonylamino sulfides 26 were obtained from alkenes 9, N-thiosuccinimides 1, and sulfonamides 25 in the presence of 20 mol % BF₃·Et₂O. While the transformation in the presence of N-(2-bromophenylthio)succinimide 1’ and copper catalyst led to intermolecular sulfenoamination of alkenes and subsequent C–N coupling to produce dihydrobenzothiazine structures 27 in a one-pot manner. Furthermore, deprotection of the amine unit by K₂CO₃ and Na metal was performed in this work.

In 2018, Anbarasan and Chaitanya developed an efficient approach for the C–H bond functionalization of aryl compounds containing a directing group using N-(thioaryl)phthalimides 14 in the presence of a palladium catalyst (Scheme 15) [53]. The thiolation occurred in the presence of Pd(OAc)₂ and acetic acid (AcOH) as a Brønsted acid, whereas i(a)midation was achieved by using Pd(OAc)₂ as catalyst and Cu(OAc)₂ as a Lewis acid. A possible mechanism for this chemodivergent C–H activation is depicted in Scheme 16. First, Pd catalyzed the formation of palladacycle I. Oxidative addition of AcOH activated the N–S bond in II, which reacted with I to obtain IV, followed by C–S reductive elimination to give the thiolated product 30 or 31. On the other hand, the interaction of I with Cu(OAc)₂ activated the N–S bond in III to afford IV, which was subjected to C–N reductive elimination to deliver the imidated product 32.

In 2018, an Fe-catalyzed carbosulfenylation and carboselenylation 33 of alkenes with N-(thio/seleno)phthalimides 14 was introduced by Lv and Li (Scheme 17) [54]. The use of Lewis acids, such as AlCl₃, ZnCl₂, InCl₃, Fe(OTf)₂ and Fe(acac)₃ was not beneficial. However, BF₃·OEt₂, SnCl₄, and TMSOTf resulted in good chemical yields. In the transformation, the selectivity of the endo or exo cyclization depended on the atom number of the chain between alkene and arene, leading to the formation of 6-, 7-, or 8-membered rings. In addition to N-(thio)phthalimides, benzenesulfenyl chloride as a sulfenylating source gave the target product in 93% yield. Knochel and co-workers found that copper acetate can catalyze the cross-coupling reaction between (hetero)aryl, alkyl and benzylic zinc halides 36 with N-thiophthalimides 14 (Scheme 18) [55]. Various metal catalysts, including CrCl₂, CoCl₂, NiCl₂, MnCl₂, FeCl₂, Fe(acac)₃ and copper salts such as Cu(OAc)₂, CuBr₂, CuBr, CuCl₂, and CuCN·2LiCl were evaluated in this coupling reaction, in which Cu(OAc)₂ showed highest product yields. Moreover, phthalimides with SCF₃, SCN, and SePh groups also worked well in this approach. Because of the low reactivity of these phthalimides, 10 mol % of catalyst was required. Cross-coupling reaction of sulfoximines 44 with N‑(arylthio)succinimides 1 catalyzed by a nanomaterial containing hexagonal boron nitride (h-BN) and γ-cyclodextrin-supported copper(II) acetate (h-BN@γ-CD@Cu(OAc)₂) was developed by Guo and Wu et al. (Scheme 19) [56]. Employment of a reusable heterogeneous nanomaterial, mild reaction conditions, avoiding the use of any additive, or base, and water/EtOH as a green solvent system were the advantages of this new method. N-Sulfenyl sulfoximines 45 were synthesized as coupling products in moderate to excellent yields.

In 2019, Gao and Yang et al. disclosed a new protocol for the synthesis of 4‑aryl/alkylsulfenylisoxazoles 48 from sulfenylation of 2-alkyn-1-one O-methyloximes 46 with N-sulfenylsuccinimides 1 (Scheme 20) [57]. The transformation proceeded via an electrophilic cyclization and sulfenylation promoted by AlCl₃. Dialkyl disulfides 47 were also well tolerated in this Lewis acid-mediated sulfenylation reaction in solvent-free conditions at room temperature. In the same year, a three-component reaction between highly substituted cyclopropanes 49, sulfonamides 25 and N-(arylthio)succinimides 1 or N-(arylseleno)succinimides 1’’ was developed under a Lewis acid catalysis system. This reaction involves ring-opening of the substituted cyclopropane 49, amination at the C1-site, and thiolation at the C3-site. In the transformation, sulfonamide acted as a nucleophile, chalcogensuccinimide as an electrophile, and cyclopropane as a zwitterion component (Scheme 21) [58].

