Facile Synthesis for Benzo-1,4-Oxazepine Derivatives by Tandem Transformation of C-N Coupling/C-H Carbonylation.

A tandem transformation of C-N coupling/C-H carbonylation has been developed for the synthesis of benzo-1,4-oxazepine pharmaceutically derivatives. Notably, this reaction was accomplished by various phenylamine with ally halides under carbon dioxide atmosphere employing 2-(2-dimethylamino-vinyl)-1H-inden-1-olcatalyzed. Furthermore, under the optimized conditions, various benzo-1,4-oxazepine derivatives were obtained in good yields. Finally, a plausible CuI/CuIII mechanism of C-N coupling/C-H carbonylation transformation was proposed.

1. Introduction

The heterocycle benzoxazepines are privileged scaffolds in natural biologically products [1,2,3,4], pharmaceutical chemistry [5,6] and functionalized materials [7,8,9,10]. As such, Sintamilv (I) is an efficient antidepressant [11]; H1 receptor antagonist (II) is a selective antihistaminic agent [12]; and Sintamil (III) is a benzoxazepine analogue (Scheme 1) [13]. Furthermore, the therapeutic applications of benzoxazepines are for the central nervous system, along with anti-breast cancer activity and inhibitors of HIV [14,15].

Scheme 1

The important benzo-1,4-oxazepine derivatives.

Currently, the challenge in organic synthesis is developing an efficient and eco-friendly protocol, especially in the area of drug discovery and natural products. Benzoxazepines are generally synthesized by condensation of 2-aryloxyethylamines with 2-formylbenzoic acid [16]. Others have also been synthesized from amides [17] and amino acids [18,19]. However, most of these methodologies are associated with several drawbacks, such as low synthetic efficiency and sensitivity. Thus, a remarkable gap remains in the search of economical synthesis methods. Tandem transformation is one of the most effective ways to achieve this goal. Considering the above points, herein we report the tandem reaction green protocol for the synthesis of benzo-1,4-oxazepine pharmaceutical derivatives.

The reaction conditions were screened based on a model reaction of phenylamine 1a and (1-chloro-vinyl)-benzene 2a (Table 1). The ligands were mainly based on the derivatives of 2-(2-dimethylamino-vinyl)-1H-inden-1-ol. It was discovered that ligand L1 was the ideal choice for this transformation (Entries 5–10). CuI exhibited superior catalytic efficiency over all other examined CuI catalysts (Entries 1–5), and Cs2CO3 turned out to be the proper base additive (Entries 11–12). Meanwhile, the reaction temperature was 100 °C (Entries 15–16).

Table 1

Optimization of the reaction conditions a.

Entry	Ligand	Cu Salt	Base	Yield (%) b
1	L1	Cu(OAc)2	Cs2CO3	8
2	L1	CuSO4	Cs2CO3	0
3	L1	CuBr	Cs2CO3	23
4	L1	CuBr2	Cs2CO3	19
5	L1	CuI	Cs2CO3	81
6	L2	CuI	Cs2CO3	29
7	L3	CuI	Cs2CO3	36
8	L4	CuI	Cs2CO3	47
9	L5	CuI	Cs2CO3	16
10	L6	CuI	Cs2CO3	38
11	L1	CuI	K2CO3	42
12	L1	CuI	K3PO4	0
13	L1	CuI	Cs2CO3	61 c
14	L1	CuI	Cs2CO3	69 d

a Unless otherwise noted, reactions conditions were 1a (0.5 mmol), 2a (0.6 mmol), Cu salt (10 mol %), ligand (10 mol %), base (2 eq.), DMSO (4 mL) reacted in CO2 at 100 °C for 12 h; b isolated yield; c reaction under 90 °C; d reaction under 110 °C.

With the optimal conditions established, the reaction scope was further investigated. A wide array of phenylamine 1 and ally halide 2 was subjected to this reaction in moderate to good yields (Table 2). Phenylamine derivatives bearing either an electron-withdrawing or electron-donating group reacted smoothly with 2. This transformation is applicable for para-substituted phenylamines. Chloroethylene bearing an electron-donating group showed better reactivity than those with an electron-withdrawing group (All the product spectrums, please see Supplementary Materials).

