Synthesis of Benzopyranophenazines via Isocyanide-Based Three-Component Reactions

ISSN: 0973-4945; CODEN ECJHAO E-Journal of Chemistry 2012, 9(4), 2315-2321 http://www.ejchem.net Synthesis of Benzopyranophenazines via IsocyanideBased Three-Component Reactions AYOOB BAZGIR* AND ALI MOHAMMAD ASTARAKI Department of Chemistry, Islamic Azad University, Doroud Branch, P.O. Box 133, Doroud, Iran Received 02 November 2011; Accepted 15 January 2012 Abstract: Benzo[a]pyrano[2,3-c]phenazines were synthesized in good yields by a three-component reaction of benzo[a]phenazin-5-oles, isocyanides and dialkyl acetylendicarboxylates In refluxing ethanol. Keywords: Isocyanide, Benzo[a]pyrano[2,3-c]phenazines, Dialkyl acetylendicarboxylate. Introduction Multi-component reactions (MCRs) have been frequently used by synthetic chemists as a facile means to generate molecular diversity from bifunctional substrates that react sequentially in an intramolecular fashion.1,2 In recent years, isocyanide-based multicomponent condensation reactions (IMCRs) by virtue of their synthetic potential, their inherent atom efficiency, convergent nature, ease of implementation, and the generation of molecular diversity, have attracted much attention because of the advantages that they offer to the field of combinatorial chemistry. 3,4 It has been shown that isocyanides add to activated alkynes to generate zwitterionic species, which have been captured by CH-acids to produce various heterocycles. 5-10 Although threecomponent reaction of isocyanide, activated alkynes and CH-acid has been applied to the synthesis of various heterocycles, to our knowledge, this synthetic strategy has not been applied to the synthesis of substituted benzo[a]pyrano[2,3-c]phenazine. More than 6000 phenazine-containing compounds have been identified and reported during the past century.11 Several hundreds of the known phenazines possess biological activities, including antimalarial,12 trypanocidal,13 fungicidal,14 and antiplatelet15 effects, and are either isolated from natural sources or synthetically constructed. Also, the antitumor activity of pyridophenazinediones and pyridazinophenazinedione derivatives was reported. 16,17 Due to ‎ ‎ ‎ ‎ ‎ 2316 AYOOB BAZGIR wide range of phenazines biological activity, research in this area is continuous to thrive and mostly is directed toward the synthesis of compounds with enhanced biological activity. 11,1820 A literature survey reveals that limited number of synthetic routes for the preparation of benzopyranophenazines have been reported. Recently, the two-step synthesis of benzopyranophenazines under harsh conditions and long reaction time was described by Perez-Sacau and co-workers.21 To the best of our knowledge, there is only two reports on synthesis of benzopyranophenazines via a multicomponent reaction.22 Due to the biological activity of phenazine derivatives, herein, we report an efficient isocyanide-based three-component method for the preparation of benzo[a]pyrano[2,3c]phenazines. Experimental Melting points were measured on an Elecrtothermal 9100 apparatus. Mass spectra were recorded on a FINNIGAN-MAT 8430 mass spectrometer operating at an ionization potential of 70 eV. 1H, 13C NMR were recorded on a BRUKER DRX-300 AVANCE spectrometer at 300.13 and 75.47 MHz, respectively. IR spectra were recorded using an FTIR apparatus. Elemental analyses were performed using a Heracus CHN-O-Rapid analyzer. The chemical used in this work were obtained from Fluka and Merck and were used without