Photoredox‐Catalyzed Chem‐ and Stereoselective Thiosulfonylation of Cyclopropylamides

ABSTRACT

While the thiosulfonylation of C─C π‐bonds is well‐established, the analogous functionalization of kinetically inert C─C σ‐bonds remains a formidable challenge, particularly regarding stereoselective control. Herein, we report a general photocatalytic strategy for the chemo‐ and stereoselective 1,3‐thiosulfonylation of cyclopropylamides. This method successfully addresses the elusive challenge of stereocontrol in σ‐bond thiosulfonylation, enabling the unprecedented asymmetric construction of metastable γ‐thio‐α‐aminosulfones with excellent enantioselectivity. The optimized protocol exhibits a broad scope, accommodating a diverse array of cycloalkylamides as well as mono‐, di‐, and even trithiosulfonates. Furthermore, the utility of this methodology is highlighted by its successful application in the late‐stage functionalization of pharmaceutically relevant compounds, diverse downstream transformations. Most crucially, we have demonstrated that the resulting chiral ɑ‐amidoalkylphenyl sulfones readily undergo stereoselective substitution in SN2‐like pathway, effectively outcompeting the typically predominant E2‐type elimination process.

We report a general photocatalytic strategy for the chemo‐ and stereoselective 1,3‐thiosulfonylation of cyclopropylamides. Crucially, we address the elusive challenge of stereocontrol in σ‐bond thiosulfonylation, which enables the first asymmetric construction of the metastable γ‐thio‐α‐aminosulfones with excellent enantioselectivity and the following stereoselective substitution. The optimized conditions accommodate assorted cycloalkylamides and various mono‐, di‐, even trithiosulfonates with broad applications in downstream transformations and late‐stage functionalization of pharmaceutically relevant compounds.

1. Introduction

The unique electronic and steric profiles of sulfur render organosulfur compounds indispensable across the fields of agrochemicals, pharmaceuticals, and functional materials. Among these, sulfide and sulfone scaffolds represent privileged structural motifs in medicinal chemistry, serving not only as key pharmacophores that modulate bioactivity but also as versatile handles in organic synthesis (Scheme 1a) [1, 2, 3, 4, 5, 6]. Given the significance of both sulfenyl (─S─) and sulfonyl (─SO₂─) moieties, strategies enabling their concomitant incorporation into a single molecular framework have garnered intense interest. Conventionally, accessing such difunctionalized architectures has relied on stepwise protocols (Scheme 1b) [7, 8, 9, 10, 11, 12]. However, these traditional methods are often plagued by poor atom‐ and step‐economy, severely restricting their broader synthetic utility.

SCHEME 1.

The state of the art in thiosulfonylation.

Atom transfer radical addition (ATRA) reactions stands as a powerful strategy in synthetic chemistry, enabling the atom‐economical functionalization of feedstocks via well‐defined radical pathways [13, 14]. Within this mainfold, thiosulfonates (R¹SO₂SR²) have emerged as versatile bifunctional reagents [15, 16]. Enabled by diverse activation modes, involving oxidation [17, 18], Lewis acid [19, 20], and photoredox chemistry [21, 22, 23, 24], thiosulfonates and their derivatives have facilitated a broad spectrum of transformations, including mono‐, di‐, even trithiosulfonylations (Scheme 1b). However, these methodologies have been predominantly confined to the functionalization of carbon–carbon double bonds (C─C π‐bonds). In contrast, the analogous activation of kinetically inert carbon–carbon single bonds (C─C σ‐bonds) remains a formidable challenge and significantly underexplored (Scheme 1c). To date, only two successful examples have been reported. The groups of Zhu and Wang independently demonstrated the 1,3‐thiosulfonylation of [1.1.1]propellane (BCP), leveraging its immense strain energy (66.6 kcal/mol) to drive the reaction [25, 26, 27]. while Anderson and coworkers extended this reactivity to [3.1.1]propellane under visible light irradiation [28]. Despite these advances, the inherent reliance on strained bicyclic skeletons severely limits structural diversity. Notably, catalytic enantioselective variants of these σ‐bond functionalizations remain entirely elusive (Scheme 1d). Consequently, the development of general strategies for the stereoselective thiosulfonylation of C─C σ‐bonds is highly desirable.

