Sulfonamides review

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<p>lable at ScienceDirect</p><p>Tetrahedron 76 (2020) 131662</p><p>Contents lists avai</p><p>Tetrahedron</p><p>journal homepage: www.elsevier .com/locate/ tet</p><p>Tetrahedron report number: 1215</p><p>Synthesis of sulfonamide and their synthetic and therapeutic</p><p>applications: Recent advances</p><p>Shovan Mondal*, Suniti Malakar</p><p>Department of Chemistry, Syamsundar College, Shyamsundar 713424, India</p><p>a r t i c l e i n f o</p><p>Article history:</p><p>Received 7 May 2020</p><p>Received in revised form</p><p>8 September 2020</p><p>Accepted 6 October 2020</p><p>Available online 10 October 2020</p><p>Keywords:</p><p>Sulfonamide</p><p>Synthesis</p><p>Mechanism</p><p>Synthetic applications</p><p>Biological applications</p><p>* Corresponding author.</p><p>E-mail address: shovanku@gmail.com (S. Mondal)</p><p>https://doi.org/10.1016/j.tet.2020.131662</p><p>0040-4020/© 2020 Elsevier Ltd. All rights reserved.</p><p>a b s t r a c t</p><p>A sulfonamide is a functional group that is the basis of several sulfa drugs and thereby are very much</p><p>important scaffolds in medicinal as well as in synthetic organic chemistry. Recently very important</p><p>methodologies have been developed for the synthesis of sulfonamide. This complex review article covers</p><p>the recent developments (mainly in the period 2013e2019) of powerful methodologies for the synthesis</p><p>of sulfonamide compounds, particularly where SO2N(R) moiety is not present in a cyclic structure and</p><p>their applications in various fields during this period. A critical view of the mechanisms of the developed</p><p>methodologies together with the scope and limitation of these methods adds an extra dimension to the</p><p>text.</p><p>© 2020 Elsevier Ltd. All rights reserved.</p><p>Contents</p><p>1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2</p><p>2. Synthesis of sulfonamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2</p><p>2.1. Transition metal-free synthesis of sulfonamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2</p><p>2.2. Transition metal-catalyzed synthesis of sulfonamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7</p><p>2.2.1. Pd-catalyzed synthesis of sulfonamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8</p><p>2.2.2. Cu-catalyzed synthesis of sulfonamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9</p><p>2.2.3. Rh-catalyzed synthesis of sulfonamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10</p><p>2.2.4. Other transition metal-catalyzed synthesis of sulfonamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10</p><p>3. Synthetic applications of sulfonamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11</p><p>3.1. Sulfonamide moiety as an activating group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11</p><p>3.2. Alkylations/arylations of sulfonamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12</p><p>3.3. Rearrangement of sulfonamide derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14</p><p>3.4. Other synthetic applications of sulfonamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16</p><p>4. Biological applications of sulfonamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18</p><p>4.1. Sulfonamide as therapeutic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19</p><p>4.2. Sulfonamide with anti-carbonic anhydrase activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21</p><p>4.3. Sulfonamide with NaV1.7 inhibitor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23</p><p>4.4. Other biological applications of sulfonamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23</p><p>5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26</p><p>Declaration of competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26</p><p>Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26</p><p>References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26</p><p>.</p><p>mailto:shovanku@gmail.com</p><p>http://crossmark.crossref.org/dialog/?doi=10.1016/j.tet.2020.131662&domain=pdf</p><p>www.sciencedirect.com/science/journal/00404020</p><p>www.elsevier.com/locate/tet</p><p>https://doi.org/10.1016/j.tet.2020.131662</p><p>https://doi.org/10.1016/j.tet.2020.131662</p><p>S. Mondal and S. Malakar Tetrahedron 76 (2020) 131662</p><p>1. Introduction</p><p>The sulfonamide structural class represents a very important</p><p>group of compounds in both synthetic and medicinal chemistry</p><p>[1e8]. Indeed, sulfonamide functionality constitutes the structural</p><p>motif of a variety of drugs and bioactive compounds endowed with</p><p>antimicrobial, antitumor, anti-inflammatory, hypoglycemic, anti-</p><p>psychotic, anticancer, and protease inhibitory activity among others</p><p>[3]. The discovery and development of the first sulfonamide drug-</p><p>Prontosil (Fig. 1), opened a new era in medicine. This compound</p><p>was first synthesized by Bayer chemists Josef Klarer and Fritz</p><p>Mietzsch as part of a research program designed to find dyes that</p><p>might act as antibacterial drugs in the body. 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Yamamoto, M. Yata, S. Ohrui, T. Okada, T. Saitoh, N. Kutsumura,</p><p>Y. Nagumo, Y. Irukayama-Tomobe, Y. Ishikawa, Y. Ogawa, S. Hirayama,</p><p>D. Kuroda, Y. Watanabe, H. Gouda, M. Yanagisawa, J. Med. Chem. 60 (2017)</p><p>1018e1040.</p><p>Dr. Shovan Mondal. Dr. Mondal received his Ph.D. from the</p><p>University of Kalyani (2010) under the guidance of Prof. K.</p><p>C. Majumdar. He did postdoctoral research work on</p><p>asymmetric</p><p>synthesis at Aix-Marseille University, France</p><p>(2011e2012), with Prof. Malek Nechab and Prof Michele</p><p>Bertrand. Dr. Mondal then moved to India and in 2012</p><p>joined, as a DST-INSPIRE Faculty Fellow, the Department</p><p>of Chemistry, Visva-Bharati University, where he started</p><p>his independent research career along with teaching. He</p><p>is currently working as an Assistant Professor at Syamsun-</p><p>dar College, West Bengal. His research interests encom-</p><p>pass asymmetric synthesis with the memory of chirality,</p><p>synthesis of heterocyclic compounds of biological interest,</p><p>and heterocycle-containing liquid crystalline compounds.</p><p>He has received several awards including an “Allocation</p><p>D’Accueil de Chercheurs Post-Doctorants” from the City</p><p>of Marseille, France, in 2011 with award money of 2500</p><p>Euros, a DST-INSPIRE FACULTY award from DST, Govt. of</p><p>India, in 2012, an “Adarsh Vidya Saraswati Rashtriya Pur-</p><p>askar”with a gold medal in 2016 from the Global Manage-</p><p>ment Council, Ahmedabad, and an Early Career Research</p><p>Award from the Science and Engineering Research Board</p><p>(SERB), Department of Science & Technology, Government</p><p>of India in 2017. He has published 52 publications so far in</p><p>peer-reviewed international journals including Angew.</p><p>Chem., Chem. Commun., Advanced Synthesis and Catal-</p><p>ysis, Chem. Rev., Chemistry-A European Journal, JOC, etc.</p><p>Dr. Suniti Malakar. Suniti Malakar received her B.Sc. from</p><p>the Ranchi University, Ranchi, Jharkhand in 2011 and</p><p>completed her M.Sc. in chemistry from Kolhan University,</p><p>Chaibasa, Jharkhand in 2013. She qualified the Visva-</p><p>Bharati research Eligibility Test (VBRET-2014) conducted</p><p>by Visva-Bharati University, West Bengal in 2014 and</p><p>then joined in the research group of Dr. Shovan Mondal</p><p>at Visva Bharati (a central University), Santiniketan for</p><p>her doctoral study in the same year. Her research interests</p><p>focus on the synthesis of heterocycles with biological sig-</p><p>nificance. 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of sulfonamide and their synthetic and therapeutic applications: Recent advances</p><p>1. Introduction</p><p>2. Synthesis of sulfonamide</p><p>2.1. Transition metal-free synthesis of sulfonamide</p><p>2.2. Transition metal-catalyzed synthesis of sulfonamide</p><p>2.2.1. Pd-catalyzed synthesis of sulfonamide</p><p>2.2.2. Cu-catalyzed synthesis of sulfonamide</p><p>2.2.3. Rh-catalyzed synthesis of sulfonamide</p><p>2.2.4. Other transition metal-catalyzed synthesis of sulfonamide</p><p>3. Synthetic applications of sulfonamide</p><p>3.1. Sulfonamide moiety as an activating group</p><p>3.2. Alkylations/arylations of sulfonamide</p><p>3.3. Rearrangement of sulfonamide derivatives</p><p>3.4. Other synthetic applications of sulfonamide</p><p>4. Biological applications of sulfonamide</p><p>4.1. Sulfonamide as therapeutic agents</p><p>4.2. Sulfonamide with anti-carbonic anhydrase activity</p><p>4.3. Sulfonamide with NaV1.7 inhibitor</p><p>4.4. Other biological applications of sulfonamide</p><p>5. Conclusions</p><p>Declaration of competing interest</p><p>Acknowledgment</p><p>References</p><p>Penoxsulam, Probenecid, Sulfadiazine, etc. for their proven thera-</p><p>peutic applications against cardiovascular, infectious, and neuro-</p><p>logical diseases [9]. In the agrochemical industry also, the</p><p>sulfonamide motif appears in a variety of pesticides, including</p><p>asulam, orzalin, fomesafen, halosafen, and sulfentrazone [10].</p><p>Although there are numbers of reviews including ours on sul-</p><p>tams i.e. cyclic sulfonamides [11e15] but there are very few on the</p><p>synthesis of sulfonamide where SO2N(R) is not in the ring [1,2]. In</p><p>this present endeavor, we have focused on the recent de-</p><p>velopments (mainly in the period 2013e2019) of powerful</p><p>methodologies for the synthesis of sulfonamide where SO2N(R)</p><p>moiety is not in the cyclic structure and their recent applications in</p><p>synthetic and biological fields. A critical view of the mechanisms</p><p>and the scope and limitations of the developedmethodologies have</p><p>also been discussed in detail in this review.