Table 2

Synthesis of benzo-1,4-oxazepin-5-one 3 a.

Entry	R1	R2	Product 3	Yield (%) b
1	H	Ph		81
2	H	4-CH3C6H4		78
3	H	4-ClC6H4		85
4	H	CH3		74
5	4-Cl	Ph		79
6	4-Cl	4-CH3C6H4		76
7	4-Cl	4-ClC6H4		86
8	4-Cl	CH3		84
9	4-CH3	Ph		76
10	4-CH3	4-CH3C6H4		75
11	4-CH3	4-ClC6H4		82
12	4-CH3	CH3		72

a Reactions conditions were 1 (0.5 mmol), 2 (0.6 mmol), CuI (10 mol %), L1 (10 mol %), Cs2CO3 (2 equiv.), DMSO (4 mL) at 100 °C reacted in CO2 for 10 h; b isolated yield.

Interestingly, we found that 1-bromo-cyclohexene 4 has also been rapidly synthesized in good yields, and the results are summarized in Table 3. In addition, the reaction works well for both bearing electron-donating and electron-withdrawing groups.

Table 3

Synthesis of benzo-1,4-oxazepin-5-one 5 a.

Entry	R1	Product 5	Yield (%) b
1	H		78
2	4-Cl		84
3	4-CH3		75

a Reactions conditions were 1 (0.5 mmol), 2 (0.6 mmol), CuI (10 mol %), L1 (10 mol %), Cs2CO3 (2 equiv.), DMSO (4 mL) at 100 °C reacted in CO2 for 10 h; b isolated yield.

On the basis of the above experimental results, we tentatively proposed a reaction mechanism as shown in Scheme 2. At the beginning, CuI activate 6 was been formed through copper iodide coordinating with ligand. Next, complex 6 reacted with vinyl halides by oxidative addition produced a CuIII complex 7. The complex 7 reacted with aniline obtained the key intermediate complex 8 [20,21]. Selective ortho-carbonylation of the phenylamine was determined by Complex 9. Through the reductive elimination of Complex 9, Complex 10 was obtained, which regenerates Complex 6 for the next catalytic cycle [22,23]. However, how the ligand promotes this transformation is a part of ongoing study.

Scheme 2

A plausible mechanism of the catalytic cycle.

2. Results and Discussion

2-Phenyl-2,3-dihydro-1H-benzo[e][1,4]oxazepin-5-one (3a): A mixture of phenylamine 1a (0.5 mmol, 46.5 mg), (1-chloro-vinyl)-benzene 2a (0.6 mmol, 83.4 mg), CuI (10 mol %, 9.5 mg), L1 (10 mol %, 20.1 mg) and Cs2CO3 (2 equiv., 325.8 mg) in DMSO (4 mL) was stirred in CO2 at 100 °C for 10 h. After completion of the reaction, the mixture was quenched with saturated salt water (10 mL); the solution was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined and dried over sodium sulfate. The pure product was obtained by flash column chromatography on silica gel to afford 3a 96.8 mg in 81% yield. The spectroscopic data of all of the products are presented below. Yellowish oil. 1H-NMR (400 MHz, CDCl3): 7.63 (m, 1H), 7.43 (br, 1H), 7.08–7.43 (m, 8H), 5.07 (dd, J = 8.0, 5.7 Hz, 1H), 4.08 (dd, J = 12.3, 8.0 Hz, 1H), 3.96 (dd, J = 12.3, 5.6 Hz, 1H); 13C-NMR (100 MHz, CDCl3): 168.3, 147.7, 139.1, 132.9, 130.3, 128.6, 127.5, 126.6, 117.8, 116.4, 109.1, 77.6, 60.2; EIMS (m/z): 239 [M+]; Anal. Calcd. for C15H13NO2: C, 75.30; H, 5.48; N, 5.85; Found: C, 75.62; H, 5.13; N, 5.68.

