Synthesis of pyrido[2,3-b][1,4]benzoxazepines via a Friedel−Crafts cyclization

An efficient and practical method has been developed for the synthesis of 6-aryl-substituted pyrido[2,3-b][1,4]benzoxazepines via a Friedel−Crafts reaction of readily accessible 2-phenoxypyridin-3-amines and aromatic acids.

The development of practical methods to provide access drug-like heterocycles often plays an important role in drug discovery projects.1 Pyrido[2,3-b][1,4]benzoxazepine derivatives represent an exciting field of research in medicinal chemistry due to their biological activity, including the effects as non-nucleoside inhibitors of HIV-1 reverse transcriptase2 and the influence on central nervous system.3 However, the synthesis of 6-aryl-substituted pyrido[2,3-b][1,4]benzoxazepine derivatives has rarely appeared in literature. Thus far only one five-stage route the synthesis of 6-aryl-substituted pyrido[2,3-b][1,4]- benzoxazepine derivatives has been reported, which entailed the Suzuki coupling of 6-chlorobenzo[f]pyrido[2,3-b]-1,4]oxazepine with phenylboronic acid.4 An efficient synthetic method to access 6-aryl-substituted pyrido[2,3-b]-1,4]benzoxazepines would be useful for the exploration of biological activity of this class of compounds. The research performed at our Center of Combinatorial Chemistry to prepare heterocyclic scaffolds and libraries led the development of several methodologies employing Friedel−Crafts cyclization reactions as the key transformations.5 ^– 7 We envisioned that 6-aryl-substituted pyrido-[2,3-b][1,4]benzoxazepines 4 could be readily prepared by the reaction of key precursors 3, prepared from simple 2-chloro-3-nitropyridine (1) and phenol, with different commercially available carboxylic acids (Scheme 1). The key precursors 3 were synthesized in a two-step sequence as depicted in Scheme 2. The commercially available 2-chloro-3-nitropyridine (1) was treated with phenols in DMF in the presence of K₂CO₃, giving the respective substituted 3-nitropyridines 2a–c in excellent yields. The reduction of nitro groups in compounds 2a–c with H₂ in the presence of Pd/C in EtOAc/MeOH8 or with Fe/NH₄Cl in refluxing EtOH/H₂O9 furnished the desired precursors 3 in high yields.

Scheme 1

Scheme 2

Initially, the precursor 3a was selected to test the reaction conditions required to generate pyrido[2,3-b][1,4]benzoxazepines 4. Previously, polyphosphoric acid (PPA)/POCl_3, 5 SnCl4/POCl3,6 and POCl₃/MeCN7 were reported to be effective reagents for promoting Friedel−Crafts cyclization reactions. When compound 3a and PhCO₂H were treated with PPA in refluxing POCl₃ for 14 h, the cyclization product 4a was obtained in only 28% yield, and the intermediate amide 5a was obtained in 48% yield (Table 1, entry 1). The treatment of precursor 3a and PhCO₂H with SnCl₄ in refluxing POCl₃ for 12 h gave the desired product 4a in 90% yield (entry 2). When the above reaction was carried out with POCl₃ in refluxing MeCN, only the intermediate amide 5a was produced (entry 3). We also attempted to expand the cyclization reaction to aliphatic acids. However, the treatment of precursor 3a and propionic acid with SnCl₄ in POCl₃ did not give the desired pyridobenzoxazepine; the amide 5b was isolated instead in 76% yield (entry 4). The amide 5b appeared to be labile under the reaction conditions, as the longer reaction time resulted in its decomposition (entry 5). Decreasing of the reaction temperature generated the amide 5b in 85% yield without the desired cyclization product (entry 6), while prolonged reaction time again led to decomposition (entry 7). Having identified the optimal reaction conditions (entry 2), we investigated the reactions of precursors 3a–c with several aromatic acids. The results are summarized in Table 2.

