Efficient S-Acylation of Thiourea

Abstract

Efficient S-acylation of thiourea using a variety of acid chlorides is reported. Structurally diverse aryl and alkyl substrates are compatible with this methodology. Confirmation that acylation occurs exclusively­ on the sulfur atom of thiourea is provided by single-crystal X-ray crystallographic analysis.

Key words

isothiourea - thiourea - organosulfur - sulfur transfer

• References and Notes

• 1a Krishnamurthy M, Basavaprabhu, Sharanabai KM, Sureshbabu VV. Tetrahedron Lett. 2014; 55: 5609
• 1b Kim H.-Y, Kwak SH, Lee G.-H, Gong Y.-D. Tetrahedron 2014; 70: 8737
• 1c Alcolea V, Garnica P, Palop J, Sanmartín C, González-Peñas E, Durán A, Lizarraga E. Molecules 2017; 22: 1314
• 1d Friebe M, Mahmood A, Spies H, Berger R, Johannsen B, Mohammed A, Eisenhut M, Bolzati C, Davison A, Jones AG. J. Med. Chem. 2000; 43: 2745
• 1e Wu Y.-J, Guernon J, Park H, Thompson LA. J. Org. Chem. 2016; 81: 3386
• 2a Hickey SM, White JM, Pfeffer FM, Ashton TD. Synlett 2015; 26: 1759
• 2b Takaya J, Mio K, Shiraishi T, Kurokawa T, Otsuka S, Mori Y, Uesugi M. J. Am. Chem. Soc. 2015; 137: 15859
• 2c Xu Z, Guo J, Yang Y, Zhang M, Ba M, Li Z, Cao Y, He R, Yu M, Zhou H, Li X, Huang X, Guo Y, Guo C. Eur. J. Med. Chem. 2016; 123: 309
• 3a Palanki MS. S, Erdman PE, Manning AM, Ow A, Ransone LJ, Spooner C, Suto C, Suto M. Bioorg. Med. Chem. Lett. 2000; 10: 1645
• 3b Zanatta N, Fortes AS, Bencke CE, Marangoni MA, Camargo AF, Fantinel CA, Bonacorso HG, Martins MA. P. Synthesis 2015; 47: 827
• 3c Kaur H, Balzarini J, de Kock C, Smith PJ, Chibale K, Singh K. Eur. J. Med. Chem. 2015; 101: 52
• 3d Murai K, Miyazaki S, Fujioka H. Tetrahedron Lett. 2012; 53: 3746
• 4a Liu C, Guo W, Shi X, Kaium MA, Gu X, Zhu YZ. Eur. J. Med. Chem. 2011; 46: 3996
• 4b Qiu K, Wang R. Synthesis 2015; 47: 3186
• 4c Yang Z, Zheng Y, Xu J. Synlett 2013; 24: 2165
• 5a Fujisaki S, Fujiwara I, Norisue Y, Kajigaeshi S. Bull. Chem. Soc. Jpn. 1985; 58: 2429
• 5b Murphy Kessabi F, Beaudegnies R, Quaranta L, Lamberth C. Tetrahedron Lett. 2016; 57: 5511
• 5c Floyd N, Vijayakrishnan B, Koeppe JR, Davis BG. Angew. Chem. Int. Ed. 2009; 48: 7798
• 5d Brown TJ, Chapman RF, Cook DC, Hart TW, McLay IM, Jordan R, Mason JS, Palfreyman MN, Walsh RJ. A. J. Med. Chem. 1992; 35: 3613
• 5e Minard TA, Oswin CT, Waldie FD. C, Howell JK, Scott BM. T, Mondo DD, Sullivan RJ, Stein B, Jennings M, Schlaf M. J. Mol. Catal. A: Chem. 2016; 422: 175
