An efficient synthesis of 16H-dibenzo[2,3:6,7][1,4]oxazepino[5,4-b]quinazolin-16-ones via an Ullmann reaction catalyzed by CuI

Yan Zhang, Jian-Quan Liu and Xiang-Shan Wang*
School of Chemistry and Materials Science, Jiangsu Key Laboratory of Green Synthesis for Functional Materials, Jiangsu Normal University, Xuzhou Jiangsu 221116, P. R. China. E-mail: xswang1974@yahoo.com

Received 2nd January 2018 , Accepted 7th February 2018

First published on 7th February 2018


CuI functions as a mild Lewis acid catalyst to promote the condensation and cyclization reaction of 2-amino-N-(2-hydroxyphenyl)benzamide and 2-bromobenzaldehyde to build the quinazoline moiety first. With the addition of Cs2CO3, it also can catalyse the subsequent intramolecular Ullmann type reaction to give 16H-dibenzo[2,3:6,7][1,4]oxazepino[5,4-b]quinazolin-16-ones in good yields.


Introduction

1,4-Oxazepane is a homologue of morpholine, which is a seven-membered heterocycle bearing both oxygen and nitrogen atoms in the 1,4-position. It has only one more carbon than morpholine whose core is found in numerous natural and synthetic active compounds. The well-known example is pyrrolo-1,5-benzoxazepine1 (PBOX-6, Fig. 1), which is a potential anti-cancer drug. Many other compounds containing 1,4-oxazepane analogues were found to possess pharmacological and biological activities, such as anti-tumor activity,2 noradrenaline reuptake inhibition,3 and anticonvulsant4 and antifungal activities.5 In addition, quinazoline is also a notable bicyclic heterocycle for its anti-tumor activity.6 A very effective drug on the market is Terazosin7 (Fig. 1), which is based on the quinazoline moiety which is used for treating symptoms of an enlarged prostate. Therefore, much attention has been devoted to the synthesis of 1,4-oxazepane8 and quinazoline derivatives9 in recent years.
image file: c8ob00005k-f1.tif
Fig. 1 Interesting molecules containing 1,4-oxazepane or quinazoline.

Oxazepinoquinazoline is a fused tricyclic skeleton and only a few synthesis methods have been reported in the literature. In 2012, the Visnevska10 group described a copper-catalyzed procedure from the reaction of 2-chloromethylquinazolin-4-one and (2-bromophenyl)methanol, with 5H-benzo[5,6][1,4]oxazepino[3,4-b]quinazolin-13(7H)-one being obtained but in poor yield (17%) (Scheme 1, (1)). The intramolecular nucleophilic substitution of 3-(2-(1-bromoethyl)-4-oxoquinazolin-3(4H)-yl)propanoic acid or 2-(3-(2-hydroxyethyl)-1-methyl-4-oxo-1,2,3,4-tetrahydroquinazolin-2-yl)acetic acid was an efficient approach to synthesise [1,4]oxazepinoquinazoline derivatives.11 However, the starting materials are not readily available (Scheme 1, (2)).


image file: c8ob00005k-s1.tif
Scheme 1 Approaches to synthesise the [1,4]oxazepinoquinazoline moiety.

As part of our continuous study of copper-catalyzed organic reactions with polycyclic heterocycles,12 herein, we would like to report the synthesis of 16H-dibenzo[2,3:6,7][1,4]oxazepino[5,4-b]quinazolin-16-one derivatives catalyzed by CuI in the presence of Cs2CO3, as depicted in Scheme 1, (3).

Results and discussion

In our initial study, 2-amino-N-(2-hydroxyphenyl)benzamide (1a), which can be easily prepared from isatoic anhydride and 2-aminophenol, together with 2-bromobenzaldehyde (2a), was employed as the model substrate for the studies. A series of copper(I) catalysts including CuI, CuBr, CuCl, Cu2O and CuOAc were initially screened in the presence of 2.0 equivalents of base (K2CO3) in dioxane under ligand-free conditions at 70 °C for 20 h. As shown in Table 1, the best result was obtained in 68% yield with 10 mol% CuI, and Cu2O was almost unreactive to this reaction because it could not promote the first step of a condensation and cyclization reaction. Furthermore, various inorganic bases, such as Na2CO3, NaHCO3, and Cs2CO3, were tested with this conversion. To our delight, Cs2CO3 gave the best outcome, which increased the yield of 3a from 68% to 76%. We suspected that ligands such as L-proline, o-phen or PPh3 might further improve the yields. However, they failed to provide better results compared to the ligand-free conditions. Lastly, the reaction solvent was changed from dioxane to toluene, DMF, DMAC and DMSO while keeping all other conditions the same. It turned out that DMF gave the highest yield among all solvents tested. After evaluating various conditions, we obtained the optimum results using 10 mol% CuI and 2.0 equiv. Cs2CO3 with DMF at 70 °C.
Table 1 Optimization of the model reactiona