Table 1 Optimization of the cyclization conditions

Table 2 Preparation of pyrido[2,3-b][1,4]benzoxazepines 4a–o

As presented in Table 2, various aromatic acids participated in the cyclization reaction effectively to produce the expected pyrido[2,3-b][1,4]benzoxazepines 4 in good to excellent yields (entries 1–7). Both electron-donating (entries 2, 3) and electron-withdrawing (entries 4, 5) substituted benzoic acids were tolerated. The reaction proceeded faster when benzoic acids with an electron-donating group were employed (entries 2 and 3 vs entries 4 and 5). Two examples of heteroaromatic acids were also tested: 2-furoic acid and nicotinic acid (entries 6 and 7), and the reactions gave lower yields of oxazepines than the reactions with benzoic acid derivatives. The application of (E)-cinnamic acid in this reaction failed to give the desired product 4h (entry 8). In order to determine the electronic effects of the substituents, precursors 3 with either electron-donating or electron-withdrawing functional groups were tested (entries 9–15). Tuning the electron density of the benzene ring had significant effects on both the reaction rates and yields (entry 9 vs entry 1 vs entry 13). The presence of a bromo substituent in precursors 3 appears to reduce both the reaction rate and yield of the final products.

In conclusion, we have developed an efficient and practical strategy for the synthesis of 6-aryl-substituted pyrido[2,3-b][1,4]benzoxazepines via a Friedel−Crafts reaction of readily accessible 2-phenoxypyridin-3-amines and aromatic acids in good to excellent yields. Drug-like structures based on these heterocycles could be of interest in chemical biology and drug discovery.

Experimental

¹H and ¹³C NMR data were obtained on a Varian Mercury 300 NMR spectrometer (300 and 75 MHz, respectively) with TMS as internal standard and CDCl₃ as solvent unless otherwise stated. Mass spectra and HPLC data was recorded on an Agilent 1100 LC/MS system with Alltech ELSD 2000 (ESI). High-resolution mass spectra (HRMS) were obtained on a time-of-flight (TOF) mass spectrometer (ESI). Melting points were determined on a XT5 melting point apparatus and were not corrected. Phosphorus oxychloride (POCl₃) was freshly distilled. DMF was dried on CaH₂ and distilled. All other commercial reagents were used as received without additional purification.

Synthesis of 3-nitro-2-phenoxypyridines 2a–c (General method). Anhydrous K₂CO₃ (10.4 g, 75.2 mmol) was added to a stirred solution of 2-chloro-3-nitropyridine (1) (10.0 g, 63.0 mmol) and the appropriate phenol (75.2 mmol) in DMF (150 ml). The resulting solution was stirred for 2–3 h at 80°C. The reaction mixture was then poured into water and the precipitate was filtered off, washed with water, and then dried to give the desired product 2.

3-Nitro-2-phenoxypyridine (2a). Yield 13.0 g (95%). Yellow solid. Mp 90–91°C (DMF–H₂O) (mp 94°C (EtOH)10). ¹H NMR spectrum, δ, ppm (J, Hz): 7.13–7.20 (3H, m, H Ph, H Py); 7.29 (1H, t, J = 7.5, H Ph); 7.43–7.48 (2H, m, H Ph); 8.33–8.38 (2H, m, H Py). ¹³C NMR spectrum, δ, ppm: 118.4; 121.8; 125.9; 129.8; 134.7; 135.5; 151.9; 152.7; 155.9. Mass spectrum, m/z: 217 [M+H]⁺.

3-Nitro-2-( p -tolyloxy)pyridine (2b). Yield 13.4 g (92%). Yellow solid. Mp 95–96°C (DMF–H₂O) (mp 112°C (benzene–petroleum ether)11). ¹H NMR spectrum, δ, ppm (J, Hz): 2.38 (3H, s, CH₃); 7.06 (2H, d, J = 8.4, H Ph); 7.11–7.15 (1H, m, H Py); 7.24 (2H, d, J = 9.0, H Ph); 8.33–8.37 (2H, m, H Py). ¹³C NMR spectrum, δ, ppm: 21.0; 118.2; 121.5; 130.4; 134.6; 135.5; 135.6; 150.4; 151.9; 156.2. Mass spectrum, m/z: 231 [M+H]⁺.