In 2020, a Lewis acid-mediated cyclization of β,γ-unsaturated oximes 51 and hydrazones 52 with N-(arylsulfenyl)succinimide 1 and N-(arylseleno)succinimide 1’’ was extended for the formation of isoxazoles 53 and dihydropyrazoles 54 as products (Scheme 22) [59]. A credible pathway for the production of isoxazole 53 is illustrated in Scheme 23. The interaction of 1 with BF₃·Et₂O resulted in intermediate I that is in balance with I’. Cleavage of the N–S bond of I afforded cationic species PhS⁺ II, which activated the double bond of 51 to give the three-membered ring III. Afterwards, intermediate IV was formed by an intramolecular ring opening of III (path I) and presumably produced IV' by path II, which through deprotonation delivered products 53 and 53' respectively. In the meantime, another Lewis acid-promoted construction of 4-chalcogenylated pyrazoles 57 and 59 was carried out starting from α,β-alkynic hydrazones 55 (Scheme 24) [60]. In the procedure, α,β-alkynic hydrazones were subjected to S- or Se-electrophiles 56 and cyclization reaction. Additionally, NCS and ArSH produced the S-electrophile for the cyclization reaction with arylpropynal hydrazones. Also, the reaction of 1-(1,3-diphenylprop-2-yn-1-ylidene)-2-phenylhydrazine 58 as the substrate with N-sulfenylsuccinimides 1 afforded fully substituted pyrazoles 59 in up to 98% yield.

In 2021, a solvent-controllable approach for the construction of 3-thiolated pyrroles 61 and pyrrolines 62 from propargylic tosylamides 60 and N-thiosuccinimides 1 was described by Gao′s group (Scheme 25) [61]. When AlCl₃ as the Lewis acid catalyst and nitromethane as the solvent were used, a series of 3-thiolated pyrrole products 61 were detected, and 3-thiolated pyrrolines 62 were obtained by changing the reaction solvent to MeCN. Also, organic fluorophore compounds such as benzothienopyrrole and bis-thiolated boron dipyrromethene can be achieved from 3-thiolated pyrroles. Mechanistic studies showed that the oxidative species HNO and HCHO were generated through a Nef reaction in MeNO₂ under acidic conditions. In the meantime, 1 was activated by AlCl₃ to form sulfenium cation I, which induced an intramolecular cyclization of 60 to produce pyrroline 62. In MeCN solvent, 3-thiolated pyrroline 62 was stable and could be isolated, but in MeNO₂, in the presence of the HNO species, the pyrroline structure could oxidize and aromatize to the pyrrole ring 61 (Scheme 26).

In 2021, Anbarasan and co-workers were able to obtain a diverse range of sulfenylated products 64 in a Co-catalyzed C2-sulfenylation and C2,C3-disulfenylation of indole derivatives with N-(arylsulfenyl)succinimide 1 (Scheme 27) [62]. The reaction involves the formation of active cobalt species I from the interaction of KOAc with the cobalt pre-catalyst. Treatment of I with 63 resulted in the five-membered cobaltocycle complex II. Next, coordination of 1 to II gave III, followed by intramolecular nucleophilic trapping of the electrophilic SAr unit to furnish C2-sulfenylated product 65 and Co-complex IV. At last, active cobalt species I regenerated from IV in the presence of AcOH. It should be noted that when R = H, C2-sulfenylated product 65 may be sulfenylated via a thermal electrophilic aromatic substitution to provide C2,C3-disulfenylated product 66 (Scheme 28). In the same year, Sutherland and Dodds disclosed a protocol for the C–H bond thioarylation of electron-rich arenes 4 like anisoles, acetanilides, phenols, and N-heterocycles in the presence of Fe(III) Lewis acid and ionic liquid [BMIM]NTf₂ as an effective catalysis system (Scheme 29) [63]. Kinetic studies in this cross coupling-reaction indicated that N-(arylthio)succinimides 1 with electron-deficient arene 4 undergoe thioarylation catalyzed by Fe(NTf₂)₃. Related molecules bearing an electron-rich arene showed an autocatalytic pathway that is enhanced due to the Lewis basic character of the final product.

