Microwave assisted, Cu-catalyzed synthesis of sulfonamides using sodium sulfinates and amines

Abstract An efficient procedure has been developed under microwave irradiation for the monosulfonylation of amines in acetonitrile:water. In this reaction, equimolar quantities of amines and sodium sulfinates were reacted in presence of CuBr2 and omitted the use of oxidants, ligands, additives, and bases. The developed methodology converts a wide array of sterically and electronically diverse sulfinate and amines into the corresponding sulfonamides in excellent yields within a short reaction time. The use of microwave and aqueous media makes this protocol potentially useful in the development of a green strategy for the synthesis of sulfonamides. Graphical abstract


Introduction
The challenges of modern society and the growing demand of high-technology sectors of industrial production brings about a new phase in the development of organic synthesis. [1]The introduction of functional groups or complex structural units into an organic framework by the employment of microwave assistance with unprecedented control over the course of chemical transformation in noteworthy. [2]In this scenario, organo sulfur compounds, [3] especially the sulfonamide functionality [4,5] have received substantial attention and has been intensively studied, in both industry and academia.Furthermore, a recent report by Ge et al. [6] describes that a microwave frequency affects the dielectric constants of organo sulfur compounds and is responsible to convert electrical energy into thermal energy due to polarization effect.This indicates that is a superior thermal effect of microwaves in sulfur chemistry.In continuation of efforts on organo sulfur derivatives, [7] we focused our attention to synthesize sulfonamides because of its key structural motif in pharmaceuticals, bioactive compounds, [8] and versatile application for protection of amine functionality. [9]here have been many efforts focused in synthesizing sulfonamide functions from a wide variety of substrates.A survey of the literature reveals that mainly there were four different degrees of strategy utilized such as (a) nucleophilic substitution of an amine with a sulfonyl chloride, [10] (b) base-catalyzed condensation of sulfonyl amides with organic halides [11] (c) a chlorination followed by amidation of corresponding sulfurated starting materials in various oxidation states, [5,12] and (d) using transition metals [13] or Grignard reagents [14] .Although these methodologies are relatively general but the issues associated with the use of unstable and mutagenic chlorinated substrates which are responsible to generates hazardous waste.On contrary, the use of stoichiometric amounts of transition metal catalysts slow down the reaction rate [15] sporadically and excess use of base reduces functional group tolerability. [16]Therefore, a novel, efficient, and eco-friendly method is desired in synthesis of sulfonamides.
To accomplish this goal, we searched for a substance that can act as a substitute for sulfonyl chloride.Ascertained from the literature, sodium sulfinates became a sustainable and convenient surrogate for sulfonyl chloride. [17]In addition, because of their moisture tolerance and easier synthesis, [18] configuration of sulfonamide using sodium sulfinates is highly warranted.21ac] Another non-catalyzed approach to prepare sulfonamide using sodium sulfinate and an amine was discovered by group of Wu et al. [22a] and Zhao et al. [22b] in the presence of phase transfer catalysts along with mCPBA and TBHP as an oxidants respectively (Scheme 1, pathb and c).Very recently Yin et al. have developed Cu-catalyzed (Scheme 1, pathd) [23] synthesis of sulfonamides using K 2 S 2 O 8 as an oxidant.All these methods to synthesize sulfonamides require the existence of an oxidizing agent and long reaction time (approx 8-60 h).Therefore, developing alternative methods to generate a diverse array of sulfonamides would provide an opportunity to form a range of pharmaceutical and agrochemical scaffolds.

Results and discussion
Herein, we wish to report a new alternative synthetic strategy in building sulfonamides using microwave irradiation.This approach involves sodium sulfinate salts as the sulfur source and stoichiometric amounts of aliphatic/aromatic amines as nitrogen donors favored to react in the proximity of a copper catalyst (Scheme 1, pathe).Thus with sodium sulfinate 1a and morpholine 2a as model substrates, the reactivity of various copper sources were studied and the results were summarized in Table 1.Gratifyingly, in the copper catalyzed oxidative coupling of 1a with 2a, CuBr 2 exhibited a superior result than other copper sources (Table 1, entries 10-22).Simultaneously, optimization of the solvent conditions becomes a more significant component with microwave heating, as microwaves directly couple with the molecules and increase the rate of the reaction through   rapid kinetic excitation of molecules present in the reaction mixture. [24]The more polar solvent is, the greater its ability to couple with the microwave energy and leads faster reaction rates due to a rapid increase in temperature.The dielectric constant of water is 78.5 at 25 C and is changed to 27.5 at 250 C (similar to acetonitrile at 25 C) and 20 at 300 C (similar to acetone at 25 C), expresses pseudo-organic solvation properties of water.On the other hand, the use of a water miscible solvent helps to isolate the product as simplified as pure products.24b] The catalyst screening in water demonstrates that the CuBr 2 became a useful catalyst to form 3a (  24).Thus, the optimal microwave heating reaction conditions for the reaction of 1a (1 mmol) and 2a (1.1 mmol) include 0.5 mol% CuBr 2 in 5 mL acetonitrile:water (1:1) as the solvent of choice due to convenience of use and environmental factors heated at 120 C for 15 min.Encouraged by our initial studies, we then investigated the generality and versatility of this procedure using a series of structurally diverse and commercially available amines under the optimized conditions.A combinatorial library of sulfonamides was smoothly prepared in excellent yields, and the results are summarized in Table 2.Both aliphatic 2 (d-g, j) and aromatic amine 2 (h,i) reacted very well with 1a to generate their corresponding sulfonamides (Table 2, entries 3ad-3ag, 3ah-aj) in good yield.The cyclohexyl amine (2 g) also reacts with equal efficacy to generate corresponding sulfonamide in excellent yield (Table 2, entry 3ag).The employment of cyclic amines such as morpholine (2a), pyrrolidine (2b), and piperidine (2c) efficiently produced the corresponding sulfonamides in good yields (Table 2, entries 3aa-3ac), with the synthesis of compound 3aa exemplified on gram scale.Also, variety of benzylic amines including furfuryl amine (2d), benzyl amine (2e), p-methoxy benzyl amine (2f), and N-methylbenzylamine (2i) underwent the developed oxidative coupling in good yields (Table 2, entries 3ad-3af, 3ai).Additionally, to assess the versatility of the method, we successfully synthesized an array of desired sulfonamides (Table 2, entries 3ba-3bi) from phenyl sulfinate (1b) under identical reaction conditions.Interestingly, the aromatic amines were reacted moderately compared to aliphatic amines and this might be due to the nucleophilicity difference of both amines.