2-(4-Bromophenoxy)-3-nitropyridine (2c). Yield 17.8 g (96%). Yellow solid. Mp 91–93°C (DMF–H₂O) (mp 95°C (benzene–petroleum ether)11). ¹H NMR spectrum, δ, ppm (J, Hz): 7.07–7.10 (2H, m, H Ph); 7.17–7.21 (1H, m, H Py); 7.54–7.57 (2H, m, H Ph); 8.33–8.40 (2H, m, H Py). ¹³C NMR spectrum, δ, ppm: 118.8; 119.0; 123.7; 132.9; 134.6; 135.7; 151.7; 151.8; 155.5. Mass spectrum, m/z: 295 [M+H]⁺.

Synthesis of 2-aryloxy-substituted pyridin-3-amines 3a,b (General method). A 10% Pd/C catalyst (1.22 g) was added to a stirred solution of 2-aryloxy-3-nitropyridine 2a (12.2 g, 56.5 mmol) or 2b (12.2 g, 53.0 mmol) in EtOAc (100 ml) and MeOH (100 ml). The resulting suspension was stirred at room temperature under H₂ atmosphere (1 bar) for 10 h. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. Purification by flash chromatography (petroleum ether–EtOAc, 3:1 (v/v)) afforded the desired product 3a or 3b.

2-Phenoxypyridin-3-amine (3a). Yield 8.6 g (82%). White solid. Mp 105–107°C (petroleum ether–EtOAc) (mp 106°C (petroleum ether)10 ^a). ¹H NMR spectrum, δ, ppm (J, Hz): 3.93 (2H, br. s, NH₂); 6.81–6.85 (1H, m, H Py); 7.01 (1H, d, J = 7.5, H Py); 7.12–7.19 (3H, m, H Ph); 7.38 (2H, t, J = 7.8, H Ph); 7.56 (1H, d, J = 4.8, H Py). ¹³C NMR spectrum, δ, ppm: 119.6; 120.8; 122.2; 124.3; 129.6; 132.1; 135.8; 151.7; 154.4. Mass spectrum, m/z: 187 [M+H]⁺.

2-( p -Tolyloxy)pyridin-3-amine (3b). Yield 9.0 g (85%). White solid. Mp 129–131°C. ¹H NMR spectrum, δ, ppm (J, Hz): 2.34 (3H, s, CH₃); 3.94 (2H, br. s, NH₂); 6.79–6.83 (1H, m, H Py); 6.99–7.04 (3H, m, H Ph, H Py); 7.18 (2H, d, J = 8.7, H Ph); 7.55 (1H, dd, J = 5.7, J = 1.5, H Py). ¹³C NMR spectrum, δ, ppm: 20.9; 119.2; 120.9; 121.9; 130.1; 131.8; 134.0; 135.8; 151.9; 152.2. Found, m/z: 201.1034 [M+H]⁺. C₁₂H₁₃N₂O. Calculated, m/z: 201.1022.

Synthesis of 2-(4-bromophenoxy)pyridin-3-amine (3c). 2-(4-Bromophenoxy)-3-nitropyridine (2c) (10.3 g, 35 mmol), iron powder (5.90 g, 105 mmol), and NH₄Cl (1.87 g, 35 mmol) were added in sequence to a mixture of water (30 ml) and EtOH (120 ml). The reaction mixture was stirred and heated to reflux for 1 h and filtered through Celite, and the filtrate was concentrated in vacuo. The residue was diluted with water (120 ml) and extracted with EtOAc (3×40 ml). The combined organic phase was washed with brine, dried over anhydrous Na₂SO₄, and

