Efficient Synthesis of 2-Methylenethiazolo[2,3-b]quinazolinone Derivatives

Abstract

Substituted o-amino-N-(prop-2-yn-1-yl) aromatic amides easily reacted with carbon disulfide (CS₂) in the presence of potassium hydroxide (KOH) in EtOH under reflux conditions. Cyclization reaction followed by a favored 5-exo-dig ring closure afforded 2-methylene-­thiazolo[2,3-b]quinazolinone derivatives in good yields.

Key words

2-methylene-thiazolo[2,3-b]quinazolinones - propargylamine - carbon disulfide - fused quinazolinone - 5-exo-dig

• References and Notes

• 1 Khan I, Ibrar A, Abbas N, Saeed A. Eur. J. Med. Chem. 2014; 76: 193
• 2 Chen X, Du Y, Sun H, Wang F, Kong L, Sun M. Bioorg. Med. Chem. Lett. 2014; 24: 884
• 3 Ugale VG, Bari SB. Eur. J. Med. Chem. 2014; 80: 447
• 4 Balakumar C, Lamba P, Kishore DP, Narayana BL, Rao KV, Rajwinder K, Rao AR, Shireesha B, Narsaiah B. Eur. J. Med. Chem. 2010; 45: 4904
• 5 Hu S, Xie G, Zhang DX, Davis C, Long W, Hu Y, Wang F, Kang X, Tan F, Ding L, Wang Y. Bioorg. Med. Chem. Lett. 2012; 22: 6301
• 6 Fowler KW, Huang D, Kesicki EA, Ooi HC, Oliver A, Ruan F, Treiberg J, Puri KD. US Patent RE44599, 2013
• 7 Gali R, Banothu J, Porika M, Velpula R, Hnamte S, Bavantula R, Abbagani S, Busi S. Bioorg. Med. Chem. Lett. 2014; 24: 4239
• 8 Saeva GA, Georgiev VS. US Patent 4738964, 1988
• 9a Seybold G, Wuerzer B. US Patent 4473391, 1984
• 9b Seybold G, Wuerzer B. US Patent 4486221, 1984
• 10 Sachdev HS, Dhami KS, Atwal MS. Tetrahedron 1961; 14: 304
• 11 Dhami KS, Sachdev HS, Narang KS. J. Sci. Ind. Res. 1956; 15: 690
• 12 Shiau C.-Y, Chern J.-W, Liu K.-C, Chan C.-H, Yen M.-H, Cheng M.-C, Wang Y. J. Heterocycl. Chem. 1990; 27: 1467
• 13a Mahdavi M, Asadi M, Saeedi M, Rezaei Z, Moghbel H, Foroumadi A, Shafiee A. Synlett 2012; 23: 2521
• 13b Mahdavi M, Foroughi N, Saeedi M, Karimi M, Foroumadi A, Alinezhad H, Shafiee A, Akbarzadeh T. Synlett 2014; 25: 385
• 13c Esmaeili-Marandi F, Saeedi M, Mahdavi M, Yavari I, Foroumadi A, Shafiee A. Synlett 2014; 25: 2605
• 14 Jablonski JJ, Basu D, Engel DA, Geysen HM. Bioorg. Med. Chem. 2012; 20: 487
• 15 Ren X.-F, Turos E, Lake CH, Churchill MR. J. Org. Chem. 1995; 60: 6468
• 16 Ren X.-F, Turos E. Tetrahedron Lett. 1993; 34: 1575
• 17a Baldwin JE. J. Chem. Soc., Chem. Commun. 1976; 734
• 17b Baldwin JE, Thomas RC, Kruse LI, Silberman L. J. Org. Chem. 1977; 42: 3846
• 18 Pura MS, Sachdev HS, Ralhan NK. Indian J. Chem. 1964; 2: 258
