new 1,10-phenanthroline derivatives with potential antitumoral activity

186 Florea Dumitraşcu et al.129.6 (C-2', C-6'); 132.6 (C-3', C-5'); 136.6 (C-4); 146.1 (C-2); 155.0 (C-8a); 165.8 (9-COOMe); 173.5 (10-COOMe);188.6 (COAr).General procedure for synthesis of esters 7a-c. 2.0 g(5 mmol) phenanthrolinium salt 3 were suspended in 25 mL ofdichloromethane and 5.5 mmol of dimethyl (or diethyl,diisopropyl) acetylenedicarboxylate were then added. Undervigorous stirring 0.75 mL (5 mmol) of triethylamine(dissolved in 5 mL methylene chloride) were added dropwise.After 1 h the reaction mixture was washed twice with waterand the solvent evaporated. The residue was refluxed withstirring in ethanol for 1 h and the precipitate was isolated byfiltration.Dimethyl 11-(4-cyanobenzoyl)-pyrrolo[1,2-a][1,10]phenanthroline-9, 10-dicarboxylate (7a).The product was recrystallized from DMF and yellow crystalswith mp 329-331 °C were obtained; yield 87 %. Anal. Calcd.C 27 H 17 N 3 O 5 : C 69.97, H 3.70, N 9.07. Found: C 70.08, H 3.93,N 9.31.1 H-NMR (300 MHz, CDCl 3 +TFA) δ: 3.74, 3.95 (2s, 6H,2 MeO); 7.55 (d, 2H, J = 8.6 Hz, H-2', H-6'); 7.66 (d, 2H,J = 8.6 Hz, H-3', H-5'); 7.93 (d, 1H, d, 1H, J = 9.6 Hz, H-7);8.21 (dd, 1H, J = 8.1, 6.3 Hz, H-3); 8.28, 8.35 (2d, 2H, J =8.8 Hz, H-5, H-6); 8.57 (d, 1H, J = 9.6 Hz, H-8); 9.13 (dd, 1H,J = 8.1, 1.3 Hz, H-4); 9.36 (dd, 1H, J = 6.3, 1.3 Hz, H-2).13 C-NMR (75 MHz, CDCl 3 +TFA) δ: 52.4, 53.2 (2 MeO);95.1 (C-9); 109.6, 114.6, 116.9, 117.6, 122.4, 126.5, 127.0,128.5, 130.6 (C-4a, C-6a, C-8a, C-10, C-11, C-12a, C-12b, C-1', CN); 123.9 (C-7); 124.6 (C-3); 125.8 (C-8); 125.7, 130.3(C-5, C-6); 126.0 (C-2', C-6'); 133.0 (C-3', C-5'); 144.1 (C-2);145.6 (C-4'); 147.2 (C-4); 163.3, 165.0 (2COO); 182.5(COAr).Diethyl 11-(4-cyanobenzoyl)-pyrrolo[1,2-a][1,10]phenanthroline-9,10-dicarboxylate (7b). The product was recrystallized fromchloroform and yellow crystals with mp 292-4 °C wereobtained; yield 79 %. Anal. Calcd. C 29 H 21 N 3 O 5 : C 70.87,H 4.31, N 8.55 Found: C 71.08, H 3.93, N 9.31.1 H-NMR (300 MHz, CDCl 3 +TFA) δ: 1.20 (t, 3H,J = 7.1 Hz, 10-Me); 1.40 (t, 3H, J = 7.1 Hz; 9-Me); 4.12-4.33(m, 2H, J = 10.8, 7.1 Hz, 10-OCH 2 ); 4.42 (q, 2H, J = 7.1 Hz,9-OCH 2 ); 7.56 (d, 2H, J = 8.6 Hz, H-2', H-6'); 7.67 (d, 2H,J = 8.6 Hz, H-3', H-5'); 7.95 (d, 1H, d, 1H, J = 9.6 Hz, H-7);8.22 (dd, 1H, J = 8.1, 6.3 Hz, H-3); 8.30, 8.37 (2d, 2H,J = 