Preparation of Unsymmetrical Disulfides via Catalytic Lewis Base Activation of N‑(Organodithio)phthalimides

Hibiki Ohno; Yuzuki Takami; Kazuya Kanemoto

doi:10.1021/acs.joc.5c03056

. 2026 Jan 19;91(4):1817–1822. doi: 10.1021/acs.joc.5c03056

Preparation of Unsymmetrical Disulfides via Catalytic Lewis Base Activation of N‑(Organodithio)phthalimides

Hibiki Ohno ^†, Yuzuki Takami ^†, Kazuya Kanemoto ^†,^‡,^*

PMCID: PMC12865762 PMID: 41549768

Abstract

N-(Organodithio)phthalimides have attracted significant attention as versatile disulfide transfer reagents, but their applications have been largely limited to substitution reactions with highly reactive nucleophiles. We report a Lewis base–catalyzed activation strategy that expands the scope of N-(organodithio)phthalimides to the bifunctionalization of less reactive olefins. Nucleophile-tethered olefins undergo smooth cyclization to furnish heterocycle-appended disulfides. With broad substrate scope and the ready availability of N-(organodithio)phthalimides from bilateral reagents, this strategy enables modular construction of unsymmetrical disulfides.

Introduction

Disulfide-containing compounds play important roles − in medicinal chemistry, food chemistry, and materials science. For example, they are found in a variety of bioactive natural products, , including metabolites of marine organisms and Allium species, and have garnered increasing attention in the development of small-molecule drugs and food additives. In medicinal chemistry, disulfide bonds are also employed in peptide-based drug design to construct cyclic structures that enhance potency, selectivity, and metabolic stability. Moreover, disulfide bonds are widely used as cleavable linkers in antibody–drug conjugates (ADCs), small molecule–drug conjugates (SMDCs), and prodrugs for drug delivery. In materials science, disulfide compounds have recently attracted attention for their potential applications in lithium-ion batteries. ^b

Despite the broad utility of disulfide bonds, the selective synthesis of unsymmetrical disulfides remains challenging due to the low selectivity of conventional methods, such as thiol oxidation or substitution reactions of thiols with sulfur electrophiles, which often entail the formation of undesired symmetrical disulfides. In this context, electrophilic disulfurating reagents − such as organoalkoxy disulfides, organodithiosulfonates, and N-(organodithio)phthalimides , have attracted considerable attention. Among them, N-organodithiophthalimides are particularly valuable owing to their excellent stability and resistance to sulfur extrusion, especially in contrast to the low thermal stability of organoalkoxy disulfides and the limited structural diversity and high susceptibility to desulfuration of organodithiosulfonates. ,, Moreover, N-(organodithio)phthalimides are readily accessible from bilateral platform reagents such as N,N′-thiobis(phthalimide) , or N-(morpholine-4-dithio)phthalimide with sulfur or carbon nucleophiles (Figure A).

Background of this work. (A) Synthesis and transformations of N-(organodithio)phthalimides. (B) Reaction modes of N-(organodithio)phthalimides. (C) This work: Lewis base activation for disulfuration of unreactive nucleophiles.

Owing to their versatility, various transformations of N-(organodithio)phthalimides have been developed; however, these have been largely limited to substitution with highly reactive nucleophiles, such as stabilized enolates, amines, and organometallic intermediates (Figure B(a)). Recently, Pan et al. reported that Lewis acid activation of N-(organodithio)phthalimides enables electrophilic aromatic substitution with indoles, and we also demonstrated their reactivity toward otherwise unreactive aniline derivatives (Figure B(b)). However, reactions involving unreactive substrates such as olefins have not yet been reported. Moreover, these transformations have so far been restricted to simple substitution reactions, and the bifunctionalization of relatively unreactive olefin nucleophiles remains unexplored (Figure B(c)). ,

To address the aforementioned gap in the transformation of N-(organodithio)phthalimides, we have developed a new strategy for their activation using a Lewis base catalyst (Figure C). This method enables the transformation of olefins with N-(organodithio)phthalimides to afford bifunctionalized products. Although the thiolation of unreactive olefins through activation of thiophthalimide moieties with Lewis base catalysts has been explored over the past decade for monosulfide synthesis, the translation of this strategy to N-(organodithio)phthalimides has remained unachieved, primarily due to the challenge of selectively activating one sulfur atom over the other, which often leads to undesired monosulfide byproducts. Furthermore, since N-(organodithio)phthalimides can be readily prepared from bilateral disulfurating reagents, this strategy allows for the modular and divergent construction of heterocycle-containing unsymmetrical disulfides.