purification. Typical procedure for the preparation of benzopyranophenazine (4) A mixture of benzo[a]phenazin-5-oles (1 mmol), isocyanides (1 mmol) and dialkyl acetylenedicarboxylates (1 mmol) in refluxing etanole (5 mL) was stirred for 20 h. After completion of the reaction (TLC; ethyl acetate/n-hexane, 1/1), the reaction mixture was filtered and the precipitate washed with ethanol (5 mL) to afford the pure product. Dimethyl 3-(cyclohexylamino)-1H-benzo[a]pyrano[2,3-c]phenazine-1,2-dicarboxylate (4a) Yellow powder (86%); mp 225-227 °C. IR (KBr) (νmax/cm-1): 3267, 1742, 1677. MS (EI, 70eV) m/z: 497 (M+). 1H NMR (300 MHz, CDCl3): δH 1.38-2.23 (10H, m, 5CH2 of cyclohexyl), 3.63 (3H, s. OCH3), 3.89 (3H, s, OCH3), 4.10 (1H, bs, CH-N), 5.78 (1H, s, CH), 7.84-8.36 (7H, m, Ar-H), 8.85 (1H, d, J = 7.4 Hz, NH), 9.38-9.41 (1H, m, Ar-H). 13C NMR (75 MHz, CDCl3): δC 24.6, 24.7, 25.6, 33.6, 33.9, 36.7, 50.6, 51.2, 52.3, 72.2, 112.7, 121.5, 125.6, 126.3, 128.6, 129.5, 129.6, 130.0, 130.1, 131.1, 141.1, 141.7, 142.6, 147.4, 160.1, 170.1, 174.1. Anal. Calcd for C29H27N3O5. C, 70.01; H, 5.47; N, 8.45. Found: C, 69.90; H, 5.41; N, 8.36. Diethyl 3-(cyclohexylamino)-1H-benzo[a]pyrano[2,3-c]phenazine-1,2-dicarboxylate (4b) Yellow powder (88%); mp 184-186 °C. IR (KBr) (νmax/cm-1): 3240, 1720, 1669. MS (EI, 70eV) m/z: 525 (M+). 1H NMR (300 MHz, CDCl3): δH 1.21 (3H, t, J = 5.6 Hz, CH 3), 1.422.22 (13H, m, 5CH2 of cyclohexyl and CH3), 4.09 (3H, bs, CH-N of and OCH2), 4.35 (2H, ABq, J = 5.6 Hz, OCH2), 5.74 (1H, s, CH), 7.85-8.33 (7H, m, Ar-H), 8.87 (1H, bs, NH), 9.40 (1H, bs, Ar-H). 13C NMR (75 MHz, CDCl3): δC 14.3, 14.8, 24.7, 25.6, 33.6, 33.9, 37.0, 50.5, 59.6, 60.8, 72.3, 112.7, 121.6, 125.5, 126.4, 128.6, 129.4, 129.5, 129.9, 130.1, 131.1, 140.5, 141.0, 141.9, 142.6, 147.4, 159.9, 169.8, 174.2. Anal. Calcd for C31H31N3O5. C, 70.84; H, 5.94; N, 7.99. Found: C, 70.72; H, 5.99; N, 7.93. Synthesis of Benzopyranophenazines via Isocyanide 2317 Dimethyl 3-(tert-butylamino)-1H-benzo[a]pyrano[2,3-c]phenazine-1,2-dicarboxylate (4c) Yellow powder (80%); mp 237-239 °C. IR (KBr) (νmax/cm-1): 3200, 1737, 1671. MS (EI, 70eV) m/z: 471 (M+). 1H NMR (300 MHz, DMSO-d6): δH 1.60 (9H, s, CH3), 3.49 (3H, s, OCH3), 3.77 (3H, s, OCH3), 5.64 (1H, s, CH), 7.97-8.37 (7H, m, Ar-H), 9.09 (1H, s, NH), 9.28-9.31 (1H, m, Ar-H). 13C NMR (75 MHz, CDCl3): δC 30.6, 36.4, 51.2, 51.3, 52.3, 52.5, 72.9, 112.7, 122.0, 125.7, 126.2, 128.4, 128.5, 129.2, 129.5, 129.6, 130.0, 131.1, 140.4, 141.1, 141.6, 142.6, 142.7, 147.7, 161.4, 170.3, 174.0. Anal. Calcd for C 27H25N3O5. C, 68.78; H, 5.34; N, 8.91. Found: C, 68.85; H, 5.41; N, 8.84. Diethyl 3-(tert-butylamino)-1H-benzo[a]pyrano[2,3-c]phenazine-1,2-dicarboxylate (4d) Yellow powder (81%); mp 239-241 °C. IR (KBr) (νmax/cm-1): 3200, 1721, 1669. MS (EI, 70eV) m/z: 499 (M+). 1H NMR (300 MHz, DMSO-d6): δH 1.08 (3H, t, J = 6.9 Hz, CH3), 1.31 (3H, t, J = 6.4 Hz, CH3), 1.60 (9H, s, CH3), 3.97 (2H, m, OCH2), 4.25 ( 2H, ABq, J = 6.4 Hz, OCH2), 5.60 (1H, s, CH), 8.00-8.38 (7H, m, Ar-H), 9.14 (1H, s, NH), 9.34-9.37 (1H, m, Ar-H). Anal. Calcd for C29H29N3O5. C, 69.72; H, 5.85; N, 8.41. Found: C, 69.63; H, 3.92; N, 8.50. (Due to very low solubility of the product 4d, we cannot report the 13C NMR data for this product.) Dimethyl 3-(2,4,4-trimethylpentan-2-ylamino)-1H-benzo[a]pyrano[2,3-c]phenazine-1,2dicarboxylate (4e) Yellow powder (83%); mp 197-199 °C. IR (KBr) (νmax/cm-1): 3300, 1744, 1674. MS (EI, 70eV) m/z: 527 (M+). 1H NMR (300 MHz, DMSO-d6): δH 0.96 (9H, s, CH3), 1.62 (3H, s, CH3), (...truncated)