concentrated in vacuo to give 2-(4-bromophenoxy)pyridin-3-amine (3c). Yield 8.2 g (88%). Light-red solid. Mp 117–119°C. ¹H NMR spectrum, δ, ppm (J, Hz): 3.91 (2H, br. s, NH₂); 6.84–6.88 (1H, m, H Py); 7.04 (3H, d, J = 9.0, H Ph, H Py); 7.49 (2H, d, J = 8.7, H Ph); 7.55 (1H, dd, J = 4.8, J = 1.5, H Py). ¹³C NMR spectrum, δ, ppm: 117.2; 119.9; 122.4; 122.8; 131.9; 132.6; 135.7; 151.4; 153.3. Found, m/z: 264.9982 [M+H]⁺. C₁₁H₁₀BrN₂O. Calculated, m/z: 264.9971.

Synthesis of pyrido[2,3- b ][1,4]benzoxazepines 4a–o and amides 5a,b,h (General method). The appropriate 2-aryloxypyridin-3-amine 3 (1.0 mmol), aromatic acid (1.5 mmol), and SnCl₄ (2.0 mmol) were dissolved in POCl₃ (5 ml). After the mixture was refluxed for the appropriate time, the mixture was poured into ice water (20 ml) and treated with 5 N aqueous NaOH to pH 9–10. The resulting solution was extracted with EtOAc (3×20 ml). The combined organic phase was washed with saturated Na₂CO₃ and brine, dried over anhydrous Na₂SO₄, and concentrated in vacuo. Purification by flash chromatography (petroleum ether–EtOAc, 10:1 (v/v)) afforded the desired product 4a–o or amide 5a,b,h.

6-Phenylpyrido[2,3- b ][1,4]benzoxazepine (4a). Yield 245 mg (90%). Yellow solid. Mp 102–104°C. ¹H NMR spectrum, δ, ppm (J, Hz): 7.19–7.26 (3H, m, H Ph, H Py); 7.44–7.56 (5H, m, H Ph); 7.80–7.83 (3H, m, H Ph, H Py); 8.15 (1H, dd, J = 4.8, J = 1.8, H Py). ¹³C NMR spectrum, δ, ppm: 122.0; 122.4; 124.8; 126.7; 128.2; 129.8; 130.8; 131.2; 133.6; 135.5; 137.2; 139.4; 145.6; 156.0; 160.0; 168.4. Found, m/z: 273.1057 [M+H]⁺. C₁₈H₁₃N₂O. Calculated, m/z: 273.1022.

6-( p -Tolyl)pyrido[2,3- b ][1,4]benzoxazepine (4b). Yield 263 mg (92%). Yellow solid. Mp 180–182°C. ¹H NMR spectrum, δ, ppm (J, Hz): 2.43 (3H, s, CH₃); 7.16–7.28 (5H, m, H Ph, H Py); 7.46 (1H, d, J =7.5, H Ph); 7.52–7.58 (1H, m, H Ph); 7.72 (2H, d, J = 7.8, H Ph); 7.80 (1H, dd, J = 7.8, J = 1.5, H Py); 8.13 (1H, dd, J = 4.5, J = 1.5, H Py). ¹³C NMR spectrum, δ, ppm: 21.4; 122.0; 122.3; 124.8; 126.8; 128.9; 129.8; 131.2; 133.4; 135.6; 136.7; 137.1; 141.2; 145.3; 156.1; 160.0; 168.3. Found, m/z: 287.1204 [M+H]⁺. C₁₉H₁₅N₂O. Calculated, m/z: 287.1179.

