Roberta Bianca - Academia.edu (original) (raw)

European Journal of Medicinal Chemistry, 2004

An efficient, facile, and practical parallel combinatorial synthesis of substituted-benzoxazines ... more An efficient, facile, and practical parallel combinatorial synthesis of substituted-benzoxazines under microwave irradiation was described. The procedure involved the use of a microwave oven especially designed for organic synthesis suitable for parallel synthesis of solution libraries. A demonstration 19-membered library of substituted N,N-dimethyl-and N-methyl-benzoxazine amide derivatives, structurally related to the potassium channel opener cromakalim, was generated by both conventional and microwave procedures, achieving a reduction from 7 h to 30-36 min in library generation time for the microwave approach. All the synthesized compounds were tested using the in vitro models of rat aorta and guinea pig trachea rings pre-contracted with phenylephrine and carbachol, respectively. All N,N-dimethyl amide derivatives showed a relaxant activity higher on guinea pig trachea rings than on rat aorta rings. ) and 1.27 ppm (t, 3H, CH 3 , J = 7.3 Hz). 5.1.2.5. 4e. Compound 4e was synthesized starting from 3e and ethyl 2-bromoacetate, yield 92%, m.p. 132-134°C (isopropylether, n-hexane). 1 H NMR (CDCl 3 ): d 7.92 (d, 1H 8 , Ar-H, J = 8.2 Hz), 7.65 (s, 1H 5 , Ar-H), 7.20 (d, 1H 7 , Ar-H, J = 8.4 Hz), 4.74 (s, 2H, CH 2 N), 4.32 (q, 2H, OCH 2 ), 1.50 (t, 6H, CH 3 ) and 1.30 ppm (t, 3H, CH 3 , J = 7.3 Hz). 5.1.2.6. 4f. Compound 4f was synthesized starting from 3f and ethyl 2-bromoacetate, yield 90%, m.p. 63-64°C (diethyl ether, n-hexane). 1 H NMR (CDCl 3 ): d 7.34 (d, 1H 8 , Ar-H, J = 8.2 Hz), 7.06 (d, 1H 7 , Ar-H, J = 8.4 Hz), 6.94 (s, 1H 5 , Ar-H), 4.4.62 (s, 2H, CH 2 N), 4.27 (q, 2H, OCH 2 ), 1.57 (s, 6H, CH 3 ) and 1.30 ppm (t, 3H, CH 3 , J = 7.3 Hz). 5.1.2.7. 4g. Compound 4g was synthesized starting from 3a and ethyl 3-bromopropionate, yield 90%, m.p. 87-88°C (diethyl ether, dichloromethane). 1 H NMR (CDCl 3 ): d 7.01 (d, 1H 8 , Ar-H, J = 8.2 Hz), 6.93 (d, 1H 7 , Ar-H, J = 8.4 Hz), 6.85 (s, 1H 5 , Ar-H), 4.60 (s, 2H, O-CH 2 C=O), 4.25 (t, 2H, CH 2 N, J = 8.2 Hz), 4.15 (q, 2H, OCH 2 ), 2.70 (t, 2H, CH 2 C=O, J = 7.3 Hz) and 1.25 ppm (t, 3H, CH 3 , J = 7.3 Hz). 