Results and Discussion

At the outset of this study, we explored the reaction conditions for the cyclization accompanied by disulfide installation of N-(tert-butyldithio)phthalimide (1a) with 4-phenyl-4-penten-1-ol (2a) (Table ). When the reaction was performed in the presence of a catalytic amount of tetrahydrothiophene (THT; cat. 1) in CH₂Cl₂ at 0 °C for 2 h, no reaction occurred (entry 1). In contrast, the desired dithioetherification product 3a was obtained in 39% yield when trifluoroacetic acid (TFA, 1 equiv) was used as an activator (entry 2). However, the reaction was not straightforward, giving rise to various byproducts, including a desulfurated compound. The use of other acid activators such as acetic acid, methanesulfonic acid, and BF₃·Et₂O did not yield the desired product (entries 3 to 5). Notably, switching the solvent to hexafluoroisopropanol (HFIP) led to a significant improvement, affording 3a in 91% yield without the use of an acid activator (entry 6). In contrast, the use of trifluoroethanol (TFE) resulted in a lower yield of 3a (entry 7). Other cyclic sulfide catalysts such as 2-methyl THT (cat. 2) and tetrahydrothiopyran (cat. 3) also afforded the desired product in excellent yields (entries 8 and 9). In contrast, other Lewis bases such as hexamethylphosphoric triamide (HMPA; cat. 4), hexamethylphosphorothioic triamide (cat. 5), hexamethylphosphoroselenoic triamide (cat. 6), diphenyl disulfide (cat. 7), and diphenyl diselenide (cat. 8) resulted in lower yields of 3a or no reaction (entries 10 to 14).

1. Optimization of Reaction Conditions .

entry	solvent	additive	cat.	yield (%)
1	CH₂Cl₂	–	1	NR
2	CH₂Cl₂	TFA	1	39
3	CH₂Cl₂	AcOH	1	NR
4	CH₂Cl₂	MsOH	1	ND
5	CH₂Cl₂	BF₃·Et₂O	1	ND
6	HFIP	–	1	91
7	TFE	–	1	20
8	HFIP	–	2	93 (85)
9	HFIP	–	3	90
10	HFIP	–	4	NR
11	HFIP	–	5	30
12	HFIP	–	6	7
13	HFIP	–	7	NR
14	HFIP	–	8	NR

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Reaction conditions: 1a (0.05 mmol), 2a (1.5 equiv), LB cat. (20 mol %), additive (1.0 equiv), solvent (0.5 mL), rt, 2 h.

Yields were determined by ¹H NMR analysis using 1,1,2,2-tetrachloroethane as an internal standard.

Reaction was conducted at 0 °C.

Isolated yield. NR: no reaction.

The optimized conditions for the cyclization (Table , entry 8) were successfully applied to a broad range of nucleophile-tethered olefins (2) (Figure A). Olefins bearing hydroxy groups underwent smooth dithioetherification to afford the corresponding cyclic ethers. The use of (E)-5-phenyl-4-penten-1-ol (2b) furnished cyclic ether 3b with exclusive trans-selectivity. Phenol-based hydroxy groups were also well tolerated, delivering 3c and 3d in good yields. This reaction was also applicable to carboxylic acid-appended olefins for the construction of lactone rings. The use of 4-phenyl-4-pentenoic acid (2e) and 5-phenylhex-5-enoic acid (2f) provided the corresponding five- and six-membered lactones 3e and 3f in excellent yields, respectively. Notably, the synthesis of 3e was successfully scaled up to 2 mmol, delivering 96% yield, demonstrating the robustness of this method. Likewise, 4-methylpent-4-enoic acid (2g) underwent smooth dithiolactonization to afford the desired product 3g in excellent yield. Furthermore, nitrogen-based nucleophiles enabled access to the pyrrolidine and pyrrolidone-substituted disulfides 3h and 3i in high yields. Notably, 3d and 3i were each obtained as a single diastereomer. An electron-rich arene was also successfully employed as a nucleophilic moiety in this cyclization reaction, affording the corresponding carbocycle-appended disulfide 3j in excellent yield.

Cyclization reaction of various N-(organodithio)phthalimides 1 with olefins 2. (A) Scope of the olefins 2. (B) Scope of the N-(organodithio)phthalimides 1. Reaction conditions: 1 (0.05 mmol), 2 (1.5 equiv), 2-methyl THT (20 mol %), HFIP (0.5 mL), rt, 2 h. Isolated yields are shown.