2-p-Tolyl-2,3-dihydro-1H-benzo[e][1,4] xazepine-5-one (3b): Yellowish oil. 1H-NMR (400 MHz, CDCl3): 7.61 (m, 1H), 7.44 (br, 1H), 7.04–7.31 (m, 7H), 5.07 (dd, J = 8.0, 5.7 Hz, 1H), 4.07 (dd, J = 12.3, 8.0 Hz, 1H), 3.95 (dd, J = 12.3, 5.7 Hz, 1H), 2.39 (s, 3H); 13C-NMR (100 MHz, CDCl3): 168.6, 147.8, 138.3, 135.3, 132.3, 130.5, 128.1, 127.6, 118.2, 115.9, 109.5, 77.5, 60.3, 25.2; EIMS (m/z): 253 [M+]; Anal. Calcd. for C16H15NO2: C, 75.87; H, 5.97; N, 5.53; Found: C, 75.50; H, 6.20; N, 5.88.

2-(4-Chloro-phenyl)-2,3-dihydro-1H-benzo[e][1,4] xazepine-5-one (3c): Yellowish oil. 1H-NMR (400 MHz, CDCl3): 7.64 (m, 1H), 7.47 (br, 1H), 7.07–7.48 (m, 7H), 5.08 (dd, J = 8.1, 5.6 Hz, 1H), 4.09 (dd, J = 12.3, 8.1 Hz, 1H), 3.95 (dd, J = 12.3, 5.6 Hz, 1H); 13C-NMR (100 MHz, CDCl3): 168.3, 147.7, 139.3, 133.3, 132.4, 130.5, 128.6, 127.8, 118.4, 116.3, 110.1, 77.3, 60.9;EIMS (m/z): 273 [M+]; Anal. Calcd. for C15H12ClNO2: C, 65.82; H, 4.42; N, 5.12; Found: C, 65.51; H, 4.61; N, 5.33.

2-Methyl-2,3-dihydro-1H-benzo[e][1,4]oxazepin-5-one (3d): Yellowish oil. 1H-NMR (400 MHz, CDCl3): 7.62 (m, 1H), 7.42 (br, 1H), 7.05–7.21 (m, 3H), 4.58 (dd, J = 12.3, 8.0 Hz, 1H), 3.96 (dd, J = 12.2, 5.6 Hz, 1H), 3.12–3.71 (m, 1H), 1.35 (d, J = 7.1 Hz, 3H); 13C-NMR (100 MHz, CDCl3): 168.2, 147.3, 132.8, 130.4, 118.7, 116.6, 109.7, 77.1, 53.1, 18.2; EIMS (m/z): 177.08 [M+]; Anal. Calcd. for C10H11NO2: C, 67.78; H, 6.26; N, 7.90; Found: C, 68.14; H, 6.55; N, 7.53.

7-Chloro-2-phenyl-2,3-dihydro-1H-benzo[e][1,4]oxazepin-5-one (3e): Yellowish oil. 1H-NMR (400 MHz, CDCl3): 7.63 (m, 1H), 7.43 (br, 1H), 7.10–7.46 (m, 7H), 5.08 (dd, J = 8.1, 5.6 Hz, 1H), 4.10 (dd, J = 12.4, 8.1 Hz, 1H), 3.97 (dd, J = 12.4, 5.6 Hz, 1H); 13C-NMR (100 MHz, CDCl3): 168.3, 147.4, 139.5, 133.2, 130.2, 128.7, 127.5, 126.8, 123.8, 115.4, 109.2, 77.5, 60.2; EIMS (m/z): 273 [M+]; Anal. Calcd. for C15H12ClNO2: C, 65.82; H, 4.42; N, 5.12; Found: C, 65.70; H, 4.61; N, 5.44.