image file: c8ob00005k-u1.tif

Entry Cat. Ligand Base Solvent Yield (%)
a Reaction conditions: 1a (114 mg, 0.5 mmol), 2a (93 mg, 0.5 mmol), catalyst (0.05 mmol), ligand (0.1 mmol), base (1.0 mmol), solvent (10.0 mL), 70 °C, 20 h.
1 CuI K2CO3 Dioxane 68
2 CuBr K2CO3 Dioxane 61
3 CuCl K2CO3 Dioxane 58
4 CuOAc K2CO3 Dioxane 56
5 Cu2O K2CO3 Dioxane 63
6 CuI Na2CO3 Dioxane 72
7 CuI NaHCO3 Dioxane 70
8 CuI Cs2CO3 Dioxane 76
9 CuI L-Proline Cs2CO3 Dioxane 68
10 CuI o-Phen Cs2CO3 Dioxane 64
11 CuI PPh3 Cs2CO3 Dioxane 71
12 CuI Cs2CO3 Toluene 69
13 CuI Cs2CO3 DMF 82
14 CuI Cs2CO3 DMAC 72
15 CuI Cs2CO3 DMSO 74


With the optimal reaction conditions established, we next examined the generality of this new protocol. Gratifyingly, a variety of 2-bromobenzaldehydes with different substituents underwent the condensation, cyclization and intramolecular Ullmann coupling with 1a to furnish the expected products 3a–3g in satisfactory yields (Table 2). Generally, reactions with both electron-donating (Me, MeO, or OCH2O) and electron-withdrawing groups (Cl or F) on the benzene ring all proceeded smoothly.

Table 2 The scope of products from reacting 1 and 2 to produce dibenzo[1,4]oxazepinoquinazolines, catalyzed by CuIa
a Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), CuI (10 mg, 0.05 mmol), Cs2CO3 (325 mg, 1.0 mmol), DMF (10.0 mL), 70 °C.
image file: c8ob00005k-u2.tif


Notably, other 2-amino-N-(2-hydroxyphenyl)benzamides with electron-donating (Me) and electron-withdrawing groups (Cl or Br) on a benzoyl moiety or hydroxyl benzene ring all worked well under the same reaction conditions to give 3h–3r in 71%–86% yields. The structure of 3c was further confirmed by X-ray diffraction analysis (CCDC 1814286, see ESI), and its crystal structure is shown in Fig. 2.


image file: c8ob00005k-f2.tif
Fig. 2 The crystal structure of 3c.

Under the optimal reaction conditions, it is worth mentioning that heteroaldehydes, such as 3-bromothiophene-2-carbaldehyde, were also able to react with 1 to produce 15H-benzo[2,3]thieno [3′,2′:6,7][1,4]oxazepino[5,4-b]quinazolin-15-ones (3s and 3t) in 76% and 81% yields, respectively. Delightfully, chlorine could also be used as a leaving group in this Ullmann C–O bond coupling reaction. 16H-Benzo[2,3]pyrido[3′,2′:6,7][1,4]oxazepino[5,4-b]quinazolin-16-one (3u) was obtained in 78% yield successfully when 2-chloronicotinaldehyde was used as a reactant to react with 1a, catalyzed by 10 mol% CuI and 2.0 equivalents of Cs2CO3 in DMF at 70 °C (Scheme 2).


image file: c8ob00005k-s2.tif
Scheme 2 The reaction involving o-halogenated heteroaldehydes.

In accordance with the literature13 and the structure of 3a, we think that the condensation of 1a and 2a takes place by first losing a molecule of H2O to give the Schiff base 4. In the presence of CuI, 4 undergoes cyclization to form 1,2-hydroquinazoline 5 followed by dehydrogenation in which the aromatized quinazoline 6 is obtained in air. In the following step, 6 converts to 7 via deprotonation in the presence of base (Cs2CO3). And then, 7 undergoes the classical oxidative addition to produce an eight-membered ring moiety 8. Lastly, reductive elimination takes place to give the final product 3a. The possible reaction mechanism is outlined in Scheme 3 (using 3a as a model).


image file: c8ob00005k-s3.tif
Scheme 3 The possible reaction mechanism.

Conclusions

In conclusion, we developed a novel procedure for rapid construction of 16H-dibenzo[2,3:6,7][1,4]oxazepino[5,4-b]quinazolin-16-ones in good yields. This copper-catalyzed reaction of N-(2-hydroxyphenyl)benzamides and 2-bromobenzaldehydes included subsequent condensation, cyclization and intramolecular Ullmann type reactions.

Experimental

Melting points were determined in open capillaries and are uncorrected. IR spectra were recorded on a Tensor 27 spectrometer with KBr pellets. NMR spectra were obtained from a solution in DMSO-d6 or CDCl3 with Me4Si as the internal standard using a Bruker-400 spectrometer. HRMS analyses were carried out using a Bruker-micro-TOF-Q-MS analyzer.

