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Synlett 2012; 23(9): 1364-1370
DOI: 10.1055/s-0031-1290962
letter
© Georg Thieme Verlag Stuttgart · New York

Quinazolinone-Directed C–H Activation: A Novel Strategy for the Acetoxylation–Methoxylation of the Arenes

B. V. Subba Reddy*
Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India, Fax: +91(40)27160512   Email: basireddy@iict.res.in
,
G. Narasimhulu
Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India, Fax: +91(40)27160512   Email: basireddy@iict.res.in
,
N. Umadevi
Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India, Fax: +91(40)27160512   Email: basireddy@iict.res.in
,
J. S. Yadav
Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India, Fax: +91(40)27160512   Email: basireddy@iict.res.in
› Author Affiliations
Further Information

Publication History

Received: 29 February 2012

Accepted after revision: 15 March 2012

Publication Date:
14 May 2012 (online)

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Abstract

2-Aryl-4-quinazolinones undergo smooth acetoxylation in the presence of 5 mol% Pd(OAc)2 and a stoichiometric amount of PhI(OAc)2 via C–H activation to produce the corresponding acetoxy-substituted 4(3H)-quinazolinone derivatives in good yields with high regioselectivity.

Key words

2-aryl-4-quinazolinone - hypervalent iodine reagent - acetoxylation - C–H activation
 

