A new electrochemical strategy for the synthesis of a new type of sulfonamide derivatives

This study is the first report of electrochemical generation of hydroxyimino-cyclohexa-dien-ylidene haloniums and their application in the synthesis of new halo-N-hydroxysulfonamide derivatives. These compounds were obtained in a one-pot process based on the reaction of halonium acceptors with arylsulfinic acids. The method is easy to carry out, as it is performed using the carbon electrodes in a simple undivided cell. The protocol has a broad substrate scope with a tolerance for a variety of functional groups. The proposed mechanism is a ping-pong type reaction mechanism, which in its first stage the halonitroarene is reduced at the cathode to related hydroxylamine and in the second stage the cathodically generated hydroxylamine by oxidation at the anode and participating in disproportionation reaction is converted to the halonium acceptor.


Materials and methods
A µ-Autolab model PGSTAT 20 potentiostat/galvanostat (Metrohm-Autolab, Netherland) was used for the preparative electrolysis, cyclic voltammetry, differential pulse voltammetry and controlled potential coulometry experiments. The cell system consisted of a glassy carbon disc with diameter of 3.0 mm, a platinum rod and an Ag/AgCl (3 M) were used as working, counter and reference electrodes, respectively. The cathode used in macroscale electrolysis (synthesis) was an assembly of four carbon rods with of 32 cm 2 area, while the anode consisted of a carbon rod with an area of 8 cm 2 . All electrodes were from AZAR Electrodes, (Iran). p-iodonitrobenzene, o-iodonitrobenzene, p-chloronitrobenzene and p-bromonitrobenzene were synthesized according to previously described methods 34,35 . p-Toluenesulfinic acid sodium salt (97%), benzensulfinic acid sodium salt (97%), p-chlorosulfinic acid sodium salt, acetic acid (99%), perchloric acid (70%) and phosphoric acid (85%) were obtained from Sigma-Aldrich.
Experimental procedures. General procedure for synthesis of 1b-3b, 1c-3c, 1d-3d and 1e-2e. In an undivided cell equipped with four carbon rods as cathode and one carbon rod as anode, a solution (ca. 80 mL) of water (phosphate buffer, pH, 2.0, c = 0.2 M)/acetonitrile or DMF (50/50 v/v) containing halonitrobenzene (0.5 mM) and arylsulfinic acid (0.5 mM) was electrolyzed at − 0.8 V vs. Ag/AgCl. The electrolysis was terminated when the current decayed to 5% of its original value. At the end of the electrolysis, the cell was placed overnight. The precipitated pale yellow was collected by filtration and purified by thin layer chromatography (n-hexane/ ethyl acetate 4/1).
The redox behavior of A 1 /C 1 is shown in Fig. 3. Two pathways are possible for the oxidation of cathodically generated phenylhydroxylamine; (1) one-electron oxidation and the formation of phenylhydroxylamine radical (PHR) (path A) and (2) two-electron oxidation and the formation of nitrosobenzene derivatives (NSB) (path B).
In order to identify the more probable oxidation pathway, the number of electrons exchanged in the oxidation of N-(4-iodophenyl)hydroxylamine was calculated using differential pulse voltammetry (DPV) method ( Supplementary Fig. S1), by measuring half-peak width (W 1/2 ) according to equation 40 : The result of this experiment is in agreement with the one-electron transfer in the oxidation step of N-(4-iodophenyl)hydroxylamine and confirms the formation of phenylhydroxylamine radical (PHR) under our experimental conditions. The structures of PHR and NSB were optimized at B3LYP/6-311G level of theory by using guassian09W (Supplementary Fig. S2). The relative Gibbs free energies of PHR and NSB were found to be 15.1 and 0.0 kcal/mol, respectively, which is another confirmation of the formation of PHR. The effect of solution pH on the half-wave potential (E 1/2 ) of N-(4-iodophenyl)hydroxylamine (PIPHA) and other phenyl hydroxylamines produced from the reduction of PCNB, PBNB, and OINB was evaluated in the range of 1-7 ( Fig. 4 and Supplementary Figs. S3-S5). It was found that half-wave potential (E 1/2 ) of PINB shifted to negative values with increasing pH which indicates that proton is involved in the electrode process. The Pourbaix diagram of PIPHA is also shown in Fig. 4. It consists of two lines with slopes 113 (line A) and 52 (line B) mV/pH (Fig. 5). The slope of 113 mV/pH is consistent with the theoretical value for a one-electron/two-proton process (118 mV/ pH). On the other hand, the slope of 52 mV/pH (line B) is in accordance with the one-electron/one-proton process (59 mV/pH).
Also    www.nature.com/scientificreports/ The cyclic voltammogram of PINB in the presence of benzenesulfinic acid (BSA) as a nucleophile is shown in Fig. 6, part I, curve b. Comparison of this voltammogram with that of in the absence of BSA shows that I pC1 decreases significantly. This decrease confirms the reaction between oxidized hydroxylamine and BSA.
Controlled-potential coulometry was performed in a solution containing PINB (0.5 mmol) and BSA (0.5 mmol) at − 0.8 V versus Ag/AgCl. The electrolysis progress was monitored by cyclic voltammetry (Fig. 6, parts II and III). Part II shows a continuous decrease in cathodic peak C 0 current over the charge passed due to the reduction of the nitro group to hydroxylamine. On the other hand, part III shows a continuous increase of the peaks A 2 and C 2 currents with increasing amounts of charge.
The proposed mechanism for the oxidation of PINB in the presence of BSA is shown in Fig. 7. According to this mechanism, cathodically generated PIPHA at the anode surface is oxidized to its corresponding radical. The disproportionation of the PIPHA radicals in the next step, to yield the starting PIPHA and 4-(hydroxyimino) cyclohexa-2,5-dien-1-ylidene) iodonium (PIPHA ox ). The reaction of PIPHA ox as an acceptor with BSA (R = H) affording the corresponding iodosulfonamide (PISA).
The optimization of conditions for the electrochemical synthesis of PISA by the change in the electrode material, solvent and aqueous solution pH was studied and the results are shown in Table 1. PISA was achieved in 75% yield with carbon electrodes in aqueous phosphate buffer (pH, 2.0, c = 0.2 M)/acetonitrile mixture (50/50 v/v) (entry 1). DMF as a co-solvent also afforded the product in 86% yield (entry 4). We think that pH is the most important factor for increasing yield, by preventing or minimizing side reactions such as PIPHA-PIPHA ox coupling reaction. At pH 2, PIPHA is mostly protonated (Fig. 2) and cannot act as an effective nucleophile to Table 2. Scope of the halosulfonamide synthesis. In an undivided cell equipped with four carbon rods as cathode and one carbon rod as anode, a solution (ca. 80 mL) of water (phosphate buffer, pH, 2.0, c = 0.2 M)/ acetonitrile(50/50 v/v) containing halonitrobenzene (0.5 mM) and arylsulfinic acid (0.5 mM) was electrolyzed at − 0.8 V vs. Ag/AgCl. The structures of the compounds were drawn using ChemOffice 12.0 (CambridgeSoft). www.nature.com/scientificreports/ compete with the reaction of BSA with PIPHA ox . At pH 2, the use of electrodes other than carbon and solvents other than DMF, reduce yield. With the optimized conditions in hand, we investigated the scope of the reaction using a range of halonitroarenes and sulfinic acids ( Table 2). The data presented in Table 2 show that we were able to develop an efficient method to synthesize new halosulfonamides in a one-pot reaction with a 63-86% overall yield. As shown in Table 2, a number of halo-N-hydroxy sulfonamides have been synthesized in a one-pot process for the first time. No data have been reported so far for the electrochemically synthesis of these types of sulfonamides. The reaction is carried out under mild conditions at room temperature and atmospheric pressure with a high atom economy and without using inorganic (or organic) oxidizing agents or catalysts. Selective electrohydrogenation of halonitroarenes (without removal of halogen) is another achievement of this method. Compared with the literature procedures (Supplementary Table S1) that require amines, metal catalysts, high temperatures, expensive, unstable and toxic reagents, this method operates under mild and sustainable reaction conditions and utilizes low-cost materials which is suitable for scalable production.