7-Chloro-2-p-tolyl-2,3-dihydro-1H-benzo[e][1,4]oxazepin-5-one (3f): Yellowish oil. 1H-NMR (400 MHz, CDCl3): 7.64 (m, 1H), 7.43 (br, 1H), 7.07–7.38 (m, 6H), 5.08 (dd, J = 8.1, 5.9 Hz, 1H), 4.10 (dd, J = 12.4, 8.1 Hz, 1H), 3.96 (dd, J = 12.4, 5.9 Hz, 1H), 2.40 (s, 3H); 13C-NMR (100 MHz, CDCl3): 168.2, 147.1, 139.2, 135.8, 133.4, 130.5, 128.7, 126.9, 123.5, 115.5, 109.3, 77.2, 60.4, 25.7; EIMS (m/z): 287.07 [M+]; Anal. Calcd. for C16H14ClNO2: C, 66.79; H, 4.90; N, 4.87; Found: C, 66.95; H, 4.63; N, 5.23.

7-Chloro-2-(4-chloro-phenyl)-2,3-dihydro-1H-benzo[e][1,4]oxazepin-5-one (3g): Yellowish oil. 1H-NMR (400 MHz, CDCl3): 7.66 (m, 1H), 7.46 (br, 1H), 7.09–7.50 (m, 6H), 5.10 (dd, J = 8.2, 5.6 Hz, 1H), 4.11 (dd, J = 12.4, 8.2 Hz, 1H), 3.96 (dd, J = 12.4, 5.6 Hz, 1H); 13C-NMR (100 MHz, CDCl3): 168.2, 147.4, 139.6, 133.2, 131.8, 130.2, 128.9, 126.7, 123.8, 115.2, 109.6, 77.5, 60.3; EIMS (m/z): 307 [M+]; Anal. Calcd. for C15H11Cl2NO2: C, 58.46; H, 3.60; N, 4.55; Found: C, 58.23; H, 3.92; N, 4.67.

7-Chloro-2-methyl-2,3-dihydro-1H-benzo[e][1,4]oxazepin-5-one (3h): Yellowish oil. 1H-NMR (400 MHz, CDCl3): 7.64 (m, 1H), 7.45 (br, 1H), 7.06–7.23 (m, 2H), 4.6 (dd, J = 12.2, 8.1 Hz, 1H), 3.98 (dd, J = 12.2, 5.6 Hz, 1H), 3.12–3.71 (m, 1H), 1.36 (d, J = 7.2 Hz, 3H); 13C-NMR (100 MHz, CDCl3): 168.5, 147.3, 133.1, 130.2, 123.1, 116.8, 109.3, 77.5, 53.4, 18.3; EIMS (m/z): 211 [M+]; Anal. Calcd. for C10H10ClNO2: C, 56.75; H, 4.76; N, 6.62; Found: C, 56.89; H, 5.18; N, 6.34.

7-Methyl-2-phenyl-2,3-dihydro-1H-benzo[e][1,4]oxazepin-5-one (3i): Yellowish oil. 1H-NMR (400 MHz, CDCl3): 7.58 (m, 1H), 7.41 (br, 1H), 7.06–7.40 (m, 7H), 5.00 (dd, J = 8.0, 5.6 Hz, 1H), 4.06 (dd, J = 12.2, 8.0 Hz, 1H), 3.92 (dd, J = 12.2, 5.6 Hz, 1H), 2.40 (s, 3H). 13C-NMR (100 MHz, CDCl3): 168.5, 147.2, 139.4, 133.3, 130.8, 128.9, 127.7, 126.9, 126.2, 116.7, 109.3, 77.8, 60.3, 25.3; EIMS (m/z): 253 [M+]; Anal. Calcd. for C16H15NO2: C, 75.87; H, 5.97; N, 5.53; Found: C, 75.65; H, 6.28; N, 5.33.

7-Methyl-2-p-tolyl-2,3-dihydro-1H-benzo[e][1,4]oxazepin-5-one (3j): Yellowish oil. 1H-NMR (400 MHz, CDCl3): 7.56 (m, 1H), 7.44 (br, 1H), 7.06–7.36 (m, 6H), 4.98 (dd, J = 7.9, 5.6 Hz, 1H), 4.02 (dd, J = 12.2, 7.9 Hz, 1H), 3.90 (dd, J = 12.2, 5.6 Hz, 1H), 2.39 (s, 6H); 13C-NMR (100 MHz, CDCl3): 168.2, 147.5, 138.3, 135.1, 132.4, 130.8, 128.8, 127.5, 126.2, 116.2, 109.1, 77.2, 60.5, 25.8, 25.3; EIMS (m/z): 267 [M+]; Anal. Calcd. for C17H17NO2: C, 76.38; H, 6.41; N, 5.24; Found: C, 76.69; H, 6.24; N, 5.53.