5.1.2.8. 4h. Compound 4h was synthesized starting from 3b and ethyl 3-bromopropionate, yield 94%, m.p. 103-104°C (diethyl ether, n-hexane). 1 H NMR (CDCl 3 ): d 7.98 (s, 1H 5 , Ar-H), 7.90 (d, 1H 8 , Ar-H, J = 8.2 Hz), 7.00 (d, 1H 7 , Ar-H, J = 8.4 Hz), 4.70 (s, 2H, O-CH 2 C=O), 4.25 (t, 2H, CH 2 N, J = 8.2 Hz), 4.10 (q, 2H, OCH 2 ), 2.70 (t, 2H, CH 2 C=O, J = 7.3 Hz) and 1.25 ppm (t, 3H, CH 3 , J = 7.3 Hz). 5.1.2.9. 4i. Compound 4i was synthesized starting from 3c and ethyl 3-bromopropionate, yield 88%, m.p. 85-87°C (n-hexane, ethyl alcohol). 1 H NMR (CDCl 3 ): d 7.15 (d, 1H 8 Ar-H, J = 8.2 Hz), 7.00 (d, 1H 7 , Ar-H, J = 8.4 Hz), 6.94 (s, 1H 5 , Ar-H), 4.72 (s, 2H, O-CH 2 C=O), 4.33 (t, 2H, CH 2 N, J = 8.2 Hz), 4.24 (q, 2H, OCH 2 ), 2.84 (t, 2H, CH 2 C=O, J = 7.3 Hz) and 1.25 ppm (t, 3H, CH 3 , J = 7.3 Hz). 5.1.2.10. 4k. Compound 4k was synthesized starting from 3f and ethyl 3-bromopropionate, yield 86%, m.p. 63-64°C (diethyl ether, ethyl alcohol). 1 H NMR (CDCl 3 ): d 7.35 (d, 1H 8 , Ar-H, J = 8.2 Hz), 7.25 (s, 1H 5 , Ar-H), 7.00 (d, 1H 7 , Ar-H, J = 8.4 Hz), 4.25 (t, 2H, CH 2 N, J = 8.2 Hz), 4.10 (q, 2H, OCH 2 ), 2.60 (t, 2H, CH 2 C=O, J = 7.3 Hz) 1.51 (s, 6H CH 3 ) and 1.25 ppm (t, 3H, CH 3 , J = 7.3 Hz). 5.1.2.11. 4l. Compound 4l was synthesized starting from 3a and ethyl 4-bromobutyrate, yield 85%, m.p. 66-67°C, diethyl ether). 1 H NMR: d 7.13 (s, 1H 5 , Ar-H), 6.96 (d, 1H 8 , Ar-H, J = 8.2 Hz), 6.91 (d, 1H 7 , Ar-H, J = 8.4 Hz), 4.58 (s, 2H, O-CH 2 C=O), 4.17 (q, 2H, OCH 2 ), 3.95 (t, 2H, CH 2 N, J = 8.2 Hz), 2.42 (t, 2H, CH 2 C=O, J = 7.3 Hz), 1.98 (m, 2H, CH 2 ) and 1.25 ppm (t, 3H, CH 3 , J = 7.3 Hz). 5.1.2.12. 4m. Compound 4m was synthesized starting from 3b and ethyl 4-bromobutyrate, yield 90%, m.p. 94-96°C (diethyl ether). 1 H NMR (CDCl 3 ): d 8.10 (s, 1H 5 , Ar-H), 8.07 (d, 1H 8 , Ar-H, J = 8.2 Hz), 7.08 (d, 1H 7 , Ar-H, J = 8.4 Hz), 4.72 (s, 2H, O-CH 2 C=O), 4.19 (q, 2H, OCH 2 ), 4.05 (t, 2H, CH 2 N, J = 8.2 Hz), 2.45 (t, 2H, CH 2 C=O, J = 7.3 Hz), 2.01 (m, 2H, CH 2 ) and 1.26 ppm (t, 3H, CH 3 , J = 7.3 Hz). 5.1.3.3. 4r. Compound 4r was synthesized starting from 4n, yield 92%, m.p. 108-109°C (diethyl ether). 