Conclusions
In this study, a ping pong reaction mechanism is proposed, which in its first stage the halonitroarene is reduced at the cathode to related hydroxylamine and then the oxidation of cathodically generated hydroxylamine along with the disproportionation reaction to form the halonium acceptor. The reaction of halonium compound with arylsulfinic acids affording the corresponding halo-N-hydroxysulfonamide. In this new strategy, we utilized the primary electrochemical principles for the synthesis of a new type of sulfonamids. These compounds have not been synthesized electrochemically so far and therefore, we were interested in the synthesis of them. In this paper, we also reported the first example of in situ generation and reaction of the unstable hydroxyimino-cyclohexa-dienylidenehaloniums intermediates for the synthesis of organic compounds. This method has several unique features which are: (1) Synthesis of halo-N-hydroxysulfonamide derivatives. This class of compounds had not yet been synthesized electrochemically. (2) This is the first example of in situ generation of the unstable hydroxyiminocyclohexa-dien-ylidenehaloniums intermediates without using any metal catalyst and electrochemical detection of them. (3) The reaction mechanism reported for the synthesis of halo-N-hydroxysulfonamide compounds (Fig. 7), including cathodic reduction, anodic oxidation, disproportionation, and addition reaction is unique and it has not been reported elsewhere. (5) The electrochemical data reported for halonitrobenzenes, PINB, PCNB, PBNB and OINB and also electrogenerated N-(halophenyl)hydroxylamines, PIPHA, PCPHA, PBPHA and OIPHA, are unique and they have not been reported elsewhere. (6) This protocol describes a detailed procedure for the formation of haloniums intermediates and provides a novel approach for the synthesis of halo-N-hydroxysulfonamide derivatives in sustainable and facile conditions.

Scientific Reports
| (2020) 10:17904 | https://doi.org/10.1038/s41598-020-74733-2 www.nature.com/scientificreports/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/.