2-(4-Chloro-phenyl)-7-methyl-2,3-dihydro-1H-benzo[e][1,4]oxazepin-5-one (3k): Yellowish oil. 1H-NMR (400 MHz, CDCl3): 7.60 (m, 1H), 7.47 (br, 1H), 7.06-7.44 (m, 6H), 5.08 (dd, J = 8.0, 5.7 Hz, 1H), 4.10 (dd, J = 12.2, 8.0 Hz, 1H), 3.98 (dd, J = 12.2, 5.7 Hz, 1H), 2.42 (s, 3H); 13C-NMR (100 MHz, CDCl3): 168.1, 147.5, 139.6, 133.5, 132.2, 131.1, 128.3, 127.5, 126.4, 115.7, 109.7, 77.4, 60.7, 25.4; EIMS (m/z): 287 [M+]; Anal. Calcd. for C16H14ClNO2: C, 66.79; H, 4.90; N, 4.87; Found: C, 67.09; H, 4.99; N, 4.54.

2,7-Dimethyl-2,3-dihydro-1H-benzo[e][1,4] xazepine-5-one (3l): Yellowish oil. 1H-NMR (400 MHz, CDCl3): 7.62 (m, 1H), 7.43 (br, 1H), 7.04–7.20 (m, 2H), 4.56 (dd, J = 12.2, 8.0 Hz, 1H), 3.93 (dd, J = 12.2, 5.4 Hz, 1H), 3.10–3.70 (m, 1H), 2.41 (s, 3H), 1.34 (d, J = 7.0 Hz, 3H); 13C-NMR (100 MHz, CDCl3): 168.3, 147.1, 133.5, 130.9, 126.8, 115.8, 109.2, 77.5, 53.4, 25.3, 18.3; EIMS (m/z): 191 [M+]; Anal. Calcd. for C11H13NO2: C, 69.09; H, 6.85; N, 7.32; Found: C, 69.41; H, 6.55; N, 7.16.

5a,6,7,8,9,9a-Hexahydro-5H-10-oxa-5-aza-dibenzo[a,d]cyclohepten-11-one (5a): Yellowish oil. 1H-NMR (400 MHz, CDCl3): 7.60 (m, 1H), 7.48 (br, 1H), 7.02–7.39 (m, 3H), 4.22 (dd, J = 11.3, 3.4 Hz, 1H), 3.11 (dd, J = 11.3, 3.5 Hz, 1H), 1.61–1.93 (m, 4H), 1.43–1.52 (m, 4H); 13C-NMR (100 MHz, CDCl3): 168.2, 147.6, 132.6, 130.1, 118.2, 115.9, 108.8, 85.8, 56.1, 28.5, 27.6, 22.9, 21.7; EIMS (m/z): 217 [M+]; Anal. Calcd. for C13H15NO2: C, 71.87; H, 6.96; N, 6.45; Found: C, 71.72; H, 6.66; N, 6.73.

2-Chloro-5a,6,7,8,9,9a-hexahydro-5H-10-oxa-5-aza-dibenzo[a,d]cyclohepten-11-one (5b): Yellowish oil. 1H-NMR (400 MHz, CDCl3): 7.62 (m, 1H), 7.49 (br, 1H), 7.05–7.43 (m, 2H), 4.26 (dd, J = 11.3, 3.5 Hz, 1H), 3.11 (dd, J = 11.3, 3.7 Hz, 1H), 1.62–1.95 (m, 4H), 1.43–1.54 (m, 4H); 13C-NMR (100 MHz, CDCl3): 168.3, 147.1, 133.1, 130.4, 122.5, 116.1, 108.2, 85.6, 56.5, 28.8, 27.2, 22.7, 21.5; EIMS (m/z): 251 [M+]; Anal. Calcd. for C13H14ClNO2: C, 62.03; H, 5.61; N, 5.56; Found: C, 62.19; H, 5.31; N, 5.34.