6-(4-Methoxyphenyl)pyrido[2,3- b ][1,4]benzoxazepine (4c). Yield 268 mg (89%). Yellow solid. Mp 126–128°C. ¹H NMR spectrum, δ, ppm (J, Hz): 3.88 (3H, s, CH₃); 6.97 (2H, d, J = 9.0, H Ph); 7.19–7.28 (3H, m, H Ph, H Py); 7.46 (1H, d, J = 8.1, H Ph); 7.52–7.55 (1H, m, H Ph); 7.76–7.81 (3H, m, H Ph, H Py); 8.12 (1H, dd, J = 4.8, J = 1.8, H Py). ¹³C NMR spectrum, δ, ppm: 55.5; 113.7; 122.1; 122.5; 124.9; 126.8; 131.3; 131.7; 132.0; 133.5; 135.8; 137.1; 145.2; 156.2; 160.1; 162.0; 167.7. Found, m/z: 303.1136 [M+H]⁺. C₁₉H₁₅N₂O₂. Calculated, m/z: 303.1128.

6-(4-Fluorophenyl)pyrido[2,3- b ][1,4]benzoxazepine (4d). Yield 255 mg (88%). Yellow solid. Mp 107–109°C. 1H NMR spectrum, δ, ppm (J, Hz): 7.14 (2H, d, J = 8.4, H Ph); 7.18–7.27 (3H, m, H Ph, H Py); 7.48 (1H, d, J = 8.1, H Ph); 7.55–7.59 (1H, m, H Ph); 7.78–7.86 (3H, m, H Ph, H Py); 8.16 (1H, dd, J = 4.5, J = 1.8, H Py). 13C NMR spectrum, δ, ppm: 115.3; 115.6; 122.3; 122.6; 125.1; 126.6; 131.1; 132.0; 132.1; 133.9; 135.5; 135.62; 135.66; 137.3; 145.8; 156.0; 160.1; 162.9; 166.3; 167.2. Found, m/z: 291.0966 [M+H]⁺. C₁₈H₁₂FN₂O. Calculated, m/z: 291.0928.

6-(3-Nitrophenyl)pyrido[2,3- b ][1,4]benzoxazepine (4e). Yield 295 mg (93%). Yellow solid. Mp 233–235°C. 1H NMR spectrum, δ, ppm (J, Hz): 7.16–7.19 (1H, m, H Ph); 7.23–7.31 (2H, m, H Py); 7.51 (1H, d, J = 8.4, H Ph); 7.60–7.68 (2H, m, H Ph); 7.87 (1H, dd, J = 7.8, J = 2.1, H Py); 8.12–8.15 (1H, m, H Ph); 8.20–8.22 (1H, m, H Py); 8.35–8.39 (1H, m, H Ph); 8.75 (1H, t, J = 1.8, H Ph). ¹³C NMR spectrum, δ, ppm: 122.5; 122.6; 124.6; 125.2; 125.3; 125.8; 129.3; 130.3; 134.3; 135.0; 135.5; 137.5; 141.0; 146.5; 148.3; 155.7; 160.2; 165.8. Found, m/z: 318.0890 [M+H]⁺. C₁₈H₁₂N₃O₃. Calculated, m/z: 318.0873.

6-(Furan-2-yl)pyrido[2,3- b ][1,4]benzoxazepine (4f). Yield 168 mg (64%). Yellow solid. Mp 131–132°C. ¹H NMR spectrum, δ, ppm (J, Hz): 6.58–6.60 (1H, m, H furan); 6.91 (1H, d, J = 3.6, H furan); 7.21–7.30 (2H, m, H Ph, H Py); 7.45–7.48 (1H, m, H Ph); 7.58 (2H, t, J = 7.2, H Ph); 7.72 (1H, t, J = 0.6, H furan); 7.84 (1H, dd, J = 7.8, J = 1.8, H Py); 8.13 (1H, dd, J = 4.8, J = 1.8, H Py). ¹³C NMR spectrum, δ, ppm: 112.3; 118.1; 122.1; 122.7; 125.2; 125.4; 130.3; 133.9; 135.5; 137.3; 145.6; 146.3; 152.2; 155.9; 157.2; 160.2. Found, m/z: 263.0831 [M+H]⁺. C₁₆H₁₁N₂O₂. Calculated, m/z: 263.0815.