Reddy and co-workers developed a simple method for the preparation of 1,2-thiosulfonylethenes 71 and 1,1-dithioethenes 69 in the presence of a nickel catalyst (Scheme 30) [64]. Various alkynyl bromides 68 as starting materials reacted with thiosulfonates 70 and N-arylthiosuccinimides 1 as thiolating reagents. 1,2-Thiosulfonylethenes 71 were obtained via vicinal thiosulfonylation. However, in the case of 1,1-dithioethenes 69, germinal disulfenylation occurred. In addition, 1,2-difunctionalization of indole-derived 1,1-bromoalkenes 72 was also investigated in the presence of Cs₂CO₃ without the need of a metal catalyst. The synthetic applicability of the procedure was demonstrated by a gram-scale synthesis of the 1,2-thiosulfonylethene product. A possible mechanism for the formation of 1,2-thiosulfonylethenes is shown in Scheme 31. Initially, homolytic cleavage of thiosulfonate 70 generated PhS· and PhSO₂· radicals. The reduction of Ni(II) to Ni(0) in the presence of Cs₂CO₃ and the reaction with 68 formed alkynyl-Ni species I. Then, the PhS· radical reacted with I to generate alkenyl radical II, which can react with the PhSO₂· radical to obtain intermediate III. Radical II underwent oxidation with PhSO₂· to form alkenyl cation IV and PhSO₂⁻. At last, H-abstraction from DMF delivered product 71 and the Ni(0) species to continue the catalytic cycle.

In 2022, Gao and co-workers introduced a new protocol for the preparation of thioesters, acyl disulfides, ketones, and amides starting from N-thiohydroxy succinimide esters (NTSEs) 1’’’, which can serve as the acylthiolating and acylating source (Scheme 32) [65]. First, they synthesized a series of N-thiohydroxy succinimide esters by treating potassium thiolates with N-chlorosuccinimide in MeCN at room temperature for 20 min. N-Thiohydroxysuccinimide esters were obtained in up to high yields (21–83%). In the next phase, they performed the reaction of NTSEs with different nucleophiles, according to hard acyl and soft acylthio electrophilic sites contained in the NTSEs to selectively transfer the acyl or acylthio moieties. Arylboronic acids 74 and amines 76 were suitable for the acyl transfer and led to ketones 78 and amides 80 as the desired products. While, Grignard reagents 75 and thiols 77 acted as soft nucleophiles and resulted in thioesters 79 and acyl disulfides 81, respectively. It should be noted that the use of a palladium catalyst was essential for the cross-coupling reaction between 1’’’ and 74. Also, the presence of ZnCl₂ could facilitate the cleavage of the N–S bond. In the case of amines and thiols, there was no need for a metal catalyst for the formation of S–N and S–S bonds. A plausible mechanism for the metal-catalyzed acylation and acylthiolation is illustrated in Scheme 33. Firstly, oxidative addition of palladium to the C–S bond of NTSE 1’’’ afforded intermediate I. The transmetalation from boron to palladium led to intermediate III, followed by reductive elimination to yield ketone 78. In the acylthiolation cycle, the azaphilic ZnCl₂ activated NTSE 1’’’ via N–Zn coordination to facilitate the leaving ability of succinimide. Then, nucleophilic substitution of arylmagnesium bromide 75 to intermediate IV provided thioester 79.

In 2022, Gao and co-workers demonstrated bisulfenylation/cyclization of homopropargylic azides 82 with N-thiosuccinimides 1 in the presence of AlCl₃ as the catalyst, 3,4-bisthiolated pyrroles 83 were obtained as the desired products in moderate to high yields (Scheme 34) [66]. The reaction involves the Lewis acid-catalyzed first thiolation and intramolecular cyclization of propargyl azides the removal of N₂ and a proton. Subsequently, monothiolated perroles were subjected to the second thiolation process to prepare 3,4-bisthiolated pyrroles. Cyclic voltammetry and DFT calculations revealed that the 3,4-bisthiolated pyrroles 83 contained higher HOMO orbital energies, and lower band gaps compared to the unsubstituted parent 2,5-diphenylpyrrole.

Organocatalyzed sulfenylation by N-(sulfenyl)succinimides/phthalimides

In 2004, direct sulfenylation of a series of aldehydes and ketones 84 with N-(phenylthio)phthalimide (14) by using an organocatalyst was reported by Wang and co-workers (Scheme 35) [67]. Several orgnocatalysts, such as piperidine, and pyrrolidine derivatives were evaluated for the coupling reaction, in which pyrrolidine trifluoromethanesulfonamide A was selected as the best catalyst for this purpose. It is noteworthy that the use of diphenyl disulfide as a sulfenylating agent was not effective in this protocol. N-(Aryl/alkylthio)phthalimide as an efficient sulfenylating reagent could also react with indoles to produce 3-thioindoles in the presence of 0.5 mol % of MgBr₂, as a Lewis acid [68]. Moreover, sulfenylation of ketoximes and secondary nitro compounds toward N-arenesulfenyl ketimines occurred by applying N-(phenylthio)phthalimide [69].