General procedure for the syntheses of 3 (using 3a as a model)

A reaction flask with a high vacuum valve was charged with 2-amino-N-(2-hydroxyphenyl)benzamide (1a, 114 mg, 0.5 mmol), 2-bromo-benzaldehyde (2a, 93 mg, 0.5 mmol), CuI (10 mg, 0.05 mmol) and DMF (10.0 mL). The mixture was stirred at 70 °C in air until all the 1a was consumed. Subsequently, it was allowed to cool down to room temperature, and Cs2CO3 (325 mg, 1.0 mmol) was added to the mixture. After three cycles of being put under vacuum and replacing with argon, the reaction mixture was continued to be stirred at 70 °C under an argon balloon before reaching completion, which was monitored by TLC. The solvent was recovered by distillation under reduced pressure, and then the residue was purified by chromatography over silica gel to give 3a using ethyl acetate and petroleum ether (1[thin space (1/6-em)]:[thin space (1/6-em)]5) as the eluent.
16H-Dibenzo[2,3:6,7][1,4]oxazepino[5,4-b]quinazolin-16-one (3a). Yield 82% (128 mg). Pale white solid, m.p. 243–245 °C; 1H NMR (CDCl3, 400 MHz): δH 7.38–7.41 (m, 1H), 7.41–7.47 (m, 3H), 7.49–7.50 (m, 1H), 7.51–7.53 (m, 2H), 7.83–7.87 (m, 1H), 7.89–7.92 (m, 1H), 8.36 (dd, J = 8.0 Hz, J′ = 1.2 Hz, 1H), 8.60 (dd, J = 7.6 Hz, J′ = 1.6 Hz, 1H), 8.70 (dd, J = 4.8 Hz, J′ = 1.6 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δC 121.3, 123.9, 124.0, 124.4, 126.9, 127.2, 127.5, 128.7, 128.9, 129.0, 129.1, 130.2, 134.3, 134.5, 134.7, 135.7, 138.1, 147.3, 150.5, 161.1. IR (KBr): ν 3070, 2901, 1682, 1645, 1618, 1596, 1499, 1466, 1381, 1328, 1267, 1248, 1180, 1142, 1038, 946, 889, 870, 851, 778, 711 cm−1. HRMS (TOF, APCI, m/z): calcd for C20H13N2O2 [M + H]+ 313.0977, found 313.1005.
8-Chloro-16H-dibenzo[2,3:6,7][1,4]oxazepino[5,4-b]quinazolin-16-one (3b). Yield 79% (137 mg). Pale white solid, m.p. 236–238 °C; 1H NMR (CDCl3, 400 MHz): δH 7.39–7.45 (m, 4H), 7.49–7.53 (m, 2H), 7.76 (d, J = 8.8 Hz, 1H), 7.88–7.91 (m, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.57 (dd, J = 7.6 Hz, J′ = 1.6 Hz, 1H), 8.71 (dd, J = 4.8 Hz, J′ = 1.6 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δC 121.5, 122.8, 123.6, 125.0, 127.0, 127.2, 127.6, 128.4, 128.9, 129.0, 132.1, 132.3, 132.6, 134.5, 134.6, 135.0, 135.9, 147.2, 150.2, 161.1. IR (KBr): ν 3058, 2919, 1682, 1637, 1603, 1560, 1486, 1429, 1375, 1333, 1172, 1113, 909, 882, 826, 761, 730 cm−1. HRMS (TOF, APCI, m/z): calcd for C20H12ClN2O2 [M + H]+ 347.0582, found 347.0602.
7-Chloro-16H-dibenzo[2,3:6,7][1,4]oxazepino[5,4-b]quinazolin-16-one (3c). Yield 86% (149 mg). Pale white solid, m.p. 225–227 °C; 1H NMR (CDCl3, 400 MHz): δH 7.23 (d, J = 8.8 Hz, 1H), 7.28–7.30 (m, 1H), 7.33–7.42 (m, 3H), 7.54–7.62 (m, 2H), 7.81–7.86 (m, 2H), 8.13 (d, J = 2.4 Hz, 1H), 8.37 (d, J = 8.0 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δC 120.7, 121.4, 121.5, 125.4, 127.5, 127.7, 127.9, 128.4, 128.6, 129.7, 129.8, 131.2, 131.5, 132.7, 135.0, 146.8, 150.1, 156.9, 160.3, 161.7. IR (KBr): ν 3059, 2959, 1678, 1637, 1600, 1459, 1466, 1439, 1383, 1279, 1217, 1184, 1170, 1077, 1003, 864, 796, 770, 740 cm−1. HRMS (TOF, APCI, m/z): calcd for C20H12ClN2O2 [M + H]+ 347.0582, found 347.0603.
