Facile Synthesis of Sulfonyl Chlorides/Bromides from Sulfonyl Hydrazides

Abstract

A simple and rapid method for efficient synthesis of sulfonyl chlorides/bromides from sulfonyl hydrazide with NXS (X = Cl or Br) and late-stage conversion to several other functional groups was described. A variety of nucleophiles could be engaged in this transformation, thus permitting the synthesis of complex sulfonamides and sulfonates. In most cases, these reactions are highly selective, simple, and clean, affording products at excellent yields.

1. Introduction

Sulfonyl chlorides are the most prevalent reagents for the installation of the sulfonyl protecting group [1], which can be converted into numerous sulfonyl derivatives [2,3,4,5,6], undergo diverse desulfitative cross-couplings [7,8], and serve as arylating agents [9,10,11,12,13]. In addition, they have been widely used as important building blocks for the manufacture of elastomers, pharmaceuticals, dyes, detergents, ion exchange resins, and herbicides [14,15,16]. Recently, they have also exhibited important applications in building synthetic receptors [17] and catalysts [18,19,20]. Given their importance in various fields, there is a strong interest in developing efficient synthetic methods for preparing them. The oxidative chlorination of thiols has been a frequently applied synthetic pathway using several combinations of oxidants and chloride sources [21,22,23,24,25,26,27,28]. In addition, chlorination with different sulfur compounds [29,30,31,32] or Grignard reactions [33] have been developed as efficient methods for the synthesis of sulfonyl chlorides. However, in the reported methods, toxic and highly corrosive reagents were required, the formation of some side products was reported, and tedious workup procedures for the isolation of the pure products were necessary. Therefore, the development of a milder and more practical method for the synthesis of sulfonyl chlorides is highly desirable. In 2017, Montelongo’s group developed an elegant strategy for the synthesis of sulfonyl chlorides and bromides by the oxidation of thiols using NCS/NBS-iPrOH as an oxyhalogenation reagent (Scheme 1a) [34]. Recently, Cornella reported highly selective conversion reactions of primary sulfonamides to the corresponding sulfonyl chlorides and fluorides using pyrylium salt as an activating reagent (Scheme 1b) [35].

Sulfonyl hydrazides are attractive targets because of their wide applications in organic synthesis, particularly in total synthesis [36]. Because of the high activity of sulfonyl chloride, they could react with hydrazine hydrate to synthesize various sulfonyl hydrazides [36]. We suspected that more stable sulfonyl hydrazides could convert to sulfonyl chloride, in which sulfonyl hydrazide can be used as a protective reagent in organic synthesis. Magnotta reported a simple strategy for the synthesis of sulfonyl bromides from sulfonyl hydrazides with bromine (Scheme 1c) [37]. This strategy represents a highly valuable synthetic tool but leaves ample opportunities to develop more green and gentle reaction systems to construct sulfonyl chlorides/bromides. Herein, we describe that the sulfonyl hydrazides react with NCS/NBS under mild reaction conditions, providing convenient and efficient access to sulfonyl chlorides/bromides (Scheme 1d).

2. Results

We commenced our study by investigating 4-methylbenzenesulfonhydrazide (1a) and a halogen source (2). Inspired by the work of Cornella, we first evaluated the reaction using MgCl₂ as the halogen source in CH₃CN at room temperature without any catalysts or additives; however, no appreciable formation of target product 3a was detected in the reaction mixture (Table 1, entry 1). Subsequent screening of a large panel of chlorides found that the use of CuCl resulted in the generation of 3a at a 38% yield (Table 1, entries 2–7). We further investigated the reactivity of organic chlorides, and the results suggested that NCS (N-chlorosuccinimide) was optimal to provide a comparable 99% yield (Table 1, entries 8–10). Furthermore, the replacement of CH₃CN with other solvents hampered product formation to various degrees (Table 1, entries 11−16). Furthermore, the replacement of NCS with NBS (N-bromosuccinimide) also smoothly provided the target product sulfonyl bromide 4a at an 87% yield (Table 1, entry 17). However, when using NIS (N-iodosuccinimide) as the substrate, the corresponding product 5a was not formed (Table 1, entry 18).

3. Discussion

With the obtained optimized reaction conditions, we explored the substrate’s scope. As shown in Scheme 2, various ortho-, meta-, and parasubstituted arylsulfonyl hydrazides, including the aryl and alkyl substitution, could react smoothly with NCS to deliver the desired products in good to excellent yields (3a–3u). The substitution in the aromatic ring of sulfonyl hydrazides, regardless of the electron-donating or electron-withdrawing groups, hardly affected the reactivity of the reaction. To our delight, the naphthyl and heterocyclic sulfonyl hydrazides, such as thiophene, also afforded the corresponding products in satisfactory yields (3p–3r). In addition, both benzylsulfonyl hydrazide and alkylsulfonyl hydrazides could undergo this process smoothly to afford the corresponding products (3s−3u) in moderate to high yields. On the other hand, NBS was subjected to the reaction under the same reaction conditions. In contrast with NCS, NBS showed relatively weak reactivity, and the corresponding sulfonyl bromide products could also be obtained in moderate to good yields (4a–4u). Unfortunately, benzylsulfonyl hydrazide was not suitable for this transformation (4s).

