Application of Saccharin as an Acidic Partner in the Ugi Reaction for the One-Pot Synthesis of 3-Iminosaccharins

Dedicated to Prof. Dr. Saeed Balalaie on the occasion of his 50^th birthday

Abstract

The use of saccharin as a replacement for the carboxylic acid component in an Ugi multicomponent condensation leading to [(1,1-dioxido-1,2-benzisothiazol-3-yl)amino]acetamide (3-iminosaccharin) derivatives is described for the first time.

Key words

multicomponent reactions - condensation - Ugi reaction - saccharin - iminosaccharins

• References and Notes

• 1 Multicomponent Reactions . Zhu J, Bienaymé H. Wiley-VCH; Weinheim: 2005
• 2 Choudhury LH, Parvin T. Tetrahedron 2011; 67: 8213-8213
• 3 Dömling A. Chem. Rev. 2006; 106: 17-17
• 4 Dömling A, Ugi I. Angew. Chem. Int. Ed. 2000; 39: 3168-3168
• 5 Ugi I, Dömling A, Hörl W. Endeavour 1994; 18: 115-115
• 6 Ugi I, Meyr R, Fetzer U, Steinbrückner C. Angew. Chem. 1959; 71: 386-386
• 7 Ruijter E, Scheffelaar R, Orru RV. A. Angew. Chem. Int. Ed. 2011; 50: 6234-6234
• 8 El Kaïm L, Grimaud L, Pravin P. Org. Lett. 2011; 14: 476-476
• 9 El Kaim L, Grimaud L, Le Goff XF, Schiltz A. Org. Lett. 2010; 13: 534-534
• 10 El Kaïm L, Grimaud L, Oble J. Angew. Chem. 2005; 117: 8175-8175
• 11 Castellano TG, Neo AG, Marcaccini S, Marcos CF. Org. Lett. 2012; 14: 6218-6218
• 12 Ugi I, Bodesheim F. Chem. Ber. 1961; 94: 2797-2797
• 13 Ugi I, Offermann K. Eur. J. Inorg. Chem. 1964; 97: 2276-2276
• 14 Ugi I, Rosendahl FK, Bodesheim F. Eur. J. Org. Chem. 1963; 666: 54-54
• 15 Bossio R, Marcaccini S, Pepino R. Liebigs Ann. Chem. 1993; 1229-1229
• 16 Ugi I, Steinbrückner C. Angew. Chem. 1960; 72: 267-267
• 17 Dömling A, Illgen K. Synthesis 2005; 662-662
• 18 El Kaim L, Grimaud L. Tetrahedron 2009; 65: 2153-2153
• 19 Aknin K, Gauriot M, Totobenazara J, Deguine N, Deprez-Poulain R, Deprez B, Charton J. Tetrahedron Lett. 2012; 53: 458-458
• 20 Neo AG, Castellano TG, Marcos CF. Synthesis 2015; 47: 2431-2431
• 21 Drews J. Science 2000; 287: 1960-1960
• 22 Scozzafava A, Owa T, Mastrolorenzo A, Supuran CT. Curr. Med. Chem. 2003; 10: 925-925
• 23 Majumdar K, Mondal S. Chem. Rev. 2011; 111: 7749-7749
• 24 Nicolas C, Verny M, Giraud I, Ollier M, Rapp M, Maurizis J.-C, Madelmont J.-C. J. Med. Chem. 1999; 42: 5235-5235
• 25 Inagaki M, Tsuri T, Jyoyama H, Ono T, Yamada K, Kobayashi M, Hori Y, Arimura A, Yasui K, Ohno K, Kakudo S, Koizumi K, Suzuki R, Kato M, Kawai S, Matsumoto S. J. Med. Chem. 2000; 43: 2040-2040
• 26 Brzozowski Z, Sączewski F, Neamati N. Bioorg. Med. Chem. Lett. 2006; 16: 5298-5298