Various N-(organodithio)phthalimides (1) were demonstrated to participate in the dithiolactonization reaction with 4-phenyl-4-pentenoic acid (2e) (Figure B). The reaction of N-(4-methoxybenzyldithio)phthalimide (1b) afforded the desired lactone 3k in good yield. In addition to the alkyl-substituted N-(organodithio)phthalimides, aryl-substituted analogues were also well tolerated. Both electron-donating and electron-withdrawing groups at the para-position of the aryl ring did not significantly affect the reaction, furnishing the desired lactone-containing disulfides 3m–3o in high yields. Notably, N-(2-naphthyldithio)phthalimide (1g) also delivered the desired product 3p in quantitative yield.

The reaction conditions are applicable not only to simple cyclization reactions but also to cascade transformations (Figure ). The polyene cyclization of (E)-2-geranylphenol (4) with N-(phenyldithio)phthalimide (1c) proceeded efficiently to afford the tricyclic disulfide 5 as a single diastereomer. Moreover, the reaction of allyltrimethylsilane (6) (3.0 equiv) led to the formation of a double-addition product 7 in good yield. We presume that the reaction proceeds via initial addition of allyltrimethylsilane (6), generating a stabilized carbocation intermediate, followed by a second addition step.

Cascade transformations. (A) Polyene cyclization of (E)-2-geranylphenol (4). Reaction conditions: 1c (0.05 mmol), 4 (1.5 equiv), 2-methyl THT (20 mol %), HFIP (0.5 mL), rt, 2 h. (B) Double-addition reaction with allyltrimethylsilane (6). Reaction conditions: 1c (0.05 mmol), 6 (3.0 equiv), 2-methyl THT (20 mol %), HFIP (0.5 mL), rt, 2 h.

A key advantage of N-dithiophthalimide reagents (1) lies in their facile synthesis through the reaction of modular-type precursors with various nucleophiles (Figure A). This feature and successful cyclization reactions in mind, we further explored the scope of the present reaction in the context of modular synthesis of unsymmetrical disulfides (Figure ). First, N-(morpholine-4-dithio)phthalimide (8), a bilateral disulfide platform molecule we recently developed, was employed to construct a cyclic ether moiety. This was followed by the lactonization developed in this study, furnishing an unsymmetrical disulfide 10 bearing both cyclic ether and lactone moieties, which is difficult to access by the conventional methods (Figure A). Next, a disulfide bond was constructed from N,N′-thiobis(phthalimide) (11) , and protected cysteine 12, followed by dithiolactonization with 2e to afford the unsymmetrical disulfide 14 bearing both cysteine and lactone moieties (Figure B). The utility of this reaction was further demonstrated by the formal dithiohydroxylation of the carboxylic acid-appended olefin 2e. Lactonization of 2e with N-tert-butyldithiophthalimide (1a), followed by hydrolysis of the ester moiety, afforded the unsymmetrical disulfide 15 bearing both hydroxy and carboxylic acid moieties.

Synthetic utility of the cyclization reaction. (A, B) Modular synthesis of unsymmetrical disulfides. (A) Introduction of two carbon nucleophiles via two distinct cyclizations. (B) Introduction of sulfur and carbon nucleophiles. (C) Formal dithiohydroxylation of a carboxylic acid-appended olefin via dithiolactonization followed by hydrolysis. Isolated yields are shown. ^aIsoleted as a 1:1.3 mixture of diastereomers. ^bIsoleted as a 1:1 mixture of diastereomers. See the Supporting Information for detailed reaction conditions.

We conducted a preliminary investigation of the asymmetric cyclization reaction (Figure ). , The reaction of olefin 2h, bearing a nitrogen-based nucleophilic moiety in the presence of chiral Lewis base catalyst (cat. 9) developed by Denmark, afforded the pyrrolidine-substituted disulfide 3h with moderate enantioselectivity. This encouraging result provides a basis for the future development of an enantioselective variant.

Preliminary study on the asymmetric dithiocyclization reaction. Reaction conditions: 1a (0.05 mmol), 2h (1.5 equiv), cat. (20 mol %), HFIP (0.5 mL), rt, 24 h.

Conclusions

In conclusion, we have developed a Lewis base–catalyzed strategy that expands the reactivity profile of N-(organodithio)phthalimides toward olefins. The optimized conditions employing HFIP and cyclic sulfide catalysts enable efficient cyclization and cascade processes, giving rise to a wide array of hetero- and carbocycle-fused disulfides. Importantly, this approach allows modular construction of unsymmetrical disulfides from readily accessible bilateral reagents, such as N-(morpholine-4-dithio)phthalimide (8) and N,N′-thiobis(phthalimide) (11), , thus providing new opportunities for the design of bioactive molecules and functional materials. We anticipate that this strategy will not only advance the synthetic toolbox for disulfide chemistry but also inspire applications in drug discovery, linker design, and materials development.

