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

B. V. Subba Reddy; G. Narasimhulu; N. Umadevi; J. S. Yadav

doi:10.1055/s-0031-1290962

Synlett, Table of Contents

Synlett 2012; 23(9): 1364-1370
DOI: 10.1055/s-0031-1290962

letter

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

Abstract

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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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References

References and Notes

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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): ν_max = 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): ν_max = 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): ν_max = 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): ν_max = 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): ν_max = 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): ν_max = 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): ν_max = 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): ν_max = 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): ν_max = 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): ν_max = 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): ν_max = 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): ν_max = 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): ν_max = 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): ν_max = 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. R_f = 0.5 (SiO₂, 30% EtOAc in hexane)