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  • 14 Preparation of 2-Aryl-4(3H)-quinazolinone (1) To a mixture of anthranilimide (544 mg, 4.0 mmol) and benzaldehyde (470 mg, 4.4 mmol) in EtOH (20 mL) was added CuCl2 (804 mg, 6 mmol) at 25 °C. The resulting mixture was stirred under reflux for 3 h as required to complete the reaction. After complete conversion, as indicated by TLC, the solvent was removed in vacuo, and the mixture was diluted with H2O and extracted with EtOAc (3 × 15 mL). The combined organic layers were dried over anhyd Na2SO4, concentrated in vacuo, and purified by column chromatography on silica gel (Merck, 60–120 mesh, EtOAc–hexane = 4:6) to afford the pure quinazolinone (1, Scheme 5)
  • 15 Typical Procedures (i) Monoacetoxylation A mixture of 2-aryl-4(3H)-quinazolinone (1 mmol), iodobenzenediacetate (1.1 mmol), Ac2O (1.1 mmol), and Pd(OAc)2 (5 mol%) in DCE (5 mL) was stirred under reflux for a specified time (Table 1). After complete conversion, as indicated by TLC, the reaction mixture was diluted with H2O (10 mL) and extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried over anhyd Na2SO4, concentrated in vacuo, and purified by column chroma-tography on silica gel (Merck, 60–20 mesh, EtOAc–hexane = 4:6) to afford pure monoacetoxy quinazolinone derivative. (ii) Bisacetoxylation A mixture of 2-aryl-4(3H)-quinazolinone (1 mmol), iodobenzenediacetate (2.2 mmol), Ac2O (2.2 mmol), and Pd(OAc)2 (5 mol%) in DCE (5 mL) was stirred at reflux temperature for a specified time (Table 2). After complete conversion, as indicated by TLC, the reaction mixture was diluted with H2O (10 mL) and extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried over anhyd Na2SO4, concentrated in vacuo, and purified by column chromatography on silica gel (Merck, 60–20 mesh, EtOAc–hexane = 4:6) to afford pure bisacetoxy quinazolinone derivative. The products thus obtained were characterized by IR, NMR, and MS and also by physical constants. Compound 3a (Table 1): solid, mp 188–190 °C. IR (neat): νmax = 3081, 2926, 1675, 1598, 1546, 1496, 1446, 1336, 1220, 1173, 1063, 939, 826, 767 cm–1. 1H NMR (500 MHz, CDCl3): δ = 2.33 (s, 3 H), 7.26 (d, 1 H, J = 7.6 Hz), 7.42 (t, 1 H, J = 7.6 Hz), 7.49 (t, 1 H, J = 6.6 Hz), 7.55 (t, 1 H, J = 6.6 Hz), 7.73–7.82 (m, 2 H), 8.08 (d, 1 H, J = 7.6 Hz), 8.26 (d, 1 H, J = 7.6 Hz), 10.54–10.65 (br s, 1 H). ESI-MS: m/z = 281 [M + H], 303 [M + Na]. Compound 3b (Table 1): solid, mp 198–200 °C. IR (neat): νmax = 3446, 2923, 2853, 1773, 1743, 1671, 1605, 1462, 1371, 1258, 1191, 1077, 1021, 965, 773 cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.08 (s, 3 H), 2.33 (s, 3 H), 7.07 (s, 1 H), 7.20–7.28 (m, 1 H), 7.44–7.57 (m, 1 H), 7.75–7.83 (m, 2 H), 7.91 (d, 1 H, J = 7.9 Hz), 8.28 (d, 1 H, J = 8.3Hz). 13C NMR (75 MHz, CDCl3): δ = 21.1, 21.4, 114.2, 122.5, 124.2, 126.4, 126.9, 127.4, 127.8, 128.1, 130.1, 134.8, 143.3, 148.3, 149.7, 162.9, 168.9. ESI-MS: m/z = 295 [M + H], 317 [M + Na]. Compound 3c (Table 1): solid, mp 159–160 °C. IR (neat): νmax = 3353, 3222, 2923, 2854, 1689, 1592, 1478, 1396, 1211, 1164, 1052, 936, 759, 682 cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.06 (s, 3 H), 7.36–7.60 (m, 3 H), 7.62–7.81 (m, 3 H), 8.23 (d, 1 H, J = 7.9 Hz). ESI-MS: m/z = 359 [M + H], 381 [M + Na]. Compound 3d (Table 1): solid, mp 272–274 °C. IR (KBr): νmax = 2923, 2853, 1782, 1687, 1609, 1467, 1348, 1296, 1178, 1053, 941, 889, 771 cm–1. 