7-Fluoro-16H-dibenzo[2,3:6,7][1,4]oxazepino[5,4-b]quinazolin-16-one (3d). Yield 72% (119 mg). Pale yellow solid, m.p. 219–221 °C; 1H NMR (CDCl3, 400 MHz): δH 6.26 (d, J = 9.2 Hz, 1H), 6.43 (d, J = 10.0 Hz, 1H), 6.65 (dd, J = 9.2 Hz, J′ = 2.0 Hz, 1H), 7.28–7.29 (m, 1H), 7.34–7.39 (m, 2H), 7.50–7.54 (m, 1H), 7.80–7.87 (m, 3H), 8.29 (d, J = 7.6 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δC 118.1 (d, JF–C = 25.5 Hz), 119.6 (d, JF–C = 23.5 Hz), 120.7, 121.4, 121.5 (d, JF–C = 8.4 Hz), 125.3, 127.5, 127.7, 127.8, 128.4 (d, JF–C = 8.6 Hz), 128.6, 129.7, 129.8, 135.0, 146.8, 150.3 (d, JF–C = 2.4 Hz), 157.2, 157.9 (d, JF–C = 2.6 Hz), 159.7 (d, JF–C = 243.2 Hz), 161.7. IR (KBr): ν 3069, 2964, 1683, 1636, 1614, 1593, 1551, 1455, 1429, 1372, 1323, 1284, 1230, 1168, 1073, 915, 878, 811, 778, 706 cm−1. HRMS (TOF, APCI, m/z): calcd for C20H12FN2O2 [M + H]+ 331.0877, found 331.0891.
8-Methyl-16H-dibenzo[2,3:6,7][1,4]oxazepino[5,4-b]quinazolin-16-one (3e). Yield 78% (127 mg). Pale white solid, m.p. 242–244 °C; 1H NMR (CDCl3, 400 MHz): δH 2.40 (s, 3H), 7.10–7.13 (m, 2H), 7.23–7.25 (m, 1H), 7.32–7.39 (m, 2H), 7.50–7.54 (m, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.78–7.83 (m, 2H), 8.03 (d, J = 7.6 Hz, 1H), 8.36 (d, J = 7.6 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δC 21.4, 120.46, 120.54, 121.5, 124.1, 125.0, 126.7, 127.1, 127.4, 127.7, 129.0, 129.5, 129.7, 131.5, 134.8, 144.2, 147.1, 151.5, 157.3, 161.7, 162.0. IR (KBr): ν 3068, 2956, 1684, 1629, 1594, 1572, 1508, 1462, 1442, 1276, 1247, 1173, 1108, 1072, 1031, 919, 877, 831, 793, 778 cm−1. HRMS (TOF, APCI, m/z): calcd for C21H15N2O2 [M + H]+ 327.1134, found 327.1152.
7-Methoxy-16H-dibenzo[2,3:6,7][1,4]oxazepino[5,4-b]quinazolin-16-one (3f). Yield 74% (127 mg). Pale white solid, m.p. 209–211 °C; 1H NMR (CDCl3, 400 MHz): δH 3.64 (s, 3H), 6.65–6.76 (m, 3H), 6.93–6.94 (m, 1H), 7.00–7.04 (m, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.56–7.60 (m, 1H), 7.83–7.87 (m, 2H), 8.38 (d, J = 8.0 Hz, 1H). 13C NMR (DMSO-d6, 100 MHz): δC 55.8, 111.7, 114.3, 116.6, 117.8, 119.4, 121.5, 124.7, 126.9, 128.0, 128.1, 128.8, 131.1, 133.2, 135.5, 137.2, 147.6, 153.3, 154.5, 158.1, 161.2. IR (KBr): ν 3066, 2972, 1681, 1633, 1618, 1594, 1550, 1514, 1461, 1442, 1417, 1389, 1264, 1173, 1116, 922, 876, 815, 786, 775 cm−1. HRMS (TOF, APCI, m/z): calcd for C21H15N2O3 [M + H]+ 343.1078, found 343.1077.