6-(Pyridin-3-yl)pyrido[2,3- b ][1,4]benzoxazepine (4g). Yield 197 mg (72%). Yellow solid. Mp 124–126°C. 1H NMR spectrum, δ, ppm (J, Hz): 7.19–7.30 (3H, m, H Ph, H Py); 7.40–7.45 (1H, m, H Ph); 7.50 (1H, d, J = 8.1, H Ph); 7.60–7.64 (1H, m, H Ph); 7.84 (1H, dd, J = 7.8, J = 1.8, H Py); 8.15–8.20 (2H, m, H Py); 8.75–8.76 (1H, m, H Py); 9.04 (1H, d, J = 1.8, H Py). ¹³C NMR spectrum, δ, ppm: 122.5; 122.7; 123.2; 125.3; 126.1; 130.7; 134.2; 135.1; 135.3; 137.1; 137.5; 146.3; 150.9; 151.6; 155.9; 160.2; 166.0. Found, m/z: 274.0989 [M+H]⁺. C₁₇H₁₂N₃O. Calculated, m/z: 274.0975.

8-Methyl-6-phenylpyrido[2,3- b ][1,4]benzoxazepine (4i). Yield 260 mg (91%). Yellow solid. Mp 149–151°C. ¹H NMR spectrum, δ, ppm (J, Hz): 2.29 (3H, s, CH₃); 7.02 (1H, s, H Ph); 7.22–7.28 (2H, m, H Ph, H Py); 7.37 (1H, s, H Ph); 7.47–7.55 (3H, m, H Ph); 7.83 (3H, t, J = 7.5, H Ph, H Py); 8.15 (1H, d, J = 3.3, H Py). ¹³C NMR spectrum, δ, ppm: 20.9; 121.8; 122.4; 126.4; 128.4; 129.9; 130.9; 131.3; 134.4; 134.7; 135.6; 137.3; 139.6; 145.6; 156.3; 158.1; 168.6. Found, m/z: 287.1187 [M+H]⁺. C₁₉H₁₅N₂O. Calculated, m/z: 287.1179.

8-Methyl-6-( p -tolyl)pyrido[2,3- b ][1,4]benzoxazepine (4j). Yield 280 mg (93%). Yellow solid. Mp 204–206°C. ¹H NMR spectrum, δ, ppm (J, Hz): 2.26 (3H, s, CH₃); 2.43 (3H, s, CH₃); 7.01 (1H, s, H Ph); 7.18–7.22 (1H, m, H Py); 7.27 (2H, d, J = 7.8, H Ph); 7.34 (2H, s, H Ph); 7.72 (2H, d, J = 8.1, H Ph); 7.77 (1H, dd, J = 7.2, J = 1.8, H Py); 8.11 (1H, dd, J = 4.5, J = 1.8, H Py). ¹³C NMR spectrum, δ, ppm: 20.7; 21.5; 121.6; 122.3; 126.4; 129.0; 129.8; 131.3; 134.1; 134.5; 135.6; 136.7; 137.0; 141.2; 145.2; 156.2; 157.9; 168.4. Found, m/z: 301.1345 [M+H]⁺. C₂₀H₁₇N₂O. Calculated, m/z: 301.1335.

6-(4-Fluorophenyl)-8-methylpyrido[2,3- b ][1,4]benzoxazepine (4k). Yield 280 mg (92%). Yellow solid. Mp 166–168°C. ¹H NMR spectrum, δ, ppm (J, Hz): 2.28 (3H, s, CH₃); 6.98 (1H, s, H Ph); 7.13–7.27 (3H, m, H Ph, H Py); 7.36 (2H, d, J = 1.2, H Ph); 7.76–7.87 (3H, m, H Ph, H Py); 8.14 (1H, dd, J = 4.5, J = 1.8, H Py). ¹³C NMR spectrum, δ, ppm: 20.9; 115.3; 115.6; 121.9; 122.5; 126.2; 131.1; 132.0; 132.1; 134.5; 134.8; 135.5; 137.2; 145.7; 156.2; 158.0; 162.9; 166.2; 167.3. Found, m/z: 305.1101 [M+H]⁺. C₁₉H₁₄FN₂O. Calculated, m/z: 305.1085.