Cyclopropylamides are readily accessible via a one‐step acylation of commercially available cyclopropylamine, affording excellent yields. The inefficient orbital overlap of the C─C σ‐bonds endows the cyclopropane moiety with high ring‐opening reactivity, making it an ideal platform for investigating C─C σ‐bond cleavage [29, 30, 31, 32, 33]. Accordingly, the development of practical thiosulfonylation protocols employing these substrates represents a significant synthetic challenge. Drawing inspiration from recent single‐electron transfer (SET) activation strategies [34, 35, 36, 37, 38, 39], substantial efforts have been devoted to the C─C bond cleavage and concomitant difunctionalization of cyclopropylamides, such as 1,3‐diamination [40], 1,3‐oxyheterarylation [41], 1,3‐oxyalkynylation [42], 1,3‐oxyhalogenation [43, 44, 45], and others [46, 47, 48] (Scheme 1e). We envisaged that a distal‐iminium radical intermediate, generated via SET oxidation and β‐scission ring‐opening of aminocyclopropanes, could be captured by thiosulfonates to forge the initial C─S bond. Subsequently, the in‐situ generated sulfenylated nucleophile would stereoselectively attack the iminium ion, ultimately, furnishing the thiosulfonylation product [49, 50, 51]. However, realizing this proposal requires overcoming two primary hurdles: (i) the potential concurrent occurrence of thiolation and sulfonylation during the initial stage may give rise to intricate chemoselectivity issues [21, 22]; (ii) the metastable nature of the α‐amidoalkylphenyl sulfone scaffold renders it prone to decomposition into imine and sulfinate species, thereby complicating enantioselective control [52, 53]. In this article, we herein present our efforts toward an unprecedented example of chemo‐ and stereoselective 1,3‐thiosulfonylation of cyclopropylamides, which provides a straightforward and sustainable platform for constructing the synthetically valuable, yet challenging, chiral γ‐thio‐α‐aminosulfones (Scheme 1f).

2. Results and Discussion

We initiated our racemic investigation using readily accessible N‐cyclopropylbenzamide 1a and S‐phenyl benzenesulfonothioate 2a as the model substrates. After a systematic evaluation of the reaction parameters, we defined the optimal reaction condition as 9‐mesityl‐10‐methylacridinium perchlorate ([Acr‐Mes‐ClO₄ ⁻], 10.0 mol%) as the photosensitizer in MeCN under 456 nm light emitting diode (LED) irradiation at room temperature for 12 h, which delivered the desired 1,3‐thiosulfonylation product 3 in an 92% isolated yield with outstanding chemoselectivity (eq 1 and details see Tables S1–S4). Notably, the transformation could also be driven by natural sunlight, affording the desired product 3 in 74% yield after 48 h of exposure.

With the optimized conditions in hand, the substrate scope of cycloalkylamides was evaluated (Scheme 2). The protocol demonstrated broad functional group tolerance, delivering a library of ɑ‐sulfone aminothioether derivatives 4–51 in good yields. Incorporation of substituents in any vacant positions of phenyl ring afforded the desired products 4–14 in 31%–92% yields. Notably, halogen substituents (Cl, Br, and I) as well as TMS‐alkyne motifs were well tolerated, providing versatile synthetic handles for further diversification. Pleasingly, the reaction proved equally effective with biologically relevant nitrogen‐ and oxygen‐containing heterocyclic scaffolds such as furanyl, thienyl, piperonyl, benzofuryl, benziodoxole, N‐Boc‐indolyl, and benzothienyl, furnishing the corresponding heterocyclic ɑ‐sulfone aminothioether derivatives 16–21 effectively. The reaction was not restricted to arylamide‐substituted cyclopropanes and various alkyl groups bearing diverse functional motifs were also compatible. Notably, a hallmark of this transformation is its exquisite chemoselectivity. When dicyclopropylamide 1t was subjected to the standard conditions, transformation occurred exclusively at the electron‐rich cyclopropane moiety. Even more significantly, for substrates 1ae‐1ag featuring alkenyl or alkynyl functionalities, the transformation exclusively targeted the strained C─C σ‐bond, leaving the C─C π‐bonds intact. Furthermore, the protocol proved applicable to tert‐butyl carbamates cyclopropane 1ah, yielding a product that could be deprotected to access the free amine. Regarding substitution patterns, vicinally substituted cyclopropanes 1ai‐1ak are all converted to their corresponding thiosulfonylation products 37–39 in yields of up to 75%. Conversely, 1,1‐disubstituted cyclopropylamides were unreactive, presumably due to prohibitive steric hindrance. In a notable example of structural diversity, the bicyclic amide 1al underwent transformation to yield the disubstituted 2,5‐dihydropyrrole 40 in 32% yield. Additionally, the protocol was successfully extended to cyclobutylamide 1am, enabling the efficient assembly of the 1,4‐thiosulfonylation product 41.