• 5f Zong J, Mague JT, Pascal JrR. A. Tetrahedron 2017; 73: 455
• 5g Rotili D, De Luca A, Tarantino D, Pezzola S, Forgione M, Morozzo della Rocca B, Falconi M, Mai A, Caccuri AM. Eur. J. Med. Chem. 2015; 89: 156
• 6a Su X, Pradaux-Caggiano F, Vicker N, Thomas MP, Halem H, Culler MD, Potter BV. L. ChemMedChem 2011; 6: 1616
• 6b Marciniec K, Pawełczak B, Latocha M, Skrzypek L, Maciążek-Jurczyk M, Boryczka S. Molecules 2017; 22: 300
• 6c Lee YS, Kim HY, Kim Y, Seo JH, Roh EJ, Han H, Shin KJ. Bioorg. Med. Chem. 2012; 20: 4921
• 7a Emerson DW, Bennett BL, Steinberg SM. Synth. Commun. 2005; 35: 631
• 7b Chukicheva IY, Sukrusheva OV, Shumova OA, Mazaletskaya LI, Shevchenko OG, Kuchin AV. Russ. J. Gen. Chem. 2016; 86: 2052
• 7c Younai A, Fettinger JC, Shaw JT. Tetrahedron 2012; 68: 4320
• 8 Aoyagi N, Furusho Y, Endo T. Synlett 2014; 25: 983
• 9a Jones DJ, O’Leary EM, O’Sullivan TP. Tetrahedron Lett. 2017; 58: 4212
• 9b Raz R, Rademann J. Org. Lett. 2011; 13: 1606
• 10a Najda-Mocarska E, Zakaszewska A, Janikowska K, Makowiec S. Synth. Commun. 2018; 48: 14
• 10b Supady A, Hecht S, Baldauf C. Org. Lett. 2017; 19: 4199
• 10c Serdyuk OV, Heckel CM, Tsogoeva SB. Org. Biomol. Chem. 2013; 11: 7051
• 10d Fang X, Wang C.-J. Chem. Commun. 2015; 1185
• 10e Lippert KM, Hof K, Gerbig D, Ley D, Hausmann H, Guenther S, Schreiner PR. Eur. J. Org. Chem. 2012; 5919
• 11 Váňa J, Sedlák M, Padělková Z, Hanusek J. Tetrahedron 2012; 68: 9808
• 12 Kammel R, Tarabová D, Brož B, Hladíková V, Hanusek J. Tetrahedron 2017; 73: 1861
• 13 Kammel R, Hanusek J. Heterocycles 2014; 89: 1183
• 14a Southan GJ, Szabo C. Biochem. Pharmacol. 1996; 51: 383
• 14b Southan GJ, Zingarelli B, O’Connor M, Salzman AL, Szabo C. Br. J. Pharmacol. 1996; 117: 619
• 14c Southan GJ, Szabo C, Thiemermann C. Br. J. Pharmacol. 1995; 114: 510
• 14d Jang D, Szabo C, Murrell GA. Eur. J. Pharmacol. 1996; 312: 341
• 15a Mostert S, Mentz W, Petzer A, Bergh JJ, Petzer JP. Bioorg. Med. Chem. 2012; 20: 7040
• 15b Booysen HP, Moraal C, Terre’Blanche G, Petzer A, Bergh JJ, Petzer JP. Bioorg. Med. Chem. 2011; 19: 7507
• 16 Ganellin CR, Hosseini SK, Khalaf YS, Tertiuk W, Arrang JM, Garbarg M, Ligneau X, Schwartz JC. J. Med. Chem. 1995; 38: 3342
• 17a Nicholson A, Perry JD, James AL, Stanforth SP, Carnell S, Wilkinson K, Anjam Khan CM, De Soyza A, Gould FK. Int. J. Antimicrob. Agents 2012; 39: 27
• 17b Barker CA, Allison SE, Zlitni S, Nguyen ND, Das R, Melacini G, Capretta AA, Brown ED. Bioorg. Med. Chem. Lett. 2013; 23: 2426