5H-[1,3]Dioxolo[4′′,5′′:4′,5′]benzo[1′,2′:6,7]benzo[2,3][1,4]oxazepino[5,4-b]quinazolin-5-one (3g). Yield 76% (135 mg). Pale white solid, m.p. 245–247 °C; 1H NMR (CDCl3, 400 MHz): δH 6.11 (dd, J = 10.8 Hz, J′ = 1.2 Hz, 2H), 6.22–6.25 (m, 1H), 6.42 (d, J = 10.0 Hz, 1H), 6.60–6.64 (m, 1H), 6.76 (s, 1H), 7.32–7.37 (m, 1H), 7.44–7.48 (m, 1H), 7.54 (s, 1H), 7.75–7.82 (m, 2H), 8.25–8.27 (m, 1H). 13C NMR (CDCl3, 100 MHz): δC 102.0, 102.3, 103.5, 119.5, 122.6, 125.4, 126.71, 126.73, 128.4, 128.5, 128.9, 129.0, 130.2, 134.9, 135.0, 140.4, 148.6, 149.8, 151.7, 152.2, 160.4. IR (KBr): ν 3078, 2925, 1673, 1633, 1596, 1553, 1510, 1490, 1459, 1383, 1328, 1298, 1260, 1175, 1140, 1114, 1031, 931, 919, 868, 831, 791, 775 cm−1. HRMS (TOF, APCI, m/z): calcd for C21H13N2O4 [M + H]+ 357.0870, found 357.0873.
2-Chloro-16H-dibenzo[2,3:6,7][1,4]oxazepino[5,4-b]quinazolin-16-one (3h). Yield 79% (137 mg). Pale white solid, m.p. 231–233 °C; 1H NMR (CDCl3, 400 MHz): δH 7.28–7.41 (m, 5H), 7.46–7.51 (m, 1H), 7.58 (dd, J = 8.0 Hz, J′ = 0.8 Hz, 1H), 7.73–7.77 (m, 2H), 8.13 (dd, J = 7.6 Hz, J′ = 1.6 Hz, 1H), 8.33 (s, 1H). 13C NMR (CDCl3, 100 MHz): δC 120.5, 121.5, 121.9, 125.8, 127.2, 127.5, 127.90, 127.94, 128.2, 130.7, 131.58, 131.61, 132.9, 134.7, 135.2, 146.7, 149.6, 157.2, 159.8, 161.5. IR (KBr): ν 3063, 2951, 1683, 1645, 1622, 1600, 1562, 1469, 1429, 1372, 1332, 1280, 1270, 1173, 1148, 880, 868, 837, 768, 733 cm−1. HRMS (TOF, APCI, m/z): calcd for C20H12ClN2O2 [M + H]+ 347.0582, found 347.0592.
2,7-Dichloro-16H-dibenzo[2,3:6,7][1,4]oxazepino[5,4-b]quinazolin-16-one (3i). Yield 73% (139 mg). Pale white solid, m.p. 262–264 °C; 1H NMR (CDCl3, 400 MHz): δH 7.36–7.40 (m, 3H), 7.44–7.48 (m, 2H), 7.50–7.54 (m, 1H), 7.82–7.89 (m, 2H), 8.34 (d, J = 8.0 Hz, 1H), 8.48 (d, J = 7.6 Hz, 1H). 13C NMR (DMSO-d6, 100 MHz): δC 120.7, 121.7, 122.8, 126.0, 127.4, 128.2, 128.5, 128.6, 128.7, 130.3, 130.5, 130.9, 131.4, 133.6, 135.9, 145.0, 146.7, 156.8, 160.3, 161.3. IR (KBr): ν 3058, 2919, 1682, 1637, 1604, 1560, 1486, 1429, 1375, 1333, 1296, 1172, 1156, 1112, 1030, 882, 862, 842, 826, 761, 730 cm−1. HRMS (TOF, APCI, m/z): calcd for C20H11Cl2N2O2 [M + H]+ 381.0192, found 381.0200.
2-Chloro-7-methoxy-16H-dibenzo[2,3:6,7][1,4]oxazepino[5,4-b]quinazolin-16-one (3j). Yield 78% (147 mg). Pale white solid, m.p. 235–236 °C; 1H NMR (CDCl3, 400 MHz): δH 3.85 (s, 3H), 7.00 (dd, J = 8.8 Hz, J′ = 3.2 Hz, 1H), 7.20 (d, J = 8.8 Hz, 1H), 7.23–7.27 (m, 1H), 7.32–7.39 (m, 2H), 7.52–7.57 (m, 1H), 7.59 (d, J = 3.2 Hz, 1H), 7.73–7.78 (m, 2H), 8.32–8.33 (m, 1H). 13C NMR (CDCl3, 100 MHz): δC 55.9, 115.3, 119.4, 121.0, 121.4, 121.6, 125.1, 126.8, 127.1, 128.5, 129.4, 129.6, 129.8, 133.2, 135.3, 145.5, 151.6, 155.8, 157.0, 157.7, 160.9. IR (KBr): ν 3042, 2922, 1679, 1604, 1560, 1512, 1485, 1460, 1383, 1256, 1174, 1143, 1115, 1045, 923, 809, 787, 763 cm−1. HRMS (TOF, APCI, m/z): calcd for C21H14ClN2O3 [M + H]+ 377.0687, found 377.0704.
