Copper(I)-catalyzed sulfonylation of (2-alkynylaryl)boronic acids with DABSO

Runyu Mao a, Danqing Zheng a, Hongguang Xia *b and Jie Wu *ac
aDepartment of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China. E-mail: jie_wu@fudan.edu.cn
bDepartment of Biochemistry and Molecular Biology, Zhejiang University School of Medicine, Hangzhou 310058, China. E-mail: hongguangxia@zju.edu.cn
cState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China

Received 17th February 2016 , Accepted 19th March 2016

First published on 21st March 2016


The scaffold of benzo[b]thiophene 1,1-dioxides can be easily constructed through a copper(I)-catalyzed insertion of sulfur dioxide into (2-alkynylaryl)boronic acids. The reaction proceeds in the presence of 10 mol% copper(I) acetate in DMF at 100 °C with high efficiency, leading to benzo[b]thiophene 1,1-dioxides in good to excellent yields. The sulfonyl group can be easily introduced via insertion of sulfur dioxide and the subsequent intramolecular 5-endo cyclization affords the core of benzo[b]thiophene 1,1-dioxide.


It is well known that sulfones are widely present in pharmaceutical and agrochemical molecules.1,2 Among cyclic sulfonyl compounds, the scaffold of benzo[b]thiophene 1,1-dioxide has attracted much attention. It was reported that a benzo[b]thiophene 1,1-dioxide derivative could act as an absorbance and fluorescence switch, leading to a multi-addressable system in the presence of ions, protons and light.3 Additionally, compounds with the benzo[b]thiophene 1,1-dioxide core have been applied in the drug discovery process as inhibitors of hepatitis C virus NS5B polymerase, as well as carbonic anhydrase inhibitors for the inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes.4 Moreover, benzo[b]thiophene 1,1-dioxides are useful synthons for the generation of complex molecules in organic synthesis.5 Therefore, it is highly desirable to provide efficient routes to diverse benzo[b]thiophene 1,1-dioxides.

Introduction of the sulfonyl unit into small molecules via insertion of sulfur dioxide is promising and attractive in organic synthesis, due to the enormous scale of annual production.6 In the past few years, much attention has been paid to this area, and advancements in the insertion of sulfur dioxide into small molecules have been witnessed.7–10 For instance, transition-metal-catalyzed or metal-free aminosulfonylation via a three-component reaction of aryl electrophiles, sulfur dioxide and hydrazines could afford N-aminosulfonamides.8a,j In most cases, DABCO-bis(sulfur dioxide) (DABSO) was used as the source of sulfur dioxide. This reagent was developed by Willis and co-workers to solve the handling problem of toxic gaseous sulfur dioxide.8a Sulfones could be generated through the reaction of organometallic reagents (such as Grignard reagents, organolithium reagents, organosilane reagents, organoboronic acids, and organozinc reagents) with sulfur dioxide and various electrophiles.9,10 For example, Toste and co-workers described the synthesis of sulfones through a gold(I)-catalyzed sulfination of arylboronic acids via insertion of sulfur dioxide.10c Willis subsequently reported a similar result using a palladium catalyst in the transformation.10d During the reaction process, a metal sulfinate was believed to be the key intermediate, which was generated via coupling of the arylboronic acid with sulfur dioxide. This intermediate then acted as a nucleophile to react with an electrophile (such as an alkyl halide, epoxide, or aryliodonium salt), providing the corresponding sulfones. Prompted by these results, we envisioned that benzo[b]thiophene 1,1-dioxides could be produced via the reaction of (2-alkynylaryl)boronic acids 1 with sulfur dioxide under appropriate conditions (Scheme 1). We conceived that the metal catalyst would play a dual role by (1) promoting the coupling of the arylboronic acid with sulfur dioxide to afford the metal sulfinate, and (2) activating the triple bond of the alkyne, thus facilitating the intramolecular attack of the metal sulfinate on the alkyne. Although benzo[b]thiophene 1,1-dioxides could also be generated from the reaction of 2-alkynylaryldiazonium tetrafluoroborates with sulfur dioxide in the presence of morpholin-4-amine,8m the advantages of the proposed route are obvious: (1) it avoids the utilization of 2-alkynylaryldiazonium tetrafluoroborates as starting materials, which are unstable and unsuitable for storage; and (2) it avoids the use of large amounts of morpholin-4-amine, which is much more atom economic.


image file: c6qo00070c-s1.tif
Scheme 1 Proposed route to benzo[b]thiophene 1,1-dioxides via insertion of sulfur dioxide.

