Synthesis of Benzopyranophenazines via Isocyanide-Based Three-Component Reactions

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.


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. 1,2In 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][7][8][9][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. 11Several hundreds of the known phenazines possess biological activities, including antimalarial, 12 trypanocidal, 13 fungicidal, 14 and antiplatelet 15 effects, and are either isolated from natural sources or synthetically constructed.Also, the antitumor activity of pyridophenazinediones and pyridazinophenazinedione derivatives was reported. 16,17Due to 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. 11,18- 20A 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. 21To the best of our knowledge, there is only two reports on synthesis of benzopyranophenazines via a multicomponent reaction. 22ue 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. 1 H, 13 C 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.

Scheme 1
The good yield and purity of products and simplicity of the present procedure makes it an interesting, convenient and acceptable one-pot method for the preparation of 1Hbenzo[a]pyrano [2,3-c] Although the mechanism of the reaction has not yet been established experimentally, a possible explanation is proposed in Scheme 2. The 1:1 zwitterionic ionic intermediate 5, formed from the isocyanide 2 and the acetylenic ester 3, is protonated by 1 to furnish intermediate 6, which is attacked by the anion of the CH-acidic 7 in a Michael fashion to produce ketenimine 8.The latter then can undergo cyclization under the reaction conditions to afford the benzopyranophenazine 4. [5][6][7][8][9][10] Scheme 2 Compounds 4 are stable solids whose structures were established by IR, 1 H and 13 C NMR spectroscopy, and elemental analysis.

Conclusion
In conclusion, we have described an efficient three-component method for the synthesis of benzo[a]pyrano[2,3-c]phenazines under neutral conditions without any activation or modifications.The products are of potential synthetic and pharmacological interest.Prominent among the advantages of this new method are operational simplicity, good yields and easy work-up procedures employed.
phenazine-1,2-dicarboxylates.The workup of these very clean reactions involves only a filtration and simple washing step with ethanol.
a Isolated yields.