Multipathways for the Synthesis of Fused Bicyclic 2-Aminothiazolyl Compounds Tuned by Ring Size

Abstract

A new methodology for the synthesis of fused bicyclic 2-aminothiazolyl compounds has been developed, using cyclo­condensation of aromatic thioureas with α,β-epoxy cycloketones in alcohol under microwave irradiation without any catalyst. The product distribution is related to the ring size of α,β-epoxy cyclo­ketones. Mechanistic studies suggest that the reactions share analogous bicyclic dihydroxy intermediates but undergo different further reactions to give diverse products.

Key words

thiazole - fused bicyclic - ring size - multipathways - ­microwave irradiation

• References and Notes

• 1a Gorczynski MJ, Leal RM, Mooberry SL, Bushweller JH, Brown ML. Bioorg. Med. Chem. 2004; 12: 1029
• 1b Wang W.-L, Yao D.-Y, Gu M, Fan M.-Z, Li J.-Y, Xing Y.-C, Nan F.-J. Bioorg. Med. Chem. Lett. 2005; 15: 5284
• 1c Di Francesco ME, Dessole G, Nizi E, Pace P, Koch U, Fiore F, Pesci S, Di Muzio J, Monteagudo E, Rowley M, Summa V. J. Med. Chem. 2009; 52: 7014
• 1d Llinàs-Brunet M, Bailey MD, Goudreau N, Bhardwaj PK, Bordeleau J, Bös M, Bousquet Y, Cordingley MG, Duan J, Forgione P, Garneau M, Ghiro E, Gorys V, Goulet S, Halmos T, Kawai SH, Naud J, Poupart M.-A, White PW. J. Med. Chem. 2010; 53: 6466
• 2 Griss G, Schneider C, Hurnaus R, Kobinger W, Pichler L, Bauer R, Mierau J, Hinzen D, Schingnitz G. EPO 186087, 1986 ; Chem. Abstr. 1987, 106, 5015.
• 3 Prasanna DS, Kavitha CV, Vinaya K, Ranganatha SR, Raghava B, Kumar YC. S, Raghavan SC, Rangappa KS. B. Chem. Soc. Jpn. 2010; 83: 689
• 4 Moyes CR, Berger R, Goble SD, Harper B, Shen D.-M, Wang L, Bansal A, Brown PN, Chen AS, Dingley KH, Di Salvo J, Fitzmaurice A, Gichuru LN, Hurley AL, Jochnowitz N, Miller RR, Mistry S, Nagabukuro H, Salituro GM, Sanfiz A, Stevenson AS, Villa K, Zamlynny B, Struthers M, Weber AE, Edmondson SD. J. Med. Chem. 2014; 57: 1437
• 5 Pinacho Crisóstomo FR, Feng Y, Zhu X, Welsh K, An J, Reed JC, Huang Z. Bioorg. Med. Chem. Lett. 2009; 19: 6413
• 6a Barchéchath SD, Tawatao RI, Corr M, Carson DA, Cottam HB. J. Med. Chem. 2005; 48: 6409
• 6b Lv P.-C, Zhou C.-F, Chen J, Liu P.-G, Wang K.-R, Mao W.-J, Li H.-Q, Yang Y, Xiong J, Zhu H.-L. Bioorg. Med. Chem. 2010; 18: 314
• 7 Ritchie TJ, Macdonald SJ. F, Young RJ, Pickett SD. Drug Discov. Today 2011; 16: 164
• 8a Zhang W, Yue Y, Yu D, Song L, Xu YY, Tian YJ, Guo YJ. Adv. Synth. Catal. 2012; 354: 2283
• 8b Wang R, Yang W.-j, Yue L, Pan W, Zeng H.-y. Synlett 2012; 23: 1643
• 8c Yang J, Li P, Wang L. Tetrahedron 2011; 67: 5543
• 8d Wang R, Chen Z, Yue L, Pan W, Zhao J.-J. Tetrahedron Lett. 2012; 53: 4529
• 8e Shen G, Lv X, Bao W. Eur. J. Org. Chem. 2009; 5897
• 8f Rout SK, Guin S, Nath J, Patel BK. Green Chem. 2012; 14: 2491
• 8g Cano R, Ramón DJ, Yus M. J. Org. Chem. 2010; 76: 654
• 8h Saha P, Ramana T, Purkait N, Ali MA, Paul R, Punniyamurthy T. J. Org. Chem. 2009; 74: 8719
• 8i McGowan MA, Henderson JL, Buchwald SL. Org. Lett. 2012; 14: 1432
• 8j Ma D, Lu X, Shi L, Zhang H, Jiang Y, Liu X. Angew. Chem. Int. Ed. 2011; 50: 1118
• 8k Zhao J, Huang H, Wu W, Chen H, Jiang H. Org. Lett. 2013; 15: 2604
• 8l Mitamura T, Iwata K, Ogawa A. J. Org. Chem. 2011; 76: 3880
• 8m Gao H, Ess DH, Yousufuddin M, Kürti LS. J. Am. Chem. Soc. 2013; 135: 7086
• 8n Esmaili R, Nematollahi D. J. Org. Chem. 2013; 78: 5018
• 9a Hantzsch A, Weber JH. Ber. Dtsch. Chem. Ges. 1887; 20: 3118
• 9b Shen S.-S, Lei M.-Y, Wong Y.-X, Tong M.-L, Teo PL.-Y, Chiba S, Narasaka K. Tetrahedron Lett. 2009; 50: 3161