</p><p>2. Synthesis of sulfonamide</p><p>Reflecting their diverse roles, many powerful methodologies</p><p>have been developed for the synthesis of sulfonamide including</p><p>CeH activation, flow-based technology, telescoped synthesis,</p><p>transition-metal-catalyzed synthesis, solid-phase synthesis, and</p><p>many others. For clear presentation, the syntheses of sulfonamide</p><p>have been divided into two categories: (i) transition metal-free</p><p>synthesis and (ii) transition metal-catalyzed synthesis of sulfon-</p><p>amide, which were then, subdivided according to their reaction</p><p>types.</p><p>2.1. Transition metal-free synthesis of sulfonamide</p><p>Most of the earlier procedures for sulfonamide synthesis</p><p>involved the nucleophilic reaction between amino compounds and</p><p>sulfonyl chlorides in presence of a base (eq. 1) (classical approach of</p><p>sulfonamide synthesis) has attracted considerable attention for</p><p>good reactivity and simplicity of the protocols [16e21].</p><p>Fig. 1. First sulfonamide drug.</p><p>2</p><p>Eq. 1.</p><p>The main drawbacks of this methodology include the use of</p><p>additional bases to scavenge the acid (HCl) that is generated during</p><p>the reaction, high temperatures needed for the less reactive sub-</p><p>strates, as well as laborious purifications often required when</p><p>competing for side reactions occur [22]. In contemporary years,</p><p>green chemistry encourages the design of products and processes</p><p>that reduce or eliminates the use and generation of hazardous</p><p>substances to sustain eco-friendly nature.</p><p>In 2013, Gioiello et al. developed the synthesis of a sulfonamide</p><p>library by employing flow-based technology [23]. The reaction</p><p>between amine (1.1) and sulfonyl chloride (1.2) using NaHCO3 as a</p><p>base in water/acetone/PEG-400 with ratio 1:2:1 (v/v/v) under flow</p><p>condition gave the sulfonamide 1.3 in good to excellent yields</p><p>(Scheme 1). Polyethylene glycol 400 (PEG-400) was used as an</p><p>organic co-solvent for smooth conducting of the flow process</p><p>which sometimes resists due to precipitation. The advantage of this</p><p>flow process methodology is that there is no need for purifications</p><p>and by this optimized procedure it is possible to large scale syn-</p><p>thesis of probenecid (1.3a). Probenecid is a prototypical uricosuric</p><p>drug also used to treat patients with renal impairment as an</p><p>adjunct to antibacterial therapy.</p><p>Here it is important to note that, Moroz and Mykhailiuk et al.</p><p>also synthesized an aliphatic sulfonamide library using two types of</p><p>aliphatic sulfonyl halides (Cl Vs F) by the classical approach of</p><p>sulfonamide synthesis [24]. Aliphatic sulfonyl fluorides showed</p><p>good results with the amines bearing an additional functionality,</p><p>while the corresponding chlorides failed. Again, aliphatic sulfonyl</p><p>chlorides reacted efficiently with amines bearing sterically hin-</p><p>dered amino group while the corresponding fluorides showed low</p><p>activity.</p><p>Ball and co-workers described a method using calcium tri-</p><p>flimide [Ca(NTf2)2] as a Lewis acid to activate sulfonyl fluorides 2.1</p><p>toward nucleophilic addition with amines 2.2 in tert-amyl alcohol</p><p>for 24 h to synthesize an array of aryl-, alkyl-, and heteroaryl-</p><p>sulfonamide 2.3 in good to excellent yields (Scheme 2) [25].</p><p>Although [Ca(NTf2)2] was not required for the reaction between an</p><p>electron-deficient sulfonyl fluoride and a highly nucleophilic</p><p>amine. The mechanism may be progressed by the interaction of</p><p>divalent cations and the triflimide anion for proficient trans-</p><p>formation. Here it is worth mentioning that, very recently Willis</p><p>et al. were prepared some sulfonamide from sulfonyl fluorides</p><p>using a similar type methodology [26].</p><p>Moreover, Buchwald et al. developed a new pathway for the</p><p>synthesis of a variety of aryl sulfonamide (3.6) from readily avail-</p><p>able phenyl chlorosulfate (3.1), aryl boronic acids (3.2), and amines</p><p>(3.5) [27]. The sulfonyl chloride intermediates (3.4) were prepared</p><p>by Pd-catalyzed (using catalyst 3.3) regioselective Suzuki-Miyaura</p><p>cross-coupling reaction between phenyl chlorosulfate (3.1), and</p><p>aryl boronic acids (3.2). The cross-coupled products (3.4) were</p><p>formed regioselectively instead of product 3.7. The sulfonyl chlo-</p><p>ride intermediates 3.4 was then converted to corresponding aryl</p><p>sulfonamide (3.6) in situ by simply adding a primary or secondary</p><p>amine (3.5) to the crude reaction mixture of 3.4 (Scheme 3).</p><p>In 2017, Bode et al. reported the synthesis of pyridyl-</p><p>sulfonamide by the reaction of the aryl sulfonyl chloride with 2-</p><p>amino-6-bromopyridine in presence of pyridine as a base in</p><p>refluxing acetonitrile for 24 h [28]. Saeidian and co-workers also</p><p>demonstrated the synthesis of 1,2,3-triazole-based sulfonamide</p><p>compounds in the same year using the conventional methods [29].</p><p>Scheme 1. Synthesis of Sulfonamide library under flow conditions.</p><p>Scheme 2. Synthesis of sulfonamide by calcium triflimide activation of sulfonyl</p><p>fluoride.</p><p>Scheme 3. Synthesis of aryl sulfonamide via</p><p>S. Mondal and S. Malakar Tetrahedron 76 (2020) 131662</p><p>3</p><p>Furthermore, Sulfinates intermediates are a great choice in the</p><p>efficient synthesis of analogs containing sulfonamide functional-</p><p>ities. Shavnya et al. developed a telescoped synthesis (a sequential</p><p>one-pot synthesis with reagents added to a reactor one at a time</p><p>and without workup is called a telescoping synthesis) of aliphatic</p><p>sulfonamide from an alkyl halide and sodium hydrox-</p><p>ymethylsulfinate (rongalite) [30]. The monoalkylation of rongalite</p><p>with 3-phenyl-propyl bromide (4.1) was found to be useful for the</p><p>efficient telescoped synthesis of aliphatic sulfonamide compounds</p><p>4.3. Under the optimized conditions, the intermediate sulfinic acid</p><p>(4.5) was released with phosphoric acid and extracted with</p><p>chlorosulfonylation of aryl boronic acid.</p><p>S. Mondal and S. Malakar Tetrahedron 76 (2020) 131662</p><p>dichloromethane�heptane (4:1). Without drying, the organic</p><p>extract was basified with Hünig’s base (N, N-diisopropylethylamine</p><p>[DIPEA]), combined with amine 4.2, and finally treated with 1,3-</p><p>dichloro-5,5-dimethylhydantoin (DCDMH) as an oxidant, thus</p><p>delivering aliphatic sulfonamide compounds 4.3 in an efficient</p><p>telescoped procedure (Scheme 4).</p><p>Yan and co-workers also explored the one-pot synthesis of</p><p>sulfonamide from sodium sulfinate and amine via sulfonyl bromide</p><p>in the presence of (n-C4H9)4NBr as bromine source and m-CPBA as</p><p>oxidant at room temperature in the air [31]. Moreover, Zeng and</p><p>Little et al. also demonstrated an electrochemical protocol for the</p><p>synthesis of sulfonamide via the oxidative amination of sodium</p><p>sulfinate [32]. This reaction was conducted in an undivided cell</p><p>where a substoichiometric amount of NH4I was used which acts</p><p>both as a redox catalyst and supporting electrolyte. Therefore, no</p><p>additional conducting salt was required for this reaction.</p><p>Optically active sulfonamide have also been known since the</p><p>discovery of Reychler’s acid derivative in the year 1938 [33]. In the</p><p>later years, chiral sulfonamide molecules used tremendously in the</p><p>asymmetric synthesis as auxiliaries [34], ligands for reagents [35],</p><p>or catalysts [36e44] and, most recently, as organocatalysts</p><p>[45e48]. In this pretext, Paras and co-workers developed a</p><p>convenient route for the stereospecific</p><p>synthesis of a-C-chiral sul-</p><p>fonamide 5.4 from a-chiral sulfinate 5.3 in good yields with the</p><p>retention of chemical purity by the treatment of the sulfinate 5.3</p><p>with hydroxylamine sulfonate in aqueous solution [49]. Pyr-</p><p>imidinyl sulfone (5.2) was cleaved with sodium methoxide in</p><p>methanol afforded a-chiral sulfinate 5.3 in excellent yields with</p><p>high enantiomeric excess. Peracid oxidation of optically pure thi-</p><p>oether 5.1, cleanly afforded pyrimidinyl sulfone (5.2) in high yields</p><p>and enantiomeric excess (Scheme 5).</p><p>In 2015, Song and Yuan’s group published two consecutive re-</p><p>ports on a green and sustainable methods for the synthesis of</p><p>sulfonamide from sodium sulfinate and primary/secondary amine</p><p>via I2-induced NeH bond cleavage [50,51]. In a subsequent report,</p><p>Yuan also described the preparation of sulfonamide via I2/t-butyl</p><p>hydroperoxide (TBHP)-mediated reaction between the tertiary</p><p>amine and sodium sulfonate inwater (scheme 6a) [52]. Water has a</p><p>great role in the reaction, it takes part in the reaction to result in the</p><p>CeN bond cleavage of tertiary amine so that sulfonamide could be</p><p>formed.</p><p>According to the possible mechanism depicted in scheme 6b,</p><p>initially, I2/I� redox cycle promotes TBHP to furnish tert-butoxyl</p><p>and tert-butylperoxyl radicals. On the other hand, sodium sulfinate</p><p>6.1 is activated by I2, to produce sulfonyl radical 6.4. tert-Butoxyl</p><p>and tert-butylperoxyl radicals then abstract hydrogen from the</p><p>tertiary amine 6.2 to generate radicals which by electron transfer</p><p>are converted to intermediate 6.5. In the presence of water, the</p><p>Scheme 4. Telescoped synthesis of alip</p><p>4</p><p>intermediate 6.5 readily undergo CeN bond cleavage to produce</p><p>aldehyde and secondary amine 6.6. Finally, the sulfonyl radical 6.4</p><p>attacks the secondary amine 6.6 to afford the sulfonamide 6.3.