1H NMR (500 MHz, CDCl3): δ = 2.58 (s, 3 H), 7.48–7.58 (m, 2 H), 7.77–7.85 (m, 2 H), 8.23–8.31 (m, 2 H), 8.34 (d, 1 H, J = 8.9 Hz), 8.50 (d, 1 H, J = 7.9 Hz). ESI-MS: m/z = 326 [M + H], 348 [M + Na]. HRMS: m/z calcd for C16H12N3O5: 326.0771; found: 326.0784. Compound 3e (Table 1): solid, mp 118–119 °C. IR (KBr): νmax = 3424, 3137, 3063, 2928, 2856, 1760, 1671, 1574, 1508, 1471, 1364, 1256, 1199, 992, 926, 838, 777 cm–1. 1H NMR (300 MHz, CDCl3): δ = 0.26 (s, 6 H), 1.02 (s, 9 H), 2.30 (s, 3 H), 6.97 (d, 1 H, J = 8.9 Hz), 7.09 (d, 1 H, J = 8.9 Hz), 7.43–7.56 (m, 2 H), 7.72–7.83 (m, 2 H), 8.27 (d, 1 H, J = 6.9 Hz), 10.53 (br s, 1 H). 13C NMR (75 MHz, CDCl3): δ = –4.4, 18.1, 21.0, 25.5, 121.2, 120.9, 123.3, 124.5, 126.5, 127, 127.8, 134.7, 142.3, 149, 149.6, 153.7, 162.6, 169.2. ESI-MS: m/z = 411 [M + H], 433 [M + Na]. HRMS: m/z calcd for C22H27N2O4Si: 411.1740; found: 411.1722. Compound 3f (Table 1): solid, mp 256–258 °C. IR (KBr): νmax = 2924, 2855, 1766, 1670, 1602, 1467, 1369, 1302, 1190, 1070, 1012, 902, 746 cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.31 (s, 3 H), 7.03–7.21 (m, 3 H), 7.28–7.60 (m, 5 H), 7.67–7.73 (m, 2 H), 7.81–7.86 (m, 1 H), 8.15 (d, 1 H, J = 7.5 Hz), 10.79–10.93 (br s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 21, 96.1, 111.8, 114.2, 119, 120.3, 122, 122.9, 123.8, 124.9, 126.5, 127.1, 127.8, 128.2, 129.9, 134.7, 143.8, 148.9, 155.1, 156.6, 162.9, 168.8; ESI-MS: m/z = 373 [M + H], 395 [M + Na]. HRMS: m/z calcd for C22H17N2O4: 373.1183; found: 373.1198. Compound 3g (Table 1): solid, mp 176–178 °C. IR (neat): νmax = 3445, 2925, 2854, 1770, 1744, 1677, 1597, 1467, 1422, 1363, 1255, 1196, 1125, 1037, 894, 829, 774, 698 cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.08 (s, 3 H), 2.45 (s, 3 H), 3.44 (s, 3 H), 7.12 (s, 1 H), 7.20 (d, 1 H, J = 7.5 Hz), 7.37 (d, 1 H, J = 8.3 Hz), 7.44–7.57 (m, 2 H), 7.72–7.79 (m, 1 H), 8.34 (d, 1 H, J = 7.5 Hz). 13C NMR (75 MHz, CDCl3): δ = 21.4, 24.8, 33.3, 114.2, 123.6, 126.6, 127, 127.1, 127.5, 129, 129.6, 131.9, 134.2, 141.9, 144.1, 147.6, 162.5, 168.7. ESI-MS: m/z = 309 [M + H], 331 [M + Na]. Compound 3h (Table 1): solid, mp 156–58 °C. IR (neat): νmax = 3425, 3316, 2923, 2853, 1681, 1590, 1555, 1463, 1317, 1253, 1168, 1026, 951, 745 cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.43 (s, 3 H), 4.07 (s, 3 H), 6.82 (s, 1 H), 6.94 (d, 1 H, J = 8.1 Hz), 7.37–7.47 (m, 1 H), 7.67–7.79 (m, 2 H), 8.24 (d, 1 H, J = 7.9 Hz), 8.44 (d, 1 H, J = 7.9 Hz), 10.81–11.00 (br s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 21.7, 55.9, 102.4, 112.3, 122.5, 126, 126.2, 127.5, 131.2, 134.2, 134.4, 144.1, 149.3, 150.7, 157.5, 161.8. ESI-MS: m/z = 267 [M + H], 289 [M + Na]. HRMS: m/z calcd for C16H15N2O2: 267.1128; found: 267.1160. Compound 4a (Table 2): solid, mp 183–184 °C. IR (KBr): νmax = 3429, 3187, 3074, 2923, 2854, 1770, 1657, 1606, 1463, 1364, 1281, 1189, 1032, 937, 854, 781 cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.15 (s, 6 H), 7.20 (d, 2 H, J = 8.1 Hz), 7.49–7.60 (m, 2 H), 7.80 (d, 2 H, J = 3.6 Hz), 8.30 (d, 1 H, J = 7.7 Hz). 