Abstract
Pseudocyclic arylbenziodoxaboroles are unique aryne precursors under neutral aqueous conditions that selectively react with organic sulfides, forming the corresponding sulfonium salts. This reaction is compatible with various substituents (alkyl, halogen, CN, NO2, CHO, and cyclopropyl) in the aromatic ring or alkyl group of the sulfide. Similar reactions of sulfoxides afford o-hydroxy-substituted sulfonium salts. The structures of key products were confirmed by X-ray analysis.
Benzyne and other aryne intermediates have found broad application in modern organic synthesis.1 Common benzyne precursors require activation via application of heat, irradiation, a strong base (NaNH2, BuLi, RMgBr, LiHMDS, etc.), or the anhydrous fluoride anion, which is also a strong base and requires special handling to avoid moisture. For example, the most frequently employed Kobayashi aryne precursors, o-silylaryl triflates, are usually activated by being treated with anhydrous CsF under absolutely dry conditions.1b The need for strongly basic, anhydrous conditions restricts the applicability of common benzyne precursors in some reactions. In particular, the synthetically important reactions of arynes A with organic sulfides under anhydrous basic conditions proceed via zwitterionic intermediates B, generally leading to various products of cyclization, rearrangement, or elimination but not to sulfonium salts (Scheme 1a).1d,1h
Scheme 1. Reactions of Aryne Intermediates with Organic Sulfides.
Pseudocyclic arylbenziodoxaboroles 1 are unique benzyne precursors that can be triggered under neutral or slightly acidic conditions in aqueous solutions at room temperature.2 We expected that in the reactions of arynes A with organic sulfides in the presence of water, initial zwitterionic intermediates B would be immediately protonated, resulting in the selective formation of various sulfonium salts C (Scheme 1b). It should be noted that sulfonium salts are important compounds with a wide range of applications, e.g., as acid generators in photolithography, photoinitiators in cationic polymerization, radical precursors, and cross-coupling partners in organic synthesis.3 In this Letter, we report reactions of benzyne precursors 1 with organic sulfides triggered by water in an organic solvent at room temperature that lead to the selective formation of various sulfonium salts.
Initially, we investigated reactions of reagent 1a with thioanisole 2a in various solvents at room temperature (Table 1). No product was formed when a solution of reagent 1a and sulfide 2 was stirred in dry CH2Cl2 for 3 h at room temperature (Table 1, entry 1). However, the addition of water to the reaction mixture resulted in a dramatic change, with the most effective organic solvent:water ratio being 9:1 (v/v). The reaction of reagent 1a with a small excess of thioanisole 2a in a 9:1 CH2Cl2/H2O mixed solvent produced expected sulfonium salt 3a in 80% yield after 3 h (Table 1, entry 2). The change in the reagent 1a:substrate 2a ratio to 1.2:1 further improved the yield to quantitative (Table 1, entry 3). Reducing the reaction time to 1 h decreased the yield to 79% (Table 1, entry 4). Using pure water, without any organic solvent, resulted in a 75% yield of sulfonium salt 3a under the optimized conditions (Table 1, entry 5), probably due to the low solubility of the reactants in water. Using aqueous acetonitrile resulted in a slightly lower yield (Table 1, entry 6), and several other organic solvents were less efficienct (Table 1, entries 7–13). The reactions of reagent 1a were highly regioselective, producing only m-fluoro-substituted sulfonium salt 3a, which is in agreement with previously reported electronic effects on the regioselectivity of reactions of substituted benzyne intermediates.1b
Table 1. Optimization of the Reaction Conditions.
| entry | reagent | solvent or additive | product (%)a |
|---|---|---|---|
| 1 | 1a | CH2Cl2 | –b |
| 2c | 1a | CH2Cl2/H2O (9:1) | 3a (80) |
| 3 | 1a | CH2Cl2/H2O (9:1) | 3a (quant) |
| 4d | 1a | CH2Cl2/H2O (9:1) | 3a (79) |
| 5 | 1a | H2O | 3a (75) |
| 6 | 1a | MeCN/H2O (9:1) | 3a (94) |
| 7 | 1a | Cl(CH2)2Cl/H2O (9:1) | 3a (60) |
| 8 | 1a | CHCl3/H2O (9:1) | 3a (81) |
| 9 | 1a | AcOEt/H2O (9:1) | 3a (86) |
| 10 | 1a | PhH/H2O (9:1) | 3a (64) |
| 11 | 1a | heptane/H2O (9:1) | 3a (63) |
| 12 | 1a | ether/H2O (9:1) | 3a (74) |
| 13 | 1a | MeOH/H2O (9:1) | 3a (29) |
| 14 | 1b | CH2Cl2/H2O (9:1) | 4 (trace) |
| 15 | 1b | CH2Cl2/saturated NaHCO3 (9:1) | 4 (85) |
Isolated yields of products.