Supplementary Material

jo5c03056_si_001.pdf^{(10.8MB, pdf)}

Acknowledgments

We thank Prof. Naohiko Yoshikai (Tohoku University) for the fruitful discussions. This study was supported by The Uehara Memorial Foundation (K.K.), the NOVARTIS Foundation (Japan) for the Promotion of Science (K.K.), the Research Foundation for Pharmaceutical Sciences (K.K.), Kobayashi Foundation (K.K.), The Noguchi Institute, the Shitagau Noguchi Research Grant (Grant Number, NJ202312 (K.K.)), Tohoku University-AIST Matching Support Program (K.K.), JSPS KAKENHI (Grant Numbers JP22K14687 (Young Scientists) and JP25K08652 (Scientific Research (C)); K.K.), JST FOREST Program (Grant Number JPMJFR2425, Japan), and Takeda Science Foundation.

The data underlying this study are available in the published article and its Supporting Information.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.5c03056.

Experimental procedures and characterization for new compounds including NMR spectra (PDF)

The authors declare no competing financial interest.

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a Matviitsuk A., Panger J. L., Denmark S. E.. Catalytic, Enantioselective Sulfenofunctionalization of Alkenes: Development and Recent Advances. Angew. Chem., Int. Ed. 2020;59:19796–19819. doi: 10.1002/anie.202005920. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Denmark S. E., Kornfilt D. J. P., Vogler T.. Catalytic Asymmetric Thiofunctionalization of Unactivated Alkenes. J. Am. Chem. Soc. 2011;133:15308–15311. doi: 10.1021/ja2064395. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Ke Z., Tan C. K., Chen F., Yeung Y.-Y.. Catalytic Asymmetric Bromoetherification and Desymmetrization of Olefinic 1,3-Diols with C2-Symmetric Sulfides. J. Am. Chem. Soc. 2014;136:5627–5630. doi: 10.1021/ja5029155. [DOI] [PubMed] [Google Scholar]; d Liu X., An R., Zhang X., Luo J., Zhao X.. Enantioselective Trifluoromethylthiolating Lactonization Catalyzed by an Indane-Based Chiral Sulfide. Angew. Chem., Int. Ed. 2016;55:5846–5850. doi: 10.1002/anie.201601713. [DOI] [PubMed] [Google Scholar]; e Tao Z., Robb K. A., Zhao K., Denmark S. E.. Enantioselective, Lewis Base-Catalyzed Sulfenocyclization of Polyenes. J. Am. Chem. Soc. 2018;140:3569–3573. doi: 10.1021/jacs.8b01660. [DOI] [PMC free article] [PubMed] [Google Scholar]; f Liang Y., Zhao X.. Enantioselective Construction of Chiral Sulfides via Catalytic Electrophilic Azidothiolation and Oxythiolation of N-Allyl Sulfonamides. ACS Catal. 2019;9:6896–6902. doi: 10.1021/acscatal.9b01900. [DOI] [Google Scholar]; g Matviitsuk A., Panger J. L., Denmark S. E.. Enantioselective Inter- and Intramolecular Sulfenofunctionalization of Unactivated Cyclic and (Z)-Alkenes. ACS Catal. 2022;12:7377–7385. doi: 10.1021/acscatal.2c01232. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

jo5c03056_si_001.pdf^{(10.8MB, pdf)}

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

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[ref19] Recent examples using saccharide and morpholine leaving groups:; a Huo Y.-X., Cao R.-F., Huang J., Li Z.-L., Wei Z.-W., Zhu D., Chen Z.-M.. N-(Acyldithio)Saccharin: Design, Synthesis and Applications in Catalytic Enantioselective Disulfuration/Amination of Alkenes. Angew. Chem., Int. Ed. 2025;64:e202503815. doi: 10.1002/anie.202503815. [DOI] [PubMed] [Google Scholar]; b Takami, Y. ; Kwon, E. ; Kanemoto, K. . Dithiofunctionalization: A Versatile Approach for Constructing Complex Disulfides from Alkenes and Alkynes ChemRxiv 2025. 10.26434/chemrxiv-2025-j73v9. (accessed December 25, 2025). [DOI]

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PERMALINK

Preparation of Unsymmetrical Disulfides via Catalytic Lewis Base Activation of N‑(Organodithio)phthalimides

Hibiki Ohno

Yuzuki Takami

Kazuya Kanemoto

Abstract

Introduction

1.