</p><p>Jang and Shyam demonstrated another strategy for the syn-</p><p>thesis of sulfonamide via sulfinate anion from thiosulfonate which</p><p>is synthesized by the catalytic aerobic dimerization of thiol [53]. In</p><p>the presence of Cs2CO3 in EtOH, the nucleophilic base attack the</p><p>divalent sulfur atom of thiosulfonate 7.1 to release the sulfonate</p><p>anion 7.4 or 7.5. The amine 7.2 undergo halogenation by NBS or I2 to</p><p>form 7.6, prior to the addition by the sulfinate anion 7.4 to afford</p><p>the sulfonamide 7.3 (Scheme 7).</p><p>Moreover, Shi et al. developed a method for the cross-coupling</p><p>(sulfoxidation) of aryl boronic acid (8.1) with DAST-type reagent</p><p>(8.2) to afford various sulfinamide derivatives (8.3) in moderate to</p><p>good yields within 5 min which then converted to the corre-</p><p>sponding sulfonamide derivatives (8.4) by simple oxidation reac-</p><p>tion (scheme 8a) [54]. Mechanistically, intermediate 8.5 can be</p><p>generated by the reaction of diethylaminosulfur trifluoride (DAST)</p><p>(8.2a) with a trace amount of H2O in the solvent or reagents. For</p><p>example, phenylboronic acid (8.1a) which is activated by a fluorine</p><p>anion generated from DAST or HF, then undergoes nucleophilic</p><p>sulfuration with intermediate 8.5 to provide the sulfinamide 8.3a</p><p>with the release of intermediate 8.6 which is then captured by</p><p>DAST to deliver intermediate 8.7. Migration of a fluorine atom from</p><p>intermediate 8.7 generates intermediate 8.5 and BF4� which again</p><p>take part in the reaction (scheme 8b).</p><p>A protocol for direct formation of substituted sulfonamide de-</p><p>rivatives from sulfonyl azides and amines via nucleophilic substi-</p><p>tution was developed by Odell and co-workers [55]. The reaction</p><p>between sulfonyl azides 9.1 with various primary and unhindered</p><p>secondary amines 9.2 proceeded smoothly in a polar solvent (here</p><p>DMA was used) in presence of base afforded the sulfonamide</p><p>complexes 9.3 in moderate to excellent yields (Scheme 9).</p><p>Another alternative route for the synthesis of alkyl sulfonamide</p><p>(10.3) was developed by Tsai et al. by the reaction between N-</p><p>tosylhydrazone (10.1), SO2 (1,4-diazabicyclo [2.2.2]octane bis (sul-</p><p>fur dioxide) known as DABSOwas used as a solid source of SO2) and</p><p>amine (10.2) in DMSO (Scheme 10) [56]. The addition of radical</p><p>inhibitor BHT (butylated hydroxytoluene) was not suppressing the</p><p>reaction yield which revealed that the reaction went through an</p><p>anionic mechanism, not by a radical mechanism.</p><p>In a similar custom,Wu et al. reported that the coupling reaction</p><p>of aryldiazonium tetrafluoroborates (11.1), DABCO.(SO2)2, and hy-</p><p>drazines (11.2) in acetonitrile under nitrogen atmosphere can lead</p><p>to various aryl N-sulfonamide derivatives (11.3) within 10 min</p><p>(Scheme 11a) [57]. Mechanistic studies reveal that the first ex-</p><p>change of sulfur dioxide occurs between DABCO.(SO2)2 and hy-</p><p>drazine 11.2 to generate the hydrazine-SO2 complex 11.4. The</p><p>hatic sulfonamide from rongalite.</p><p>Scheme 5. Synthesis of a-C-chiral sulfonamide from 2-pyrimidinyl thioether.</p><p>Scheme 6. Synthesis of sulfonamide via I2/TBHP-mediated reaction between tertiary amine and sodium sulfinate.</p><p>S. Mondal and S. Malakar Tetrahedron 76 (2020) 131662</p><p>complex 11.5 is formed through electrostatic interaction between</p><p>complex 11.4 and 11.1. Homolytic cleavage of the NeS bond and a</p><p>single-electron transfer produces the aryldiazonium radical 11.6,</p><p>SO2, and radical cation intermediate 11.7. Then, radical 11.6 releases</p><p>one equivalent of nitrogen, leading to the aryl radical 11.8 which</p><p>attacks SO2 to generate radical 11.9. On the other hand, deproto-</p><p>nation of the radical cation intermediate 11.7 produces hydrazi-</p><p>nium radical 11.10 which reacts with radical 11.9 to form the</p><p>desired sulfonamide 11.3 (Scheme 11b). They also modified their</p><p>methodology for the synthesis of similar sulfonamide by amino-</p><p>sulfonylation of aromatic amines, sulfur dioxide, and hydrazines</p><p>[58].</p><p>5</p><p>Another important methodology has been developed by Willis</p><p>et al. for the effective synthesis of aryl sulfonamide compounds by</p><p>combining Grignard reagents with bench-stable solid reagent 1,4-</p><p>diazabicyclo-[2.2.2]octane (DABCO)-bis(sulfur dioxide) (DABSO)</p><p>as an SO2 source to form sulfinates which then converted to the</p><p>corresponding sulfonamide compounds by the treatment with</p><p>sulfonyl chloride followed by various amines [59]. Later on, the</p><p>same group extended this methodology for the synthesis of sul-</p><p>fonamide by avoiding the use of sulfonyl chloride [60]. Instead of</p><p>the use of sulfonyl chloride, investigators used readily generated</p><p>sulfinates 12.2 as suitable precursors that were prepared from the</p><p>combination of organometallic reagents 12.1 and DABSO. The in</p><p>Scheme 7. Synthesis of sulfonamide from thiosulfonate.</p><p>Scheme 8. Synthesis of sulfonamide from aryl boronic acid and DAST-type reagent.</p><p>Scheme 9. Synthesis of sulfonamide from sulfonyl azide.</p><p>S. Mondal and S. Malakar Tetrahedron 76 (2020) 131662</p><p>6</p><p>situ generated sulfinates 12.2were converted to the corresponding</p><p>sulfonamide derivatives 12.4 with the treatment with various</p><p>amines 12.3 (Scheme 12).</p><p>In 2013, Waldmann and co-workers are also synthesized aryl</p><p>sulfonamide (13.2) by bromine-lithium exchange reaction of aryl</p><p>bromide (13.1) with tert-butyllithium (t-BuLi) (Scheme 13) [61].</p><p>Tucker et al. validated that reaction between sulfamoyl inner</p><p>salt (14.1) with organometallic species can lead to the formation of</p><p>sulfonamide (14.2) (Scheme 14) [62]. Nishimura and co-workers</p><p>also opened N-alkyl thiadiazolidinone 1,1-dioxides with methyl</p><p>Scheme 10. Synthesis of sulfonamide from N-tosylhydrazone.</p><p>Scheme 11. Synthesis of sulfonamide from aryldiazonium tetrafluoroborate.</p><p>S. Mondal and S. Malakar Tetrahedron 76 (2020) 131662</p><p>magnesium bromide to form methanesulfonamide [63].</p><p>In 2015, Tucker et al. also demonstrated the utility of thioether</p><p>as a valuable synthon for the elegant generation of heterocyclic</p><p>sulfonamides for drug discovery programs via a 3-step parallel</p><p>medicinal chemistry (PMC) protocol [64]. Condensation of amines</p><p>(15.2) (hydrochloride salts) with thioether (15.1) in refluxing</p><p>ethanol smoothly provided the functionalized pyrazoles 15.3which</p><p>on oxidation with a solution of N-chlorosuccinimide and HCl in</p><p>MeCN gave the pyrazole-4-sulfonyl chloride derivatives 15.4.</p><p>Treatment of</p><p>15.4 with versatile amines 15.5 in pyridine cleanly</p><p>provided the pyrazole-4-sulfonamide derivatives 15.6 with overall</p><p>yields up to 74% (Scheme 15).</p><p>Recently, Fokin and Thomas also reported the synthesis of 4-</p><p>sulfonamidotriazoles from 4-fluorosulfonyl 1,2,3-triazoles by the</p><p>treatment with versatile amines. By this process, they could syn-</p><p>thesize various naturally occurring sulfonamide and their</p><p>7</p><p>derivatives by using various primary amines, such as optically</p><p>active leelamine, L-tyrosine tert-butyl ester, and aminosteroid</p><p>funtamine [65]. Fascinatingly, our group also synthesized indole-2-</p><p>methylsulfonamide derivatives by domino Sonogashira coupling</p><p>and hydroamination reaction [66].</p><p>2.2. Transition metal-catalyzed synthesis of sulfonamide</p><p>Although many efforts have been made towards the develop-</p><p>ment of novel sulfonamide by the metal-free synthesis involving</p><p>either the reaction of amino compounds with sulfonyl chlorides or</p><p>by using sulfinate salts as the intermediates. However, the methods</p><p>for the synthesis of sulfonyl chlorides (such as electrophilic aro-</p><p>matic substitution with chlorosulfonic acid, oxidative chlorination</p><p>of organosulfur) generally suffer from harsh reaction conditions,</p><p>the scope of limitations and usually require hazardous and</p><p>Scheme 12. Synthesis of sulfonamide using organometallic reagents, DABSO, and amines.</p><p>Scheme 13. Synthesis of sulfonamide by the bromine-lithium exchange of aryl bro-</p><p>mide with tert-butyllithium.</p><p>Scheme 14. Synthesis of sulfonamide from sulfamoyl inner salt.</p><p>S. Mondal and S. Malakar Tetrahedron 76 (2020) 131662</p><p>polluting chlorinating agents or oxidants. Recently, however, a</p><p>number of transition metal-catalyzed reactions like the use of Pd,</p><p>Rh, Ru, Cu, Ni, Fe as transition metal catalyst have been evolved to</p><p>overcome the problems in conventional synthesis. In principle, a</p><p>transition-metal-catalyzed cross-coupling reaction can be used for</p><p>the direct introduction of an eSO2- moiety into suitably</p><p>Scheme 15. PMC protocol for the synthesis of pyra</p><p>8</p><p>functionalized substrates, such as aryl halides or aryl boronic acids</p><p>[67,68]. However, research in this area was extremely limited until</p><p>2010, when Willis first reported a breakthrough study on a direct</p><p>aminosulfonylation of aryl halides in the presence of a palladium</p><p>catalyst [69]. The recent development of transition metal-catalyzed</p><p>synthesis of sulfonamide is discussed in the following section</p><p>categorically.</p><p>2.2.1. Pd-catalyzed synthesis of sulfonamide</p><p>Palladium complexes are frequently used as catalysts because of</p><p>their higher chemical stability for oxidations. Shavnya et al. used</p><p>aryl and heteroaryl [(het)Ar] sulfinate salt for the Pd-catalyzed</p><p>synthesis of medicinally relevant sulfonamide including sildenafil</p><p>(Viagra) which is a familiar drug for the treatment of erectile</p><p>dysfunction via one-pot protocol [70]. The palladium-catalyzed</p><p>reaction of aryl or heteroaryl halide and triflate 16.1 in the pres-</p><p>ence of potassium metabisulfite (K2S2O5), sodium formate</p><p>(NaO2CH) (SO2 and hydrogen donors respectively), PPh3 (as an</p><p>additive) and phen (as a ligand) gave the sulfinate intermediate</p><p>16.2which was converted to N-substituted sulfonamide 16.4 by the</p><p>addition of amine 16.3 followed by NBS in THF (Scheme 16).