2-Methyl-5a,6,7,8,9,9a-hexahydro-5H-10-oxa-5-aza-dibenzo[a,d]cyclohepten-11-one (5c): Yellowish oil. 1H-NMR (400 MHz, CDCl3): 7.58 (m, 1H), 7.46 (1H, br), 7.00–7.35 (m, 2H), 4.20 (dd, J = 11.2, 3.2 Hz, 1H), 3.09 (dd, J = 11.2, 3.4 Hz, 1H), 2.40 (s, 3H), 1.60–1.91 (m, 4H), 1.42–1.50 (m, 4H); 13C-NMR (100 MHz, CDCl3): 168.4, 147.3, 133.4, 130.8, 126.1, 116.1, 108.5, 85.4, 56.3, 28.7, 27.8, 22.8, 21.5; EIMS (m/z): 231 [M+]; Anal. Calcd. for C14H17NO2: C, 72.70; H, 7.41; N, 6.06; Found: C, 72.99; H, 7.28; N, 6.48.

3. Experimental Section

3.1. General Procedure for Preparation of –

Dimethylformamide dimethyl acetal (DMF-DMA) (10 mmol, 1.19 g) and 1-(1-hydroxy-1H-inden-2-yl)-ethanone (10 mmol, 1.74 g) were dissolved in p-xylene (5 mL). Additionally, the mixture was refluxed during a period of 5–12 h, during which time a yellow precipitate formed. The precipitate was filtered out and washed with petroleum ether three times. The solid was vacuum-dried, and 1.89 g (yield 94%) of a yellow solid were obtained, L1 2-(2-dimethylamino-vinyl)-1H-inden-1-ol. 1H-NMR (400 MHz, CDCl3): δ 7.23 (m, 2H), 7.17–7.07 (t, J = 8.0 Hz, 2H), 7.01–6.90 (t, J = 7.8 Hz, 1H), 6.60 (s, 1H), 6.07–6.05 (d, J = 12 Hz, 1H), 2.47 (s, 3H), 2.42 (s, 3H); 13C-NMR (100 MHz, CDCl3): δ 146.1, 141.2, 133.8, 130.2, 127.9, 126.9, 123.2,121.2, 120.6, 104.1, 75.4, 46.1, 38.6.

3.2. 2-Phenyl-2,3-dihydro-1H-benzo[e][1,4]oxazepin-5-one (

A mixture of phenylamine 1a (0.5 mmol, 46.5 mg), (1-chloro-vinyl)-benzene 2a (0.6 mmol, 83.4 mg), CuI (10 mol %, 9.5 mg), L1 (10 mol %, 20.1 mg) and Cs2CO3 (2 equiv., 325.8 mg) in DMSO (4 mL) was stirred in CO2 at 100 °C for 10 h. After completion of the reaction, the mixture was quenched with saturated salt water (10 mL); the solution was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined and dried over sodium sulfate. The pure product was obtained by flash column chromatography on silica gel to afford 3a 96.8 mg in 81% yield. The spectroscopic data of all of the products are represented below. Yellowish oil. 1H-NMR (400 MHz, CDCl3): 7.63 (m, 1H), 7.43 (br, 1H), 7.08–7.43 (m, 8H), 5.07 (dd, J = 8.0, 5.7 Hz, 1H), 4.08 (dd, J = 12.3, 8.0 Hz, 1H), 3.96 (dd, J = 12.3, 5.6 Hz, 1H); 13C-NMR (100 MHz, CDCl3): 168.3, 147.7, 139.1, 132.9, 130.3, 128.6, 127.5, 126.6, 117.8, 116.4, 109.1, 77.6, 60.2; EIMS (m/z): 239 [M+]; Anal. Calcd. for C15H13NO2: C, 75.30; H, 5.48; N, 5.85; Found: C, 75.62; H, 5.13; N, 5.68.

4. Conclusions

In conclusion, we have found a green protocol for the synthesis of benzo-1,4-oxazepine derivatives involving tandem transformation of C-N coupling/C-H carbonylation. The method was economically viable and relevant to green chemistry.