Having established a protocol for synthesizing highly versatile sulfonyl chlorides and considering that the importance of complex sulfonamide and sulfonates in drug discovery, we next assessed the scope of the reaction between different nucleophiles in the presence of a base in one pot. As listed in Scheme 3, both aromatic and aliphatic primary amines reacted smoothly with 1a and 2a under air, giving the corresponding sulfonamides in moderate to excellent yields (7a–7i). It was discovered that secondary alkyl amines were suitable participants (7j–7l), as along with ammonia (7m). Phenol was able to furnish corresponding sulfonate 7p at a good yield. In addition, we turned our attention to biologically active compounds bearing various functional groups embedded in their structure. Paroxetine was successfully applied in this transformation and afforded an 87% yield of the corresponding sulfonamides over two steps (7o). As we predicted, ethynyl estradiol was also compatible in sulfonate formation via a simple two-step process (7q).

To further illustrate the robustness of the protocol, we scaled up this sulfonyl chloride synthesis. Without modification of the original protocol, 6 mmol of 1a could successfully be converted to 3a at a 94% yield (Scheme 4a). By adding aniline to the above reaction system without any separation, sulfonamide 7a could be obtained at a yield of 92% (Scheme 4b).

To gain insight into the reaction mechanism, several control experiments were designed to understand the mechanism of this process. We performed experiments with the addition of the radical inhibitor TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) or BHT (butylated hydroxytoluene), and the product yield was significantly reduced in both cases (Scheme 5).

On the basis of the above results and literature, a plausible mechanism was proposed, as shown in Scheme 6. Initially, nitrogen center radical I and chlorine radical were generated from NCS [38,39,40]. Then, sulfonyl hydrazide could transfer to sulfonyl radical II with the release of nitrogen gas under oxidative conditions [38,39,40]. Finally, sulfonyl radical II went through a coupling reaction with chlorine radical to afford the final product 3.

4. Materials and Methods

4.1. General Information

NMR data were obtained for ¹H at 400 MHz and for ¹³C at 100 MHz. Chemical shifts were reported in ppm from tetramethylsilane with the solvent resonance as the internal standard in CDCl₃ solution. Column chromatography was performed on silica gel (300–400 mesh) eluting with ethyl acetate/petroleum ether. TLC was performed on glass-backed silica plates. UV light and I₂ were used to visualize products. All chemicals were used without purification as commercially available unless otherwise noted.

4.2. General Procedure for Synthesis of Sulfonyl Chloride 3 or Sulfonyl Bromide 4

N-Chlorosuccinimide 2a or N-bromosuccinimide 2b (0.6 mmol, 2.0 equiv) was added to a solution of sulfonyl hydrazide 1 (0.3 mmol) in CH₃CN (2 mL) in one portion. The mixture was stirred at room temperature for 2 h. The solvent was removed, and the residue was purified by flash column chromatography (petroleum ether/ethyl acetate) to provide the corresponding sulfonyl chloride 3 or sulfonyl bromide 4.

4.3. Large-Scale Reaction for the Synthesis of Sulfonyl Chloride 3a

N-Chlorosuccinimide 2a (12 mmol, 2.0 equiv, 1.6 g) was added to a solution of 4-methylbenzenesulfonhydrazide 1a (6 mmol, 1.12 g) in CH₃CN (10 mL) in one portion. The mixture was stirred at room temperature for 2 h. The solvent was removed, and the residue was purified by flash column chromatography (PE/EA = 20:1) to provide the corresponding p-toluenesulfonyl chloride 3a (white solid, 1.14 g, 94%).

4.4. General Procedure for One-Port Reaction with Nucleophile

N-Chlorosuccinimide 2a (0.6 mmol, 2.0 equiv) was added to a solution of 4-methylbenzenesulfonhydrazide 1a (0.3 mmol) in CH₃CN (2 mL) in one portion. The mixture was stirred at room temperature for 2 h. Then, Et₃N (0.6 mmol, 2.0 equiv) and nucleophile (0.6 mmol, 2.0 equiv) were added to the above reaction system, and the mixture was stirred at room temperature for 2 h. The solvent was removed, and the residue was purified by flash column chromatography (PE/EA) to provide the corresponding sulfonamides and sulfonate 7.