1 H NMR (CDCl 3 ): d 7.70 (s, 1H 5 , Ar-H), 7.55 (d, 1H 8 , Ar-H, J = 8.2 Hz), 7.10 (d, 1H 7 , Ar-H, J = 8.4 Hz), 4.81 (s, 2H, O-CH 2 C=O), 4.60 (s, 2H, CH 2 N), 4.35 (t, 2H, CH 2 N=, J = 8.2 Hz), 4.21 (m, 2H, CH 2 ), 4.15 (q, 2H, OCH 2 , J = 7.3 Hz), 3.52 (t, 2H, CH 2 S, J = 8.2 Hz), 2.44 (t, CH 2 C=O, J = 7.3 Hz) and 1.26 ppm (t, 3H, CH 3 , J = 7.3 Hz). 5.1.3.4. 4s. Compound 4s was synthesized starting from 4o, yield 90%, m.p. 60-61°C (diethyl ether). 1 H NMR (CDCl 3 ): d 7.68 (s, 1H 5 , Ar-H), 7.49 (d, 1H 8 , Ar-H, J = 8.2 Hz), 7.00 (d, 1H 7 , Ar-H, J = 8.4 Hz), 4.57 (s, 2H, CH 2 N), 4.32 (t, 2H, CH 2 N=, J = 8.2 Hz), 4.15 (m, 2H, CH 2 ), 4.02 (q, 2H, OCH 2 , J = 7.3 Hz), 3.48 (t, 2H, CH 2 S, J = 8.2 Hz), 2.42 (t, CH 2 C=O, J = 7.3 Hz), 1.54 (s, 6H, CH 3 ) and 1.26 ppm (t, 3H, CH 3 , J = 7.3 Hz). 5.1.4.1. 5a. Compound 5a was synthesized starting from 4g and dimethylamine, yield 90%, m.p. 104-105°C (diethyl ether, ethyl alcohol). 1 H NMR (CDCl 3 ) d 7.10 (s, 1H 5 , Ar-H), 6.98 (d, 1H 8 , Ar-H, J = 8.2 Hz), 6.90 (d, 1H 7 , Ar-H, J = 8.4 Hz), 4.60 (s, 2H, O-CH 2 C=O), 4.22 (t, 2H, CH 2 N, J = 8.2 Hz), 3.00 (s, 3H, N(CH 3 ) 2 ), 2.96 (s, 3H, N(CH 3 ) 2 ) and 2.68 ppm (t, 2H, CH 2 CON, J = 8.1 Hz). ESI-MS: m/z = 283.1 [M + H] + . 5.1.4.2. 5b. Compound 5b was synthesized starting from 4h and dimethylamine, yield 86%, m.p. 160-161°C (diethyl ether, ethyl alcohol). 1 H NMR (CDCl 3 ): d 8.01 (s, 1H 5 , Ar-H), 7.91 (d, 1H 8 , Ar-H, J = 8.2 Hz), 7.06 (d, 1H 7 , Ar-H, J = 8.4 Hz), 4.70 (s, 2H, O-CH 2 C=O), 4.28 (t, 2H, CH 2 N, J = 8.2 Hz), 2.98 (s, 3H, N(CH 3 ) 2 ), 2.94 (s, 3H, N(CH 3 ) 2 ) and 2.72 ppm (t, 2H, CH 2 CON, J = 8.1 Hz). ESI-MS: m/z = 294.2 [M + H] + . 5.1.4.3. 5c. Compound 5c was synthesized starting from 4i and dimethylamine, yield 84%, m.p. 120-121°C (diethyl ether, ethyl alcohol). 1 H NMR (CDCl 3 ): d 7.40 (s, 1H 5 , Ar-H), 7.31 (d, 1H 8 , Ar-H, J = 8.2 Hz), 7.05 (d, 1H 7 , Ar-H, J = 8.4 Hz), 4.70 (s, 2H, O-CH 2 C=O), 4.25 (t, 2H, CH 2 N, J = 8.2 Hz), 2.98 (s, 3H, N(CH 3 ) 2 ), 2.90 (s, 3H, N(CH 3 ) 2 ) and 2.71 ppm (t, 2H, CH 2 CON, J = 8.1 Hz). ESI-MS: m/z = 274.2 [M + H] + . 5.1.4.4. 5d. Compound 5d was synthesized starting from 4k and dimethylamine, yield 80%, m.p. 185-186°C (diethyl ether, ethyl alcohol). 1 H NMR (CDCl 3 ): d 7.74 (s, 1H 5 , Ar-H), 7.57 (d, 1H 8 , Ar-H, J = 8.2 Hz), 7.00 (d, 1H 7 , Ar-H, J = 8.4 Hz), 4.29 (t, 2H, CH 2 N, J = 8.2 Hz), 2.99 (s, 3H, N(CH 3 ) 2 ), 2.91 (s, 3H, N(CH 3 ) 2 ), 2.68 (t, 2H, CH 2 CON, J = 8.1 Hz) and 1.48 ppm (s, 6H, CH 3 ). ESI-MS: m/z = 302.3 [M + H] + . 