2-Methyl-16H-dibenzo[2,3:6,7][1,4]oxazepino[5,4-b]quinazolin-16-one (3k). Yield 85% (138 mg). Pale white solid, m.p. 254–255 °C; 1H NMR (CDCl3, 400 MHz): δH 2.53 (s, 3H), 7.23–7.29 (m, 2H), 7.30–7.36 (m, 2H), 7.38–7.40 (m, 1H), 7.43–7.48 (m, 1H), 7.59–7.65 (m, 2H), 7.72 (d, J = 8.0 Hz, 1H), 8.12–8.16 (m, 2H). 13C NMR (CDCl3, 100 MHz): δC 21.5, 120.4, 121.4, 121.5, 125.4, 126.9, 127.7, 128.5, 128.7, 129.7, 129.9, 131.2, 131.4, 132.5, 136.5, 138.1, 144.8, 149.3, 156.9, 160.2, 161.7. IR (KBr): ν 3032, 2971, 1684, 1603, 1591, 1560, 1488, 1443, 1385, 1309, 1186, 1169, 1134, 1054, 873, 825, 797, 760 cm−1. HRMS (TOF, APCI, m/z): calcd for C21H15N2O2 [M + H]+ 327.1134, found 327.1161.
7-Chloro-2-methyl-16H-dibenzo[2,3:6,7][1,4]oxazepino[5,4-b]quinazolin-16-one (3l). Yield 83% (149 mg). Pale white solid, m.p. 226–228 °C; 1H NMR (CDCl3, 400 MHz): δH 2.53 (s, 3H), 7.22 (d, J = 8.8 Hz, 1H), 7.25–7.29 (m, 1H), 7.32–7.41 (m, 3H), 7.58–7.60 (m, 1H), 7.64–7.67 (m, 1H), 7.72 (d, J = 8.8 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H), 8.16 (s, 1H). 13C NMR (CDCl3, 100 MHz): δC 21.4, 120.0, 120.3, 121.5, 125.1, 125.8, 126.8, 127.2, 127.6, 129.0, 129.5, 129.8, 131.7, 132.8, 136.4, 137.7, 145.0, 150.6, 157.3, 161.8, 161.9. IR (KBr): ν 3056, 2958, 1682, 1643, 1620, 1606, 1489, 1439, 1379, 1330, 1304, 1290, 1262, 1241, 1229, 1206, 1183, 1151, 1092, 1018, 849, 827, 765 cm−1. HRMS (TOF, APCI, m/z): calcd for C21H14ClN2O2 [M + H]+ 361.0738, found 361.0759.
12-Chloro-16H-dibenzo[2,3:6,7][1,4]oxazepino[5,4-b]quinazolin-16-one (3m). Yield 78% (135 mg). Pale white solid, m.p. 238–240 °C; 1H NMR (CDCl3, 400 MHz): δH 7.39–7.45 (m, 5H), 7.49–7.53 (m, 2H), 7.88 (d, J = 2.0 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.56–8.59 (m, 1H), 8.70–8.72 (m, 1H). 13C NMR (DMSO-d6, 100 MHz): δC 120.7, 121.8, 121.9, 125.8, 126.3, 126.5, 126.7, 128.8, 130.3, 130.5, 130.7, 132.3, 132.3, 134.2, 135.8, 145.7, 151.7, 157.2, 160.6, 161.7. IR (KBr): ν 3068, 2969, 1682, 1634, 1622, 1604, 1561, 1514, 1462, 1389, 1332, 1261, 1174, 1116, 1045, 881, 819, 770 cm−1. HRMS (TOF, APCI, m/z): calcd for C20H12ClN2O2 [M + H]+ 347.0582, found 347.0595.
7,12-Dichloro-16H-dibenzo[2,3:6,7][1,4]oxazepino[5,4-b]quinazolin-16-one (3n). Yield 76% (145 mg). Pale white solid, m.p. 241–243 °C; 1H NMR (CDCl3, 400 MHz): δH 7.22 (d, J = 8.4 Hz, 1H), 7.25–7.27 (m, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.42–7.45 (m, 1H), 7.54–7.59 (m, 2H), 7.81–7.87 (m, 2H), 8.13 (d, J = 2.4 Hz, 1H), 8.36 (d, J = 7.6 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δC 119.9, 123.1, 123.7, 123.8, 127.0, 127.1, 128.4, 128.6, 128.9, 129.0, 129.8, 130.4, 132.3, 134.5, 135.1, 135.2, 140.5, 148.5, 152.5, 160.7. IR (KBr): ν 3055, 3026, 1683, 1643, 1623, 1603, 1562, 1492, 1473, 1461, 1439, 1377, 1316, 1272, 1237, 1216, 1138, 1065, 877, 825, 772, 740 cm−1. HRMS (TOF, APCI, m/z): calcd for C20H11Cl2N2O2 [M + H]+ 381.0192, found 381.0206.
