Microwave induced synthesis of a new class of pyrano isoxazoline and isoxazole annulated chromones-an intramolecular nitrile oxide cycloaddition with tethered olefins and alkynes

A variety of new highly substituted 6-6-6-5-membered tetracyclic pyrano isoxazoline/isoxazole annulated chromone derivatives have been synthesized via eco-friendly microwave assisted/ceric ammonium nitrate (CAN) as an oxidant, intramolecular 1,3-dipolar cycloaddition with in situ generated nitrile oxides from aldoximes of alkene/alkyne tethered chromones. This protocol is practically simple and efficient to construct diverse range of substituted pyrano isoxazoline/isoxazole annulated chromone derivatives and gave higher yields of products in microwave irradiation compared to conventional heating. The structures of all the synthesized compounds were established by IR, NMR and MASS spectral analysis.


Results and Discussion
7-hydroxy-8-formyl-2,3-dimethylchromones 1a-b were synthesized using our earlier reported procedure. 31 The key intermediates, alkene appended chromone-8-aldoxime derivatives 2a-h were prepared in one pot by treating the bifunctional hydroxy aldehydes 1a-b with substituted allyl bromides, hydroxylamine hydrochloride, in the presence of sodium acetate in DMF at 70 o C. The allylation and hydroxylamine hydrochloride condensation with aldehyde at one time in a single step smoothly proceeded to furnish products 2a-h in good yields. By the routine method these are prepared in two separate steps, initially allylation at phenolic function followed by condensation of hydroxylamine hydrochloride with aldehyde. A number of oxidants and Lewis catalysts were evaluated using suitable solvents for the in situ generation of nitrile oxide from the aldoxime intermediate 2a (Table-1) followed by dipolar cycloaddition at alkene to afford pyrano isoxazoline annulated chromones 3a. Among the oxidants and catalysts employed, we found to furnish CAN (0.002 mol) mediated intramolecular nitrile oxide addition product 3a in a little higher yield (60%) compared to all other variants. Under these optimized conditions the derivatives 3b-h were prepared from their corresponding substrates (Scheme-1). With a view to increase the yields of products 3a-h and to reduce reaction time compare to conventional method, we have performed intramolecular cycloaddition using CAN (0.002 mol) as an oxidizing agent under microwave irradiation by taking substrate 2a as model compound and screened with various solvents. Interestingly in the microwave medium, afforded product 3a in higher yields (90%) in short reaction time in acetonitrile solvent compared to conventional heating (Table-2). The increase in temperature and higher oxidant loading did not improve the yield of product 3a. The reaction furnished very low yields of the product 3a under the oxidant free conditions. The formation of low yields of products probably due to aireal oxidation. After the optimization of microwave assisted reaction conditions, several pyrano isoxazoline chromone derivatives 3a-h prepared in higher yields in short time compare to conventional method. (Table 3  Encouraged by these results, we next planned for the synthesis of diverse bicyclic pyrano isoxazole annulated chromones having high substitution. Similar to the preparation of compounds 2a-h as discussed above, 7propargyloxychromone-8-aldoximes 4a-f were prepared in one pot by coupling 7-hydroxy-8-formylchromone with propargyl bromide and hydroxyl amine hydrochloride in alkaline sodium acetate in DMF. The intermediates 4a-f were subjected to in situ generated nitrile oxide 1,3-dipolar cycloaddition at alkyne under conventional as well as microwave conditions using optimized CAN (0.002 mol) as oxidant in acetonitrile solvent to afford pyrano isoxazole fused chromone derivatives. The microwave irradiation furnished the products 5a-f in good yields (84-91%) compare to conventional method (Scheme-2). The reaction conditions and yields of products summarized in Table-
We obtained higher yields of products 3a-h and 5a-f in eco-friendly microwave irradiation compared to conventional heating. We believe that these newly developed chromone based isoxazoline/isoxazole scaffolds will find diverse applications in chemical biology and medicinal chemistry.

Experimental Section
General. Silica gel (60-120 mesh) for column chromatography was purchased from M/s Acme Synthetic Chemicals (Mumbai, India) and pre-coated TLC plates (Silica gel 60F254) were purchased from Merck (Darmstadt, Germany). All the chemicals, reagents and solvents were purchased from M/s SD Fine Chemicals (Mumbai, India) with highest grade of purity. Microwave reactions were performed in a Multi synth series microwave system (Milestone). The 1 H NMR and 13 C NMR spectra were recorded on a Bruker spectrometer at 400 and 100 MHz and TMS used as an internal standard. Chemical shifts relative to TMS as internal standards were given as δ values in ppm. Mass spectra were recorded using electron spray ionization on Waters e2695 Separators module (Waters, Milford, MA, USA) mass spectrometer. IR spectra were recorded on a Fourier transform (FT-IR), USA (Perkin-Elmer model 337) instrument. The melting points were determined on a Barnstead Electro Thermal 9200 Instrument.

General procedure for the synthesis of 2,3-dimethyl-7-O-allylated-8-aldoxime chromones (2a-h)
To the stirred solution of compounds 1a-b (1.0 mmol) and potassium carbonate (0.2 mmol) in DMF (10 mL) allyl bromides (1.2 mmol) were added and the reaction mixture was stirred at 70 o C for 2 h, then reaction mixture was cooled to rt and added sodium acetate (3.63 mmol), Hydroxylamine hydrochloride (1.0 mmol) to the mixture and stirred for 1 h. After completion of reaction pale yellow colour solids appeared which were poured in water (20 mL) the solid precipitate was collected by filtration, washed with water and dried at 50 o C to afford 2a-h as white solids with good yields (70-90%).   General procedure for the synthesis 9,10-dimethyl-7-O-propargylated-8-aldoxime chromones (4a-f) Propargyl bromides (1.2 mmol) were added to the stirred solution of compound 1a-b (1.0 mmol) and potassium carbonate (0.2 mmol) in DMF (10 mL) and the reaction mixture was stirred at 70 o C for 2 h, after completion of the reaction indicated by TLC, the reaction mixture was cooled to RT then Sodium acetate (1.0 mmol) and Hydroxylamine hydrochloride (1.0 mmol) was added to the reaction mixture and stirred for 1 h. After completion of reaction pale yellow colour solid was appeared which was poured in water (20 mL), the solid precipitate was collected by filtration, washed with water and dried at 50 o C to afford 4a-f as white solids with good yields (75-91%). To the stirred solution of compound 4a-f (1 mmol) in acetonitrile (10 mL) was added ceric ammonium nitrate (CAN) (2 mmol) at 0 o C then the reaction mixture was stirred for 6 h at 40 o C. The reaction progress was monitored by TLC, after completion of the reaction; 20 mL of water was added to reaction mixture to get solid precipitate it was collected by filtration, washed with water and dried at 50 °C to afford final product 5a-f as white solid with good yields.

Microwave.
To the stirred solution of compounds 4a-f (1.0 mmol) in acetonitrile (10 mL) was added ceric ammonium nitrate (CAN) (2 mmol) at 0 o C then the reaction mixture was placed in a quartz tube inserted into a screw capped Teflon vial and subjected to microwave irradiation (200 W) for 15 min the progress of reaction