8-Methyl-6-(4-nitrophenyl)pyrido[2,3- b ][1,4]benzoxazepine (4l). Yield 315 mg (95%). Yellow solid. Mp 220–222°C. ¹H NMR spectrum, δ, ppm (J, Hz): 2.29 (3H, s, CH₃); 6.91 (1H, s, H Ph); 7.26–7.30 (1H, m, H Py); 7.36–7.43 (2H, m, H Ph); 7.84 (1H, dd, J = 7.8, J = 1.8, H Py); 8.02 (2H, d, J = 8.4, H Ph); 8.19–8.21 (1H, m, H Py); 8.33 (2H, d, J = 8.7, H Ph). ¹³C NMR spectrum, δ, ppm: 20.7; 122.0; 122.5; 123.4; 125.5; 130.4; 130.6; 134.8; 134.9; 135.0; 137.5; 145.1; 146.4; 148.9; 155.7; 157.9; 166.2. Found, m/z: 332.1045 [M+H^]+. C₁₉H₁₄N₃O₃. Calculated, m/z: 332.1030.

8-Bromo-6-phenylpyrido[2,3- b ][1,4]benzoxazepine (4m). Yield 239 mg (68%). Yellow solid. Mp 136–138°C. ¹H NMR spectrum, δ, ppm (J, Hz): 7.25–7.29 (1H, m, H Py); 7.34–7.37 (2H, m, H Ph); 7.47–7.58 (3H, m, H Ph); 7.66 (1H, dd, J = 8.4, J = 2.4, H Ph); 7.82 (3H, d, J = 7.8, H Ph, H Py); 8.16 (1H, dd, J = 4.8, J = 1.5, H Py). ¹³C NMR spectrum, δ, ppm: 118.1; 122.8; 124.0; 128.5; 128.6; 129.9; 131.3; 133.6; 135.3; 136.5; 138.9; 146.0; 148.4; 155.7; 159.1; 167.0. Found, m/z: 351.0138 [M+H]⁺. C₁₈H₁₂BrN₂O. Calculated, m/z: 351.0128.

8-Bromo-6-( p -tolyl)pyrido[2,3- b ][1,4]benzoxazepine (4n). Yield 233 mg (64%). Yellow solid. Mp 177–179°C. 1H NMR spectrum, δ, ppm (J, Hz): 2.45 (3H, s, CH₃); 7.23–7.36 (5H, m, H Ph, H Py); 7.65 (1H, dd, J = 8.7, J = 2.7, H Ph); 7.71 (2H, d, J = 8.1, H Ph); 7.80 (1H, dd, J = 7.5, J = 1.8, H Py); 8.14 (1H, dd, J = 4.8, J = 1.8, H Py). ¹³C NMR spectrum, δ, ppm: 21.5; 117.8; 122.6; 123.7; 128.3; 129.1; 129.6; 133.5; 135.2; 135.9; 136.2; 137.2; 141.6; 145.5; 155.5; 158.8; 166.6. Found, m/z: 365.0299 [M+H]⁺. C₁₉H₁₄BrN₂O. Calculated, m/z: 365.0284.

8-Bromo-6-(4-nitrophenyl)pyrido[2,3- b ][1,4]benzoxazepine (4o). Yield 285 mg (72%). Yellow solid. Mp 235–237°C. ¹H NMR spectrum, δ, ppm (J, Hz): 7.26 (1H, s, H Ph); 7.30–7.34 (1H, m, H Ph, H Py); 7.39 (1H, d, J = 8.7, H Ph); 7.72 (1H, dd, J = 8.4, J = 2.1, H Ph); 7.86 (1H, dd, J = 7.8, J = 1.8, H Py); 8.02 (2H, d, J = 8.7, H Ph); 8.22 (1H, dd, J = 4.8, J = 1.8, H Py); 8.35 (2H, d, J = 8.4, H Ph). ¹³C NMR spectrum, δ, ppm: 118.4; 123.0; 123.8; 124.4; 127.7; 130.7; 132.9; 134.8; 137.1; 137.9; 144.4; 147.0; 148.3; 155.2; 159.1; 164.7. Found, m/z: 395.9981 [M+H]⁺. C₁₈H₁₁BrN₃O₃. Calculated, m/z: 395.9978.