</p><p>In 2016, Willis and co-workers also developed a Pd(II)-catalyzed</p><p>conversion of the boronic acids into the corresponding sulfinates in</p><p>combinationwith DABSO which then transformed into the suitable</p><p>sulfonamide derivatives with the treatment of N electrophiles [71].</p><p>When boronic acids (17.1) were treated with DABSO in presence of</p><p>Pd(OAc)2 as the catalyst with TBAB as an additive in 1,4-dioxane/</p><p>MeOH solvent for 30min at 80 �C, the corresponding sulfinates 17.2</p><p>were generated. The in situ generated sulfinates 17.2 were then</p><p>converted into the corresponding sulfonamide compounds 17.3</p><p>with the treatment of either O-hydroxylaminesulfonic acid or N-</p><p>chloramines (Scheme 17).</p><p>zole-4-sulfonamide derivatives from thioether.</p><p>Scheme 16. One-pot protocol for the synthesis of sulfonamide from aryl and heteroaryl halides.</p><p>S. Mondal and S. Malakar Tetrahedron 76 (2020) 131662</p><p>2.2.2. Cu-catalyzed synthesis of sulfonamide</p><p>Among transition metals, copper salts stand out because they</p><p>are inexpensive and nontoxic, and many of them are commercially</p><p>available. Furthermore, copper-mediated CeH activation reactions</p><p>generally do not require ligands or co-catalyst.</p><p>In 2013, Kim et al. demonstrated the synthesis of N-arylsulfo-</p><p>namide derivatives via Cu-catalyzed Chan-Lam CeN cross-coupling</p><p>reactions employing various sulfonyl azides and boronic acids [72].</p><p>The Chan-Lam CeN cross-coupling reactions between sulfonyl</p><p>azides 18.2 and boronic acids 18.1 proceeded smoothly with 10 mol</p><p>% CuCl as a catalyst in an open flask using MeOH as a solvent to</p><p>furnish the desired sulfonamide derivatives 18.3 in good to excel-</p><p>lent yields (Scheme 18).</p><p>Jiang also described copper-catalyzed oxidative coupling be-</p><p>tween sodium sulfinates (19.1) and amines (19.2) in DMSO for the</p><p>synthesis of sulfonamide derivatives 19.3 (Scheme 19) [73]. The</p><p>choice of DMSO as the solvent was crucial for the reaction. Mech-</p><p>anistic studies showed that the reaction may go through a single</p><p>electron transfer (SET) pathway.</p><p>Copper(I)-oxide-catalyzed cross-coupling reactions between</p><p>methanesulfonamide and aryl iodides in water were efficiently</p><p>applied in the synthesis of N-arylated methanesulfonamide com-</p><p>plexes by Teo and co-workers [74]. The treatment of aryl halides</p><p>20.2 (1.47 mmol) with methanesulfonamide 20.1 (2.21 mmol) in</p><p>presence of Cu2O (2 mol%), Cs2CO3 (2.94 mmol), and water (0.3 mL)</p><p>at 130 �C for 24 h afforded the N-arylated methanesulfonamide</p><p>20.3 in good to excellent yields (Scheme 20).</p><p>Moreover, Chen et al. developed a new strategy for the synthesis</p><p>of primary biaryl sulfonamide derivatives (21.4) via a tandem</p><p>process consisting of palladium-catalyzed CeH arylation of aryl</p><p>sulfonamino acids 21.1 with aryl halides 21.2 to form biaryl sulfo-</p><p>namino acids 21.3 and copper-catalyzed oxidative CeN bond</p><p>cleavage of the formed biaryl sulfonamino acids 21.3 [75]. When</p><p>aryl sulfonamino acid 21.5was separately treated with 10 mol% CuI</p><p>in acetonitrile at 100 �C for 8 h, the reaction underwent smoothly to</p><p>produce the aryl sulfonamide 21.6 in 97% yield (Scheme 21a).</p><p>According to the proposed mechanism, Cu(I) was first oxidized</p><p>into Cu(II) intermediate by air, and then 21.5 underwent the Cu-</p><p>catalyzed oxidative decarboxylation to generate iminium</p><p>Scheme 17. One-pot protocol for the synthe</p><p>9</p><p>intermediate 21.8 which by deprotonation was converted to in-</p><p>termediate 21.9. Finally, the imine intermediate 21.9 was hydro-</p><p>lyzed to afford the primary aryl sulfonamide 21.6 and benzaldehyde</p><p>21.7 (Scheme 21b).</p><p>Cu-catalyzed or -mediated CeH sulfonamidation is the best</p><p>alternative for the synthesis of diversely functionalized heterocycle</p><p>containing medicinally important natural or non-natural sulfon-</p><p>amide derivatives. Generally, a removable directing group (DG) is</p><p>needed for a successful CeH sulfonamidation reaction, and that DG</p><p>should contain two donor sites so that it can make a complex with</p><p>copper. For example, in 2016, Daugulis et al. published copper-</p><p>catalyzed sulfonamidation of compound 22.1 to synthesize sul-</p><p>fonamide 22.2 by employing 1,1,3,3-tetramethylguanidine (TMG) as</p><p>the organic base and 8-aminoquinoline as the removable directing</p><p>group (eq 1, Scheme 22a) [76]. Yu and co-workers employed</p><p>copper-mediated sulfonamidation of arenes and heteroarenes 22.3</p><p>using 2-(4,5-dihydrooxazol-2-yl)aniline as the removable DG and</p><p>10 mol% Cu(OAc)2 catalyst for the formation of sulfonamide de-</p><p>rivatives 22.4 (eq 2, Scheme 22a) [77]. Li et al. also reported copper-</p><p>mediated CeH sulfonamidation of 22.5 using 2-aminophenyl-1H-</p><p>pyrazole as a removable directing group and TMG as a base for the</p><p>synthesis of sulfonamide derivatives 22.6 (eq 3, Scheme 22a) [78].</p><p>The mechanism for the copper-mediated CeN bond formation</p><p>has not been well understood, but a possible mechanism is that</p><p>chelation of Cu(OAc)2 with N,N-bidentate substrate 22.5a affords</p><p>Cu(II)-complex 22.7. With the aid of the base, complex 22.7 un-</p><p>dergoes CeH cupration to afford Cu(II)-complex 22.8 which is</p><p>oxidized by Cu(OAc)2 to produce Cu(III)-complex 22.9. Ligand ex-</p><p>change with methanesulfonamide then gives rise to intermediate</p><p>22.10, which subsequently undergoes a reductive elimination to</p><p>deliver sulfonamide 22.6a (Scheme 22b).</p><p>Synthesis of aromatic sulfonamide through a copper-catalyzed</p><p>three-component coupling reaction of aryldiazonium tetra-</p><p>fluoroborate, SO2 (DABSOwas used as sulfur dioxide surrogate), and</p><p>N-Chloroamine is described by Wu et al. [79]. The said three-</p><p>component reaction was carried out with aryldiazonium tetra-</p><p>fluoroborates (23.1) (0.2 mmol, 1 equiv.), DABCO.(SO2)2 (1.5 equiv.)</p><p>as a source sulfonyl as well as a reductant,N-chloramines (23.2) (1.2</p><p>equiv.) as the amine source, and iPrOH (1 equiv.) as the additive in</p><p>sis of sulfonamide from boronic acids.</p><p>Scheme 18. Copper-catalyzed Chan-Lam coupling for the synthesis of sulfonamide derivatives.</p><p>Scheme 19. Copper-catalyzed oxidative coupling for the synthesis of sulfonamide</p><p>derivatives.</p><p>Scheme 20. Copper-catalyzed N-arylations of methanesulfonamide for the synthesis</p><p>of N-arylated methanesulfonamide derivatives.</p><p>S. Mondal and S. Malakar Tetrahedron 76 (2020) 131662</p><p>presence of 5 mol% Cu(OTf)2 catalyst in 1,2-dichloroethane (DCE)</p><p>solvent at 80 �C for 30min under nitrogen atmosphere to afford the</p><p>aromatic sulfonamide derivatives (23.3) in good yields (Scheme</p><p>23a). Moreover, amines can be used instead of N-chloramines via</p><p>in situ chlorination in a one-pot, two-step process.</p><p>According to the proposedmechanism, first sulfonyl radical 23.5</p><p>will generate from 23.1 and DABCO.(SO2)2 by homolytic cleavage of</p><p>the NeS bond followed by single electron transfer. On the other</p><p>hand, DABCO.(SO2)2 would reduce Cu(II) to Cu(I) with the assis-</p><p>tance of iPrOH. Subsequent oxidative addition gave rise to Cu(III)</p><p>intermediate 23.4, which would react with the sulfonyl radical 23.5</p><p>to afford a Cu(IV) intermediate 23.6. Finally, reductive elimination</p><p>of intermediate 23.6 would provide the desired sulfonamide 23.3</p><p>with the regeneration of Cu(II) catalyst (Scheme 23b).</p><p>A copper-catalyzed three-component coupling reaction of trie-</p><p>thoxysilanes (24.1), SO2 (DABSO was used as sulfur dioxide surro-</p><p>gate), and hydrazines (24.2) has also been described by Wang et al.</p><p>for the synthesis of aromatic sulfonamide derivatives (24.3)</p><p>(Scheme 24) [80]. Here it is worth mentioning that not only trie-</p><p>thoxy(aryl) silanes but also triethoxy(alkyl) silanes were compat-</p><p>ible during the process of insertion of sulfur dioxide. Moreover,</p><p>diethoxydiarylsilanes (24.1′) instead of triethoxysilanes (24.1) were</p><p>also suitable for this three-component reaction.</p><p>Willis et al. also developed a single-step sulfonamide synthesis</p><p>by combining (hetero)aryl boronic acids 25.1 and amines 25.2 along</p><p>with sulfur dioxide (DABSO was used as sulfur dioxide surrogate)</p><p>using copper(II) triflate as a catalyst and bipyridine 25.3 as a ligand</p><p>[81]. The corresponding sulfonamide compounds 25.4 were ob-</p><p>tained in 40e77% yields and the details are depicted in Scheme 25.</p><p>10</p><p>2.2.3. Rh-catalyzed synthesis of sulfonamide</p><p>Rh-catalyst for CeH functionalization has also attracted atten-</p><p>tion due to its high catalytic activity and excellent functional group</p><p>tolerance. In 2013, a novel Rh(III)-catalyzed method for the N-</p><p>chelator directed ortho-sp2 CeH bond amidation has been devel-</p><p>oped by Su et al. for the synthesis of a range of aryl sulfonamide</p><p>derivatives [82]. When N-chelator-containing arenes (26.1) were</p><p>treated with aromatic and aliphatic sulfonamide derivatives (26.2)</p><p>in presence of PhI(OAc)2 as an oxidant and [Cp*Rh(III)](SbF6)2 as</p><p>catalyst (which was generated in situ from [Cp*RhCl2]2 in the</p><p>presence of AgSbF6) in CH2Cl2 at 60 �C for 24 h, the desired sul-</p><p>fonamide derivatives 26.3were obtained in good to excellent yields</p><p>(Scheme 26). In similar content, Harrity et al. extended the Su’s</p><p>methodology by considering 2-aryloxazolines as the directing</p><p>group for the synthesis of sulfonamide complexes [83].