Abstract
The synthesis of 17 phenoxy substituted 4-chloro-N-(aryl/alkyl)thiophene-2-sulfonamides using a PMB protection/deprotection strategy is described. Nucleophilic displacement of p-methoxybenzyl (PMB) protected 4,5-dichloro-N-(aryl/alkyl)-thiophene-2-sulfonamides was carried out with different phenols under mild basic conditions. Reaction times of 3–6 h and overall yields of 78–98% were achieved with the PMB group in place compared to no reaction without this protecting group. The PMB group was easily and selectively removed in 68–98% yield using TFA in DCM.
Similar content being viewed by others
References
Cole AG, Metzger A, Brescia MR, Qin LY, Appell KC, Brain CT, Hallett A, Ganju P, Denholm AA, Wareing JR, Ritchie TJ, Drake GM, Bevan SJ, MacGloinn A, McBryde A, Patel V, Oakley PJ, Nunez X, Gstach H, Schneider P, Baldwin JJ, Dolle RE, McDonald E, Henderson I (2009) Sulfonamido-aryl ethers as bradykinin B1 receptor antagonists. Bioorg Med Chem Lett 19: 119–122. doi:10.1016/j.bmcl.2008.11.005
Kumar YCS, Malviya M, Chandra JNNS, Sadashiva CT, Kumar CSA, Prasad SBB, Prasanna DS, Subhas MN, Rangapp KS (2008) Effect of novel N-aryl sulfonamide substituted 3-morpholinoarecoline derivatives as muscarinic receptor 1 agonists in Alzheimer’s dementia models. Bioorg Med Chem 16: 5157–5163. doi:10.1016/j.bmc.2008.03.019
Ganesh T, Thepchatri P, Li L, Du Y, Fu H, Snyder JP, Sun A (2008) Synthesis and SAR study of N-(4-hydroxy-3-(2-hydroxynaphthalene-1-yl)phenyl)-arylsulfonamides: heat shock protein 90 (Hsp90) inhibitors with submicro-molaractivity in an in vitro assay. Bioorg Med Chem Lett 18: 4982–4987. doi:10.1016/j.bmcl.2008.08.022
Wang GT, Mantei RA, Kawai M, Tedrow JS, Barnes DM, Wang J, Zhang Q, Lou P, Garcia LA, Bouska J, Yates M, Park C, Judge RA, Lesniewski R, Sheppard GS, Bell RL (2007) Lead optimization of methionine aminopeptidase-2 (MetAP2) inhibitors containing sulfonamides of 5,6-disubstituted anthranilic acids. Bioorg Med Chem Lett 17: 2817–2822. doi:10.1016/j.bmcl.2007.02.062
Mader MM, Shih C, Considine E, Dios AD, Grossman CS, Hipskind PA, Shen H-L, Lobb KL, Lopez B, Lopez JE, Cabrejas LMM, Richett ME, White WT, Cheung Y-Y, Huang Z, Reilly JE, Dinn SR (2007) Acyl sulfonamide anti-proliferatives. Part 2: activity of heterocyclic sulfonamide derivatives. Bioorg Med Chem Lett 15: 617–620. doi:10.1016/j.bmcl.2004.11.041
Caldirola P, Jossan S, Sakariassen KS, Svartengren J (2002) Aryl sulfonamides as serotonin antagonists for the treatment of obesity. WO 2002008179 A1
Ruckle T, Biamonte M, Grippi-Vallotton T, Arkinstall S, Cambet Y, Camps M, Chabert C, Church DJ, Halazy S, Jiang X, Martinou I, Nichols A, Sauer W, Gotteland J-P (2004) Design, synthesis, and biological activity of novel, potent, and selective (benzoylaminomethyl)thiophene sulfonamide inhibitors of c-Jun-N-terminal kinase. J Med Chem 47: 6921–6934. doi:10.1021/jm031112e
Grundner C, Perrin D, Van Huijsduijnen RH, Swinnen D, Gonzalez J, Gee CL, Wells TN, Alber T (2007) Structural basis for selective inhibition of Mycobacterium tuberculosis protein tyrosine phosphatase PtpB. Structure 15: 499–509. doi:10.1016/j.str.2007.03.003