5.1.4.5. 5e. Compound 5e was synthesized starting from 4l and dimethylamine, yield 85%, m.p. 89-90°C (diethyl ether, ethyl alcohol). 1 H NMR (CDCl 3 ): d 7.34 (s, 1H 5 , Ar-H), 6.97 (d, 1H 8 , Ar-H, J = 8.2 Hz), 6.88 (d, 1H 7 , Ar-H, J = 8.4 Hz), 4.60 (s, 2H, O-CH 2 C=O), 3.95 (t, 2H, CH 2 N, J = 8.2 Hz), 3.01 (s, 3H, N(CH 3 ) 2 ), 2.98 (s, 3H, N(CH 3 ) 2 ), 2.40 (t, 2H, CH 2 CON, J = 8.1 Hz) and 2.00 ppm (m, 2H, CH 2 ). ESI-MS: m/z = 297.8 [M + H] + . 5.1.4.6. 5f. Compound 5f was synthesized starting from 4m and dimethylamine, yield 92%, m.p. 120-121°C (diethyl ether, ethyl alcohol). 1 H NMR (CDCl 3 ): d 8.29 (s, 1H 5 , Ar-H), 7.91 (d, 1H 8 , Ar-H, J = 8.2 Hz), 7.04 (d, 1H 7 , Ar-H, J = 8.4 Hz), 4.69 (s, 2H, O-CH 2 C=O), 4.04 (t, 2H, CH 2 N, J = 8.2 Hz), 2.97 (s, 3H, N(CH 3 ) 2 ), 2.96 (s, 3H, N(CH 3 ) 2 ), 2.42 (t, 2H, CH 2 CON, J = 8.1 Hz) and 2.03 ppm (m, 2H, CH 2 ). ESI-MS: m/z = 308.2 [M + H] + . 5.1.4.7. 5g. Compound 5g was synthesized starting from 4r and dimethylamine, yield 94%, m.p. 142-144°C (diethyl ether, ethyl alcohol). 1 H NMR (CDCl 3 ): d 7.72 (s, 1H 5 , Ar-H), 7.44 (d, 1H 8 , Ar-H, J = 8.2 Hz), 6.98 (d, 1H 7 , Ar-H, J = 8.4 Hz), 4.62 (s, 2H, O-CH 2 C=O), 4.43 (t, 2H, CH 2 N=, J = 8.2 Hz), 4.05 (t, 2H, CH 2 N, J = 8.2 Hz), 3.41 (t, 2H, CH 2 S, J = 8.2 Hz), 2.95 (s, 3H, N(CH 3 ) 2 ), 2.94 (s, 3H, N(CH 3 ) 2 ), 2.39 (t, 2H, CH 2 CO, J = 8.1 Hz) and 2.03 ppm (m, 2H, CH 2 ). ESI-MS: m/z = 348.2 [M + H] + . 5.1.4.8. 5h. Compound 5h was synthesized starting from 4s and dimethylamine, yield 90%, m.p. 105-106°C (diethyl ether, ethyl alcohol). 1 H NMR (CDCl 3 ): d 7.65 (s, 1H 5 , Ar-H), 7.42 (d, 1H 8 , Ar-H, J = 8.2 Hz), 6.92 (d, 1H 7 , Ar-H, J = 8.4 Hz), 4.05 (t, 2H, CH 2 N=, J = 8.2 Hz), 3.42 (t, 2H, CH 2 S, J = 8.2 Hz) 2.94 (s, 3H, N(CH 3 ) 2 ), 2.93 (s, 3H, N(CH 3 ) 2 ), 2.38 (t, 2H, CH 2 CO, J = 8.1 Hz), 2.10 (m, 2H, CH 2 ) and 1.51 ppm (m, 6H, CH 3 ). ESI-MS: m/z = 376.5 [M + H] + . 5.1.4.9. 6a. Compound 6a was synthesized starting from 4a and methylamine, yield 95%, m.p. 202-203°C (diethyl ether). 1 H NMR (CDCl 3 ): d 7.26 (s, 1H 5 , Ar-H), 7.12 (d, 1H 8 , Ar-H, J = 8.2 Hz), 6.99 (d, 1H 7 , Ar-H, J = 8.4 Hz), 6.19