• 9c Guernon JM, Wu Y.-J. Tetrahedron Lett. 2011; 52: 3633
• 9d Lübbers T, Flohr A, Jolidon S, David-Pierson P, Jacobsen H, Ozmen L, Baumann K. Bioorg. Med. Chem. Lett. 2011; 21: 6554
• 9e Schwarz O, Jakupovic S, Ambrosi H.-D, Haustedt LO, Mang C, Müller-Kuhrt L. J. Comb. Chem. 2007; 9: 1104
• 9f Alam M, Khan S, Shaheen Khan M. J. Chil. Chem. Soc. 2008; 53: 1714
• 9g Hong S.-P, Liu KG, Ma G, Sabio M, Uberti MA, Bacolod MD, Peterson J, Zou ZZ, Robichaud AJ, Doller DO. J. Med. Chem. 2011; 54: 5070
• 9h John OR, Killeen NM, Knowles DA, Yau SC, Bagley MC, Tomkinson NC. Org. Lett. 2007; 9: 4009
• 10 Yadav JS, Reddy BV. S, Rao YG, Narsaiah AV. Tetrahedron Lett. 2008; 49: 2381
• 11 Gasteiger J, Herzig C. Tetrahedron 1981; 37: 2607
• 12 Ohler E. Monatsh. Chem. 1993; 124: 763
• 13 Bicyclic dihydroxy intermediates for the seven-membered ring were not obtained due to the low reaction activities of benzothioamide and α,β-epoxycyclopentanone.
• 14a Kasturi T, Chandra R. J. Org. Chem. 1988; 53: 3178
• 14b Kasturi TR, Chandra R, Reddy SM, Venkatesan K, Srikrishnan T, Row TN. G, Puranik VG, Tavale SS. J. Chem. Soc., Chem. Commun. 1987; 75
• 15 Schmittel M, Steffen J.-P, Auer D, Maywald M. Tetrahedron Lett. 1997; 38: 6177
• 16 General Procedure for the Preparation of Fused Bicyclic 2-Aminothiazolyl Compounds To a microwave vial (2–5 mL) were added aryl thiourea 1 (1 mmol), α,β-epoxy cycloketone 2 (1.05 mmol), and the corresponding alcohol (2 mL). The sealed vial was heated in the Biotage Initiator Synthesizer for an appropriate time. The mixture was then cooled to r.t., and the residue was obtained after evaporating under vacuum. The residue was subjected to purification over silica gel chromatography eluting with PE–EtOAc (9:1, v/v) to afford target compounds. N-(4-Chlorophenyl)-7-methoxy-4,5,6,7-tetrahydrobenzo[d]thiazol-2-amine (3a) White solid; yield: 273 mg (93%); mp 113.5–114.2 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ =10.25 (s, 1 H), 7.65 (d, J = 8.6 Hz, 2 H), 7.34 (d, J = 8.6 Hz, 2 H), 4.37 (t, J = 4.2 Hz, 1 H), 3.33 (s, 3 H), 2.62–2.48 (m, 2 H), 1.89–1.78 (m, 4 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 162.4, 148.8, 140.5, 129.2, 124.8, 118.7, 118.5, 72.6, 55.9, 28.7, 27.1, 19.3. ESI-HRMS: m/z [M + H]⁺ calcd for C₁₄H₁₆ ³⁵ClN₂OS⁺: 295.0672; found: 295.0674; calcd for C₁₄H₁₆ ³⁷ClN₂OS⁺: 297.0642; found: 297.0642. 2-[(4-Chlorophenyl)amino]-4,5-dihydro-3aH-cyclopenta[d]thiazol-6(6aH)-one (4a) White solid; yield: 226 mg (85%); mp 147.0–148.2 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.26 (d, J = 8.8 Hz, 2 H), 7.12 (d, J = 8.8 Hz, 2 H), 6.68 (s, 1 H), 4.89–4.84 (m, 1 H), 3.96 (d, J = 7.2 Hz, 1 H), 2.64–2.52 (m, 1 H), 2.43–2.32 (m, 1 H), 2.32–2.17 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 214.0, 159.4, 143.7, 129.2, 129.0, 122.2, 66.6, 54.1, 34.4, 27.9. ESI-HRMS: m/z [M + H]⁺ calcd for C₁₂H₁₂ ³⁵ClN₂OS⁺: 267.0359; found: 267.0366; calcd for C₁₂H₁₂ ³⁷ClN₂OS⁺: 269.0329; found: 269.0335. N-(4-Chlorophenyl)-5,6-dihydro-4H-cyclohepta[d]thiazol-2-amine (5a) Light yellow solid; yield: 190 mg (69%); mp 126.5–128.0 °C.¹H NMR (400 MHz, DMSO-d ₆): δ = 10.21 (s, 1 H), 7.62 (d, J = 8.8 Hz, 2 H), 7.33 (d, J = 8.8 Hz, 2 H), 6.17 (d, J = 11.6 Hz, 1 H), 5.77–5.70 (m, 1 H), 2.92 (t, J = 5.6 Hz, 2 H), 2.41–2.36 (m, 2 H), 1.85 (dt, J = 11.2, 5.6 Hz, 2 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 160.2, 150.6, 140.5, 129.4, 129.2, 124.8, 118.7, 118.3, 118.0, 33.5, 30.6, 22.9. ESI-HRMS: m/z [M + H]⁺ calcd for C₁₄H₁₄ ³⁵ClN₂S⁺: 277.0566; found: 236.0568; calcd for C₁₄H₁₄ ³⁷ClN₂S⁺: 279.0537; found: 279.0542.