Effect of Nucleophile Deprotonation on SuFEx: Synthesis of Sulfonamides

Abstract

In a quest for efficient SuFEx-type transformations we studied reactions of amines with 4-fluorobenzenesulfonyl fluoride. The substrate may react by fluoride substitution at the aromatic ring (S_NAr) and at the sulfonyl group (SuFEx). Analysis of the reaction course revealed that deprotonation of the N-nucleophile controls the reaction course: neutral amines in DMF attack at the aromatic ring, whereas amine anions, generated in equilibrium with LiHMDS in toluene, favor sulfonyl substitution. Using the base-promoted conditions we synthesized a set of substituted sulfonamides in high yields.

Key words

SuFEx - sulfonyl fluorides - amines - sulfonamides - nucleophilic substitution

• References


For recent examples of synthesis of sulfonamides see:
• 1a Zhang F, Zheng D, Lai L, Cheng J, Sun J, Wu J. Org. Lett. 2018; 20: 1167
• 1b Davies TQ, Tilby MJ, Skolc D, Hall A, Willis MC. Org. Lett. 2020; 22: 9495
• 1c Blum SP, Karakaya T, Schollmeyer D, Klapars A, Waldvogel SR. Angew. Chem. Int. Ed. 2021; 60: 5056
• 1d Andriashvili VA, Zhersh S, Tolmachev AA, Grygorenko OO. J. Org. Chem. 2022; 87: 6237
• 2 For a review on synthesis and properties of sulfonamides, see: Mondal S, Malakar S. Tetrahedron 2020; 76: 131662
• 3a Bogolubsky AV, Moroz YS, Mykhailiuk PK, Pipko SE, Konovets AI, Sadkova IV, Tolmachev A. ACS Comb. Sci. 2014; 16: 192
• 3b Tolmachova KA, Moroz YS, Konovets A, Platonov MO, Vasylchenko OV, Borysko P, Zozulya S, Gryniukova A, Bogolubsky AV, Pipko S, Mykhailiuk PK, Brovarets VS, Grygorenko OO. ACS Comb. Sci. 2018; 20: 672
• 4 Sosunovych B, Vashchenko BV, Andriashvili VA, Grygorenko OO. Chem. Rec. 2024; 24: e202300258
• 5a Dong J, Krasnova L, Finn MG, Sharpless KB. Angew. Chem. Int. Ed. 2014; 53: 9430
• 5b Barrow AS, Smedley CJ, Zheng Q, Li S, Dong J, Moses JE. Chem. Soc. Rev. 2019; 48: 4731
• 5c Zeng D, Deng W.-P, Jiang X. Chem. Eur. J. 2023; 29: e202300536
• 6a Smedley CJ, Homer JA, Gialelis TL, Barrow AS, Koelln RA, Moses JE. Angew. Chem. Int. Ed. 2022; 61: e202112375
• 6b Liang D.-D, Streefkerk DE, Jordaan D, Wagemakers J, Baggerman J, Zuilhof H. Angew. Chem. Int. Ed. 2020; 59: 7494
• 6c Tribby AL, Rodríguez I, Shariffudin S, Ball ND. J. Org. Chem. 2017; 82: 2294
• 7 Lee C, Ball ND, Sammis GM. Chem. Commun. 2019; 55: 14753
• 8a Smedley CJ, Zheng Q, Gao B, Li S, Molino A, Duivenvoorden HM, Parker BS, Wilson DJ. D, Sharpless KB, Moses JE. Angew. Chem. Int. Ed. 2019; 58: 4552
• 8b Okusu S, Hirano K, Tokunaga E, Shibata N. ChemistryOpen 2015; 4: 581