12-Methyl-16H-dibenzo[2,3:6,7][1,4]oxazepino[5,4-b]quinazolin-16-one (3o). Yield 81% (132 mg). Pale white solid, m.p. 241–245 °C; 1H NMR (CDCl3, 400 MHz): δH 2.51 (s, 3H), 7.36–7.41 (m, 2H), 7.42–7.46 (m, 2H), 7.50–7.52 (m, 2H), 7.67 (dd, J = 8.4 Hz, J′ = 2.0 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 8.14 (s, 1H), 8.56–8.58 (m, 1H), 8.67–8.69 (m, 1H). 13C NMR (DMSO-d6, 100 MHz): δC 21.4, 120.3, 120.6, 121.7, 125.7, 126.4, 126.7, 126.9, 127.9, 129.1, 130.3, 130.8, 132.2, 133.8, 137.1, 138.0, 145.0, 150.4, 157.2, 161.4, 161.6. IR (KBr): ν 3071, 2914, 1672, 1604, 1513, 1491, 1468, 1385, 1334, 1298, 1268, 1203, 1178, 1140, 1113, 1032, 935, 921, 885, 861, 828, 787, 747 cm−1. HRMS (TOF, APCI, m/z): calcd for C21H15N2O2 [M + H]+ 327.1134, found 327.1163.
7-Chloro-12-methyl-16H-dibenzo[2,3:6,7][1,4]oxazepino[5,4-b]quinazolin-16-one (3p). Yield 71% (128 mg). Pale white solid, m.p. 262–265 °C; 1H NMR (CDCl3, 400 MHz): δH 2.41 (s, 3H), 7.29–7.34 (m, 4H), 7.38–7.45 (m, 2H), 7.88 (d, J = 1.6 Hz, 1H), 8.26 (d, J = 8.8 Hz, 1H), 8.56–8.59 (m, 1H), 8.71 (dd, J = 4.8 Hz, J′ = 1.6 Hz, 1H). 13C NMR (DMSO-d6, 100 MHz): δC 21.4, 120.4, 121.7, 122.7, 126.0, 126.7, 128.1, 128.6, 128.8, 130.3, 130.4, 130.9, 131.3, 133.4, 137.1, 138.4, 144.7, 149.1, 156.8, 160.2, 161.2. IR (KBr): ν 3065, 2939, 1687, 1637, 1618, 1604, 1567, 1498, 1471, 1439, 1387, 1345, 1298, 1266, 1248, 1172, 1084, 873, 839, 772, 758 cm−1. HRMS (TOF, APCI, m/z): calcd for C21H14ClN2O2 [M + H]+ 361.0738, found 361.0711.
2-Chloro-7-fluoro-16H-dibenzo[2,3:6,7][1,4]oxazepino[5,4-b]quinazolin-16-one (3q). Yield 76% (138 mg). Pale white solid, m.p. 253–255 °C; 1H NMR (CDCl3, 400 MHz): δH 7.14–7.19 (m, 1H), 7.24–7.30 (m, 2H), 7.35–7.41 (m, 2H), 7.57–7.59 (m, 1H), 7.74–7.79 (m, 2H), 7.81–7.84 (m, 1H), 8.32–8.33 (m, 1H). 13C NMR (CDCl3, 100 MHz): δC 118.1 (d, JF–C = 25.5 Hz), 119.9 (d, JF–C = 22.5 Hz), 121.4, 121.6, 121.7 (d, JF–C = 8.4 Hz), 125.4, 126.8, 128.1 (d, JF–C = 8.6 Hz), 128.4, 129.5, 129.7, 130.0, 133.5, 135.5, 145.3, 150.5 (d, JF–C = 2.4 Hz), 157.2, 157.9 (d, JF–C = 2.6 Hz), 159.8 (d, JF–C = 243.5 Hz), 160.8. IR (KBr): ν 3024, 2909, 1669, 1622, 1600, 1499, 1470, 1387, 1374, 1270, 1179, 1144, 1038, 940, 909, 862, 837, 765, 724, 713 cm−1. HRMS (TOF, APCI, m/z): calcd for C20H11ClFN2O3 [M + H]+ 365.0488, found 365.0489.
7-Fluoro-2-methyl-16H-dibenzo[2,3:6,7][1,4]oxazepino[5,4-b]quinazolin-16-one (3r). Yield 77% (132 mg). Pale white solid, m.p. 241–242 °C; 1H NMR (CDCl3, 400 MHz): δH 2.39 (s, 3H), 7.06–7.09 (m, 1H), 7.12–7.17 (m, 1H), 7.19 (d, J = 1.2 Hz, 1H), 7.22–7.26 (m, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.53–7.57 (m, 1H), 7.79–7.86 (m, 3H), 8.37 (d, J = 8.4 Hz, 1H). 13C NMR (CDCl3, 100 MHz): δC 21.1, 118.1 (d, JF–C = 25.5 Hz), 119.5 (d, JF–C = 23.4 Hz), 120.7, 121.5 (d, JF–C = 8.6 Hz), 121.6, 125.8, 126.1, 127.5, 127.6, 127.8, 128.5 (d, JF–C = 8.9 Hz), 129.3, 134.9, 139.7 (d, JF–C = 4.5 Hz), 140.4, 146.8, 150.5, 157.0, 159.2 (d, JF–C = 245.8 Hz), 161.7. IR (KBr): ν 3068, 2981, 1683, 1643, 1616, 1602, 1561, 1489, 1464, 1377, 1328, 1281, 1148, 1079, 893, 872, 831, 773, 757 cm−1. HRMS (TOF, APCI, m/z): calcd for C21H14FN2O2 [M + H]+ 345.1033, found 345.1041.
