{"paper_id":"03db75f1-9c6f-406a-af07-6dd9ec35ac46","body_text":"License and Terms: This document is copyright 2019 the Author(s); licensee Beilstein-Institut.\nThis is an open access publication under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0). Please note that the reuse,\nredistribution and reproduction in particular requires that the author(s) and source are credited.\nThe license is subject to the Beilstein Archives terms and conditions: https://www.beilstein-archives.org/xiv/terms.\nThe definitive version of this work can be found at: doi: https://doi.org/10.3762/bxiv.2019.33.v1\nThis open access document is published as a preprint in the Beilstein Archives with doi: 10.3762/bxiv.2019.33.v1 and is\nconsidered to be an early communication for feedback before peer review. Before citing this document, please check if a final,\npeer-reviewed version has been published in the Beilstein Journal of Organic Chemistry.\nThis document is not formatted, has not undergone copyediting or typesetting, and may contain errors, unsubstantiated scientific\nclaims or preliminary data.\nPreprint Title Installation of sulfonyl fluorides onto primary amides\nAuthors Jing Liu, Shi-Meng Wang and Hua-Li Qin\nArticle Type Letter\nSupporting Information File 1 181108c.cif; 14.6 KB\nSupporting Information File 2 Crystal 4e checkcif.pdf; 212.2 KB\nSupporting Information File 3 Supporting Information-BJOC.docx;  1.9 MB\nORCID® iDs Hua-Li Qin - https://orcid.org/0000-0002-6609-0083\n\n \n1 \nInstallation of sulfonyl fluorides onto primary amides \nJing Liu, Shi-Meng Wang, and Hua-Li Qin* \nState Key Laboratory of Silicate Materials for Architectures; School of Chemistry, Chemical \nEngineering and Life Science, Wuhan University of Technology, 205 Luoshi Road, Wuhan \n430070, China. \nE-mail: qinhuali@whut.edu.cn \nAbstract \nA protocol of SO 2F2 mediated installation of sulfonyl fluoride onto primary amide \nwas developed providing a new portal to sulfur(VI) fluoride exchange (SuFEx) click \nchemistry. The generated molecules contain pharmaceutically important amide and -SO2F \nmoieties for application in discovery of new therapeutics. \n \nKeywords: N-fluorosulfonyl amides; Sulfuryl fluoride (SO2F2); primary amides \n \nIntroduction \nSulfur(VI) fluoride exchange (SuFEx), is a new class of click chemistry developed by \nProfessor K. B. Sharpless and coworkers in 2014, for creating molecular connections based \non the unique stability -reactivity pattern of S VI-F bond with absolute reliability and \nunprecedented efficiency , which has been widely applied in organic synthesis, chemical \nbiology and drug discovery  [1-19]. Among all the developed S(VI) -F species, sulfonyl \nfluoride (RSO 2F) was specifically recognized as unique scaffold for covalent protein \ninhibitors and biological probes with the affinity -driven activation for forming covalent \nlinkages with the amino acid residues of protein binding sites ( Figure 1) [20]. The smallest \nmember of this family, methyl sulfonyl fluoride (MSF), is known as a selective and \nirreversible inhibitor of acetylcholinesterase (AChE) [21-22]. The sulfonyl fluoride inhibitors \nNSC 127755 was found for specifically modifying tyrosine -31 of DHFR in chicken liver  \n[23]. The nucleotide -derived probe 5’ -p-fluorosulfonylbenzoyl adenosine (5’ -FSBA) was \nused for labelling the second nucleotide binding site, the adenine nucleotide regulatory site  \n[24]. In addition, aryl fluorosulfates have also been widely applied as sustainable alternative \nto aryl halides in coupling reactions and as potential coval ent probes in protein profiling  [14, \n25-28]. \nPhenols (or