N -(2-Phenoxypyridin-3-yl)benzamide (5a). Yield 255 mg (88%). White solid. Mp 120–122°C. ¹H NMR spectrum, δ, ppm (J, Hz): 7.05–7.09 (1H, m, H Py); 7.18–7.26 (3H, m, H Ph); 7.28–7.60 (5H, m, H Ph, H Py); 7.86–7.93 (3H, m, H Ph); 8.58 (1H, s, H Py); 8.91 (1H, d, J = 8.1, NH). ¹³C NMR spectrum, δ, ppm: 119.3; 121.6; 123.7; 125.4; 127.2; 128.1; 129.0; 129.8; 132.3; 134.4; 141.0; 152.7; 153.4; 165.9. Found, m/z: 291.1147 [M+H]⁺. C₁₈H₁₅N₂O₂. Calculated, m/z: 291.1128.

N -(2-Phenoxypyridin-3-yl)propionamide (5b). Yield 206 mg (85%). White solid. Mp 86–87°C. ¹H NMR spectrum, δ, ppm (J, Hz): 1.28 (3H, t, J = 7.5, CH₃); 2.49 (2H, q, J = 7.5, CH₂); 6.99–7.03 (1H, m, H Py); 7.13–7.16 (2H, m, H Ph); 7.22–7.27 (1H, m, H Ph); 7.40–7.46 (2H, m, H Ph, H Py); 7.81 (2H, dd, J = 5.1, J = 1.8, H Ph, H Py); 8.76 (1H, dd, J = 8.1, J = 1.8, NH). ¹³C NMR spectrum, δ, ppm: 9.6; 31.0; 119.3; 121.5; 123.7; 125.3; 128.0; 129.8; 140.7; 152.3; 153.4; 172.7. Found, m/z: 243.1142 [M+H]⁺. C₁₄H₁₅N₂O₂. Calculated, m/z: 243.1128.

N -(2-Phenoxypyridin-3-yl)cinnamamide (5h). Yield 253 mg (80%). White solid. Mp 117–118°C. ¹H NMR spectrum, δ, ppm (J, Hz): 6.64 (1H, d, J = 15.3, PhCH=CHCO); 7.03–7.07 (1H, m, H Py); 7.16–7.19 (2H, m, H Ph); 7.23–7.28 (1H, m, H Ph); 7.39–7.47 (5H, m, H Ph, H Py); 7.56–7.59 (2H, m, H Ph); 7.80 (1H, d, J = 15.6, PhCH=CHCO); 7.82–7.86 (1H, m, H Ph); 8.01 (1H, s, H Py); 8.89 (1H, dd, J = 7.8, J = 1.8, NH). ¹³C NMR spectrum, δ, ppm: 119.3; 120.7; 121.5; 123.9; 125.2; 128.2; 128.4; 129.0; 129.8; 130.2; 134.6; 140.9; 143.0; 152.5; 153.5; 164.5. Found, m/z: 317.1294 [M+H]⁺. C₂₀H₁₇N₂O₂. Calculated, m/z: 317.1285.

The Supplementary information file containing LC-MS data and NMR spectra of the synthesized compounds is available online at http://springerlink.bibliotecabuap.elogim.com/journal/10593.

This work was supported by a grant from the Sci-Tech Development Project of Jilin Province in China (No. 20160520039JH) and a grant from the Norman Bethune Program of Jilin University (No. 2015330). Additional support was provided by Changchun Discovery Sciences, Ltd.