In 2011, Shi et al. developed a method for the sulfenylation of unsaturated alcohols 86 by N-(benzylthio)succinimide 1 access to tetrahydrofurans 87 and tetrahydropyrans 88 (Scheme 36) [70]. In this protocol, by controlling acid catalyst (camphorsulfonic acid (CSA) or trifluoromethanesulfonic acid (TfOH)), two different products were achieved and tetrahydrofurans 87 could be converted to tetrahydropyrans 88 by stereoselective rearrangement. In the same year, Zhu and Cheng et al. developed a convenient approach for the thiolation of β-keto phosphonates 89 by using N-(arylthio)phthalimides 14 under α,α-diaryl-ʟ-prolinols B organocatalytic system (Scheme 37) [71].

Sulfenylation of 3-aryloxindoles 91 with N-(arylsulfenyl)phthalimides 14 as the electrophilic sulfur reagents resulted in thiolated products 92 up to 99% ee, in the presence of quinidine as the organocatalyst (Scheme 38) [72]. For the study of enantioselectivity of products, different N-substituted oxindoles with H, Me, phenyl, and benzyl groups were investigated. As the size of N-protecting groups increased, the percentage of enantioselectivity decreased, where in the case of NH-oxindoles, the product was achieved with only 6% ee. Another sulfenylation at the 3-position of unprotected oxindoles with N-(phenylthio)phthalimide was reported by Feng et al. [73]. A chiral N,N′-dioxide-Sc(OTf)₃ complex as a catalyst and a Brønsted base were applied in the procedure. It is interesting to note that in such a method, sulfenylation of NH-oxindoles resulted in the thiolated products with excellent enantioselectivities (up to 99% ee).

In 2013, sulfenylation and chlorination of β-ketoesters 93, and 95 with N-(arylthio)phthalimide 14 and N-chlorophthalimide (96) under phase-transfer conditions was developed by Maruoka and co-workers (Scheme 39) [74]. The presence of chiral bifunctional catalysts C and D with the amide, or sulfonamide moieties could improve the enantioselectivity. Also, the heterogeneous medium coming from H₂O and toluene was beneficial for the progress of the transformation.

In 2014, Denmark and Chi successfully synthesized a wide variety of pyrrolidines 99, piperidines 100, and azepanes via intramolecular sulfenoamination of olefins 98 (Scheme 40) [75]. The reduction of endo to exo ratio was either related to the electron density of the alkene or the steric effect of a substituent. The tether lengths could affect the cyclization. For example, the two-carbon-tethered substrate completely showed endo selectivity, while the four-carbon-tethered substrate exclusively led to azepane. A possible mechanism was suggested for this Lewis base catalysis system. Methanesulfonic acid (MsOH) activated reagent 14, which coordinated with the Lewis base (S)-E, to form complex I. Then, the transfer of the sulfenium ion to the alkene resulted in chiral thiiranium ion II. Capture of the thiiranium ion by the tosylamide and deprotonation led to the final product 99 or 100 (Scheme 41). Through the coupling reaction of N-(aryl/alkylthio)succinimides 1 with 5H-oxazol-4-ones 101 in the presence of an organocatalyst named cinchona alkaloid-derived squaramide F, a series of α-sulfenylated products 102 were obtained in moderate to excellent yields with good to excellent enantioselectivities (Scheme 42) [76]. It should be noted that the authors did not define the exact role of the organocatalyst in the reaction mechanism.