</p><p>Moreover, Su�arez and Chiara developed a new methodology for</p><p>the direct intermolecular C(sp3)-H amination of simple hydrocar-</p><p>bons using shelf-stable nonafluorobutanesulfonyl azide in the</p><p>presence of a dirhodium(II) tetracarboxylate catalyst for the syn-</p><p>thesis of sulfonamide [84]. For example, when simple indane (27.1)</p><p>was treated with 2 equivalents of nonafluorobutanesulfonyl azide</p><p>(27.2) in presence of 5 mol% Rh2(OAc)4-catalyst in 1,2-</p><p>dichloroethane (DCE) solvent at 90 �C for 12 h, the sulfonamide</p><p>(27.3) was obtained in 83% yield (Scheme 27). Based on the control</p><p>experiments, a concerted asynchronous pathway can be reasonably</p><p>proposed for this nitrene CeH insertionwith only partial CeH bond</p><p>breaking in the transition state. Here it is worth mentioning that,</p><p>the use of azides is particularly appealing in this context since the</p><p>reaction is environmentally friendly, producing only gaseous ni-</p><p>trogen as a by-product and not requiring the addition of an oxidant.</p><p>2.2.4. Other transition metal-catalyzed synthesis of sulfonamide</p><p>Besides the above discussed Pd-, Cu-, and Rh-catalyzed reaction</p><p>for the sulfonamide synthesis there are some recent references on</p><p>Fe- and Ru-catalyzed reactions for the same. In 2015, Luo et al.</p><p>reported an iron-catalyzed synthesis of N-arylsulfonamide com-</p><p>plexes via the construction of NeS bonds from the direct coupling</p><p>of sodium arylsulfinates with nitroarenes which were used as ni-</p><p>trogen sources here [85]. The coupling reactions of sodium sulfi-</p><p>nates (28.1) with nitroarenes (28.2) were performed with 3</p><p>equivalents of NaHSO3 as reductant, 10 mol% FeCl2 as a catalyst, and</p><p>20 mol% trans-N,N0-dimethyl-1,2-diaminocyclohexane (DMDACH)</p><p>as an additive in DMSO at 60 �C for 12 h for the synthesis of N-</p><p>arylsulfonamide complexes (28.3) (Scheme 28).</p><p>Many pharmaceutical scaffolds include 7-sulfonamide-</p><p>substituted indolines or their derivatives. For example, indisulam</p><p>(E7070), a sulfonamide drug in combination CPT-11 is very much</p><p>effective for cancer treatment [86]. Therefore, the directing-group-</p><p>assisted selective CeH bond functionalization of indolines at the C7</p><p>position is synthetically very attractive. In this point of view, Zhu</p><p>et al. developed a ruthenium-catalyzed direct C7 amidation of</p><p>indoline CeH bonds with sulfonyl azides for the synthesis of 7-</p><p>sulfonamide substituted indolines [87]. When indolines (29.1)</p><p>Scheme 21. Pd(II)/Cu(I)-catalyzed one-pot synthesis of biaryl sulfonamide derivatives.</p><p>S. Mondal and S. Malakar Tetrahedron 76 (2020) 131662</p><p>were treated with sulfonyl azides (29.2) in presence of [RuCl2(p-</p><p>cymene)]2 (5 mol%), AgSbF6 (20 mol%) and additive AgOAc (50 mol</p><p>%) in DCE at 80 OC for 10 h to afford 7-sulfonamide substituted</p><p>indolines (29.3) in good yields (Scheme 29).</p><p>An another Ru(II)-catalyzed intermolecular amidation of weakly</p><p>coordinating ketones (30.1) with sulfonyl azides (30.2) via CeH</p><p>bond activation for the synthesis sulfonamide derivatives 30.3</p><p>has been described by Jiao and co-workers (Scheme 30) [88]. Here</p><p>Cu(OAc)2 was used as an additive whereas in the former case that</p><p>was AgOAc.</p><p>3. Synthetic applications of sulfonamide</p><p>Over the past several years, sulfonamide have emerged as</p><p>valuable scaffolds that offer novel possibilities for asymmetric and</p><p>non-asymmetric transformations [89e91]. In various cases, sul-</p><p>fonamide group can act as a directing group in promoting CeH</p><p>activation, sometime rearrangement of sulfonamide derivatives</p><p>gives valuable synthons, and recently transition metal-catalyzed</p><p>coupling reactions with sulfonamide complexes offered some</p><p>natural and non-natural drugs. The synthetic applications of sul-</p><p>fonamide are discussed in the following section categorically.</p><p>11</p><p>3.1. Sulfonamide moiety as an activating group</p><p>In 2014, Rh(III)-catalyzed ortho CeH olefination of aryl sulfon-</p><p>amide directed by the SO2NHAc group has been reported by Li and</p><p>co-workers [92]. Oxidative olefination of sulfonamide derivatives</p><p>(31.1) with styrenes (31.2) in presence of 5 mol% [Cp*RhCl2]2 as</p><p>catalyst and AgOAc (4.0 equiv.) as an oxidant in t-AmOH (2.0 mL) as</p><p>solvent at 120 �C for 36 h to afford the dialkenylated derivatives</p><p>(31.3) in good to excellent yields (Scheme 31).</p><p>In similar context, the same group also published Rh(III)-</p><p>catalyzed oxidative olefination of N-allyl sulfonamide derivatives</p><p>[93]. Oxidative olefination of N-sulfonyl allylamines (32.1) with</p><p>activated olefins (32.2) in presence of 4 mol% [Cp*RhCl2]2 as cata-</p><p>lyst and AgOAc (2.1 equiv.) as an oxidant in acetone (3.0 mL) as</p><p>solvent at 100 �C under sealed tube for 24 h to afford the coupling</p><p>products (32.3) in moderate to good yields (Scheme 32). Here it is</p><p>worth mentioning that, Zhou et al. also described copper-catalyzed</p><p>oxidative coupling reactions between aldehydes and electron-</p><p>deficient olefins [94].</p><p>In 2015, iridium-catalyzed ortho CeH activation and deuteration</p><p>of aryl sulfonamide directed by the SO2NH2 group have been</p><p>explored by Kerr and co-workers [95]. Ortho-deuteration of pri-</p><p>mary sulfonamide derivatives (33.1) were done by the use of</p><p>Scheme 22. Cu-catalyzed or -mediated CeH sulfonamidation for the synthesis of heterocycle containing sulfonamide.</p><p>S. Mondal and S. Malakar Tetrahedron 76 (2020) 131662</p><p>6.5 mol% [(COD)Ir(NHC)Cl] complexes (NHC ¼ N-heterocyclic car-</p><p>bene) (33.2) under D2 (ballon) in DCM for 2 h at rt to afford prod-</p><p>ucts (33.3) in good to excellent yields (Scheme 33).</p><p>Furthermore, Bisz and Szostak demonstrated that sulfonamide</p><p>acts as the one of most reactive activating groups for iron-catalyzed</p><p>alkylative cross-coupling and also investigated that the sulfon-</p><p>amide group is poised for applications as a traceless activating</p><p>group [96]. A variety of benzosulfonamides (34.3) were prepared by</p><p>the iron-catalyzed C(sp2)-C(sp3) cross-coupling of electronically-</p><p>and sterically-varied chlorobenzosulfonamides (34.1) with alkyl</p><p>Grignard reagents containing b-hydrogen (34.2) in presence of</p><p>NMP (N-methyl-2-pyrrolidone) ligand (Scheme 34).</p><p>3.2. Alkylations/arylations of sulfonamide</p><p>Alkylated/arylated sulfonamide lay a backbone structure in</p><p>12</p><p>many organic syntheses, such as in pharmaceuticals, agrochemi-</p><p>cals, and plasticizers, etc [97e102]. As a concern, the alkylation/</p><p>arylation of sulfonamide derivatives is of key importance.</p><p>In 2014, Li et al. explored that thewater soluble iridium complex</p><p>{Cp*Ir-[6,6’-(OH)2bpy](H2O)}[OTf]2 (Cp* ¼ h5-pentam-</p><p>ethylcyclopentadienyl, bpy ¼ 2,20-bipyridine) was very efficient</p><p>catalyst for the alkylation of sulfonamide derivatives with alcohols</p><p>in water [103]. The presence of OH units in the bpy ligand was very</p><p>crucial for the catalytic activity of the iridium complex. In the</p><p>presence of catalyst 35.3 (1 mol%) and Cs2CO3 (0.1 equiv.), the re-</p><p>actions of 35.1with 35.2were carried out at 120 �C in water (1 mL)</p><p>for 15 h to afford the N-alkylated sulfonamide derivatives 35.4 in</p><p>good to excellent yields (Scheme 35).</p><p>An intermolecular alkylation of sulfonamide complexes with</p><p>trichloroacetimidates under thermal conditions was also reported</p><p>by Chisholm and Wallach [104]. Unsubstituted sulfonamide was</p><p>Scheme 23. Cu-catalyzed three-component reaction of aryldiazonium tetra-</p><p>fluoroborates, SO2 and N-chloramines for the synthesis of aromatic sulfonamide</p><p>derivatives.</p><p>Scheme 24. Cu-catalyzed three-component reaction of triethoxysilanes, SO2, and hy-</p><p>drazines for the synthesis of N-aminosulfonamide complexes.</p><p>S. Mondal and S. Malakar Tetrahedron 76 (2020) 131662</p><p>found to undergo alkylation well, but N-substituted sulfonamide</p><p>was not effectively alkylated. With the portion wise addition of</p><p>imidates 36.2 over 2.5 h in refluxing solution of sulfonamide</p><p>complexes 36.1 in THF and further reflux up to a total 18 h, afforded</p><p>the alkylated sulfonamide derivatives 36.3 in good to excellent</p><p>yields (Scheme 36).</p><p>In 2015, Hu et al. developed a stereoselective, palladium-</p><p>catalyzed aza-Wacker-type reaction between electron-deficient</p><p>olefins and N-alkylsulfonamide derivatives [105]. The presence of</p><p>Scheme 25. Cu-catalyzed three-component reaction of boron</p><p>13</p><p>the stoichiometric amount of methanesulfonic acid as an additive</p><p>was very crucial for this transformation. Treatment of compound</p><p>37.1 and 37.2 with palladium acetate (5%) as a catalyst, 1.5 equiv.</p><p>Selectfluor {1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]oc-</p><p>tane bis(tetrafluoroborate)} as oxidant and 2 equiv. meth-</p><p>anesulfonic acid as an additive in ethyl acetate solvent at 50 �C gave</p><p>the compounds 37.3 in good yields with excellent E-type stereo-</p><p>selectivities (Scheme 37).</p><p>A direct copper-promoted N-arylation of sulfonamide de-</p><p>rivatives with sodium sulfinates via desulfitative pathway was</p><p>demonstrated by An and co-workers [106]. When sulfonamide</p><p>derivatives (38.1) and sodium arylsulfinates (38.2) were heated at</p><p>120 �C in DMSO for 12 h in the presence of CuCl2 (50 mol%), K2CO3</p><p>(2 equivalent) and powdered molecular sieves, afforded arylated</p><p>products 38.3 in good yields (Scheme 38). Control experiments</p><p>were studied to understand the mechanistic pathway which sup-</p><p>ports anion exchange interaction.