8.8 Hz, H-5, H-6); 8.59 (d, 1H, J = 9.6 Hz, H-8); 9.15 (dd,1H, J = 8.1, 1.3 Hz, H-4); 9.38 (dd, 1H, J = 6.3, 1.3 Hz, H-2).13 C-NMR (75 MHz, CDCl 3 +TFA) δ: 13.4, 13.9 (2Me);62.4, 63.8 (2CH 2 O); 94.2 (C-9); 108.9, 114.3, 116.4, 117.5,122.8, 126.3, 127.1, 128.5, 130.7 (C-4a, C-6a, C-8a, C-10, C-11, C-12a, C-12b, C-1', CN); 124.3 (C-7); 124.8 (C-3); 125.0(C-8); 125.9, 130.4 (C-5, C-6); 126.0 (C-2', C-6'); 133.2 (C-3',C-5'); 144.2 (C-2); 145.6 (C-4'); 147.6 (C-4); 163.4, 165.8(2COO); 182.6 (COAr).Diisopropyl 11-(4-cyanobenzoyl)-pyrrolo[1,2-a][1,10]phenanthroline-9, 10-dicarboxylate (7c). The product was recrystallized fromacetonitrile and yellow crystals with mp 263-4 °C wereobtained; yield 81 %. Anal. Calcd. C 31 H 25 N 3 O 5 : C 71.67,H 4.85, N 8.09 Found: C 71.88, H 5.15, N 8.22.1 H-NMR (300 MHz, CDCl 3 ) δ: 0.94, 1.12 (2d, 6H, J = 6.3 Hz,10-CHMe 2 ); 1.37, 1.40 (2d, 6H, J = 6.2 Hz, 9-CHMe 2 ); 4.80(sep, 1H, J = 6.2 Hz, 10-CHMe 2 ); 5.31 (sep, 1H, J = 6.2 Hz,9-CHMe 2 ); 7.35 (dd, 1H, J = 8.2, 4.3 Hz, H-3); 7.69 (d, 1H, d,1H, J = 9.5 Hz, H-7); 7.79 (d, 2H, J = 8.6 Hz, H-3', H-5');7.80, 7.87 (2d, 2H, J = 8.8 Hz, H-5, H-6); 7.91 (dd, 1H,J = 4.3, 1.7 Hz, H-2); 8.18 (dd, 1H, J = 8.2, 1.7 Hz, H-4); 8.23(d, 2H, J = 8.6 Hz, H-2', H-6'); 8.57 (d, 1H, J = 9.5 Hz, H-8).1 H- NMR (300 MHz, CDCl 3 +TFA) δ: 1.15, 1.29 (2d, 6H,J = 6.2 Hz, 10-CHMe 2 ); 1.40, 1.41 (2d, 6H, J = 6.2 Hz,9-CHMe 2 ); 5.11 (sep, 1H, J = 6.2 Hz, 10-CHMe 2 ); 5.29 (sep,1H, J = 6.2 Hz, 9-CHMe 2 ); 7.53 (d, 2H, J = 8.6 Hz, H-2',H-6'); 7.65 (d, 2H, J = 8.6 Hz, H-3', H-5'); 7.94 (d, 1H, d, 1H,J = 9.6 Hz, H-7); 8.22 (dd, 1H, J = 8.1, 6.3 Hz, H-3); 8.29,8.36 (2d, 2H, J = 8.8 Hz, H-5, H-6); 8.57 (d, 1H, J = 9.6 Hz,H-8); 9.14 (dd, 1H, J = 8.1, 1.3 Hz, H-4); 9.43 (dd, 1H,J = 6.3, 1.3 Hz, H-2).13 C-NMR (75 MHz, CDCl 3 ) δ: 21.1, 21.5, 21.9, 22.1(4Me); 68.1, 69.7 (CHMe 2 ); 104.8 (C-9); 115.3, 118.2 (C-1',CN); 120.4 (C-8); 122.3 (C-3); 125.4, 126.8 (C-5, C-6); 125.7(C-7); 125.8, 126.0, 127.7, 128.6 (C-4a, C-6a, C-8a, C-10,C-11); 130.3 (C-2', C-6'); 132.0 (C-3', C-5'); 136.3 (C-4);136.9, 137.1 (C-12a, C-12b); 145.1 (C-1'); 145.2 (C-2); 162.8,164.8 (2COO); 181.7 (COAr).13 C-NMR (75 MHz, CDCl 3 +TFA) δ: 21.1, 21.7 (4Me);70.6, 72.7 (CHMe 2 ); 94.5 (C-9); 109.4, 114.3, 116.6, 117.1,123.2, 126.4, 127.0, 128.5, 130.5 (C-4a, C-6a, C-8a, C-10, C-11, C-12a, C-12b, C-1', CN); 124.2 (C-7); 124.8 (C-3); 