13C NMR (75 MHz, CDCl3): δ = 20.7, 120.6, 120.9, 126.5, 127.5, 131.5, 134.8, 146.7, 148.4, 149.1, 161.9, 168.6. ESI-MS: m/z = 339 [M + H], 361 [M + Na]. HRMS: m/z cald for C18H14N2O5Na: 361.0800; found: 361.0788. Compound 4b (Table 2): solid, mp 323–325 °C. IR (KBr): νmax = 3178, 3068, 2923, 2855, 1779, 1660, 1620, 1467, 1366, 1283, 1190, 1057, 936, 878, 776 cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.16 (s, 6 H), 2.46 (s, 3 H), 6.96 (s, 2 H), 7.46–7.56 (m, 1 H), 7.64–7.83 (m, 2 H), 8.28 (d, 2 H, J = 8.3 Hz), 9.58 (br s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 20.7, 29.6, 121.6, 126.6, 127.4, 127.7, 134.8, 142.9, 146.7, 148.7, 148.9, 161.6, 168.9. ESI-MS: m/z = 353 [M + H], 375 [M + Na]. Compound 4c (Table 2): solid, mp 197–199 °C. IR (KBr): νmax = 3182, 3071, 2923, 2853, 1784, 1762, 1656, 1600, 1468, 1364, 1272, 1180, 1145, 1048, 938, 875, 780, 690 cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.13 (s, 6 H), 7.29 (s, 2 H), 7.43–7.56 (m, 2 H), 7.65–7.81 (m, 2 H), 8.26 (d, 1 H, J = 7.7 Hz). ESI-MS: m/z = 373 [M + H]. HRMS: m/z calcd for C18H13N2O5NaCl: 395.0410; found: 395.0395. Compound 4d (Table 2): solid, mp 178–180 °C. IR (neat): νmax = 2923, 2853, 1785, 1664, 1603, 1466, 1369, 1296, 1181, 1047, 833, 774 cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.17 (s, 6 H), 3.86 (s, 3 H), 6.71 (s, 2 H), 7.48–7.57 (m, 1 H), 7.78 (d, 2 H, J = 3.6 Hz), 8.29 (d, 1 H, J = 7.9 Hz). 13C NMR (75 MHz, CDCl3): δ = 20.8, 55.9, 107.1, 126.6, 127.4, 134.9, 138.4, 139.2, 146.8, 150.2, 161.6, 163.9, 168.7. ESI-MS: m/z = 369 [M + H]. HRMS: m/z calcd for C19H17N2O6: 369.1081; found: 369.1083. Compound 4e (Table 2): solid, mp 165–166 °C. IR (KBr): νmax = 3331, 2924, 2855, 1761, 1681, 1602, 1465, 1368, 1310, 1190, 1081, 971, 937, 887, 771 cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.14 (s, 6 H), 2.18 (s, 6 H), 7.23 (s, 1 H), 7.44–7.56 (m, 1 H), 7.68–7.80 (m, 2 H), 8.28 (d, 1 H, J = 7.9 Hz), 9.43 (br s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 15.8, 20.2, 121.1, 121.3, 126.4, 127.2, 127.7, 129.3, 134.6, 145.3, 147.1, 148.6, 161.3, 168.7. ESI-MS: m/z = 367 [M + H], 389 [M + Na]. Compound 4f (Table 2): solid, mp 199–201 °C. IR (KBr): νmax = 3452, 3159, 2923, 2855, 1659, 1596, 1467, 1295, 1250, 1111, 1022, 939, 893, 757 cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.76 (s, 6 H), 6.60 (d, 2 H, J = 8.3 Hz), 7.36 (t, 1 H, J = 8.3 Hz), 7.46 (t, 1 H, J = 7.3 Hz), 7.76 (d, 2 H, J = 6.4 Hz), 8.15–8.30 (m, 1 H), 10.21 (br s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 29.6, 55.9, 104.0, 112.3, 126.3, 126.7, 127.8, 132.0, 134.4, 149.1, 149.4, 158.4, 162.7. ESI-MS: m/z = 283 [M + H]. HRMS: m/z calcd for C16H15N2O3: 283.1082; found: 283.1075
  • 16 Reductive Cleavage of 2-Aryl-4(3H)-quinazolinone A solution of 3a (400 mg, 1.43 mmol) in anhyd THF (8 mL) and liquid NH3 (20 mL) was treated with lithium metal (60 mg, 8.5 mmol) at –78 °C (Scheme 6). After stirring for 20 min, the mixture was quenched with solid NH4Cl (1.5 g). The color of the mixture was turned from blue to colorless. Excess NH3 was allowed to evaporate, and the residual mixture was quenched with H2O (5 mL) and Et2O (5 mL). The organic layers were separated, and the aqueous layer was extracted with Et2O (3 × 5 mL). The combined organic layers were dried over anhyd Na2SO4 and concentrated under reduced pressure. The resulting crude product was purified by column chromatography on silica gel to give ortho-hydroxybenzamide as yellow color oil. Rf  = 0.5 (SiO2, 30% EtOAc in hexane)