</p><p>Fu et al. developed nickel-catalyzed stereoconvergent Negishi</p><p>arylations and alkenylations of a-bromosulfonamide complexes</p><p>(39.1) with an array of reaction partners (39.2) in the presence of</p><p>10% NiCl2.glyme catalyst and 13% chiral ligand (39.3) in THF</p><p>at �20 �C to obtain the desired coupling products (39.4) in very</p><p>good ee and yields (Scheme 39) [107].</p><p>A palladium-catalyzed Negishi-type a-arylation of sulfonamide</p><p>derivatives (40.1) with a broad range of aryl bromides (40.2) has</p><p>also been developed by Knauber and Tucker using 2,2,6,6-</p><p>tetramethylpiperidine.ZnCl.LiCl as a base, Pd(dba)2 as a catalyst,</p><p>and XPhos ligand in THF for the synthesis of desired monoarylated</p><p>a-branched benzyl sulfonamide complexes (40.3) in good yields</p><p>(Scheme 40) [108]. Simple aryl bromides were converted overnight</p><p>at 60 �C in THF while heteroaryl bromides were efficiently coupled</p><p>within 2 h at 130 �C in a microwave reactor.</p><p>Moreover, very recently, Qin et al. have used CuBr2 as an efficient</p><p>catalyst for the coupling between sulfonamide with alkylamine for</p><p>the successful synthesis of (E)-N-sulfonylformamidine [109]. Under</p><p>the optimal conditions, i.e. when sulfonamide derivatives 41.1were</p><p>employed with 2 equivalents of alkylamines 41.2, in the presence of</p><p>20 mol% CuBr2 in DMSO at 100 �C for 24 h, the desired product (E)-</p><p>41.3 were obtained as single (E)-stereoisomer in good yields</p><p>(Scheme 41).</p><p>Furthermore, Manolikakes et al. described palladium-catalyzed</p><p>enantioselective three-component synthesis of a-arylglycines</p><p>(42.5) in high yields and excellent enantioselectivities starting from</p><p>sulfonamide derivatives (42.1), glyoxylic acid derivatives (42.2),</p><p>and aryl boronic acids (42.3) in presence of 10 mol% Pd(TFA)2 as a</p><p>catalyst, 15 mol% chiral Box-ligand (42.4) in nitromethane at 40 �C</p><p>for 64 h (Scheme 42) [110].</p><p>Moura-Letts et al. demonstrated that the reaction of aldehydes</p><p>and sulfonamide derivatives can be used for the synthesis of sul-</p><p>fonylamidonitriles with rutile (TiO2 in its natural form) as a recy-</p><p>clable catalyst [111]. Sulfonamide derivatives (43.1), aldehydes</p><p>(43.2) and rutile were mixed in H2O and then NaCN was added as a</p><p>ic acid, amine, and SO2 for the synthesis of Sulfonamide.</p><p>Scheme 26. Rh-catalyzed N-chelator-directed aromatic CeH amidation for the synthesis of heterocycle containing sulfonamide.</p><p>Scheme 27. Rh-catalyzed intermolecular sulfamidation reaction for the synthesis of sulfonamide.</p><p>Scheme 28. Fe-catalyzed N-arylsulfonamide formation.</p><p>Scheme 29. Ru-catalyzed C7 amidation of indoline CeH bonds.</p><p>S. Mondal and S. Malakar Tetrahedron 76 (2020) 131662</p><p>4 M solution in water and stirred for 3e6 h to synthesize sulfony-</p><p>lamidonitriles (43.3) in good to excellent yields (Scheme 43).</p><p>3.3. Rearrangement of sulfonamide derivatives</p><p>Sulfonylation reactions via the rearrangement of sulfonyl groups</p><p>are limited but</p><p>very beautiful art in organic synthesis. In 2013, Zhan</p><p>et al. developed a DMAP-catalyzed synthesis of 4-sulfonyl-1H-</p><p>14</p><p>pyrazole (44.3) from N-propargylic sulfonylhydrazone derivatives</p><p>(44.1) via allenic sulfonamide formation (44.2), sulfonyl rear-</p><p>rangement followed by cyclization (Scheme 44, eq. 1) [112]. Here it</p><p>is important to mention that in a previous report, Wan et al.</p><p>demonstrated a Cs2CO3-catalyzed synthesis of b-sulfonylmethyl-</p><p>substituted pyrroles (44.5) from N-sulfonyl-protected 3-aza-1,5</p><p>enyne derivatives (44.4) by the same reactions sequence i.e. via</p><p>allenic sulfonamide formation, sulfonyl rearrangement followed by</p><p>Scheme 30. Ru-catalyzed CeH functionalization with ketone as a directing group for the synthesis of sulfonamide derivatives.</p><p>Scheme 31. Rh-catalyzed oxidative CeH olefination.</p><p>Scheme 32. Rh-catalyzed oxidative olefination of N-sulfonyl allylamines.</p><p>Scheme 33. Ir-catalyzed o-deuteration of primary sulfonamide derivatives.</p><p>S. Mondal and S. Malakar Tetrahedron 76 (2020) 131662</p><p>cyclization (Scheme 44, eq. 2) [113]. Here it is also worth</p><p>mentioning that, Hsung, Zhang, and co-workers also reported the</p><p>synthesis of a-sulfonyl nitriles (44.8) via 1,3-sulfonyl rearrange-</p><p>ment of allyl ketenimines (44.7), that are formed in situ by a</p><p>thermal aza-Claisen rearrangement of N-allyl-N-sulfonyl ynamides</p><p>(44.6) (Scheme 44, eq. 3) [114].</p><p>Additionally, a 1,3-rearrangement of sulfonyl group in N-allenyl-</p><p>15</p><p>N-siloxysulfonamides (45.1) via the formation of nitrosoallenes</p><p>(45.2) as an intermediate was achieved by Tanimoto and co-</p><p>workers in the presence of 1.2 equiv. of TBAB and 1.5 equiv. of</p><p>AcOH in THF to provide a-sulfonyl enoximes (45.3) in very good</p><p>yields (Scheme 45) [115].</p><p>Maulide et al. succeeded a synthesis of imidazole derivatives</p><p>(46.3) via the addition of nitriles (46.2) to 2-[(methyl)</p><p>Scheme 34. Ir-catalyzed cross-coupling of sulfonamide derivatives with alkyl Grignard reagents.</p><p>Scheme 35. N-Alkylation of sulfonamide derivatives with alcohols in water.</p><p>Scheme 36. Alkylation of sulfonamide with trichloroacetimidate.</p><p>S. Mondal and S. Malakar Tetrahedron 76 (2020) 131662</p><p>sulfonylamido]acetic amides (46.1), followed by the rearrangement</p><p>of sulfonyl group (Scheme 46) [116].</p><p>Very recently, Moriyama and Watanabe performed a CeH sul-</p><p>fonylation of N-protected 3-bissulfonimidoindole derivatives (47.1)</p><p>via a 1,3-rearrangement of a sulfonyl group on a bissulfonimide</p><p>Scheme 37. The Aza-Wacker-type reaction betwee</p><p>Scheme 38. Copper-promoted desulfitative arylation of</p><p>16</p><p>moiety using tetra-n-butylammonium fluoride (TBAF) to provide 2-</p><p>sulfonyl-3-sulfonamidoindole derivatives (47.2) in good yields</p><p>(Scheme 47, eq. 1) [117]. We also synthesized a series of 2-</p><p>aminodiarylsulfones (47.4) in very high yields by Brønsted acid-</p><p>mediated 1,3-rearrangement of N-alkyl-N-arylbenzenesulfona-</p><p>mides (47.3) (Scheme 47, eq. 2) [118].</p><p>3.4. Other synthetic applications of sulfonamide</p><p>Besides the above discussed synthetic applications of sulfon-</p><p>amide, there are some more important applications of sulfonamide</p><p>which were used in crucial organic transformations. Recently, a</p><p>very simple and practical approach for the synthesis of sufonyl</p><p>fluorides from sulfonamide derivatives is reported by Cornella and</p><p>P�erez-Palau [119]. Sulfonamide derivatives (48.1) react with Pyry-</p><p>n olefins and N-alkylsulfonamide derivatives.</p><p>sulfonamide derivatives with sodium arylsulfinates.</p><p>Scheme 39. Stereoconvergent Negishi arylation of a-bromosulfonamide complexes.</p><p>Scheme 40. Palladium-catalyzed Negishi-type a-arylation of sulfonamide derivatives with aryl bromides.</p><p>Scheme 41. Copper-catalyzed coupling of sulfonamide derivatives with alkylamines.</p><p>Scheme 42. Palladium-catalyzed three-component synthesis of a-arylglycines.</p><p>Scheme 43. Rutile promoted synthesis of sulfonylamidonitrile from sulfonamide.</p><p>S. Mondal and S. Malakar Tetrahedron 76 (2020) 131662</p><p>17</p><p>BF4 and MgCl2 to form sulfonyl chlorides, which were converted in</p><p>situ into sulfonyl fluorides (48.2) in the presence of KF (Scheme 48).</p><p>Willis et al. have also studied the synthesis of sulfones (49.3) by</p><p>the reactions of dialkyl-N-aminosulfonamide derivatives (49.1)</p><p>with a range of electrophiles (49.2) by employing two comple-</p><p>mentary methods (Scheme 49) [120]. Method II gave a much</p><p>cleaner reaction for the synthesis of a,b-unsaturated sulfones, and</p><p>aryl sulfones.</p><p>Moreover, Song, Li, and co-workers developed oxidative 1,2-</p><p>arylmethylation cascades of acryl sulfonamide derivatives (50.1)</p><p>with di-tert-butyl peroxide (DTBP) (50.2) in PhCl under an argon</p><p>atmosphere at 120 �C for 5 h afforded the desired products 50.3 in</p><p>Scheme 44. Rearrangement of alkynylsulfonamide derivatives.</p><p>Scheme 45. Rearrangement of allenyl sulfonamide derivatives.</p><p>Scheme 46. Rearrangement of sulfonamide derivatives involving the addition of</p><p>nitriles.</p><p>S. Mondal and S. Malakar Tetrahedron 76 (2020) 131662</p><p>moderate to good yields (Scheme 50a) [121]. Mechanistically, DTBP</p><p>(50.2) readily generates methyl radical and acetone under heating.</p><p>The addition of the methyl radical across the CeC double bond in</p><p>50.1 affords the radicals 50.4, followed by intramolecular 5-ispo-</p><p>cyclization, which gives the intermediates 50.5. The intermediates</p><p>50.5 then convert into the amidyl radical intermediates 50.6 via</p><p>desulfonylation. Finally, hydrogen abstraction of the intermediates</p><p>50.6 affords the desired product 50.3 (Scheme 50b).</p><p>During the preparation of this review article, one interesting</p><p>paper came on the web by Lian et al. who demonstrated nickel-</p><p>18</p><p>catalyzed intramolecular desulfitative CeN coupling for the syn-</p><p>thesis of aromatic amines [122]. This method can be applied for the</p><p>synthesis of dialkyl aryl amines, alkyl diaryl amines, and triaryl</p><p>amines. When sulfonamide complexes 51.1 were treated with</p><p>10 mol% Ni(COD)2 as a catalyst, 1.5 equiv. NaOtBu as a base, 20 mol%</p><p>IPr.HCl as NHC ligands and a catalytic amount of Lewis acid, BPh3 in</p><p>Xylene at 60 �C, the desulfitative products 51.2 were obtained in</p><p>good yields (Scheme 51). Here it is important to note that, the use of</p><p>catalytic amount of BPh3 allows the transformation to take place</p><p>under much milder conditions (60 �C) compared to previously re-</p><p>ported CeN coupling reactions by CO or CO2 extrusion</p><p>(160e180 �C).