125.0(C-8); 125.9 (C-2', C-6'); 126.2, 130.4 (C-5, C-6); 133.3 (C-3',C-5'); 143.9 (C-2); 145.7 (C-4'); 147.6 (C-4); 162.9, 165.7(2COO); 182.6 (COAr).The procedure for synthesis of esters 7d,e. 2.0 g (5 mmol)Phenanthrolinium salt 3 were suspended in 25 mL ofdichloromethane and then 6 mmol of ethyl or isopropylpropiolate were added. Under vigorous stirring 0.7 mL(5 mmol) of triethylamine (dissolved in 10 mL of methylenechloride) were added dropwise. After 20 min the reactionmixture was washed with water and the solvent evaporated.The residue was purified by column chromatography onneutral Al 2O 3using CH 2Cl 2as eluent.Methyl 11-(4-cyanobenzoyl)-pyrrolo[1,2-a][1,10]phenanthroline-9- carboxylate (7d). The product was recrystallized fromnitromethane and yellow crystals with mp 246-7 °C wereobtained; yield 41 %. Anal. Calcd. for C 25 H 15 N 3 O 3 : C 74.07,H 3.73, N 10.36. Found: C 74.23, H 4.11, N 10.52.1 H-NMR (300 MHz, CDCl 3 ) δ: 3.94 (s, 3H, MeO); 7.38(dd, 1H, J = 8.2, 4.3 Hz, H-3); 7.55 (s,1H, H-10); 7.74 (d, 1H,J = 9.2 Hz, H-7); 7.82, 7.95 (2d, 1H, J = 8.6 Hz, H-5, H-6);7.85 (d, 2H, J = 8.6 Hz, H-3', H-5'); 8.19-8.23 (m, 2H, H-2,H-4); 8.31 (d, 2H, J = 8.6 Hz, H-2', H-6'); 8.59 (d, 1H, J =9.2 Hz, H-8).13 C-NMR (75 MHz, CDCl 3 ) δ: 51.3 (OMe); 106.0 (C-9);115.4, 118.2 (C-1', CN); 119.8 (C-8); 121.7 (C-10); 122.5(C-3); 125.4, 126.6 (C-5, C-6); 125.5, 127.8, 129.2, 131.6(C-4a, C-6a, C-8a, C-10); 126.2 (C-7); 130.5 (C-2', C-6');132.2 (C-3', C-5') 136.0 (C-4); 137.8, 138.9 (C-12a, C-12b);141.4 (C-4'); 146.0 (C-2); 164.8 (COO); 183.0 (COAr).Ethyl 11-(4-cyanobenzoyl)-pyrrolo[1,2-a][1,10]phenanthroline-9-carboxylate (7e). The product was recrystallized fromnitromethane and yellow crystals with mp 242-4 °C wereobtained; yield 37 %. Anal. Calcd. for C 26 H 17 N 3 O 3 : C 74.45,H 4.09, N 10.02. Found: C 74.58, H 4.18, N 10.21.1 H-NMR (300 MHz, CDCl 3 ) δ: 1.41 (t, 3H, J = 7.1 Hz;Me); 4.35-4.67 (m, 2H, J = 10.4, 7.1 Hz, CH 2 ); 7.37 (dd, 1H,J = 8.2, 4.3 Hz, H-3); 7.53 (s,1H, H-10); 7.73 (d, 1H,J = 9.2 Hz, H-7); 7.82, 7.90 (2d, 1H, J = 8.6 Hz, H-5, H-6);7.85 (d, 2H, J = 8.6 Hz, H-3', H-5'); 8.19-8.23 (m, 2H, H-2,H-4); 8.26 (d, 2H, J = 8.6 Hz, H-2', H-6'); 8.59 (d, 1H, J =9.2 Hz, H-8).13 C-NMR (75 MHz, CDCl 3 ) δ: 14.6 (Me); 60.2 (CH 2 );106.5 (C-9); 114.9, 118.4 (C-1', CN); 120.1 (C-8); 121.8(C-10); 122.7 (C-3); 125.3, 126.7 (C-5, C-6); 125.6, 127.8,