Transition-metal-free C–H sulfenylation of electron-rich arenes 103 by N-(alkyl/arylthio)succinimides 1 led to aryl sulfides 104 (Scheme 43) [77]. The cross-coupling reaction involves protonation of the succinimide moiety by trifluoroacetic acid (TFA) to create electrophilic thio intermediate I. Nucleophilic attack of arene 103 on I led to target product 104. Also, TFA-catalyzed C–H sulfenylation at the C2-position of protected and unprotected indoles 105 to form 2-thioindoles 106 (Scheme 44) [78]. The reaction initiated with TFA-promoted electrophilic addition of 1 to 105 towards C3-sulfenylated indole I, which was protonated by TFA, led to intermediate II. Then, CF₃CO₂SR, which was produced in the previous step, as a sulfenylating reagent, reacted with I to form the 3,3-bis-sulfide indolenium III. The migration of a sulfide group to the C2-site of indole, generated 2,3-disubstituted indole V. Protonation of V resulted in indolenium intermediate VI. Finally, desulfenylation of VI by anion CF₃CO₂, afforded 2-thioindole 107 (Scheme 45).

The enantioselective synthesis of a broad spectrum of 3-thio-3-pyrrolyloxindoles 109 and 3-seleno-3-pyrrolyloxindoles 110 via sulfenylation and selenenylation of 3-pyrrolyloxindoles 108 was described by Yuan′s research group in 2015 (Scheme 46) [79]. By testing several alkaloids as organocatalysts for the transformation, cinchonidine G proved to be the best catalyst for C–H sulfenylation and selenenylation of substrates in toluene at −20 or 0 °C. The reaction occurred in shorter times in the presence of N-(arylsulfanyl)succinimide, while the coupling reaction using N-(alkylsulfanyl)succinimide and N-(heteroarylsulfanyl)succinimide longed several days. The gram-scale synthesis demonstrated the practicality of this method. In the same year, sulfenylation of different types of S-based nucleophiles 111 and 113 with N-(organosulfanyl)succinimide 1 catalyzed by dihydroquinine as an easily available organocatalyst was reported by Zhou et al. (Scheme 47) [80]. This is the first example of the preparation of chiral dithioketals. The presence of the OH group was essential in dihydroquinine H. By changing OH into a OMe group, the enantioselectivity and the product yield were reduced. Although, the authors did not further explain the catalytic pathway.

The use of organocatalysts in sulfenylation of N-heterocyclic compounds was investigated by Gustafson′s group in 2017 (Scheme 48) [81]. In their work, a series of conjugate Lewis base Brønsted acid organocatalysts were evaluated for sulfenylation on C3, or C2 position of N-heterocycles 115, including indoles, peptides, pyrrole, and 1-methyl-1H-pyrrolo[2,3-b]pyridine. The authors hypothesized a mechanism for the activation of N-sulfanylsuccinimides 1 or 14 by conjugate Lewis base Brønsted acid catalyst I, leading to the formation of an electrophilic sulfenium source (Scheme 49). The use of dimeric cinchona alkaloid J as another organocatalyst for α-sulfenylation of deconjugated butyrolactam substrates 117 with N-(arylsulfanyl)succinimides 1 demonstrated in Mukherjee′s work (Scheme 50) [82]. In the method, functionalized γ-lactams 102 were produced in aqueous media with high enantioselectivities. However, N-(alkylsulfanyl)succinimides and α-isobutyl containing butyrolactam did not work in this reaction. Another work by Denmark on intramolecular sulfenylation of alkenes 119 with phenols by using N-(arylthio)phthalimide 14 as a sulfur source was reported in the same year (Scheme 51) [83]. Benzopyrans 120 and benzoxepins were obtained in the presence of a Lewis base catalyst in good to high yields.

In 2018, Liang and Chen et al. extended 1,3-difunctionalizations of a series of Morita–Baylis–Hillman carbonates from isatins by using a Lewis base catalytic system (Scheme 52) [84]. Screening several organocatalysts showed that the 1,3-oxo-ethynylation of starting materials with silylethynyl-1,2-benziodoxol-3(1H)-ones 123 was obtained by using catalyst N, while 1,3-aminosulfenylation with N-(aryl/alkylthio)imides 1 or 14 occurred in the presence of catalyst L. Meanwhile, Zhou and Chen′s research team was able to synthesize a broad range of enantioenriched naphthalenone structures 126 by utilizing another organocatalyst (Scheme 53) [85]. In the procedure, β‑naphthols 125 reacted with N-(arylthio)succinimide 1 or N-(arylthio)phthalimide 14 as the sulfenylating reagents in the presence of cinchona-derived thiourea O as a catalyst to afford the corresponding chiral naphthalenone products 126 under mild reaction conditions.

