Organic solvent-free synthesis of sulfonyl hydrazides in water

A B S T

Previous synthesis of sulfonyl hydrazides including the reaction of sulfonyl chloride and hydrazine in suitable organic solvents with the presence of triethyl amine [1], alumina as a catalyst [11], and silica [12] Reactions in ionic liquid [13] and solvent free conditions under microwave irradiation [14] have also been reported. Furthermore, synthesis using copper-catalyzed cross-coupling of aryl halides with hydrazine in PEG-400 [15], microwave-assisted synthesis of sulfonamides directly from sulfonic acids [16], and synthesis from thiols using H 2 O 2 -TAPC reagent system [17].
Due to the importance of sulfonyl hydrazides for potential biological interests and synthetic applications, there still remains for the development of further facile and practical synthesis of this class of molecules. It would be desirable for the reduction of organic solvent through the chemical process due to the recent unprecedented rising the price for fossil fuel. In this report, we describe the simple and practical synthesis of sulfonyl hydrazides in water without the use of organic solvent [18].
Traditional method for sulfonylation reaction in water uses aqueous alkali hydroxide solution (Hinsberg reaction), which limits the substrate scope for alkali resistant compounds [19] (see Scheme 1). Acidification of solvent by hydrochloric acid is required for the liberation of product from the hydrophobic sodium salt after the reaction, which also limit the substrate scope for acid resistant compounds. One of the advantages for this reaction is completed in aqueous phase.

General experimental information
All reactions were monitored by thin-layer chromatography on silica gel plates (60 Å, F254), visualizing with ultraviolet light, unless otherwise stated. 1 H NMR (500 MHz) and 13 C NMR (125 MHz) spectra were recorded on a JEOL JNM-ECZ500R spectrometer using DMSO-d 6 as a solvent at room temperature. Chemical shifts (δ) were determined in parts per million relative to DMSO-d 6 (δ ¼ 2.49 ppm) for 1 H NMR spectra and DMSO-d 6 (δ ¼ 39.5 ppm) for 13 C NMR spectra. Spin multiplicities are given as s (singlet), d (doublet), t (triplet), m (multiplet), and br (broad). Coupling constants (J value) are given in hertz. Melting points were determined by using a micro melting point equipment B-540. Highresolution mass spectrometry (HRMS) were performed on Bruker microTOF (ESI). Unless otherwise noted, all materials obtained from commercial suppliers were used without further purification.

General procedure for synthesis of sulfonyl hydrazides 3
Sulfonyl chloride 1 (5.24 mmol) was suspended in water (20 mL) and hydrazine 2 (5.24 mmol) was added. When hydrazine is hydrochloride salt, triethylamine (5.24 mmol) was added. The reaction mixture was stirred at 60 C for 1 h and monitored by TLC. Upon completion of the reaction, the solvent was removed by filtration without further purification.

Results and discussion
The survey for the solvents were conducted using p-toluenesulfonyl chloride 1a and phenylhydrazine 2a as model substrates ( Table 1). The reactions were carried out by mixing the equimolar amounts of substrates in solvent at room temperature for 1 h. Some polar and non-polar organic solvents, such as toluene, dioxane, ethanol, and acetonitrile provided moderate yields (entries 3, 4, 6, and 7), however, n-hexane, THF, and Table 3 Reactions of sulfonylchlorides and amines and/or alcohol in water. a  methanol disclosed the poor yields. When water was utilized as a solvent, the reaction took place smoothly under gently heating condition to afford the desired product 3a with better yield and purity after filtration (78%, entry 8). The same reaction afforded the desired product 3a in 70% and 45% yields at 40 C and 80 C, respectively (entry 8). The partial decomposition of sulfonyl chloride and product occurred in the reaction at 80 C. The gram scale synthesis was also performed without the loss of efficiency under the same conditions (entry 8). Due to the experimental simplicity and efficiency, we chose water as a solvent in this reaction system.
Based on the optimized reaction conditions, we next focused on the substrate scope for this transformation (Table 2). It was found that when hydrazine is hydrochloride, the addition of equimolar amount of triethylamine promoted the reaction. Both electron rich and deficient aromatics of hydrazines tolerated the conversion with moderate to good yield (compounds 3b-3g, 3j, and 3n). This transformation also accepted the aromatic ring of sulfonyl chloride with both electron rich and deficient nature (compounds 3b-3l and 3n-3p). Sterically demand sulfonyl chloride 1l suppressed the transformation (compound 3l, 56% yield). Alkyl sulfonyl chloride 1m displayed moderate efficiency (compound 3m, 48% yield). Pyridine ring also accepted the transformation with good yield (3n). Due to the high polarity of sulfonyl hydrazide 3o, the yield was moderate. Alkyl hydrazine 2p also afford the desired sulfonyl hydrazide 3p in moderate yield (51%). The reaction has found to be feasible for benzoylhydrajine (3q) and di-and tri-substituted hydrazine (3r and 3s).
To evaluate the feasibility of the present method for another amines and alcohols, we nest investigated the sulfonylation of a series of amine and alcohol derivatives (Table 3). Anilines have found to be good substrates for this reaction with high yields (90%, 5a and 5b). Amines with nitrogen heterocycles also provide sulfonamide 5c in moderate yield (46% yield). Benzimidamide afforded corresponding product 5e in moderate yield (64%). Amines including benzyl, sterically-hindered, and secondary ones were found to be good substrates to furnish corresponding sulfonamides in excellent yields (51-93%, 5c, 5f and 5g). Phenol and alcohol also afforded sulfonylated products in moderate to good yields in the same conditions (87 and 50%, 5h and 5i). The transformation also accepted for heterocyclic sulfonyl chloride and amine, multi-substituted phenol, amines with heterocycles (69-91%, compounds 5j-5l).
Finally, calculation of bioactivity score of synthesized compounds has been conducted using Molinspiration bioactivity score v2021.03 [36] and OSIRIS Property Explorer [37] to predict the biological activity of synthesized compounds. Selected examples for bioactivity score including GPCR ligand, ion channel modulator, kinase inhibitor, nuclear receptor ligand, protease inhibitor, enzyme inhibitor, druglikeness, and drug score have been represented in Table 4 [38]. Relatively high scores have been observed for some compounds (data indicated as bold) to imply promising bioactive compounds for further biological study.

Conclusion
In conclusions, we have developed a simple and practical synthesis of sulfonyl hydrazides from readily available staring materials without the use of organic solvent, aqueous alkali, and concentrated hydrochloride as deleterious substances. The reactions proceeded smoothly in water under mild reaction conditions with moderate to good efficiency. The gram scale synthesis was also easy to perform. The work-up procedure was simple, which included a simple filtration. This method could reduce the cost for the use of organic solvents and their disposal which would contribute environmental benignness and sustainability.

Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Table 4 Calculation of bioactivity score. compound GPCR ligand [a] Ion channel modulator [a] Kinase inhibitor [a] Nuclear receptor ligand [a] Protease inhibitor [a] Enzyme inhibitor [a] druglikeness [b] drugscore [b]