alcohols) and amines as the most common nucleophiles have been found \nto undergo SuFEx with different S VI connectors to provide diversified sulfonyl fluoride \n\n \n2 \nderivatives. The reactions of phenols (or alcohols) with SO 2F2 [29] or the fluorosulfuryl \nimidazolium salt were developed for mild and effective formation of the corresponding \nfluorosulfates to act as biology probes in chemical proteomics studies (Scheme 1, a) [1, 30]. \nOn the other hand, the reactions of primary and secondary aliphatic amines as well as \nanilines with SO 2F2 or the fluorosulfuryl imidazolium salt have been achieved for assembly \nof N-sulfonyl fluorides  [1, 30], and the corresponding products have served as important \nactive precursors for the development of noncovalent inhibitors ( Scheme 1 , a) [1, 30, 31]. \nAmides are the key connections in proteins, amides, and a vast number of synthetic \nstructures, such as polymers, biologically active compounds and pharmaceutical products  \n[32-35]. However, the installation of sulfonyl fluoride (SO 2F) onto nitrogen atoms of amides \nhas not been achieved, which, if accomplished, would provide a very important class of \nsulfonyl fluorides, namely, N-fluorosulfonyl amides, for the development of potent ial \ncovalent inhibitors  [1-24]. The Roesky group described a pioneering protocol for the \nsynthesis of N-fluorosulfonyl amides from fluorosulfonylisocyanate (Scheme 1, b) [36]. And \nthe available procedures for the preparation of N-fluorosulfonyl amides are very limited \nwhich relied on using either the isocyanate approach, or theamidosulfofluoride (FSO 2NH2) \n[37-39]. Therefore, the development of new method for the assembly of N-fluorosulfonyl \namides from cheap and abundant reagent is highly desirable. Herein, we report the first, to the \nbest of our knowledge, SO 2F2 mediated N-fluorosulfonylation [40-42] of amides by using \nDBU as base for the constructions of a series N-acyl-substituted sulfamoyl fluorides (Scheme \n1, c). \n \n\n \n3 \n \nFigure 1. Representative sulfonyl fluorides compounds applied in medicinal chemistry and \nchemical biology. \n \nScheme 1. Background of synthesis of N-fluorosulfonyl amides and fluorosulfates. \n \n \nResults and discussion \n \nInitially, benzamide 1a was selected as model substrate to test the feasibility of this \nproposed N-fluorosulfonylation reaction in the presence of Cs 2CO3 in DMSO under SO 2F2 \natmosphere (balloon) at 50 oC, and excitingly, the desired product benzoylsulfamoyl fluoride \n2a was obtained in 25% yield ( Table 1 , entry 1). Encouraged by this preliminary success, \nseveral common bases were evaluated, among which, 1,8 -diazabicycloundec-7-ene (DBU) \ncatalysed the proposed transformation most effectively to  provide the desired product 2a in \nnearly quantitative yield ( Table 1 , entries 2 -7). Subsequently, possible solvent effects were \ninvestigated with different solvents, among which, DMSO was found to be the best solvent. \nDecreasing the temperature from 50 oC to 40 oC or even room temperature, or cutting down \nthe amount of DBU to 4 equivalent resulted in decreased yields (Table 1, entries 13-15). \n \nTable 1. Optimization of the reaction conditions.a \n\n \n4 \n \nEntry Base Solvent Temp. (oC) Yield (2a, %)b \n1 Cs2CO3 DMSO 50 25 \n2 K2CO3 DMSO 50 13 \n3 KOH DMSO 50 19 \n4 NaOH DMSO 50 15 \n5 DBU DMSO 50 99 \n6 Et3N DMSO 50 - \n7 DIPEA DMSO 50 - \n8 DBU NMP 50 81 \n9 DBU MeCN 50 75 \n10 DBU Toluene 50 87 \n11 DBU Dioxane 50 60 \n12 DBU THF 50 79 \n13 DBU DMSO 40 82 \n14 DBU DMSO R.T. 51 \n15c DBU DMSO 50 69 \na Reaction condition: benzoyl amide 1a (1.0 mmol, 1.0 eq.), DBU (5.0 eq.), and DMSO (1 .0 \nmL) stirred with a SO2F2 balloon for 12h. b Isolated yield. c 4 equiv of DBU was used. \n \n With the optimized conditions in hand, we next turned our efforts to investigate the \nscope of substrates. Under the standard conditions, a variety of substituted amides were \nexamined which were smoothly converted to their corresponding substituted \nbenzoylsulfamoyl fluoride derivatives ( Scheme 2) in moderate to excellent isolated yields. \nBoth electron-withdrawing groups, such as halogen atoms ( 1b-1d, 1j, 1m-1n), NO2 (1e, 1k) \nand CF 3 (1f), and electron -donating groups, such as Me ( 1g, 1l, 1o), tert-butyl (1h) and 2-\nnaphthyl (1i) on the aromatic rings, were well tolerated under this condition. It was worth \nnoting that not only para-(1b-1h) but also meta- (1j-1l) and ortho- (1m-1o) substituted \nbenzamides a ff orded the desired products in generally good yields. Arylcarboxylic amides \n(1p-1q) bearing bis -substitutions also behaved well under the standard conditions. \n\n\n \n5 \nHeterocyclic aromatic carboxylic amides ( 1r-1u), tolerated well and afforded the target \nproducts in 56 -94% yields. In addition, alkyl carboxylic amides  were also smoothly \ntransformed into the corresponding products (2v-2z). \n \na Reaction conditions: a mixture of amides ( 1, 1.0 mmol), DBU (5.0 mmol, 5.0 eq.), DMSO \n(1.0 mL) was added to a reaction flask before SO 2F2 was introduced into the stirred reaction \nmixture by slowly bubbling from a balloon, and the mixture was allowed to stir at 50 oC for \n12h. b Isolated yields. c 50 oC, 18 h. \nScheme 2. Screening of substrate scope of amides a, b \n \n Interestingly, during the work -up process of drying 2a with Na 2SO4, a colourless \ncrystal 4e was observed and its structure was confirmed by XRD analysis. We speculate that \nthe tautomerism of amides [43] may occur in the reaction process and the tautomers 3e could \nreact with Na 2SO4 to generate 4e, which indicated that N -H connected with two electron -\nwithdrawing groups (carbonyl, and SO 2F) can behave as an acid to donate a proton for \n\n \n6 \nchemical transformations. This property of fluoro sulfonyl amides 2 may attract significant \nattention for further applications. \n \nScheme 3. Amide resonance model and X -ray single crystal structure of 4e (CCDC \n1906002). \n \nConclusions \nIn conclusion, we have developed a novel method for N-fluorosulfonylation of \namides. This simple, convenient, mild and protocol provides a portal to a class of novel \nsulfonyl fluorides for SuFEx click chemistry with great potential to be applied in the \ndevelopment of covalent inhibitors. Further studies of th is class of molecules in chemical \nbiology and drug discovery are underway in our laboratory. \n \nConflicts of interest \nThe authors declare no competing financial interest. \n \nAcknowledgements  \nWe are grateful to the National Natural Science Foundation of China (Grant No. 21772150), \nthe Wuhan applied fundamental research plan of Wuhan Science and Technology Bureau \n(grant NO. 2017060201010216), the 111 Project (No. B18038) and Wuhan University of \nTechnology for the financial support. \n \nReferences \n1. Dong, J.; Krasnova, L.; Finn, M. G.; Sharples, K. B. Angew. Chem., Int. Ed. 2014, 53, \n9430-9448. doi :10.1002/anie.201309399; Angew. Chem. , 2014, 126, 9584 -9602. \ndoi:10.1002/ange.201309399. \n2. Wang, H.; Zhou, F.; Ren, G.; Zheng, Q.; Chen, H.; Gao, B.; Klivansky, L.; Liu, Y.; \nWu, B.; Xu, Q.; Lu, J.; Sharpless K. B.; Wu, P. Angew. Chem., Int. Ed.  2017, 56, \n11203-11208. doi:10.1002/anie.201701160; Angew. 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