Another work from Anbarasan and Chaitanya on the use of N-(arylsulfanyl)succinimide 1 and N-(arylseleno)succinimide 1’’ in an oxychalcogenation process was reported in 2018 (Scheme 54) [86]. In this method, they succeeded in applying methanesulfonic acid (MsOH) as a promoter for oxythiolation and oxyselenation of o-vinylanilides 127 through the formation of three-membered cyclic sulfonium ion II followed by ring-opening of sulfonium ion and intramolecular cyclization. The use of a Lewis base/Brønsted acid catalysis system for the sulfenylation of aromatic substrates 4 was reported by Gustafson et al. (Scheme 55) [87]. In the method, catalyst P acted as a Lewis base, where TfOH acted as a Brønsted acid. It is worth noting that coupling reactions without Lewis base catalyst P occurred in much lower yields. The mechanistic investigations showed that electron-rich sulfenyl groups can participate in an autocatalytic mechanism due to their Lewis basic nature. However, the electron-poor ones exhibited less autocatalysis effect requiring the use of the Lewis base catalyst P.

In 2019, Denmark and Panger disclosed a novel method for the preparation of γ‑lactams 133 through the reaction of alkenes 132 with N-thiophthalimides 14 in the presence of Lewis base organocatalysts (Scheme 56) [88]. In this procedure, the cyclized products were obtained via the activation of the sulfur electrophile by a Lewis base to generate the thiiranium ion intermediate from the β,γ-unsaturated sulfonyl carboxamide. The attack of the sulfonamide nitrogen atom on this intermediate led to intramolecular cyclization. In 2020, electrophilic cyclization of allylic amides 134 using N-(phenylthio)succinimide 1 in the presence of camphorsulfonic acid (CSA) as a Brønsted acid and tetrabutylammonium chloride (TBAC) led to 5-[(phenylthio)methyl]oxazoline scaffolds 135 (Scheme 57) [89]. Combination of CSA/TBAC formed an efficient activator system for this sulfenylation/intramolecular cyclization.

In the same year, Zhao and co-workers reported the thiocarbocyclization of allenes 136 with N-(organothio)succinimides 1 as electrophilic aryl/alkylthio reagents for the assembly of indene-based sulfide molecules 137 (Scheme 58) [90]. The Lewis basicity nature of PhSePh as a catalyst and the presence of Lewis acid TMSOTf improved the chemical yields. It is interesting to note that the reaction carried out at a lower temperature because of the high reactivity of allene 136. When the reaction was performed at room temperature, no desired product was observed, and performing the reaction at 0 °C enhanced the regioselectivity but still in low yield. By further lowering the temperature to −60 °C the yield was increased. The authors suggested a possible mechanism for this organoselenium-catalyzed cyclization transformation involving activation of the electrophilic sulfur reagent by PhSePh with the assistance of TMSOTf to form transition state I. Intermediate II formed through capturing of sulfonium by selenium. Then, II reacted with 136 to give regioselective cyclic thiiranium ion III. Nucleophilic attack of the aromatic ring on the thiiranium ion moiety furnished products 137 and reproduced the selenide catalyst (Scheme 59).

Zhao and co-workers found that N-thiosuccinimides are also suitable promoters for the enantioselective hydrothiolation of alkenes at low temperatures (Scheme 60) [91]. The synthesis of chiral sulfides up to 97% ee was achieved in this method. A wide range of cyclic alkenes 138 and acyclic alkenes 52 and 9 were smoothly tolerated in this organocatalysis strategy. According to the proposed mechanism, initially, the organocatalyst activated the electrophilic sulfur species to form intermediate I with the assistance of the Lewis acid. Intermediate I reduced by Et₃SiH 139 to give thiol. Through the reaction of thiol with I, disulfide as a byproduct was formed, and intermediate II was generated by the reaction of I with 138. Product 140 was obtained via direct hydride reduction of II by silane. On the other hand, most of II were converted to intermediate III, which underwent hydride reduction to render product 140 (Scheme 61). Another organocatalysis system was disclosed by Liu and co-workers for sulfenylation of α-fluoro-β-ketoamides 143 and azlactones 145 (Scheme 62) [92]. Besides α-fluoro-β-ketoamides, α-chloro-substituted ketoamide was also tolerated well in this transformation. Screening several chiral guanidines as the bifunctional catalyst revealed that these organocatalysts were suitable for the synthesis of α-fluoro/chloro-α-sulfenyl-β-ketoamides 144 and azlactone 146 skeletons. The presence of two heteroatom-bearing tetrasubstituted chiral carbon centers in a one-step fashion, avoiding the use of the heavy metal catalysts, and the performance of the reaction at ambient temperature are the prominent features of the protocol.