</p><p>4. Biological applications of sulfonamide</p><p>Since the discovery of the first sulfonamide drug- Prontosil in</p><p>1932, which showed antibacterial activity, sulfonamide drugs are</p><p>taking a prodigious position in the drug market still today. They</p><p>possess enormous appeal in the biological field for their immense</p><p>multifunctional activities which include antibacterial, antitumor,</p><p>anticancer, antifungal, antithyroid, diuretic, hypoglycemia, and</p><p>Scheme 47. 1,3-Rearrangement of sulfonamide complexes.</p><p>Scheme 48. Synthesis of sulfonyl fluorides from sulfonamide derivatives.</p><p>Scheme 49. Synthesis of sulfone derivatives from sulfonamide derivatives.</p><p>S. Mondal and S. Malakar Tetrahedron 76 (2020) 131662</p><p>anti-HIV properties [3]. Many new developments of these prolific</p><p>drugs are achieved recently and this review covers mainly the de-</p><p>velopments during the period 2013e2019.</p><p>4.1. Sulfonamide as therapeutic agents</p><p>In 2013, Gonz�alez-Rosende and co-workers synthesized a series</p><p>of novel N-substituted benzene- and N-naphthalenesulfonamide</p><p>derivatives and tested their in vivo and in vitro antileishmanial and</p><p>antitrypanocidal activities [123]. Among the tested compounds,</p><p>52a and 52b showed promising in vivo activity against Leishmania</p><p>and Trypanosoma parasites (Fig. 2).</p><p>In 2014, Tripathi et al. designed and synthesized a series of novel</p><p>C-linked phenyl butenonyl glycoside bearing sulfonamidyl moiety</p><p>19</p><p>and tested their in vitro antimalarial activities against Plasmodium</p><p>falciparum 3D7 and K1 strains [124]. Among the screened com-</p><p>pounds, compound 53 showed promising antimalarial activity</p><p>against both the strains with high selectivity index and low cyto-</p><p>toxicity (Fig. 3).</p><p>Recently, Hussein, Ahmed, and co-workers designed and syn-</p><p>thesized new 2-(arylamino)acetamide</p><p>and N-arylacetamide de-</p><p>rivatives containing sulfonamide moieties and studied their</p><p>antimicrobial and anticancer activity against human lung carci-</p><p>noma (A-549) and human breast carcinoma (MCF-7) cell lines</p><p>[125]. Most of the newly synthesized compounds showed signifi-</p><p>cant anticancer activity and some of them showed remarkable</p><p>antibacterial and antifungal activities also. For example, compound</p><p>54 showed significant anticancer, antibacterial, and antifungal ac-</p><p>tivities (Fig. 4). From amolecular docking study, it was revealed that</p><p>the newly synthesized compounds have good binding interactions</p><p>with the active sites of dihydrofolate reductase (DHFR) through</p><p>which they showed these activities.</p><p>Debbabi et al. also introduced a series of novel pyridine-N-ethyl-</p><p>N-methylbenzene sulfonamide derivatives as promising anticancer</p><p>and antimicrobial agents [126]. Among the synthesized sulfon-</p><p>amides, compounds 55a, 55c, and 55d proficiently displayed</p><p>effective cytotoxic activities against the human breast cancer cell</p><p>line (MCF-7). And compounds 55a, 55b, and 55e displayed anti-</p><p>bacterial activity against gram-negative bacteria (Klebsiella pneu-</p><p>moniae) (Fig. 5). As discussed in the above examples, the</p><p>mechanism of action also through the inhibition of the DHFRwhich</p><p>was confirmed through a molecular docking experiment.</p><p>Recently, Brabander et al. developed small molecule therapeu-</p><p>tics by synthesizing TASIN-1 analogs (56), that target specially</p><p>oncogenotypes and showed activity against colorectal cancers</p><p>(Fig. 6) [127].</p><p>Li, Cui, and co-workers designed and synthesized a new series of</p><p>2-substituted aminocycloalkylsulfonamide derivatives and studied</p><p>their fungicidal activities against different strains of Botrytis ciner-</p><p>eal and Pyricularia grisea [128]. Among the newly synthesized</p><p>compounds, sulfonamides containing 2-chlorothiazol-5-yl-methyl</p><p>group, for example sulfonamide 57, were selected as the best active</p><p>compounds to show effective fungicidal activities (Fig. 7).</p><p>The high throughput screening (HTS) of 87,926 compounds</p><p>against Trypanosoma brucei, Baell and Keller et al. found that the</p><p>tetrahydroisoquinoline disulfonamide 58 could be a lead com-</p><p>pound for antitrypanocidal activity (Fig. 8) [129]. After getting the</p><p>Scheme 50. Oxidative 1,2-arylmethylation of acryl sulfonamide derivatives.</p><p>Scheme 51. Nickel-catalyzed dedulfitative CeN coupling.</p><p>Fig. 2. Sulfonamide as potent antileishmanial and antitrypanocidal agents.</p><p>Fig. 3. Sulfonamide as potent antimalarial agent.</p><p>Fig. 4. Sulfonamide as a potent anticancer, antibacterial, and antifungal agent.</p><p>S. Mondal and S. Malakar Tetrahedron 76 (2020) 131662</p><p>20</p><p>Fig. 5. Sulfonamide as potent anticancer and antimicrobial agent.</p><p>Fig. 6. Sulfonamide targeting colorectal cancer cells.</p><p>Fig. 8. Sulfonamide as potent antitrypanocidal agent.</p><p>Fig. 9. Sulfonamide as potent JAK3 covalent inhibitor.</p><p>S. Mondal and S. Malakar Tetrahedron 76 (2020) 131662</p><p>lead compound, they synthesized 26 derivatives of compound 58</p><p>and studied their structure-activity analysis against Trypanosoma</p><p>brucei and found that the newly synthesized compounds showed</p><p>good activities as antitrypanocidal agents within the range 2e4 mМ.</p><p>The Janus kinases (JAKs) are attractive targets to the developers</p><p>for the treatment of a number of therapeutic indications including</p><p>cancer and autoimmune disease [130e132]. By searching JAK3 in-</p><p>hibitors as therapeutic agents for the treatment of autoimmune and</p><p>inflammatory diseases, Casimiro-Garcia et al. discovered in 2018</p><p>that sulfonamide 59 proved to be an efficient JAK3 covalent in-</p><p>hibitor as a stimulating aim in the cure of innumerable physiolog-</p><p>ical activities (Fig. 9) [133].</p><p>Transient receptor potential vanilloid-4 (TRPV4) regulates Ca2þ/</p><p>Naþ influx into pulmonary vascular endothelial cells and upregu-</p><p>lated in heart failure (HF) patients. Increased pulmonary venous</p><p>pressure due to stimulation of TRPV4 causes contraction and</p><p>detachment in cells which in response disrupts normal action of</p><p>the alveolar septal barrier which may be the cause of heart failure.</p><p>Brnardic et al. and Pero et al. designed pyrrolidine sulfonamides</p><p>60a, 60b as effective TRPV4 antagonists (Fig. 10) [134,135].</p><p>Recently, Rescourio et al. developed a sulfonamide derivative 61</p><p>containing an a-hydroxy phenylacetic acid pharmacophore which</p><p>is a potent McI-1 inhibitor with good pharmacokinetic property</p><p>and excellent in vivo efficacy in an OPM-2 multiple myeloma</p><p>xenograft model (Fig. 11) [136].</p><p>Fig. 7. Sulfonamide promotes fungicidal activity.</p><p>21</p><p>4.2. Sulfonamide with anti-carbonic anhydrase activity</p><p>Metalloenzyme-carbonic anhydrase has 15 different isoforms</p><p>involved in varied physiologic and pathologic processes such as pH</p><p>homeostasis, cell differentiation, proliferation, and neurotrans-</p><p>mission. Subsequently, abnormal activity in these processes leads</p><p>to varied health issues. Supuran and Akdemir et al. synthesized a</p><p>series of halogeno/methoxyphenacetamido tails containing aro-</p><p>matic or heterocyclic sulfonamides of which sulfonamide de-</p><p>rivatives 62a and 62b are showed the highest activity to inhibit</p><p>TcCA (a-carbonic anhydrase-enzyme of protozoan in Chagas dis-</p><p>ease) without alarming human off target isoforms hCA I and II</p><p>(Fig. 12) [137].</p><p>CA IX isoform assists in survival, proliferation, and metastasis of</p><p>Fig. 10. Sulfonamide as bioavailable antagonists of TRPV4.</p><p>Fig. 11. Sulfonamide as a potent McI-1 inhibitor.</p><p>S. Mondal and S. Malakar Tetrahedron 76 (2020) 131662</p><p>the hostile hypoxic tumor. Since CAs catalyzes the interconversion</p><p>of CO2 and H2O with HCO3</p><p>�and an Hþ to execute pH regulation so</p><p>researches aim is to disrupt cancer cell pH homeostasis by the</p><p>synthesis of selective and efficient inhibitors of CA IX in case of</p><p>Hypoxic cancer therapies. In this pretext, Supuran and Poulsen et al.</p><p>demonstrated cyclic secondary sulfonamide 63 with hydrophobic</p><p>or hydrophilic substituents which attempted to show enhanced</p><p>cancer-selective CA inhibitors (Fig. 13) [138].</p><p>CA I deals in retinal and cerebral edema, CA II constitutes</p><p>glaucoma, epilepsy, and prevention of acute mountain sickness, CA</p><p>IX and CA XII are targets of anticancer drugs, CA XIV is likely to be</p><p>the aim of epileptic agents and retinopathies. In 2015, Silvestri and</p><p>group designed sulfonamide 64 as an effective hCA XIV isoform</p><p>Fig. 12. Sulfonamide act as a strong</p><p>22</p><p>inhibitor (Fig. 14) [139].</p><p>Carbonic anhydrase act as effective anticonvulsant agents by</p><p>modifying some neuronal signaling set-ups in response to seizures</p><p>in epilepsy. In the year 2017, Supuran and Tiwari designed sulfon-</p><p>amide derivatives 65a-c as potent CA inhibitors with enhanced</p><p>anticonvulsant potential (Fig. 15) [140].</p><p>Moreover, the selective inhibitors of human carbonic anhydrase</p><p>(hCAs) are permanent importance and for the synthesis of these</p><p>particular inhibitors “glycomimetic approach” is superior than the</p><p>“sugar approach” because glycomimetics are considered more se-</p><p>lective than the parent sugar in inhibiting the carbohydrate-</p><p>processing enzyme. In this context, very recently, Supuran, Car-</p><p>dona, and co-workers developed two hCAs inhibitors 66a and 66b</p><p>by combining the sulfonamide moiety with a sugar analog residue</p><p>(Fig. 16) [141].