SCHEME 2.

Substrate scopes of cycloalkylamides.

To underscore the robustness and synthetic utility of this protocol, we applied it to the late‐stage functionalization of complex bioactive molecules (Scheme 2, bottom). A diverse array of cyclopropylamides derived from Isoxepac (1an), Fenbufen (1ao), Oxaprozin (1ap), 2‐Propylpentanoic acid (1aq), Febuxostat (1ar), Naproxen (1as), Ibuprofen (1at), Dehydroabietic acid (1au), Diflunisal (1av), and Adapalene (1aw) proved amenable to the reaction conditions. Consequently, the corresponding pharmaceutical analogues 42–51 were accessed in moderate‐to‐good yields. These successful transformations attest to the exceptional functional group compatibility of the method and highlight its potential for the rapid structural diversification of pharmaceutical scaffolds. It should be noted that higher‐order cyclic amides (cyclopentylamide and cyclohexylamide) failed to afford the desired product, likely due to the lack of sufficient ring strain. Moreover, arylcyclopropanes and cyclopropyl phenyl ketone also exhibited no reactivity under the current reaction conditions.

The scope of the reaction was next evaluated with respect to the thiosulfonating reagents (Scheme 3). The protocol demonstrated remarkable robustness, accommodating both symmetrical and unsymmetrical S‐phenyl benzenesulfonothioates regardless of the electronic nature or position of substituents on the aryl ring. Heteroaryl‐containing thiosulfonates were successful under the current conditions, delivering the corresponding products 56–58 with yields in the range of 53%–79%. Notably, while S‐alkyl arenethiosulfonates are typically challenging in visible light photocatalysis, they proceeded smoothly under these conditions, tolerating functional groups such as chlorides, ethers, and nitriles. The synthetic utility of the method was further underscored by the preparation of deuterated analog 2o using an S‐methyl‐d₃ reagent. Furthermore, privileged pharmacophores, including trifluoromethylthio (─SCF₃) and seleno (─Se) groups, were efficiently installed employing S‐(fluoroalkyl) thiosulfonates 2p and sulfonoselenoates 2q‐2s, respectively. Beyond the arylthiosulfonates, the alkylthiosulfonates 2ab‐2ae are also amenable to this transformation, delivering the corresponding products 70–72 in moderate‐to‐good yields. The electron‐ deficient thiosulfonate 2p was also compatible, affording the product 73 in acceptable yield. Perhaps most remarkably, this strategy enabled the modular assembly of di‐ and trisulfur‐functionalized ɑ‐amidosulfones. By utilizing di‐ and trithiosulfonates (R¹SO₂S _n R², n = 2, 3), medicinally relevant polysulfide motifs were introduced in an atom‐economical manner, affording products 74–79 in good yields.

SCHEME 3.

Substrate scopes of thio(seleno)sulfonates.

Recognizing that ɑ‐amidoalkylphenyl sulfones serve as versatile precursors to reactive N‐acylimines, we explored the one‐pot diversification of thiosulfonylation product 3 with external nucleophiles (Scheme 4). Treatment with various Grignard reagents facilitated smooth arylation, alkylation, and alkenylation, delivering the corresponding derivatives 80–82 in excellent yields. Other stabilized carbanions (cyano group and nitromethane) could be readily introduced at the vicinal position of the amide. Furthermore, Friedel–Crafts reaction with electron‐rich arenes (1‐naphthol and 3‐methly indole) proceeded with high regiocontrol, yielding the C2‐functionalized adducts 85 and 86, respectively. Except carbon nucleophiles, diverse heteroatom‐based nucleophiles were also well‐compatible. Oxygen nucleophiles, including methanol and water, afforded the α‐hydroxyl and α‐methoxylaminothioether 87–88 in 65%–85% yields, while selective reduction was efficiently accomplished using NaBH₄ (89). Moreover, substitution with thiophenols furnished unsymmetric 1,3‐dithioethers 90. N,N‐acetals 91–92 can be easily accessed with nitrogen nucleophiles. Collectively, these transformations demonstrate that our protocol serves as a modular platform for accessing structurally diverse and highly functionalized aminothioethers, which are challenging to access through conventional methods.