Unreacted reagent 1a was recovered from the reaction mixture; product 3 was not formed.
1a:2 ratio of 1:1.2.
Reaction time of 1 h.
Compared to reagent 1a, reagent 1b is less reactive in this reaction. Only a trace amount of the corresponding product 4 was detected when a solution of reagent 1b and sulfide 2a was stirred in a 9:1 CH2Cl2/H2O mixed solvent for 3 h at room temperature (Table 1, entry 14). However, the addition of saturated aqueous NaHCO3 to the reaction mixture improved the yield to 85% (Table 1, entry 15). Considering the higher reactivity of reagent 1a, we used this reagent under the optimized conditions in our next studies.
On the basis of the results presented above (Table 1, entry 3), the preparation of various sulfonium salts 3 from sulfides 2 and reagent 1a was carried out under the optimized reaction conditions (Scheme 3). The reaction of various alkyl aryl sulfides 2 afforded the corresponding diaryl alkyl sulfonium salts 3a–m in excellent yields, demonstrating compatibility with various substituents (alkyl, halogen, CN, NO2, CHO, and cyclopropyl) in the aromatic ring or alkyl group of sulfide 2. Interestingly, the cyano and aldehyde functional groups do not react with aryne under these conditions. It is noteworthy that the reaction of phenyl ethyl sulfide with aryne generated from reagent 1a and water produced sulfonium salt 3j in quantitative yield. For comparison, the previously reported similar reaction of aryl ethyl sulfides with benzyne generated from benzenediazonium-2-carboxylate under anhydrous conditions proceeded with elimination of ethylene leading to the corresponding diaryl sulfides (ArSPh) in 90–96% yields.4 2-Chloroethyl phenyl sulfide reacts with reagent 1a to afford the product of intermolecular cyclization 3v, which is in agreement with initial zwitterionic intermediate B (Scheme 1) in this reaction. The involvement of intermediate B is also supported by the control experiment using a 9:1 CH2Cl2/D2O mixed solvent, which yielded deuterated product 5 (Scheme 2). For comparison, the reaction of 1a in a 9:1 CD2Cl2/H2O mixed solvent under the same conditions afforded exclusively nondeuterated product 3n. It should be noted that in the previously reported D-labeling experiments for the reactions of benzyne with diaryl sulfides under anhydrous conditions,5 the organic solvent (acetonitrile) was found to be the main source of the hydrogen atom in this reaction.
Scheme 3. Substrate Scope and Products (3a–v) of the Reactions of Organic Sulfides 2 with Reagent 1a,
All reactions were conducted with 0.1 mmol of sulfide 2 and 0.12–0.2 mmol of reagent 1a in dichloromethane (0.9 mL) and water (0.1 mL) under stirring.
Isolated yields of products 3.
Scheme 2. Reactions in the Presence of D2O or CD2Cl2.
To gain additional insight into the reaction mechanism, we performed a Hammett plot study of the reaction of reagent 1a with five para-substituted thioanisoles (see the Supporting Information for details). The results showed that the introduction of an electron-donating group such as methyl accelerated the reaction, while the introduction of electron-withdrawing groups such as Cl, CHO, and NO2 decelerated it. The Hammett plot showed the good correlation of the relative rate factors with σp constants and gave a reaction constant ρ of −0.65 (r = 0.98). The small negative ρ values could be consistent with the results suggesting that generated aryne species 8 are highly active electrophilic species.6
It is important to note that the reactions of diphenyl sulfide and dibenzothiophene with reagent 1a at room temperature afforded triaryl sulfonium salts 3n and 3u, respectively, in excellent yields. For comparison, the most common approach to triaryl sulfonium salts is based on the transfer of an aryl from diaryliodonium(III) salts to diaryl sulfides at 120–230 °C.7 Recently, a milder preparation of triaryl sulfonium salts using the Kobayashi aryne precursor was reported.5 However, this method works only under anhydrous conditions, and acetonitrile serves as the source of protons, as proven by the labeling experiments with CD3CN.5 The reactions of dialkyl sulfides with reagent 1a afford the respective dialkyl aryl sulfonium salts 3o–t, including cyclic sulfonium salts 3q–t. Interestingly, the reaction with 1,4-dithiane 2s selectively afforded product of monoarylation 3s, even with an excess of 1a.
