Synthesis of fully functionalised spiropyran pyrazolone skeletons via a formal [4 + 2] cascade process using β-nitro-styrene-derived MBH-alcohols

An efficient protocol was established to construct spiro pyrazolone tetrahydropyran scaffolds at ambient temperature under metal-free conditions. The reaction proceeded via formal [4 + 2] cyclisation of trans-β-nitro-styrene-derived Morita–Baylis–Hillman (MBH) alcohol with α-arylidene pyrazolone. The reaction followed an oxa-Michael/Michael cascade pathway, resulting in the formation of new C–C and C–O bonds. Organocatalytic synthesis of spiropyrazolones using quinine-derived catalyst resulted in 94% enantiomeric excess (ee) and excellent (>20 : 1) diastereoselectivity.

General procedure for the synthesis of spiropyrazolone teterhydropyran using secondary alcohol 5: To a solution of arylidene pyrazolone 1 (100 mg, 0.38 mmol, 1.0 equiv.) was added nitro allylic secondary alcohol 4 (143 mg, 0.57 mmol, 1.5 equiv.) and Cs2CO3 (310 mg, 0.95 mmol, 2.5 equiv.) in CHCl3 (2 mL). The reaction mixture was stirred at room temperature till the completion reaction. After the completion of the reaction, the organic layer was extracted with ethyl acetate, washed with brine solution and dried over Na2SO4, and concentrated under reduced pressure. The resulted crude was subjected to flash column chromatography on silica gel (200-400) by eluting ethyl acetate in hexane (4:96) to afford the desired products 5.
General procedure for the synthesis of chiral tetrahydrochromene 3a using thiourea catalyst: To a solution of arylidene pyrazolone 1 (50 mg, 0.190 mmol, 1.0 equiv.) was added nitro allylic primary alcohol 2 (51 mg, 0.286 mmol, 1.5 equiv.) and 10 mol% of quinine derived thiourea catalyst in CH3CN (1.5 mL). The reaction mixture was stirred at room temperature till the completion reaction. After the completion of the reaction, the organic layer was extracted with ethyl acetate, washed with brine solution and dried over Na2SO4, and concentrated under reduced pressure. The resulted crude was subjected to flash column chromatography on silica gel (200-400) by eluting ethyl acetate in hexane (4:96) to afford the desired products 3a. We have performed HPLC chromatogram by using chiral cel OD-H column to furnished 3a as 94% of enantiomeric excess using IPA:Hex (20:80).
General procedure for the synthesis of nitro styrene derived MBH-primary alcohol 1 : To a stirred solution of nitrostyrene in dry THF as a solvent, imidazole and anthranilic acid was added to the rection mixture at room temperature. The reaction was allowed to stir at room temperature for 15 min. Then add drop wise addition of formalehyde to the reaction mixture was allowed to stir at rt for 12h. After the completion of the reaction, the organic layer was extracted with ethyl acetate, washed with brine solution and dried over Na2SO4, and concentrated under reduced pressure. The formation of crude was seapearared by column chromatography by the combination of (6:94%) ethyl acetate and hexane.
General procedure for the synthesis of nitro styrene derived MBH-secondary alcohol 2 : To a stirred solution of Nitrostyrene in dry THF as a solvent, imidazole and DMAP was added to the rection mixture at room temperature. The reaction was allowed to stir at room temperature for 15min. Then add drop wise addition of ethlglyoxylate to the reaction mixture was allowed to stir at rt for 4h. After the completion of the reaction, the organic layer was extracted with ethyl acetate, washed with brine solution and dried over Na2SO4, and concentrated under reduced pressure. The formation of crude was seapearared by column chromatography by the combination of (7:93%) ethyl acetate and hexane.
General procedure for the synthesis of unsaturated arylidene pyrazolone 3 : To a stirred solution of pyrazolone in acetic acid as a solvent, sodium acetate and benzaldehyde was added to the rection mixture at room temperature. The reaction was allowed to stir at room temperature for 3 h. After the completion of the reaction, the organic layer was extracted with ethyl acetate, washed with brine solution and dried over Na2SO4, and concentrated under reduced pressure. The formation of crude was seapearared by column chromatography by the combination of (4:96%) ethyl acetate and hexane.