SCHEME 4.

One‐pot ring‐opening/nucleophilic substitutions.

Building on our success in the 1,3‐thiosulfonylation of mono‐donor cyclopropanes, we sought to address the more challenging asymmetric variant. Initial systematic screenings indicated that the combination of chiral phosphoric acid (CPA) L5 and DCM delivered product 93 with a promising enantiocontrol (Table 1a and details see Tables S6 and S7). Interestingly, reaction monitoring revealed a gradual erosion of enantiomeric excess (ee) with increasing conversion, presumably due to acid‐mediated racemization of 93 (Table 1b). We hypothesized that attenuating the catalyst acidity via the formation of chiral metal phosphates would suppress this deleterious pathway [54, 55, 56]. Indeed, evaluation of various chiral phosphate salts revealed that the bidentate Mg²⁺‐phosphate complex L9 afforded the target product in 83% yield with 85% ee. The addition of 4 Å molecular sieves further enhanced efficiency and enantioselectivity (91% yield, 92% ee). Control experiment with catalyst L9 showed no erosion of enantiopurity over the course of the reaction (Table 1c). In contrast, either chiral CPA L5 or a protonic acid led to a decrease in enantiopurity (Figure S7).

TABLE 1.

Optimization of asymmetric 1,3‐thiosulfonylation reaction.

.

Subsequently, we investigated the generality of this enantioselective transformation with respect to both cyclopropane and thiosulfonate partners (Scheme 5) The catalytic system exhibited broad tolerance toward diverse electronic environments, effectively accommodating cyclopropylamides bearing either electron‐withdrawing or electron‐donating phenyl substituents with outstanding high enantioselectivities (81%–92% ee). The scope was also successfully extended to alkyl‐substituted amides. Notably, increasing the steric bulk of the amide groups resulted in enhanced enantiocontrol, ranging from 83–94% ee (103‐107). The absolute configuration of desired product 104 was unambiguously determined by x‐ray crystallographic studies, and all other products were assigned by analogy [57]. Additionally, the chiral δ‐thio‐α‐amidoalkylphenyl sulfone derivative 111 was obtained with high enantiopurity. Furthermore, a diverse array of unsymmetrical thiosulfonate, selenosulfonates, dithiosulfonates, even trithiosulfonates with different substituent groups proved amenable to this transformation, affording the corresponding chiral targets 112–123 with excellent enantiocontrol (85%–96% ee). Finally, to demonstrate synthetic utility, selective oxidation of 97 yielded the sulfoxide 124 and disulfone 125 with complete retention of enantiomeric purity.

SCHEME 5.

Asymmetric thiosulfonylation of aminocyclopropanes.

The high nucleofugality of the RSO₂ group typically promotes E2‐type elimination [52], making the preservation of stereochemical integrity at newly formed chiral centers a formidable synthetic challenge. Consequently, successful stereoretentive substitutions of these substrates remain unprecedented. Overcoming this limitation requires a judiciously selected nucleophile that outcompetes competitive deprotonation in favor of an SN2‐type pathway [58]. While evaluations of various organometallic reagents and strong nucleophiles uniformly resulted in complete racemization, we remarkably discovered that sodium thiophenolate uniquely enables the desired 1,3‐disulfidation, affording 129 with absolute retention of enantiopurity (Scheme 6 and Table S9).

SCHEME 6.

Representative examples of chirality transfer.