• 19 Synthesis of 2-Methylene-thiazolo[2,3-b]quinazolinone Derivatives 11 – General ProcedureA mixture of substituted o-amino-N-(prop-2-yn-1-yl) aromatic amides 9 (1 mmol), CS₂ (10, 2 mmol), and KOH (1 mmol) in EtOH (8 mL) was heated at reflux for 3–8 h. After completion of reaction (checked by TLC), the reaction mixture was cooled to r.t. and poured into cold H₂O. The precipitate was filtered off to obtain pure products 11 with no need for further purification.2-Methylene-2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-one (11a)Yield 0.18 g (85%); white solid; mp 220–222 °C (lit.¹¹ 202 °C). IR (KBr): 2937, 1665, 1582, 1553 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 5.12 (t, J = 2.4 Hz, 2 H, CH₂), 5.37 (q, J = 2.4 Hz, 1 H, =CH₂), 5.50 (q, J = 2.4 Hz, 1 H, =CH₂), 7.42 (td, J = 7.6, 0.8 Hz, 1 H, H₇), 7.56 (dd, J = 7.6, 0.8 Hz, 1 H, H₉), 7.72 (td, J = 7.6, 1.5 Hz, 1 H, H₈), 8.22 (dd, J = 7.6, 1.5 Hz, 1 H, H₆). ¹³C NMR (100 MHz, CDCl₃): δ = 54.2, 108.3, 119.3, 126.2, 126.3, 126.6, 133.1, 134.8, 148.8, 158.1, 159.9. Anal. Calcd for C₁₁H₈N₂OS: C, 61.09; H, 3.73; N, 12.95. Found: C, 60.87; H, 3.58; N, 13.14.7-Methyl-2-methylene-2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-one (11b)Yield 0.18 g (80%); deep yellow solid; mp 160–162 °C (lit.¹¹ 150 °C). IR (KBr): 1669, 1621, 1581 m^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.47 (s, 3 H, CH₃), 5.11 (t, J = 2.4 Hz, 2 H, CH₂), 5.35 (q, J = 2.4 Hz, 1 H, =CH₂), 5.48 (q, J = 2.4 Hz, 1 H, =CH₂), 7.45 (d, J = 8.4 Hz, 1 H, H₉), 7.53 (dd, J = 8.4, 1.6 Hz, 1 H, H₈), 8.00 (s, 1 H, H₆). ¹³C NMR (100 MHz, CDCl₃): δ = 21.2, 54.2, 108.1, 119.0, 126.0, 126.1, 133.3, 136.1, 136.4, 146.8, 157.0, 159.9. Anal. Calcd for C₁₂H₁₀N₂OS: C, 62.59; H, 4.38; N, 12.16. Found: C, 62.41; H, 4.52; N, 11.97.7,8-Dimethoxy-2-methylene-2H-thiazolo[2,3-b]quinazolin-5(3H)-one (11c)Yield 0.21 g (75%); deep yellow solid; mp 221–223 °C. IR (KBr): 1672, 1605, 1580 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 3.98 (s, 3 H, OCH₃), 4.00 (s, 3 H, OCH₃), 5.12 (t, J = 2.4 Hz, 2 H, CH₂), 5.35 (q, J = 2.4 Hz, 1 H, =CH₂), 5.48 (q, J = 2.4 Hz, 1 H, =CH₂), 6.98 (s, 1 H, H₉), 7.52 (s, 1 H, H₆). ¹³C NMR (100 MHz, CDCl₃): δ = 54.3, 56.2, 56.3, 105.5, 106.9, 108.1, 117.2, 133.4, 145.2, 148.5, 155.1, 156.4, 159.4. Anal. Calcd for C₁₃H₁₂N₂O₃S: C, 56.51; H, 4.38; N, 10.14. Found: C, 56.34; H, 4.50; N, 9.96.8-Chloro-2-methylene-2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-one (11d)Yield 0.17 g (70%); off-white solid; mp 170–171 °C (lit.¹⁸ 167 °C). IR (KBr): 2918, 1685, 1602, 1568 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 5.27 (t, J = 1.9 Hz, 2 H, CH₂), 5.37 (q, J = 1.9 Hz, 1 H, =CH₂), 5.61 (q, J = 1.9 Hz, 1 H, =CH₂), 7.37 (dd, J = 8.8, 2.0 Hz, 1 H, H₇), 7.62 (d, J = 2.0 Hz, 1 H, H₉), 8.27 (d, J = 8.8 Hz, 1 H, H₆). ¹³C NMR (100 MHz, CDCl₃): δ = 53.6, 115.2, 117.2, 123.3, 125.5, 125.8, 128.4, 149.0, 157.6, 159.5, 163.8. Anal. Calcd for C₁₁H₇ClN₂OS: C, 52.70; H, 2.81; N, 11.17. Found: C, 52.91; H, 2.68; N, 10.92.7-Chloro-2-methylene-2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-one (11e)Yield 0.17 g (70%); white solid; mp 192–192 °C (lit.