An expeditious synthesis of novel pyranopyridine derivatives involving chromenes under controlled microwave irradiation

An efficient synthesis of novel pyrano[2,3-b ]pyridine derivatives has been achieved by the cyclocondensation of 2-amino-3-cyano-4 H -chromenes and cyclohexanone in the presence of aluminium chloride under controlled microwave irradiation. The experimental conditions have been thoroughly optimized and established, allowing significant rate enhancements and excellent yields. The starting 4 H -chromenes were obtained using one pot DBU-catalysed microwave induced multicomponent condensation of resorcinol, malononitrile and aromatic aldehydes.


Introduction
Pyranopyridines constitute an important class of heterocyclic compounds having diverse biological activities such as anti-allergic, anti-inflammatory, and estrogenic. 1,2Among the different substitution patterns that are known, benzopyrano [2,3-b]pyridines exhibit antiproliferative, 3 cancer chemopreventive, 4 anti-bacterial (including anti-tubercular), 5 antimyopic, 6 anti-histamic, 7 hypotensive, 8 anti-rheumatic, 9 and antiasthmatic activities. 10][24][25][26][27] Pyranopyridines have become the object of current synthetic developments and many strategies for their synthesis have been adopted. 28The most simple and straightforward approach for the synthesis of polysubstituted pyridines and related azaheterocycles happens to be the Friedländer annulation.Among various Friedländer syntheses, cyclocondensation of o-aminobenzonitrile with various ketones has been less explored.Previous investigations 29,30 on condensation of these derivatives required prolonged reaction times, use of hazardous reagents and low yields.In view of the above, the development of an efficient and convenient protocol for the synthesis of pyranopyridines is of considerable interest.Multicomponent reactions (MCRs) have recently emerged as valuable tool in the preparation of structurally diverse chemical libraries of drug-like heterocyclic compounds. 31There is great current interest in microwave assisted organic synthesis (MAOS), 32 because such environmentally benign chemical methodologies are strongly required in light of the paradigm shift to "Green Chemistry".According to the current synthetic requirements, environmentally benign multi-component procedures employing microwave (MW) methodology are particularly welcome due to their intrinsic advantages. 33n view of the above, a facile, fast and high yielding synthesis of novel 11-amino-12-aryl-7,9,10,12-tetrahydro-8H-5-oxa-6-aza-naphthacen-3-ols 6a-h has been achieved by the cyclocondensation of 2-amino-3-cyano-7-hydroxy-4-aryl-4H-chromenes 4a-h with cyclohexanone in the presence of AlCl3 under controlled MW irradiation.The substrates 2amino-3-cyano-4H-chromenes 4a-l have been accomplished by the multicomponent reaction of resorcinol, malononitrile, and aromatic aldehydes using controlled MW irradiation in the presence of catalytic amount of DBU (5 mol%) in ethanol at an ambient temperature 50ºC.(Scheme 1).

Scheme 1
Various substituted chromenes 4 were made to react with cyclohexanone using a molar ratio of 1:1.3 with AlCl3 (1.2 equivalent) in dry CH2Cl2 using safe pressure regulation 10-mL pressurized vials with "snap-on" cap under microwave (150W, 45 ºC) heating for 6-8 minutes.The results are given in Table 4.The progress of the reaction was monitored by TLC.After completion of reaction, the mixture was poured into a beaker containing ice cold water and was extracted with CH2Cl2 (3  15 mL).The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.The crude product was purified through column chromatography (40% ethyl acetate in hexane) to afford pure product 6 in good yield.It is important to mention that under the investigated set of reaction conditions, pyranopyridines 6 are exclusively obtained as the only isolable product with no measurable side product.In conclusion, the present report demonstrates a facile DBU-catalysed multicomponent condensation of resorcinol, malononitrile and aromatic aldehydes to afford 2-amino-4H-3-cyanochromenes, which are subsequently made to react with cyclohexanone to furnish novel pyranopyridine derivatives in the presence of aluminium chloride.The advantages include improved yield, easier work-up, shorter reaction time and mild reaction conditions.

Experimental Section
General.IR spectra were recorded on a JASCO FT/IR-5300 spectrophotometer, whereas NMR was run on a JEOL AL300 FTNMR spectrometer.The chemical shifts are given in  ppm with respect to TMS as internal standard.Elemental analysis (C, H, N) for final compounds were performed on a model CE-440 CHN analyzer.The tlc spots were detected using iodine chamber.Microwave irradiation was made using a CEM Discover single mode microwave reactor (Benchmate Model, USA) with infrared temperature probe and adjustable 0-300 W output power.All commercially available chemicals were purchased from Aldrich and Merck.

Table 1 .
Optimization of reaction conditions for the multi-component synthesis of 4a a Isolated mass yield based on resorcinol

Table 3 .
Optimization of the reaction conditions using compound 4a as reference bReaction was carried out in ethanol c Reaction was carried out in methanol d Reaction was carried out in acetonitrile