Sahoo and co-workers found that sulfenylation of yne-tethered ynamide 147 with N-thiosuccinimides 1 was possible in the presence of only methanesulfonic acid in dichloromethane at room temperature (Scheme 63) [93]. The electrophilic activation of propargylalkyne 147 generated in situ a sulfonium cation 1-I. Afterwards, 6-endo-dig cyclization of polarized ketene-N,O-acetal to the alkyne β-carbon and trapping of the sulfonium cation at the alkyne-α-carbon afforded 5-(arylthio)-3,6-dihydropyridin-2(1H)-one 148. The coordination of a sulfonium electrophile to the C–C triple bond of 1-I occurred through cyclopropyl intermediate 1-I. The conversion of 1-I to 2-II was confirmed by mechanistic studies due to the stability of the benzyl carbocation, followed by 6-endo-dig cyclization. In this method, toxic transition metal catalysts, oxidants, or bases are not used, which made it economically and environmentally reliable.

In 2023, Gao et al. developed a metal-free procedure for the synthesis of functionalized alkynyl disulfides 149 and acyl disulfides 151 under acid catalysis (Scheme 64) [94]. In this regard, they used N-alkynylthiophthalimides in the reaction with thiols to make a series of bioactive disulfides. Various simple thiols, cystines, peptides, drugs and saccharides reacted smoothly with N-alkynylthiophthalimides in the presence of TFA as a catalyst. Also, aliphatic and aromatic thiols reacted with N-alkynylthiophthalimide and sulfoxide 149 to obtain acyl disulfides 151 through alkynylthiolation and hydrative oxyarylation in the presence of TMSOTf.

Catalyst-free sulfenylation by N-(sulfenyl)succinimides/phthalimides

In 2015, oxysulfenylation of styrene derivatives 9 utilizing 1-(arylthio)pyrrolidine-2,5-diones 1 and alkyl/benzyl alcohols 86 toward β-alkoxy sulfides was developed by Fu et al. (Scheme 65) [95]. In this metal-free method, diverse β-alkoxy sulfides were synthesized without the need to any catalyst, or additive. The reaction proceeded through the formation of carbonium ion intermediate I, which underwent electrophilic addition of alcohol to provide product 152. In the meantime, N-(arylthio)succinimide 1 as a thiolating reagent was used by another research team for the arylthiolation of arylamines 76 in acetonitrile as a solvent under metal-free conditions (Scheme 66) [96]. A broad spectrum of mono-, or diarylthiolated anilines 153 was obtained in low to excellent yields. Arylthiolation occurred predominantly at the para-position to the amino group, and when the para-position of aniline was occupied by another group, ortho-substituted products were identified.

Fu′s research group established an isothiocyanatoalkylthiation of styrenes 9 in the presence of isothiocyanate 154 and N-(organothio)succinimides 1 under catalyst-free conditions (Scheme 67) [97]. The reaction proceeded through the formation of a three-membered cyclic intermediate II by the cleavage of 1 under thermal conditions. Between the nitrogen or sulfur atom in TMSNCS, electrophilic attack of nitrogen on II led to thermodynamically favored product 155.

In 2017, sulfenylation of (E)-β-chlorovinyl ketones 156 using N-(alkyl/arylthio)phthalimides 14 access to 3,4-dimercaptofuran skeletons 159 was presented by Kim and Oh et al. (Scheme 68) [98]. In the first step, by using Et₃N and t-BuOK in the reaction of (E)-β-chlorovinyl ketones 156 and N-(phenylthio)phthalimide 14, a series of α,γ-dithioallenyl ketones 157 and α,α-dithiopropargyl ketones 158 were obtained in a different ratio. In the second phase, by adding copper chloride as a catalyst in the reaction medium, 3,4-dimercaptofurans 159 were formed via 1,2-sulfur migration.

In 2018, Shen′s research team disclosed a new protocol for 1,2-thiofunctionalization of arylalkenes 160 with N-arylthiophthalimide 14 and various nucleophiles, including aryl ethers, carboxylic acids, indoles, and pyrroles in the presence of HCl (Scheme 69) [99]. The procedure utilized no toxic metal catalyst, or additive, which made it economically and environmentally reliable. According to the mechanism, two pathways occurred after the formation of intermediate I by the reaction of 14 with HX. In path I, intermediate I reacted with alkene 160 to give intermediate II, which underwent a nucleophilic attack of 161 to give the product 162 and regenerated HX. In path II, I reacted with nucleophile 161 to produce a byproduct, phthalimide, and HX (Scheme 70). The coupling reaction was influenced by nucleophilic properties and the steric effect of the nucleophile reagents. In the same year, the treatment of amines with N-thiophthalimides led to sulfenamides promoted by 2-ethoxyethanol under microwave irradiation [100]. Alkylamines, such as morpholine, cyclohexylamine, pyrrolidine, and tert-butylamine were participated in this coupling process. All reactions occurred in a shorter time with higher chemical yields compared to the traditional heating methods.