To elucidate the reaction mechanism, we conducted a series of control experiments (Scheme 7). First, the addition of the radical scavenger 2,2,6,6‐tetramethylpiperidinooxy (TEMPO) to the standard reaction completely suppressed the desired transformation. Furthermore, a TEMPO‐trapped adduct was detected via HRMS analysis, strongly corroborating the radical nature of the process (Scheme 7a). Evidence for a carbon‐centered radical intermediate was further provided by the reaction of vinyl‐cyclopropane 1ax, which yielded the ring‐opened 1,5‐thiosulfonylation product (Scheme 7b). In contrast, N‐methyl cyclopropylamide 1ay failed to deliver the desired product, likely due to the kinetically slower rate of ring opening associated with the removal of the amide proton [59]. The Stern–Volmer luminescence quenching studies indicated that the excited state of the photocatalyst is effectively quenched by cyclopropylamide 1a, supporting a reductive quenching pathway (Scheme 7c). Additionally, the on/off experiment revealed that the reaction was halted in the absence of light and resumed once illumination was restored, indicating that light is essential for the reaction to proceed. Furthermore, the photochemical quantum yield (Φ = 0.60) of the reaction could partially exclude the propagative mechanistic pathway (Scheme 7e) [60, 61]. Based on these results and literature precedence [34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48], a speculative reaction mechanism is proposed (Scheme 7f). Initially, the excited photocatalyst (*PC) undergoes single‐electron transfer (SET) with cyclopropylamide 1a, resulting in the reductive quenching of the catalyst to form reductive species PC¯ and the corresponding amide radical cation. Subsequent spontaneous β‐scission affords the radical cation intermediate II. This carbon‐centered radical likely reacts with the thiosulfonate via an SH2 (bimolecular homolytic substitution) pathway [62], installing the thio‐group with concomitant release of a sulfonyl radical. Alternatively, a pathway involving the coupling of radical intermediate II with disulfides, potentially generated in situ via PC* induced energy transfer (EnT), cannot be entirely ruled out at this stage [63, 64]. Finally, the sulfonyl radical undergoes SET reduction by the reduced photocatalyst to generate the corresponding sulfinate nucleophile. This species then engages in an asymmetric nucleophilic attack on the iminium ion, mediated by the chiral metal phosphate, to furnish the stereoselective sulfonylation product. Although a detailed mechanism has yet to be elucidated, we propose an enantiocontrol model for the chiral induction, highlighting the bifunctional role of the chiral magnesium phosphate in simultaneously activating both the nucleophile and the electrophile (see Figure S6). The mono‐liganded (S)‐TS‐1 or bidentate (S)‐TS‐2 conformations exhibit greater steric hindrance between the bulky ⁱ Pr group and the iminium moiety compared to their (R)‐counterparts [65, 66]. Furthermore, the coordination of the substrate carbonyl group to the metal center provides additional stabilization to the (R)‐transition states, ultimately favoring the formation of (R)‐93. This stereochemical model is in fully agreement with both the absolute configuration and the high levels of enantioselectivity observed experimentally.

SCHEME 7.

Mechanism studies.

3. Conclusion

In summary, we have developed a novel photocatalytic strategy for the chemo‐ and stereoselective 1,3‐thiosulfonylation of mono‐donor cyclopropanes. By transcending the conventional reliance on high‐strain propellane systems for C─C bond thiosulfonylation, this protocol offers a robust platform that operates under mild conditions with exquisite chemoselectivity. A pivotal advance of this work is the realization of the first asymmetric variant of this transformation, enabling streamlined access to synthetically challenging chiral γ‐thio‐ɑ‐aminosulfones and polysulfide motifs with high enantiopurity. The synthetic utility of this method is further underscored by its amenability to the late‐stage functionalization of complex bioactive molecules and the versatile downstream diversification of the products. Ultimately, this study not only fills a critical gap in radical‐mediated asymmetric thiosulfonylation of cyclopropylamides, but also achieves the first example of chirality transfer involving aminosulfones.

Author Contributions

Lebin Qian: methodology, investigation, formal analysis, data curation. Yi Wang: methodology, investigation, formal analysis, data curation. Lei Zhu: data curation. Xiaotian Qi: data curation. Xinjun Luan: project administration. Zhijun Zuo: conceptualization, project administration, writing – original draft, writing – review and editing.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Supporting File 1: anie72833‐sup‐0001‐SuppMat.pdf.

Supporting File 2: anie72833‐sup‐0002‐cif.zip.

Dedicated to Professor Barry M. Trost on the occasion of his 85th birthday.

Data Availability Statement

The data that support the findings of this study are available in the Supporting Information of this article.