Highly Efficient Chemoselective Synthesis of Pyrrolo[2,3-c]pyrazole Bearing Oxindole via Sequential Condensation–Michael Addition–Intramolecular Cyclization Reactions

Abstract

An efficient and highly chemoselective approach for the synthesis of novel scaffolds based on pyrrolo[2,3-c]pyrazole bearing oxindole is accomplished by the acid-promoted sequential reactions between benzoylacetonitriles, phenylhydrazine, and 3-phenacylideneoxindoles as readily available starting materials. This value structure is dexterously embraced with oxindole, pyrrole, and pyrazole heterocycles, which are famous for their enriched biological properties. Besides, this is an eco-friendly and atom-economy approach, and water is the only side product of the reaction. In this protocol, the requirement of column chromatography is completely avoided, and the products were isolated by recrystallization in crude reactions. These compounds due to their excellent fluorescence features and bioactive scaffolds may be attracted great interest in biomedical applications and clinical diagnostics in the future.

Key words

oxindole - pyrazole - pyrrole - multicomponent reactions - chemoselective

• References and Notes

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• 13 3-{1,3,5-Triphenyl-1,6-dihydropyrrolo[2,3-c]pyrazol-4-yl}indolin-2-one (5a); Typical Procedure Benzoylacetonitrile (1a, 0.25 mmol) and phenylhydrazine (2a, 0.25 mmol) were mixed in neat conditions and heated at 120 °C for 2.0 h. After completion of the reaction, the reaction mixture was cooled to room temperature. Then, 3-(2-aryl-2-oxoethylidene)indolin-2-one (4a, 0.25 mmol) PTSA·H₂O (0.05 mmol) and EtOH (2.5 mL) were added to the reaction mixture. Afterwards, the mixture was stirred for 6 h under reflux conditions. Upon the completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature. The precipitate was collected by filtration and washed with cold ethanol to give the pure product 5a (93 mg, yield 80%).
• 14 3-{1,3,5-Triphenyl-1,6-dihydropyrrolo[2,3-c]pyrazol-4-yl}indolin-2-one (5a) White powder (92 mg, 80%); mp 214–216 °C. Anal. Calcd (%) for C₃₁H₂₂N₄O: C, 79.81; H, 4.75. Found: C, 79.73; H, 4.70. IR (ATR): ν_max = 3146 (NH), 1708 (CO), 1467 (C=C) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ (mixture of tautomers) = 4.91 (s, 0.85 H, H₃), 5.16 (s, 0.15 H, H₃), 6.71 (s, 1 H, H_Ar), 6.88–6.96 (m, 2 H, H_Ar), 7.08–7.28 (m, 10 H, H_Ar), 7.39–7.52 (m, 5 H, H_Ar), 7.69–7.76 (m, 5 H, H_Ar), 8.10–8.23 (br s, 1 H, NH), 8.49 (br s, 1 H, NH). ¹³C NMR (125 MHz, CDCl₃): δ (mixture of tautomers) = 179.8 (CO), 146.1, 141.6, 141.6, 141.2, 139.3, 133.4, 132.2, 130.2, 129.7, 129.2, 128.7, 128.4, 128.3, 128.2, 127.8, 127.6, 125.5, 124.5, 122.6, 118.6, 115.4, 110.0 (C_Ar), 44.9 (C₃). MS (EI, 70 eV): m/z = 466 (100) [M⁺], 437 (25), 334 (47), 231 (23), 104 (29), 77 (91).