Mechanism
The plausible mechanism for the formation of sulfonamide is represented in Scheme 2. Thus as depicted in Scheme 2, the Cu(II) catalyst complexes with sodium sulfinates and generates intermediate (A). [25]Further on nucleophilic attack of the amines or bases produces intermediate (B).Eventually the complex (B) on reductive elimination furnish the desired product sulfonamide with the release of a Cu(0)species. [26]Finally, the Cu(0) becomes oxidized into Cu(II)Br 2 due to release of oxygen via water oxidation in presence of copper(II) complexes [27] or disproportionation of CuBr 2 into CuBr and Br 2 which releases nascent oxygen by reacting with water for the next catalytic cycle. [28]mparative study In order to show the merit of current process we have summarized several results in Table 3, in comparison with the other catalysts used for the synthesis of 4-tosylmorpholine (3aa) from sodium sulfinate 1a and morpholine 2a.It is evident from these results that CuBr 2 under microwave assistance (Table 3, entry 7) acts as highly efficient catalyst for the synthesis of sulfonamide in excellent yields within a short reaction time.

General procedure
Sodium sulfinate (1, 1 mmol), amine (2, 1.1mmol) and CuBr 2 (0.5 mol%) were suspended in acetonitrile:water (1:1, 5 mL) at 25 C.The resulting mixture was irradiated to 120 C (50W MW power) for 10-15 min in a sealed tube (10 mL pressure-rated reaction vials) in a self-tuning single mode irradiating synthesizer.After passing compressed air through the microwave cavity, there action mixture allowed to cool rapidly to room temperature.The obtained precipitate was filtered and diluted with methylene dichloride, and washed with coupes amount of water, diluted HCl, aqueous Na 2 CO 3, and brine.The desired product was recovered in pure form, simply by solvent concentration under reduced pressure.The solid product obtained was crystallized from toluene/methanol (see Supplemental Materials for characterization details).

Conclusion
In conclusion, we have developed a microwave assisted method that employs CuBr 2 activation of sodium sulfinates to synthesize sulfonamides.We believe that the described methodology becomes novel, convenient and handy technique for the synthesis of sulfonamides even in large scale, as it uses cheap and commercially available reagents and friendly reaction conditions.With the contribution of this new method, we envision that the sodium sulfinate will emerge as the preferred sulfonyl halide surrogate for a myriad of sulfonylation reactions.

Disclosure statement
No potential conflict of interest was reported by the authors.

References
[1] Aziz, J.; Hamze, A. An Update on the Use of Sulfinate Derivatives as Versatile Coupling Partners in Organic Scheme 2. Plausible mechanism for the formation of sulphonamide.

Table 1 .
Optimization of catalyst and solvent conditions for the synthesis of sulfonamide a .
Table 1, entries 1-10).In non-aqueous solvents such as THF, MeOH, DMF, NMP, DMSO, AcOH, CH 2 Cl 2 , and toluene (Table 1, entries 11-18) moderate yields of sulfonamide 3a were realized except for the case of acetonitrile (Table 1, entry 19).Interestingly, a small change in the solvent combination offered formation of desired product exclusively (Table 1, entry 20) with 95% yield.Further, the reduced amounts of CuBr 2 showed a moderate yield (Table 1, entry 21) and no significant increase of the yield was observed even in the high loading of CuBr 2 (Table1, entry 22).To our disappointment, the comparative experimentation on conventional heating conditions (e.g., 120 C temp and 1.5 equiv. of sodium aryl sulfinates, Table1, entry 23) was not sympathetic to this reaction, which limits its practical application.It is noteworthy that in the absence of a catalyst, the model reaction proceeded with little to no sulfonamide formation, highlighting the crucial role of the Cu-catalyst in activating the sulfinates toward nucleophilic addition (Table1, entry

Table 2 .
Synthesis of sulfonamide a .