In the meanwhile, Qiu and Xu et al. reported the coupling reaction between diazo compounds 163 and N-sulfenylsuccinimides 1 under catalyst-, base-, and additive-free conditions (Scheme 71) [101]. The reaction proceeded via a radical pathway, in which a free carbene was generated under heating, followed by the formation of ylide, N–S bond cleavage, and C–N bond formation along with the release of N₂.

In 2019, Sun and co-workers introduced an unprecedented method for the synthesis of isothiourea derivatives via the activation of diaryl/alkyl disulfides 47 with N-halosuccinimides in the presence of TEMPO, followed by insertion of an isocyanide molecule 166 or other nucleophiles 161 (Scheme 72) [102]. By studying the spectroscopic evidence, the authors found that both sulfenyl halide 165 and N-sulfenylsuccinimide 1 intermediates were involved in the reaction. Removal of TEMPO as a radical initiator from the reaction mixture did not result in product formation so, it seems that the reaction moved through a radical route for the formation of sulfenyl halide I, and N-sulfenylsuccinimide II. The use of azobisisobutyronitrile (AIBN) instead of TEMPO also resulted in 85% yield of the product, while benzoyl peroxide (BPO) gave a low yield. Various nucleophiles 161, including ammonia, alkylamines, hydrazines, alcohols and alkoxides, indole, N-alkylpyrrole, N-substituted anilines, PhSH, and PhMgBr worked well under these conditions. Asymmetric thiolation of 4-substituted pyrazolone derivatives with N-thiophthalimides catalyzed by 1 mol % of chiral iminophosphorane organocatalyst was carried out under mild conditions [103]. Solvent control in the procedure can affect the yield of products due to the solubility of the catalysts. Various solvents, such as acetone, ethyl acetate, tetrahydrofuran, methanol, toluene, hexane, and n-pentane were employed, in which the products in non-polar hydrocarbon solvents like hexane and n-pentane were obtained in excellent efficiency and enantioselectivity.

Song et al. found that the chemoselective α-sulfenylation and β-thiolation of α,β-unsaturated carbonyl compounds 168 can be achieved with N-thiophthalimides 14 and diaryl disulfides 47, respectively (Scheme 73) [104]. They remarked that the presence of B₂pin₂ was essential in the coupling reaction of disulfides with α,β-unsaturated carbonyl compounds 168. The sulfenylation involved a 1,4-addition of the phthalimide anion to the β-carbon of chalcone, followed by electrophilic sulfur attack and deprotonation. In the thiolation, in situ formation of thiophenol occurred, followed by thio-Michael addition of chalcone with thiophenol. N-Calcogenophthalimide also can be used to prepare thiophosphates, thiophosphinates and selenophosphates by reaction with the P(O)H moieties of H-phosphonates [105].

Conclusion

To date, both metal-catalyzed and organocatalyzed C–S bond formations have been widely expanded. In particular, organocatalytic methodologies are effective for direct construction of stereogenic carbon centers bearing a sulfur atom. Although, significant efforts have been made to form enantioselective C–S bonds, the direct sulfenylation with more green, economical, and environmentally friendly sulfenylating reagents remains a challenge for organic chemists. N-(Sulfenyl)succinimides/phthalimides as new alternative sulfenylating reagents can meet this demand. In this context, we observed that most of the reactions have used unactivated C–H bonds, such as C(sp²)–H and C(sp³)–H bonds. In some reactions, chiral organocatalysts catalyzed asymmetric sulfenylation processes. In most cases, there is no need to use a metal catalyst, base, or additive. N-(Sulfenyl)succinimide/phthalimide acted as an active electrophilic sulfur source, acted in the reaction mechanisms. However, mechanistic studies need further exploration to define a valid reaction pathway. Therefore, we believe that the use of N-(sulfenyl)succinimide/phthalimide in chemical syntheses will be widely seen in the future.