For recent applications of Ca(NTf₂)₂ for the formation of the S–N bonds, see:
• 9a Chrominski M, Ziemkiewicz K, Kowalska J, Jemielity J. Org. Lett. 2022; 24: 4977
• 9b Liang D.-D, Lional N, Scheepmaker B, Subramaniam M, Li G, Miloserdov FM, Zuilhof H. Org. Lett. 2023; 25: 5666
• 10a Mukherjee P, Woroch CP, Cleary L, Rusznak M, Franzese RW, Reese MR, Tucker JW, Humphrey JM, Etuk SM, Kwan SC, am Ende CW, Ball ND. Org. Lett. 2018; 20: 3943
• 10b Mahapatra S, Woroch CP, Butler TW, Carneiro SN, Kwan SC, Khasnavis SR, Gu J, Dutra JK, Vetelino BC, Bellenger J, am Ende CW, Ball ND. Org. Lett. 2020; 22: 4389
• 10c Yassa TD, Fang Y, Ravelo LK, Anand S, Arora S, Ball ND. Org. Lett. 2024; 26 ASAP, doi:
• 10d For mechanistic studies, see: Han B, Khasnavis SR, Nwerem M, Bertagna M, Ball ND, Ogba OM. Inorg. Chem. 2022; 61: 9746
• 11 Wei M, Liang D, Cao X, Luo W, Ma G, Liu Z, Li L. Angew. Chem. Int. Ed. 2021; 60: 7397
• 12 Lin M, Luo J, Xie Y, Du G, Cai Z, Dai B, He L. ACS Catal. 2023; 13: 14503
• 13 Tryniszewski M, Barbasiewicz M. Synthesis 2022; 54: 1446
• 14 Talko A, Barbasiewicz M. ACS Sustainable Chem. Eng. 2018; 6: 6693
• 15 Nowak J, Tryniszewski M, Barbasiewicz M. Synlett 2024; 35: 1190
• 16a Górski B, Talko A, Basak T, Barbasiewicz M. Org. Lett. 2017; 19: 1756
• 16b Górski B, Basiak D, Talko A, Basak T, Mazurek T, Barbasiewicz M. Eur. J. Org. Chem. 2018; 1774
• 16c Tryniszewski M, Basiak D, Barbasiewicz M. Org. Lett. 2022; 24: 4270
• 17 Talko A, Antoniak D, Barbasiewicz M. Synthesis 2019; 51: 2278
• 18 Lyapkalo IM, Reissig H.-U, Schäfer A, Wagner A. Helv. Chim. Acta 2002; 85: 4206
• 19 Meng Y.-P, Wang S.-M, Fang W.-Y, Xie Z.-Z, Leng J, Alsulami H, Qin H.-L. Synthesis 2020; 52: 673
• 20 Leng J, Alharbi NS, Qin H.-L. Eur. J. Org. Chem. 2019; 6101
• 21 Qin H.-L, Zheng Q, Bare GA. L, Wu P, Sharpless KB. Angew. Chem. Int. Ed. 2016; 55: 14155
• 22 Liu M, Tang W, Qin H.-L. J. Org. Chem. 2023; 88: 1909
• 23a Yuen R, Wagner M, Richter S, Dufour J, Wuest M, West FG, Wuest F. Org. Biomol. Chem. 2021; 19: 3241
• 23b See also: Samarakoon TB, Loh JK, Rolfe A, Le LS, Yoon SY, Lushington GH, Hanson PR. Org. Lett. 2011; 13: 5148
• 24 Naumchyk V, Andriashvili VA, Radchenko DS, Dudenko D, Moroz YS, Tolmachev AA, Zhersh S, Grygorenko OO. J. Org. Chem. 2024; 89: 3161
• 25 Kopyt M, Tryniszewski M, Barbasiewicz M, Kwiatkowski P. Org. Lett. 2023; 25: 6818
• 26 For reactions of silylated amines with sulfonyl chlorides and fluorides, see Ref. 10c and: Naredla RR, Klumpp DA. Tetrahedron Lett. 2013; 54: 5945
• 27 Silverstein TP, Heller ST. J. Chem. Educ. 2017; 94: 690
• 28 A similar observation was mentioned in: Mukherjee H, Debreczeni J, Breed J, Tentarelli S, Aquila B, Dowling JE, Whitty A, Grimster NP. Org. Biomol. Chem. 2017; 15: 9685
• 29 Bourbon P, Appert E, Martin-Mingot A, Michelet B, Thibaudeau S. Org. Lett. 2021; 23: 4115
• 30 Under reaction conditions tested in the studies compound 1 predominantly favored monosubstitution with amines (S_NAr or SuFEx) that enabled analysis of the reaction course and strengthened its synthetic application.
• 31 Li B.-Y, Voets L, Van Lommel R, Hoppenbrouwers F, Alonso M, Verhelst SH. L, De Borggraeve WM, Demaerel J. Chem. Sci. 2022; 13: 2270
• 32 Luy J.-N, Tonner R. ACS Omega 2020; 5: 31432
• 33a Moors SL. C, Brigou B, Hertsen D, Pinter B, Geerlings P, Van Speybroeck V, Catak S, De Proft F. J. Org. Chem. 2016; 81: 1635
• 33b Filatov AA, Boiko VN, Yagupolskii YL. J. Fluorine Chem. 2012; 143: 123