</p><p>SLC-0111(67) is a sulfonamide carbonic anhydrase IX/XII inhib-</p><p>itor that is being investigated for the treatment of hypoxic tumors</p><p>complicated with metastases (Fig. 17) [142]. Recently, Supuran et al.</p><p>synthesized analogs of SLC-0111 of which most of the analogs</p><p>showed effective inhibition of the tumor-associated isoform and</p><p>some showed selective CA IX/XII inhibitory profiles [143].</p><p>Moreover, Peyron, Imbert and co-workers investigated that</p><p>sulfonamides 68a and 68b can act as CA XII inhibitor which de-</p><p>creases cell proliferation and induces cell apoptosis in T-cell lym-</p><p>phomas (Fig. 18) [144].</p><p>Guglielmi, Supuran and co-workers also synthesized a series of</p><p>novel open saccharin-based secondary sulfonamides and studied</p><p>their selective inhibition property against four different isoforms of</p><p>human carbonic anhydrase namely hCA</p><p>I, II, IX and XII [145]. All the</p><p>synthesized compounds are inactive against hCA I and II but</p><p>inhibited hCA IX and XII in the low nanomolar range with Kis</p><p>ranging between 4.3 and 432 nM. For example, compounds 69a and</p><p>69b inhibited both hCA IX and XII predominantly (Fig. 19).</p><p>Moreover, there are several sulfonamide CA inhibitors which are</p><p>clinically used as antiobesity, diuretics, antiglaucoma, etc. for past</p><p>decades [146e148].</p><p>a-carbonic anhydrase inhibitor.</p><p>Fig. 13. Sulfonamide act as a potent cancer-related carbonic anhydrase inhibitor.</p><p>Fig. 14. Sulfonamide as an effective and selective Carbonic Anhydrase XIV inhibitor.</p><p>Fig. 15. Sulfonamide as effective hCA inhibitor and anticonvulsant agent.</p><p>Fig. 17. SLC-0111, a sulfonamide carbonic anhydrase IX/XII inhibitor.</p><p>S. Mondal and S. Malakar Tetrahedron 76 (2020) 131662</p><p>4.3. Sulfonamide with NaV1.7 inhibitor</p><p>The voltage-gated sodium channel has 9 isoforms, among them</p><p>Nav1.7 encoded by the SCN9A gene plays a vital role in pain related</p><p>issues. Investigators have observed that some sulfonamide portray</p><p>can act as effective NaV1.7 inhibitors with high levels of selectivity</p><p>over other NaV isoforms. 70a-e are some selective NaV1.7 inhibitors</p><p>which act as analgesics (Fig. 20) [149e153].</p><p>Fig. 16. Sulfonamide as selective of hCAs.</p><p>23</p><p>4.4. Other biological applications of sulfonamide</p><p>Hepatitis C virus (HCV) infections are one of the scariest threats</p><p>to living beings as it causes prolonged illness like fibrosis, cirrhosis,</p><p>and hepatocellular carcinoma, and also leads to liver trans-</p><p>plantation. Zhang et al. introduced Sulfonamide 71 as a powerful</p><p>and selective HCV RNA replication inhibitor (Fig. 21) [154].</p><p>A-Raf, B-Raf, and C-Raf are themain three isoforms of Raf serine/</p><p>threonine kinases which are key components of mitogen-activated</p><p>protein kinase (MAPK). Among the three isoforms, mutations in B-</p><p>Raf leads to human cancers [155]. Ren and Ding et al. designed and</p><p>presented N-(3-ethynyl-2,4-difluorophenyl)-sulfonamide 72 as an</p><p>active B-Raf inhibitor (Fig. 22) [156].</p><p>The serum and glucocorticoid kinase 1 (SGK1) (serine/threonine</p><p>kinase familyeAGC kinases) regulates transport, hormone release,</p><p>cell proliferation, and apoptosis. Disruption of SGK1may be the sole</p><p>motive causing cancer, hypertension, diabetes, and thrombotic</p><p>events to neurodegeneration. Halland and Nazare et al. synthesized</p><p>and investigated that methyl-1H-pyrazolo[3,4-b]pyrazine 73 could</p><p>acts as a prolific SGK1 inhibitor by its activity and selectivity</p><p>(Fig. 23) [157].</p><p>Researchers have witnessed that genetic modulation of SMYD3</p><p>(Set and Mynd Domain containing 3)- a lysinemethyl transferase</p><p>(KMT) deactivates a variety of cancer cell lines. In 2016, Mitchell</p><p>and co-worker designed sulfonamide derivatives 74a and 74b as</p><p>potent SMYD3 inhibitor (Fig. 24) [158].</p><p>Most concerned Alzheimer’s disease (AD) can be to some extent</p><p>cure by modifying the level of acetylcholine (specific areas of the</p><p>brain liable for learning and memory dysfunctions). The mecha-</p><p>nism of cure is to reestablish the acetylcholine level by using</p><p>reversible inhibitors to inhibit cholinesterases that include acetyl-</p><p>cholinesterase (AChE) and butyrlcholinesterase (BuChE). Alptuzun</p><p>et al. designed and synthesized a series of new 4-</p><p>phthalimidobenzenesulfonamide derivatives of which 75a and</p><p>Fig. 18. Sufonamides as potent CA XII inhibitor.</p><p>Fig. 19. Sufonamides as potent hCA XI and XII inhibitors.</p><p>Fig. 20. Sulfonamide as effective and selective N</p><p>Fig. 21. Sulfonamide as an effective and selective (HCV)NS4B agent.</p><p>S. Mondal and S. Malakar Tetrahedron 76 (2020) 131662</p><p>24</p><p>75b can act as effective inhibitors of acetylcholinesterase (AChE)</p><p>and butyrylcholinesterase (BuChE) (Fig. 25) [159].</p><p>Insulin-regulated aminopeptidase (IRAP) resides in the hippo-</p><p>campus and other brain regions bind with hexapeptide angiotensin</p><p>IV which intensifies the number of dendritic spines in hippocampal</p><p>regions and leads to enhance intellectual ability. It is observed that</p><p>when hexapeptide binds to insulin-regulated aminopeptidase</p><p>(IRAP) in its catalytic site result in the obstruction of its enzymatic</p><p>av1.7 inhibitors for the treatment of pain.</p><p>Fig. 22. Sulfonamide as a selective B-Raf inhibitor.</p><p>Fig. 23. Sulfonamide as highly active and selective SGK1 inhibitor.</p><p>Fig. 24. Sulfonamide as SMYD3 inhibitor.</p><p>Fig. 25. Sulfonamides act as inhibitors of acetylcholinesterase and butyrylcholinesterase.</p><p>Fig. 27. Sulfonamide as T-type calcium channel blocker.</p><p>Fig. 28. Sulfonamide act as effective and selective CB2 receptor inverse agonists.</p><p>S. Mondal and S. Malakar Tetrahedron 76 (2020) 131662</p><p>activity. Hallberg and co-workers observed that aryl sulfonamide</p><p>derivatives 76a-c which are analogs of angiotensin IV can act as</p><p>effective IRAP inhibitors (Fig. 26) [160].</p><p>Voltage-gated calcium channels (VGCC) plays a key role in</p><p>treating several neurophysiological related disorders (such as epi-</p><p>lepsy, pain, and hypertension, sleep disorders, tremor, and Par-</p><p>kinson’s disease) regulating calcium influx into cells. Among low-</p><p>voltage activated T-type channels, ABT-639 (77) designated as se-</p><p>lective Cav3.2 T-type calcium channel blocker (Fig. 27) [161].</p><p>Cannabinoid receptors 1 and 2 are members of the G-protein-</p><p>coupled receptor (GPCR) superfamily receptor ligands responsible</p><p>for pain, appetite stimulation, nausea, neurodegeneration, hyper-</p><p>motility, and inflammation. It was observed that CB1 receptor li-</p><p>gands cause side effects in the CNS which encourage working for</p><p>CB2 receptor ligands. In 2013, Xie et al. investigated Cannabinoid</p><p>receptors property of sulfonamide derivatives 78a and 78b which</p><p>revealed the significant CB2 receptor (in peripheral cells and tissues</p><p>Fig. 26. Sulfonamide act</p><p>25</p><p>derived from the immune system) affinity with selective CB1 re-</p><p>ceptor (in the brain) and osteoclast inhibitors (Fig. 28) [162,163].</p><p>Moreover, in 2017, Bregman et al. discovered and hit-to-lead</p><p>optimization of a series of tricyclic sulfonamides which revealed</p><p>that sulfonamides 79a-c can act as effective allosteric glycine</p><p>as inhibitors of IRAP.</p><p>Fig. 29. Sulfonamide as effective glycine receptors.</p><p>Fig. 30. Sulfonamide as potent and highly selective Orexin 1 receptor antagonist.</p><p>S. Mondal and S. Malakar Tetrahedron 76 (2020) 131662</p><p>receptors (GlyRs) (Fig. 29) [164].</p><p>Furthermore, Nagase and group designed and synthesized</p><p>complex 80 which displayed selective antagonist activities toward</p><p>the orexin 1 receptor (OX1R) without affecting OX2R (Fig. 30) [165].</p><p>5. Conclusions</p><p>Sulfonamide structures, owning to its versatile behavior, have</p><p>fascinated the attention of many innovative kinds of research in the</p><p>medical arena. Thousands of sulfonamide structures are still under</p><p>investigation for excellent formulations with superior efficacy and</p><p>less toxicity. Nowadays, Sulfa drugs are not only effective towards</p><p>the treatment of infections caused by bacteria but also display</p><p>resistance to other antibiotics, acne, and urinary tract infections.</p><p>The literary survey encompasses the innovative approaches to</p><p>sulfonamide particularly where SO2N(R) moiety is not in the ring</p><p>and investigation of their synthetic and biological applications. We</p><p>believe that all these significant developments of sulfonamide in</p><p>terms of synthesis, synthetic applications, and therapeutics will</p><p>interest the broad readership of the chemical community.</p><p>Declaration of competing interest</p><p>The authors declare that they have no known competing</p><p>financial interests or personal relationships that could have</p><p>appeared to influence the work reported in this paper.</p><p>Acknowledgment</p><p>This article is dedicated to Professor Amit Basak, IIT Kharagpur,</p><p>26</p><p>on the occasion of his 68th birthday and for his extensive contri-</p><p>butions to organic synthesis. Science and Engineering Research</p><p>Board, Department of Science and Technology, Government of In-</p><p>dia, is greatly acknowledged for giving a research grant to Dr.</p><p>Shovan Mondal through the Early Career Research Award (Sanction</p><p>no. ECR/2017/000537).</p><p>References</p><p>[1] A. Scozzafava, T. Owa,</p>