Due to its operational ease and availability, DABCO·(SO2)2 (DABSO) was selected as the source of sulfur dioxide.7 So far, bench-stable solid DABSO has been widely utilized as a source of sulfur dioxide. Encouraged by recent advancements in the insertion of sulfur dioxide, we therefore started to explore the practicability of the projected route as shown in Scheme 1.

Initially, the reaction of (2-(p-tolylethynyl)phenyl)boronic acid 1a with DABSO was selected as the model for reaction development (Table 1). As mentioned above, it was anticipated that the metal catalyst would play a dual role of promoting the coupling of the arylboronic acid with sulfur dioxide as well as activating the triple bond of the alkyne. Thus, palladium salt was used as the catalyst at the outset. To our surprise, the desired product 2a was not detected when the reaction was catalyzed by 10 mol% palladium acetate in the presence of sodium acetate in 1,4-dioxane at 80 °C (Table 1, entry 1). Since the power of cooperative catalysis has been demonstrated,11 copper(I) bromide was added to the catalytic system with the expectation that it might promote the transformation (Table 1, entry 2). However, the result was the same. A similar result was observed when the solvent was changed to toluene or 1,2-dichloroethane (Table 1, entries 3 and 4). To our delight, the corresponding benzo[b]thiophene 1,1-dioxide 2a was obtained in 19% yield when the reaction was carried out in acetonitrile (Table 1, entry 5). Gratifyingly, the yield of product 2a was increased to 43% when DMF was used as the solvent (Table 1, entry 6). An inferior result was observed when the reaction temperature was changed to 60 °C (Table 1, entry 7). A better yield was obtained when the reaction was performed at 100 °C (Table 1, entry 8). The benzo[b]thiophene 1,1-dioxide 2a was isolated in 20% yield when palladium acetate was replaced by palladium chloride (Table 1, entry 9). Interestingly, a 64% yield of 2a was obtained in a control experiment without the addition of palladium catalyst (Table 1, entry 10). This result means that the copper catalyst is effective for the coupling of arylboronic acid with sulfur dioxide and meanwhile could activate the triple bond of the alkyne to facilitate the subsequent intramolecular 5-endo cyclization. We further screened other bases in this reaction. A similar yield was obtained when potassium acetate was used as a base (Table 1, entry 11). The yield could not be improved when potassium carbonate or sodium carbonate were employed (Table 1, entries 12 and 13). Since DMF could be regarded as a strong Lewis base, a control experiment was performed in the absence of base (Table 1, entry 14). Interestingly, the corresponding product 2a was generated without loss of yield (66%). We subsequently surveyed other copper catalysts. It was found that copper(I) acetate was the best choice (Table 1, entries 15–18), leading to the expected product in 75% yield. A similar yield was obtained when the amount of DABSO was decreased to 0.7 equivalents (Table 1, entry 19). To our delight, the desired product 2a was afforded in 91% yield when 2.0 equivalents of DABCO·(SO2)2 were employed in the reaction (Table 1, entry 20).

Table 1 Initial studies for the reaction of (2-(p-tolylethynyl)phenyl)boronic acid 1a with DABSOa