• 18a Bonez PC, Rossi GG, Bandeira JR, Ramos AP, Mizdal CR, Agertt VA, Dalla Nora ES. S, de Souza ME, dos Santos Alves CF, dos Santos FS, Gündel A, de Almeida Vaucher R, Santos RC. V, de Campos MM. A. Microb. Pathog. 2017; 111: (Supplement C) 6
• 18b Bonez PC, Ramos AP, Nascimento K, Copetti PM, Souza ME, Rossi GG, Agertt VA, Sagrillo MR, Santos RC. V, Campos MM. A. Microb. Pathog. 2016; 99: (Supplement C) 14
• 19 Matsuno K, Takai K, Isaka Y, Unno Y, Sato M, Takikawa O, Asai A. Bioorg. Med. Chem. Lett. 2010; 20: 5126
• 20 Ferreira M, Assunção LS, Silva AH, Filippin-Monteiro FB, Creczynski-Pasa TB, Sá MM. Eur. J. Med. Chem. 2017; 129: (Supplement C) 151
• 21a Jamaleddini A, Mohammadizadeh MR. Tetrahedron Lett. 2017; 58: 78-81
• 21b Ingham RJ, Riva E, Nikbin N, Baxendale IR, Ley SV. Org. Lett. 2012; 14: 3920
• 21c Huang Y, Zhang J, Yu Z, Zhang H, Wang Y, Lingel A, Qi W, Gu J, Zhao K, Shultz MD, Wang L, Fu X, Sun Y, Zhang Q, Jiang X, Zhang J, Zhang C, Li L, Zeng J, Feng L, Zhang C, Liu Y, Zhang M, Zhang L, Zhao M, Gao Z, Liu X, Fang D, Guo H, Mi Y, Gabriel T, Dillon MP, Atadja P, Oyang C. J. Med. Chem. 2017; 60: 2215
• 21d Geies AA, Abdel MoneamM. I, Kamal El-DeanA. M, Zaki RM, Abd El-NaeemE. E. J. Heterocycl. Chem. 2017; 54: 2012
• 21e Mousdis GA, Ganotopoulos N.-M, Barkaoui H, Abid Y, Psycharis V, Savvidou A, Raptopoulou CP. Eur. J. Inorg. Chem. 2017; 3401
• 21f Elacqua E, Manning KB, Lye DS, Pomarico SK, Morgia F, Weck M. J. Am. Chem. Soc. 2017; 139: 12240
• 21g Abul-Futouh H, Almazahreh LR, Harb MK, Görls H, El-khateeb M, Weigand W. Inorg. Chem. 2017; 56: 10437
• 21h Manos-Turvey A, Al-Ashtal HA, Needham PG, Hartline CB, Prichard MN, Wipf P, Brodsky JL. Bioorg. Med. Chem. Lett. 2016; 26: 5087
• 21i Tong S, Zhang M, Wang S, Yin R, Yu R, Wan S, Jiang T, Zhang L. Eur. J. Med. Chem. 2016; 123: (Supplement C) 849
• 22a Dixon AE, Hawthorne J. J. Chem. Soc., Trans. 1907; 91: 122
• 22b Dixon AE, Taylor J. J. Chem. Soc., Trans. 1920; 117: 720
• 23 Hemalatha P, Veeravazhuthi V. Acta Crystallogr., Sect. E: Struct. Rep. Online . 2008, 64; , 1805. CCDC Deposition Number: 695520
• 24 Biancalana L, Batchelor LK, De Palo A, Zacchini S, Pampaloni G, Dyson PJ, Marchetti F. Dalton Trans. 2017; 12001
