Facile Synthesis of Sulfonyl Chlorides/Bromides from Sulfonyl Hydrazides

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.


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 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).

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 (Niodosuccinimide) as the substrate, the corresponding product 5a was not formed (Table 1, entry 18).

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 MgCl 2 as the halogen source in CH 3 CN 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 CH 3 CN 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). 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).

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 (Niodosuccinimide) as the substrate, the corresponding product 5a was not formed (Table 1, entry 18).

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. 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 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).   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. Scheme 6. Proposed reaction mechanism.

General Information
NMR data were obtained for 1 H at 400 MHz and for 13 C 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 glassbacked silica plates. UV light and I2 were used to visualize products. All chemicals were used without purification as commercially available unless otherwise noted.

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.

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 4methylbenzenesulfonhydrazide 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, 1.14g, 94%).

General Information
NMR data were obtained for 1 H at 400 MHz and for 13 C at 100 MHz. Chemical shifts were reported in ppm from tetramethylsilane with the solvent resonance as the internal standard in CDCl 3 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 I 2 were used to visualize products. All chemicals were used without purification as commercially available unless otherwise noted.

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 CH 3 CN (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.

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 4methylbenzenesulfonhydrazide 1a (6 mmol, 1.12 g) in CH 3 CN (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%).

General Procedure for One-Port Reaction with Nucleophile
N-Chlorosuccinimide 2a (0.6 mmol, 2.0 equiv) was added to a solution of 4methylbenzenesulfonhydrazide 1a (0.3 mmol) in CH 3 CN (2 mL) in one portion. The mixture was stirred at room temperature for 2 h. Then, Et 3 N (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.

Large-Scale Reaction for the Synthesis of 7a
N-Chlorosuccinimide 2a (12 mmol, 2.0 equiv) was added to a solution of 4methylbenzenesulfonhydrazide 1a (6 mmol, 1.12 g) in CH 3 CN (10 mL) in one portion. The mixture was stirred at room temperature for 2 h. Then, Et 3 N (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%).

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.