Innocenti A, Villar R, Martinez-Merino V, Gil MJ, Scozzafava A, Vullo D, Supuran CT (2005) Carbonic anhydrase inhibitors: inhibition of cytosolic/tumor-associated carbonic anhydrase isozymes I, II, and IX with benzo[b]thiophene 1,1-dioxide sulfonamides. Bioorg Med Chem Lett 15: 4872–4876. doi:10.1016/j.bmcl.2005.04.078
Hu B, Ellingboe J, Han S, Largis E, Lim K, Malamas M, Mulvey R, Niu C, Oliphant A, Pelletier J, Singanallore T, Sum F-W, Tillett J, Wong V (2001) Novel (4-Piperidin-1-yl)-phenyl sulfonamides as potent and selective human β3 agonists. Bioorg Med Chem 9: 2045–2059. doi:10.1016/S0968-0896(01)00114-6
Wu C, Decker ER, Blok N, Li J, Bourgoyne AR, Bui H, Keller KM, Knowles V, Li W, Stavros FD, Holland GW, Brock TA, Dixon RA (2001) Acyl substitution at the ortho position of anilides enhances oral bioavailability of thiophene sulfonamides: TBC3214, an ETA selective endothelin antagonist. J Med Chem 44: 1211–1216. doi:10.1021/jm000349x
Chen G, Wang H, Robinson H, Cai J, Wan Y, Ke H (2008) An insight into the pharmacophores of phosphodiesterase-5 inhibitors from synthetic and crystal structural studies. Biochem Pharmacol 75: 1717–1728. doi:10.1016/j.bcp.2008.01.019
Gubler M, Haap W, Hebeisen P, Kitas EA, Kuhn B, Minder RE, Schott B, Wessel HP (2007) Preparation of sulfonylureido thiazoles as fructose-1,6-bisphosphatase (FBPase) inhibitors for the treatment of diabetes. WO 2007137962 A1
Guile SD, Bantick JR, Cooper ME, Donald DK, Eyssade C, Ingall AH, Lewis RJ, Martin BP, Mohammed RT, Potter TJ, Reynolds RH, St-Gallay SA, Wright AD (2007) Optimization of monocarboxylate transporter 1 blockers through analysis and modulation of atropisomer interconversion properties. J Med Chem 50: 254–263. doi:10.1021/jm060995h
Morley JO, Matthews T (2006) Studies on the biological activity of some nitrothiophenes. Org Biomol Chem 4: 359–366. doi:10.1039/b514441h
Herpin TF, Morton GC, Rehfuss RP, Lawrence RM, Poss MA, Roberge JY, Gungor T (2005) Preparation of aminobenzazoles and analogs as P2Y1 receptor inhibitors for treating thromboembolic disorders. WO 2005070920 A1
Binder D, Pyerin M, Pusterer F (1999) Synthesis of substituted alkoxythiophenes. Thiophene analogs of dazoxiben. Monatsh Chem 130: 645–651. doi:10.1007/PL00010245
Stanetty P, Puschautz E (1989) Herbicidal thienylureas. II. Monatsh Chem 120: 65–72. doi:10.1007/BF00809650
Gilchrist TL (1992) Heterocyclic chemistry, 3rd edn. Addison Wesley, Essex, p 226 pp
Park C-M, Oie T, Petros AM, Zhang H, Nimmer PM, Henry RF, Elmore SW (2006) Design, synthesis, and computational studies of inhibitors of Bcl-X L . J Am Chem Soc 28: 16206–16212. doi:10.1021/ja0650347
Author information
Authors and Affiliations
Corresponding author
Electronic Supplementary Material
The Below is the Electronic Supplementary Material.
Rights and permissions
About this article
Cite this article
Williams, A.L., Dandepally, S.R. & Kotturi, S.V. A p-methoxybenzyl (PMB) protection/deprotection approach toward the synthesis of 5-phenoxy-4-chloro-N-(aryl/alkyl) thiophene-2-sulfonamides. Mol Divers 14, 697–707 (2010). https://doi.org/10.1007/s11030-009-9208-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11030-009-9208-y