For recent examples of deprotonated N-nucleophiles reacting with sulfonyl compounds, see:
• 34a Gilles P, Veryser C, Vangrunderbeeck S, Ceusters S, Van Meervelt L, De Borggraeve WM. J. Org. Chem. 2019; 84: 1070
• 34b van den Boom AF. J, Zuilhof H. Org. Lett. 2023; 25: 788
• 34c Galley G, Gobbi L, Guba W, Mazunin D, Pinard E, Ricci A. WO Patent 2024017858, 2024 (examples 48 and 53 at pages 77 and 80).
• 35 Lithium salts of secondary amines, generated in situ with n-BuLi, also may cause side reactions with fluoroarenes running via aryne mechanism, see: Lin Y, Li M, Ji X, Wu J, Cao S. Tetrahedron 2017; 73: 1466
• 36 Bordwell FG, Zhang X.-M, Cheng J.-P. J. Org. Chem. 1993; 58: 6410
• 37 For a review of alkali metal amide bases (LiHMDS, LDA, etc.), see: Mulvey RE, Robertson SD. Angew. Chem. Int. Ed. 2013; 52: 11470
• 38 Mandler MD, Suss N, Ramirez A, Farley CA, Aulakh D, Zhu Y, Traeger SC, Sarjeant A, Davies ML, Ellsworth BA, Regueiro-Ren A. Org. Lett. 2022; 24: 7643
• 39 Li G, Szostak M. Nat. Commun. 2018; 9: 4165
• 40 Due to presence of the sulfonyl group N-monosubstituted sulfonamides are more acidic, than substrates (amines), and thus favorably deprotonate under the reaction conditions. Therefore for reactions with primary amines we applied 2.1 equivalents of LiHMDS, whereas with secondary amines 1.1 equivalents. Moreover, we observed that lithium salts of N-monosubstituted sulfonamides were sparingly soluble in THF, and resulted in white precipitates, which caused mixing problems. However, in toluene the problem (specific for primary amines) was practically absent.
• 41 For a similar application of LiHMDS with alkyl amines, see: Vrijdag JL, Delgado F, Alonso N, De Borggraeve WM, Pérez-Macias N, Alcázar J. Chem. Commun. 2014; 50: 15094
• 42 High selectivity of neutral dialkyl amines toward S_NAr at 1 was observed exclusively in DMF. In other solvents, such as THF, acetonitrile, and toluene mixtures of products were formed (according to GC). In turn, analogous reaction of primary n-nonylamine in DMF gave arylamine (S_NAr) isolated in 61% yield, accompanied with a mixture of SuFEx and disubstitution byproducts (see the SI for details).
• 43 Model reaction of 1 with aniline, using KHMDS/THF/HMPA system gave sulfonamide 3f, isolated in 98% of yield. Under these conditions Lewis-acid activation or Complex-Induced Proximity Effect are expected to be absent. Therefore amine deprotonation seems to be a key factor to promote the SuFEx reactions. For a discussion of structure of the sulfonyl group, see: Denehy E, White JM, Williams SJ. Inorg. Chem. 2007; 46: 8871
• 44a Narayanan A, Jones LH. Chem. Sci. 2015; 6: 2650
• 44b Lucas SW, Qin RZ, Rakesh KP, Kumar KS. S, Qin H.-L. Bioorg. Chem. 2023; 130: 106227
• 44c Carneiro SN, Khasnavis SR, Lee J, Butler TW, Majmudar JD, am Ende CW, Ball ND. Org. Biomol. Chem. 2023; 21: 1356
• 45 Polgár L. Cell. Mol. Life Sci. 2005; 62: 2161
• 46 Lu J, Koo SC, Weissman BP, Harris ME, Li N.-S, Piccirilli JA. Biochemistry 2018; 57: 3465
• 47 Lai J, Chang L, Yuan G. Org. Lett. 2016; 18: 3194
• 48 Qu P, Sun C, Ma J, Li F. Adv. Synth. Catal. 2014; 356: 447
• 49 Dong K, Fang X, Jackstell R, Beller M. Chem. Commun. 2015; 51: 5059
• 50 Hopkins MD, Witt RC, Flusche AM. E, Philo JE, Ozmer GL, Purser GH, Sheaff RJ, Lamar AA. Org. Biomol. Chem. 2022; 20: 6680
• 51 Cuccu F, Porcheddu A. Green Chem. 2024; 26: 2684
• 52 Fu Y, Li Q.-Z, Xu Q.-S, Hügel H, Li M.-P, Du Z. Eur. J. Org. Chem. 2018; 6966
• 53 Baxter NJ, Rigoreau LJ. M, Laws AP, Page MI. J. Am. Chem. Soc. 2000; 122: 3375
• 54 Tan BY.-H, Teo Y.-C, Seow A.-H. Eur. J. Org. Chem. 2014; 1541
• 55 Katagiri K, Ikeda T, Tominaga M, Masu H, Azumaya I. Cryst. Growth Des. 2010; 10: 2291
• 56 Kim T, McCarver SJ, Lee C, MacMillan DW. C. Angew. Chem. Int. Ed. 2018; 57: 3488
• 57 Alba A, Schopp A, De Sousa Delgado A.-P, Cherif-Cheikh R, Martín-Vaca B, Bourissou D. J. Polym. Sci., Part A: Polym. Chem. 2010; 48: 959