15H-Benzo[2,3]thieno[2′,3′:6,7][1,4]oxazepino[5,4-b]quinazolin-15-one (3s). Yield 76% (121 mg). Pale white solid, m.p. 272–275 °C; 1H NMR (DMSO-d6, 400 MHz): δH 6.87–6.91 (m, 2H), 7.19–7.23 (m, 2H), 7.27–7.29 (m, 1H), 7.46–7.49 (m, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.77–7.82 (m, 2H), 8.05–8.07 (m, 1H). 13C NMR (DMSO-d6, 100 MHz): δC 116.5, 119.8, 121.2, 122.3, 126.3, 126.8, 127.5, 128.9, 130.0, 131.8, 131.9, 132.1, 135.0, 139.6, 149.3, 150.1, 154.7, 161.8. IR (KBr): ν 3070, 2945, 1682, 1643, 1618, 1594, 1552, 1462, 1439, 1416, 1313, 1274, 1230, 1072, 918, 890, 882, 868, 827, 779, 748 cm−1. HRMS (TOF, APCI, m/z): calcd for C18H11N2O2S [M + H]+ 319.0541, found 319.0569.
2-Bromo-11-methyl-15H-benzo[2,3]thieno[2′,3′:6,7][1,4]oxazepino[5,4-b]quinazolin-15-one (3t). Yield 81% (166 mg). Pale white solid, m.p. 271–275 °C; 1H NMR (CDCl3, 400 MHz): δH 2.58 (s, 3H), 7.40 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 5.2 Hz, 1H), 7.71–7.76 (m, 2H), 7.79 (d, J = 5.2 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 8.24 (s, 1H), 8.27 (s, 1H). 13C NMR (CDCl3, 100 MHz): δC 21.4, 118.7, 119.7, 121.3, 126.2, 126.5, 127.3, 127.5, 129.6, 130.3, 130.7, 131.1, 136.6, 137.5, 137.6, 145.9, 148.4, 152.9, 163.2. IR (KBr): ν 3063, 2952, 1684, 1589, 1558, 1493, 1474, 1456, 1421, 1353, 1278, 1211, 1195, 1157, 1140, 1118, 950, 877, 809, 772 cm−1. HRMS (TOF, APCI, m/z): calcd for C19H12BrN2O2S [M + H]+ 410.9797, found 410.9795.
16H-Benzo[2,3]pyrido[3′,2′:6,7][1,4]oxazepino[5,4-b]quinazolin-16-one (3u). Yield 78% (122 mg). Pale white solid, m.p. 246–247 °C; 1H NMR (DMSO-d6, 400 MHz): δH 7.35–7.39 (m, 1H), 7.45–7.49 (m, 1H), 7.54–7.57 (m, 2H), 7.65–7.68 (m, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.94–7.97 (m, 1H), 8.26 (d, J = 7.6 Hz, 1H), 8.49 (d, J = 2.0 Hz, 1H), 8.56 (d, J = 6.8 Hz, 1H). 13C NMR (DMSO-d6, 100 MHz): δC 120.7, 121.7, 122.4, 123.6, 126.1, 127.4, 128.0, 128.4, 128.7, 130.5, 130.7, 135.9, 142.8, 146.8, 150.0, 151.7, 154.7, 161.3, 164.6. IR (KBr): ν 3079, 2925, 1669, 1601, 1559, 1540, 1522, 1469, 1457, 1444, 1410, 1361, 1341, 1294, 1256, 1206, 1148, 920, 897, 779, 758 cm−1. HRMS (TOF, APCI, m/z): calcd for C19H12N3O2 [M + H]+ 314.0924, found 314.0951.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was financially supported by the NSFC (No. 21702078), the Natural Science Foundation of Jiangsu Higher Education Institution (17KJA150003), the Priority Academic Program Development of Jiangsu Higher Education Institution, and TAPP.

Notes and references

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Footnote

Electronic supplementary information (ESI) available: Copies of 1H and 13C NMR spectra for compounds 3a–3u. CCDC 1814286. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c8ob00005k

This journal is © The Royal Society of Chemistry 2018