• 25 General Procedure: To a stirred solution of thiourea (78 mg, 1.00 mmol, 1.00 equiv) in acetonitrile (10 mL) at 50 °C was added a solution of the required acid chloride (1.00 mmol, 1.00 equiv) in acetonitrile (10 mL) dropwise. The resulting thick suspension was allowed to stir at this temperature for a further one hour to ensure complete reaction. After one hour, the reaction mixture was cooled on ice and then vacuum filtered. The cake was washed with ethyl acetate (2 × 10 mL) to afford the products. The products were obtained quantitatively unless otherwise stated.Representative Examples: S-(3-Methoxybenzoyl)isothiouronium Chloride (5)Mp 166–168 °C (MeCN). ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.80 (s, 3 H, OCH₃ ), 7.19 (dd, J = 8.15, 1.83 Hz, 1 H, ArC(2)H), 7.39–7.44 (m, 2 H, overlapping ArC(6)H and ArC(3)H), 7.53 (d, J = 8.15 Hz, 1 H, ArC(4)H), 9.62 (bs, 4 H, NH ₂=C-NH ₂). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 55.2, 113.8, 118.9, 121.5, 129.7, 132.1, 159.2, 167.1. IR (KBr): 3329, 3281, 3163, 3085, 2954, 2836, 1697, 1609, 1583, 1526, 1470, 1420, 1311, 1293, 1267, 1051, 755 cm^–1. HRMS (ESI⁺): m/z calcd. for C₉H₁₁N₂O₂S⁺: 211.0536; found: 211.0528. Anal. Calcd. for C₉H₁₁N₂O₂ClS: C, 44.00; H, 4.10; N, 11.40; Found: C, 44.31; H, 4.18; N, 11.71. S-(Decanoyl)isothiouronium Chloride (14)Mp 115–117 °C (MeCN).¹H NMR (400 MHz, DMSO-d ₆): δ = 0.86 (t, J = 7.51 Hz, 3 H, CH ₃(10)), 1.24 (m, 12 H, CH ₂(9-4)), 1.46–1.50 (m, 2 H, CH ₂(3)), 2.18 (t, J = 7.88 Hz, 2 H, CH ₂(2)), 9.18 (bs, 4 H, NH ₂=C-NH ₂). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 13.9, 22.1, 24.5, 28.5, 28.6, 28.7, 31.2, 33.6, 174.5. IR (KBr): 3385, 3261, 3175, 3031, 2822, 2859, 1748, 1676, 1427, 732 cm^–1. HRMS (ESI⁺): m/z calcd for C₁₁H₂₃N₂OS: 231.1531; Found: 231.1536. Anal. Calcd for C₁₁H₂₃N₂OClS: C, 49.52; H, 8.69; N, 10.50; Found: C, 49.18; H, 8.75; N, 10.71.Indomethacin Analogue 21Mp 168–171 °C (MeCN).¹H NMR (400 MHz, DMSO-d ₆): δ = 2.22 (s, 3 H, ArCH ₃), 3.67 (s, 2 H, CH ₂), 3.76 (s, 3 H, OCH ₃), 6.72 (dd, J = 8.18, 1.33 Hz, 1 H, C(6)H), 6.92 (d, J = 8.18 Hz, 1 H, C(7)H), 7.05 (d, J = 1.33 Hz, 1 H, C(4)H). 7.64–7.70 (m, 4 H, Ar(2′, 3′, 5′ and 6′)H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 13.2, 29.5, 55.4, 101.7, 111.3, 113.4, 114.6, 116.5, 129.0, 130.2, 130.71, 131.1, 134.1, 135.1, 137.6, 155.5, 167.8, 172.0. IR (KBr): 3332, 3312, 2952, 1727, 1687, 1657, 1482, 1308, 1227, 1047, 792 cm^–1. HRMS (ESI⁺): m/z calcd for C₂₀H₁₉ClN₃O₃S⁺: 416.0830; Found: 416.0851. Anal. Calcd for C₂₀H₁₉Cl₂N₃O₃S: C, 53.10; H, 4.23; N, 9.29; Found: C, 53.33; H 4.29; N, 9.45