The reactions of reagent 1a can be further extended to organic selenides and sulfoxides. In particular, reagent 1a reacts with Ph2Se in a 9:1 CH2Cl2/H2O mixed solvent at room temperature to give the corresponding triaryl selenonium salt in 98% yield (see product 3w in the Supporting Information). Dimethyl sulfoxide 6a or methyl phenyl sulfoxide 6b reacts with 1a under the standard conditions, forming o-hydroxy-substituted sulfonium salts 7a and 7b (Scheme 4). The structure of product 7a was confirmed by X-ray analysis. We suggest that the mechanism of this reaction involves initial nucleophilic addition of sulfoxide to aryne 8 forming zwitterionic intermediate 9 and four-membered cyclic intermediate 10 that finally reacts with water to give product 7 (Scheme 4). Note that mesityl iodide, formed as a byproduct by reductive elimination, was detected by nuclear magnetic resonance (NMR) in the reaction mixture. This mechanism is in agreement with previously reported reactions of benzyne generated from the Kobayashi precursor with diaryl sulfoxides.1e,8 The previously reported reaction of sulfoxide under aprotic conditions forms o-aryloxy arylsulfonium salts as final products via intermediates 9 and 10.8
Scheme 4. Reactions of Aryne Intermediates with Organic Sulfoxides.
Sulfonium salts 3 and 7 prepared by our procedure are potentially important products with many possible applications.3 As one of the additional applications, we have found that sulfonium salt 3a is an efficient methylating reagent in reactions with arylsulfinate anions and the carboxylate anion (see section 8 of the Supporting Information for the preparation of products 11–13).
In summary, we have demonstrated that pseudocyclic arylbenziodoxaborole 1a is a unique benzyne precursor under neutral aqueous conditions that reacts with organic sulfides, producing the corresponding sulfonium salts. This reaction is compatible with various substituents (alkyl, halogen, CN, NO2, CHO, and cyclopropyl) in the aromatic ring or alkyl group of sulfide. Sulfoxides react with reagent 1a under these conditions, forming o-hydroxy-substituted sulfonium salts 7. The structures of key products were confirmed by X-ray crystallography, and a mechanistic rationalization has been provided.
Acknowledgments
This work was supported by the National Science Foundation (CHE-2243793). A.S. is thankful for a research grant from JST CREST (JPMJCR19R2). M.S.Y. is thankful for a research grant from the Russian Science Foundation (RSF-21-73-20031).
Data Availability Statement
The data underlying this study are available in the published article and its Supporting Information.
Supporting Information Available
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.4c00197.
Experimental procedures, compound characterization data, and NMR spectra for all new compounds (PDF)
The authors declare no competing financial interest.
Supplementary Material
References
- a Tadross P. M.; Stoltz B. M. A Comprehensive History of Arynes in Natural Product Total Synthesis. Chem. Rev. 2012, 112, 3550–3577. 10.1021/cr200478h. [DOI] [PubMed] [Google Scholar]; b Shi J.; Li L.; Li Y. o-Silylaryl Triflates: A Journey of Kobayashi Aryne Precursors. Chem. Rev. 2021, 121, 3892–4044. 10.1021/acs.chemrev.0c01011. [DOI] [PubMed] [Google Scholar]; c Yang Y.; Jones C. R. The Aryne Ene Reaction. Synthesis 2022, 54, 5042–5054. 10.1055/a-1827-2987. [DOI] [Google Scholar]; d Hazarika H.; Gogoi P. Access to diverse organosulfur compounds via arynes: a comprehensive review on Kobayashi’s aryne precursor. Org. Biomol. Chem. 2021, 19, 8466–8481. 10.1039/D1OB01436F. [DOI] [PubMed] [Google Scholar]; e Neog K.; Gogoi P. Recent advances in the synthesis of organophosphorus compounds via Kobayashi’s aryne precursor: a review. Org. Biomol. Chem. 2020, 18, 9549–9561. 10.1039/D0OB01988G. [DOI] [PubMed] [Google Scholar]; f Rahman M.; Bagdi A. K.; Kopchuk D. S.; Kovalev I. S.; Zyryanov G. V.; Chupakhin O. N.; Majee A.; Hajra A. Recent advances in the synthesis of fluorinated compounds via an aryne intermediate. Org. Biomol. Chem. 2020, 18, 9562–9582. 