¹⁰ 193 °C). IR (KBr): 2915, 1681, 1609, 1574 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 5.11 (s, 2 H, CH₂), 5.37 (d, J = 2.0 Hz, 1 H, =CH₂), 5.50 (d, J = 2.0 Hz, 1 H, =CH₂), 7.60 (d, J = 7.1 Hz, 1 H, H₉), 7.62 (dd, J = 7.1, 2.0 Hz, 1 H, H₈), 8.27 (d, J = 2.0 Hz, 1 H, H₆). ¹³C NMR (100 MHz, CDCl₃): δ = 54.2, 108.6, 117.1, 123.6, 126.1, 127.8, 130.8, 135.1, 146.7, 157.2, 158.5. Anal. Calcd for C₁₁H₇ClN₂OS: C, 52.70; H, 2.81; N, 11.17. Found: C, 52.57; H, 2.93; N, 11.28.2-Methylene-2,3-dihydro-5H-benzo[g]thiazolo[2,3-b]quinazolin-5-one (11f)Yield 0.17 g (65%); yellow solid; mp 190–192 °C. IR (KBr): 1628, 1573, 1401 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 5.13–5.15 (m, 2 H, CH₂), 5.37–5.38 (m, 1 H, =CH₂), 5.50–5.51 (m, 1 H, =CH₂), 7.52 (t, J = 6.5 Hz, 1 H, H₉), 7.62 (t, J = 6.5 Hz, 1 H, H₈), 7.98 (d, J = 6.5 Hz, 1 H, H₁₀), 8.00 (s, 1 H, H₁₁), 8.07 (d, J = 6.5 Hz, 1 H, H₇), 8.13 (s, 1 H, H₆). ¹³C NMR (100 MHz, CDCl₃): δ = 53.9, 108.1, 116.8, 123.1, 123.6, 125.8, 126.2, 128.3, 128.6, 128.7, 128.8, 129.4, 137.0, 163.2, 163.6. Anal. Calcd for C₁₅H₁₀N₂OS: C, 67.65; H, 3.78; N, 10.52. Found: C, 67.83; H, 3.57; N, 10.37.2-Methylene-8-nitro-2H-thiazolo[2,3-b]quinazolin-5(3H)-one (11g)Yield 0.13 g (50%); yellow solid; mp 180–182 °C. IR (KBr): 1669, 1535, 1613, 1488, 1350 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 5.12 (t, J = 1.9 Hz, 2 H, CH₂), 5.35 (q, J = 1.9 Hz, 1 H, =CH₂), 5.48 (q, J = 1.9 Hz, 1 H, =CH₂), 6.49 (dd, J = 1.7 Hz, 1 H, H₉), 6.66 (dd, J = 6.9, 1.7 Hz, 1 H, H₇), 7.72 (d, J = 6.9 Hz, 1 H, H₆). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 53.8, 105.9, 108.2, 114.1, 127.3, 133.3, 150.3, 154.5, 156.7, 157.7, 158.4. Anal. Calcd for C₁₁H₇N₃O₃S: C, 50.57; H, 2.70; N, 16.08. Found: C, 50.39; H, 2.57; N, 15.87.2-Methylene-2,3-dihydro-5H-pyrido[2,3-d]thiazolo[3,2-a]pyrimidin-5-one (11h)Yield 0.10 g (45%); deep yellow solid; mp 180–182 °C. IR (KBr): 2915, 1681, 1609 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 5.22 (t, J = 1.5 Hz, 2 H, CH₂), 5.63 (q, J = 1.5 Hz, 1 H, =CH₂), 5.65 (q, J = 1.5 Hz, 1 H, =CH₂), 6.60 (dd, J = 6.2, 3.8 Hz, 1 H, H₇), 8.04 (dd, J = 6.2, 1.5 Hz, 1 H, H₆), 8.17 (dd, J = 3.8, 1.5 Hz, 1 H, H₈). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 51.9, 105.5, 111.8, 120.3, 120.9, 123.3, 140.0, 153.4, 159.7, 168.6. Anal. Calcd for C₁₀H₇N₃OS: C, 55.29; H, 3.25; N, 19.34. Found: C, 55.42; H, 3.36; N, 19.52.