4.5. Large-Scale Reaction for the Synthesis of 7a

N-Chlorosuccinimide 2a (12 mmol, 2.0 equiv) was added to a solution of 4-methylbenzenesulfonhydrazide 1a (6 mmol, 1.12 g) in CH₃CN (10 mL) in one portion. The mixture was stirred at room temperature for 2 h. Then, Et₃N (12 mmol, 2.0 equiv) and aniline (12 mmol, 2.0 equiv) were added to the above reaction system, and the mixture was stirred at room temperature for 2 h. The solvent was removed, and the residue was purified by flash column chromatography (PE/EA) to provide the corresponding sulfonamide 7a (brown solid, 1.39 g, 94%).

5. Conclusions

In conclusion, we successfully developed an efficient, simple, practical approach for the construction of sulfonyl chlorides/bromides from sulfonyl hydrazide. This methodology allows a wide substrate scope, utilizes readily available starting materials, and provides operational simplicity. Efforts to develop more direct applications in the chemical community are in progress in our laboratory.

Supplementary Materials

The following are available online, Characterization of products and ¹H and ¹³C-NMR spectra are available online (see manuscript-supplementary).

Author Contributions

R.C., F.S., C.X., K.W. and Z.W. participated in the purification and characterization of the compounds. S.X. and L.L. participated in the interpretation of the results, writing, revision, and correspondence with the journal Molecules until the manuscript was accepted. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the National Natural Science Foundation of China (nos. 21572126 and 21801214), the Natural Science Foundation of Henan (no. 202300410016), the Higher Education Institution Key Research Project Plan of Henan Province of China (no. 20B150019), and the University Student Innovation Program of Henan Province (no. 202111071021).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article and the supplementary material.

Acknowledgments

We are grateful for the National Natural Science Foundation of China (no. 21572126 and 21801214), the Natural Science Foundation of Henan (no. 202300410016), the Higher Education Institution Key Research Project Plan of Henan Province of China (no. 20B150019), and the University Student Innovation Program of Henan Province (no. 202111071021).

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Sample Availability

Samples of the compounds are available from the authors.

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Schemes and Table

Scheme 1. Synthesis of sulfonyl halides. (a) The oxidation of thiols using NCS/NBS-iPrOH; (b) Sulfonyl chloride formation from sulfonamides enabled by pyrylium salt; (c) The synthesis of sulfonyl bromides from sulfonyl hydrazides with bromine; (d) The reaction of sulfonyl hydrazides with NCS/NBS.

Scheme 2. Scope of the conversion of sulfonyl hydrazides to sulfonyl chlorides and sulfonyl bromides. Conditions: 1 (0.3 mmol), 2 (0.6 mmol), and CH3CN (2.0 mL), rt for 2 h under air.

Scheme 3. Synthesis of sulfonamides or sulfonates under the optimum conditions. Conditions: (1) 1a (0.3 mmol), 2a (0.6 mmol), and CH3CN (2.0 mL), rt for 2 h under air; (2) NEt3 (0.6 mmol), nucleophile (0.6 mmol), rt for 2 h under air.

Scheme 4. (a) Formation of sulfonyl chloride at a gram scale; (b) Formation of sulfonamide at a gram scale.

Scheme 5. Preliminary research mechanism.

Scheme 6. Proposed reaction mechanism.

Table 1

Optimization of reaction conditions ^a.

Scheme 6. Proposed reaction mechanism.

Entry	X Source	Solvent	Product	Yield (%) b
1	MgCl2	CH3CN	3a	N.R.
2	NaCl	CH3CN	3a	N.R.
3	CaCl2	CH3CN	3a	N.R.
4	ZnCl2	CH3CN	3a	N.R.
5	HCl	CH3CN	3a	N.R.
6	CuCl	CH3CN	3a	38
7	FeCl3	CH3CN	3a	8
8	SOCl2	CH3CN	3a	trace
9	PCl5	CH3CN	3a	65
10	NCS	CH3CN	3a	99
11	NCS	CH2Cl2	3a	91
12	NCS	EtOAc	3a	94
13	NCS	DME	3a	87
14	NCS	THF	3a	56
15	NCS	DCE	3a	58
16	NCS	Dioxane	3a	75
17	NBS	CH3CN	4a	87
18	NIS	CH3CN	5a	N.R.

^a Unless noted otherwise, reactions were performed with 1a (0.3 mmol) and X source (0.6 mmol, 2 equiv) in 2 mL solvent and room temperature under open air for 2 h. ^b Isolated yield. N.R.: no reaction, NCS: N-chlorosuccinimide, NBS: N-bromosuccinimide, NIS: N-iodosuccinimide.