10.1039/D0OB01638A. [DOI] [PubMed] [Google Scholar]; g Roy T.; Biju A. T. Recent advances in molecular rearrangements involving aryne intermediates. Chem. Commun. 2018, 54, 2580–2594. 10.1039/C7CC09122B. [DOI] [PubMed] [Google Scholar]; h Matsuzawa T.; Yoshida S.; Hosoya T. Recent advances in reactions between arynes and organosulfur compounds. Tetrahedron Lett. 2018, 59, 4197–4208. 10.1016/j.tetlet.2018.10.031. [DOI] [Google Scholar]; i Yoshimura A.; Saito A.; Zhdankin V. V. Iodonium Salts as Benzyne Precursors. Chem. - Eur. J. 2018, 24, 15156–15166. 10.1002/chem.201802111. [DOI] [PubMed] [Google Scholar]; k Zhu G.; Gao W.-C.; Jiang X. Rh(I)-Catalyzed Carbene Migration/Carbonylation/Cyclization: Straightforward Construction of Fully Substituted Aryne Precursors. J. Am. Chem. Soc. 2021, 143, 1334–1340. 10.1021/jacs.0c13012. [DOI] [PubMed] [Google Scholar]; l Feng M.; Tang B.; Xu H.-X.; Jiang X. Collective Synthesis of Phenanthridinone through C-H Activation Involving a Pd-Catalyzed Aryne Multicomponent Reaction. Org. Lett. 2016, 18, 4352–4355. 10.1021/acs.orglett.6b02109. [DOI] [PubMed] [Google Scholar]; m Feng M.; Tang B.; Wang N.; Xu H.-X.; Jiang X. Ligand Controlled Regiodivergent C1 Insertion on Arynes for Construction of Phenanthridinone and Acridone Alkaloids. Angew. Chem., Int. Ed. 2015, 54, 14960–14964. 10.1002/anie.201508340. [DOI] [PubMed] [Google Scholar]
- Yoshimura A.; Fuchs J. M.; Middleton K. R.; Maskaev A. V.; Rohde G. T.; Saito A.; Postnikov P. S.; Yusubov M. S.; Nemykin V. N.; Zhdankin V. V. Pseudocyclic Arylbenziodoxaboroles: Efficient Benzyne Precursors Triggered by Water at Room Temperature. Chem. - Eur. J. 2017, 23, 16738–16742. 10.1002/chem.201704393. [DOI] [PubMed] [Google Scholar]
- a Kozhushkov S. I.; Alcarazo M. Synthetic Applications of Sulfonium Salts. Eur. J. Inorg. Chem. 2020, 2020, 2486–2500. 10.1002/ejic.202000249. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Peter A.; Perry G. J. P.; Procter D. J. Radical C-C Bond Formation using Sulfonium Salts and Light. Adv. Synth. Catal. 2020, 362, 2135–2142. 10.1002/adsc.202000220. [DOI] [Google Scholar]
- Nakayama J.; Fujita T.; Hoshino M. Preparation of phenyl aryl sulfides by reaction of benzyne with ethyl aryl sulfides. Chem. Lett. 1983, 12, 249–250. 10.1246/cl.1983.249. [DOI] [Google Scholar]
- Zhang L.; Li X.; Sun Y.; Zhao W.; Luo F.; Huang X.; Lin L.; Yang Y.; Peng B. Mild synthesis of triarylsulfonium salts with arynes. Org. Biomol. Chem. 2017, 15, 7181–7189. 10.1039/C7OB01596H. [DOI] [PubMed] [Google Scholar]
- Fine Nathel N. F.; Morrill L. A.; Mayr H.; Garg N. K. Quantification of the Electrophilicity of Benzyne and Related Intermediates. J. Am. Chem. Soc. 2016, 138, 10402–10405. 10.1021/jacs.6b06216. [DOI] [PMC free article] [PubMed] [Google Scholar]
- a Takenaga N.; Yoto Y.; Hayashi T.; Miyamoto N.; Nojiri H.; Kumar R.; Dohi T. Catalytic and non-catalytic selective aryl transfer from (mesityl)iodonium(III) salts to diarylsulfide compounds. ARKIVOC 2023, 2022, 7–18. 10.24820/ark.5550190.p011.732. [DOI] [Google Scholar]; b Crivello J. V.; Lam J. H. W. A new preparation of triarylsulfonium and -selenonium salts via the copper(II)-catalyzed arylation of sulfides and selenides with diaryliodonium salts. J. Org. Chem. 1978, 43, 3055–3058. 10.1021/jo00409a027. [DOI] [Google Scholar]; c Racicot L.; Kasahara T.; Ciufolini M. A. Arylation of Diorganochalcogen Compounds with Diaryliodonium Triflates: Metal Catalysts Are Unnecessary. Org. Lett. 2014, 16, 6382–6385. 10.1021/ol503177q. [DOI] [PubMed] [Google Scholar]; d Fananas-Mastral M. Copper-Catalyzed Arylation with Diaryliodonium Salts. Synthesis 2017, 49, 1905–1930. 10.1055/s-0036-1589483. [DOI] [Google Scholar]
- Li X.; Sun Y.; Huang X.; Zhang L.; Kong L.; Peng B. Synthesis of o-Aryloxy Triarylsulfonium Salts via Aryne Insertion into Diaryl Sulfoxides. Org. Lett. 2017, 19, 838–841. 10.1021/acs.orglett.6b03840. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data underlying this study are available in the published article and its Supporting Information.