image file: c6qo00070c-u1.tif

Entry [M] Base Solvent T (°C) Yieldb (%)
a Reaction conditions: (2-(p-tolylethynyl)phenyl)boronic acid 1a (0.2 mmol), DABSO (0.2 mmol), palladium catalyst (10 mol%), copper catalyst (10 mol%), base (1.5 equiv.), solvent (2.0 mL), N2. b Isolated yield based on (2-(p-tolylethynyl)phenyl)boronic acid 1a. c In the presence of 0.7 equivalents of DABSO. d In the presence of 2.0 equivalents of DABSO.
1 Pd(OAc)2 NaOAc Dioxane 80 n.d.
2 Pd(OAc)2/CuBr NaOAc Dioxane 80 n.d.
3 Pd(OAc)2/CuBr NaOAc PhMe 80 n.d.
4 Pd(OAc)2/CuBr NaOAc DCE 80 n.d.
5 Pd(OAc)2/CuBr NaOAc MeCN 80 19
6 Pd(OAc)2/CuBr NaOAc DMF 80 43
7 Pd(OAc)2/CuBr NaOAc DMF 60 37
8 Pd(OAc)2/CuBr NaOAc DMF 100 55
9 PdCl2/CuBr NaOAc DMF 100 20
10 CuBr NaOAc DMF 100 64
11 CuBr KOAc DMF 100 60
12 CuBr K2CO3 DMF 100 51
13 CuBr Na2CO3 DMF 100 54
14 CuBr DMF 100 66
15 CuCl DMF 100 61
16 Cu2O DMF 100 45
17 CuOAc DMF 100 75
18 Cu(OAc)2 DMF 100 56
19c CuOAc DMF 100 73
20d CuOAc DMF 100 91


The scope of the sulfonylation reaction of (2-alkynylaryl)boronic acids 1 with DABSO was then investigated under the above optimized reaction conditions (10 mol% copper(I) acetate, DMF, 100 °C). The results are shown in Table 2. A range of (2-alkynylaryl)boronic acids 1 were coupled with DABSO efficiently, leading to the corresponding benzo[b]thiophene 1,1-dioxides 2 in good to excellent yields. (2-Alkynylaryl)boronic acids 1 bearing electron-donating or electron-withdrawing groups on the aromatic ring were all good partners for the reaction with sulfur dioxide under the standard conditions. For instance, fluoro-substituted benzo[b]thiophene 1,1-dioxide 2l was generated in 95% yield. (2-Alkynylaryl)boronic acids 1 bearing different substituents attached to the triple bond were examined as well, and reacted efficiently to afford the corresponding products. The substituents included aryl, alkyl, and heterocyclic groups. For example, the reaction of thiophenyl-substituted (2-alkynylaryl)boronic acid provided the desired product 2h in 63% yield. It was noteworthy that the presence of a sulfur atom in the thiophenyl group did not deactivate the copper(I) catalyst.

Table 2 Scope investigation of the sulfonylation reaction of (2-alkynylaryl)boronic acids 1 with DABSOa,b
a Reaction conditions: CuOAc (10 mol%), (2-alkynylaryl)boronic acid 1 (0.2 mmol), DABSO (0.4 mmol), DMF (2.0 mL), 100 °C. b Isolated yield based on (2-alkynylaryl)boronic acid 1.
image file: c6qo00070c-u2.tif


A plausible mechanism was proposed, as shown in Scheme 2. We reasoned that a transmetallation of (2-alkynylaryl)boronic acid 1 with the copper catalyst would occur first, which would afford the intermediate A. Then, sulfur dioxide would be incorporated, leading to intermediate B. In the meantime, the presence of copper catalyst would activate the triple bond of intermediate B, which would then facilitate the subsequent intramolecular 5-endo cyclization to produce the corresponding benzo[b]thiophene 1,1-dioxide 2.


image file: c6qo00070c-s2.tif
Scheme 2 A plausible mechanism for the sulfonylation reaction of (2-alkynylaryl)boronic acids 1 with DABSO.

In conclusion, we have described a facile route to benzo[b]thiophene 1,1-dioxides via a copper(I)-catalyzed insertion of sulfur dioxide into (2-alkynylaryl)boronic acids. The reaction proceeds in the presence of 10 mol% copper(I) acetate in DMF at 100 °C with high efficiency, leading to benzo[b]thiophene 1,1-dioxides in good to excellent yields. The sulfonyl group could be easily introduced with the formation of the benzo[b]thiophene 1,1-dioxide scaffold via insertion of sulfur dioxide and intramolecular 5-endo cyclization.

Financial support from the National Natural Science Foundation of China (no. 21372046 and 21532001) is gratefully acknowledged.

Notes and references

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Footnote

Electronic supplementary information (ESI) available. See DOI: 10.1039/c6qo00070c

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