• 27 Fanelli R, Schuurman T, Glaser T, Traber J. Prog. Clin. Biol. Res. 1990; 361: 461-461
• 28 Wells GJ, Tao M, Josef KA, Bihovsky R. J. Med. Chem. 2001; 44: 3488-3488
• 29 Combrink KD, Gulgeze HB, Thuring JW, Yu K.-L, Civiello RL, Zhang Y, Pearce BC, Yin Z, Langley DR, Kadow KF, Cianci CW, Li Z, Clarke J, Genovesi EV, Medina I, Lamb L, Yang Z, Zadjura L, Krystal M, Meanwell NA. Bioorg. Med. Chem. Lett. 2007; 17: 4784-4784
• 30 Vicini P, Amoretti L, Ballabeni V, Tognolini M, Barocelli E. Bioorg. Med. Chem. 2000; 8: 2355-2355
• 31 Vicini P, Amoretti L, Ballabeni V, Barocelli E, Chiavarini M. Eur. J. Med. Chem. 1995; 30: 809-809
• 32 Amin KM, Georgey HH, Awadallah FM. Med. Chem. Res. 2011; 20: 1042-1042
• 33 Han L, Wang L, Hou X, Fu H, Song W, Tang W, Fang H. Bioorg. Med. Chem. 2014; 22: 1529-1529
• 34 Saccharin Derivatives 10a–o; General Procedure A solution of aldehyde 6 (1 mmol), amine 7 (1 mmol), isocyanide 8 (1 mmol), and saccharin 9 (1 mmol) in EtOH (4 mL) was stirred for 24 h at r.t. while the progress of the reaction was monitored by TLC (hexane–EtOAc, 3:1). When the reaction was complete, the precipitate was collected by filtration and washed with EtOH. 2-[Benzyl(1,1-dioxido-1,2-benzisothiazol-3-yl)amino]-N-cyclohexyl-2-(4-methoxyphenyl)acetamide (10a) White powder; yield: 310 mg (60%); mp 247–250 °C (dec.). IR (KBr): 1308, 1549, 1673, 3310 cm⁻¹; ¹H NMR (300 MHz, CDCl₃): δ = 1.00–1.29 (m, 5 H, H_cHex), 1.50–1.70 (m, 5 H, H_cHex), 3.52–3.61 (m, 1 H, –CH, H_cHex), 3.63 (s, 3 H, –CH₃), 4.96 (d, J = 17.2 Hz, 1 H, CHN), 5.33 (d, J = 17.2 Hz, 1 H, CHN), 6.23 (s, 1 H, –CHN), 6.71 (d, J = 7.6 Hz, 2 H, H_Ar), 7.00 (d, J = 7.6 Hz, 2 H, H_Ar), 7.06–7.15 (m, 3 H, H_Ar), 7.20 (d, J = 8.6 Hz, 2 H, H_Ar), 7.50–7.62 (m, 2 H, H_Ar), 7.70–7.75 (m, 1 H, H_Ar), 8.03 (d, J = 7.5 Hz, 1 H, H_Ar), 8.24 (d, J = 6.1 Hz, 1 H, NH). ¹³C NMR (75 MHz, CDCl₃): δ = 24.5, 25.1, 32.0, 47.9, 55.1, 66.5, 113.5, 122.1, 125.7, 125.9, 126.2, 126.6, 126.8, 128.0, 131.6, 133.2, 133.4, 136.6, 143.8, 159.3, 161.7, 167.4. HRMS (ESI-POS): m/z [M + Na]⁺ calcd for C₂₉H₃₁N₃NaO₄S: 540.19406; found: 540.19386; [M + K]⁺ calcd for C₂₉H₃₁KN₃O₄S: 556.16847; found: 556.16820, [2M + Na]⁺ calcd for C₅₈H₆₂N₆NaO₈S₂: 1057.39908; found: 1057.39884; [2M + K]⁺ calcd for C₅₈H₆₂KN₆O₈S₂: 1073.37378; found: 1073.37348.
• 35 El Kaim L, Gizolme M, Grimaud L, Oble J. J. Org. Chem. 2007; 72: 4169-4169
• 36 CCDC 1419875 contains the supplementary crystallographic data for 10a. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.