Facile synthesis and antimicrobial activity of pyrazol-4-yl- and 2H-chromene-based substituted anilines via Michael addition followed by aromatization

Abstract

Herein, we report a facile one-pot synthetic method for a new class of pyrazol-4-yl- and 2H-chromene-based substituted anilines (arenes) from ethyl 2-cyanoacetate, pyrazole aldehydes, and various nitrostyrenes in the presence of the catalyst Et₃N (5 mol%) in ethanol under reflux conditions. This method requires a common organocatalyst, inexpensive starting materials, and short reaction times. A wide range of substrate scaffolds were tolerated well to afford the desired products in good to excellent yields (85–95%). Two compounds of pyrazolyl based anilines bearing the electron donating methoxy groups exhibited emissions in the redshift region and could have potential applications as fluorescence probes in biological imaging. Seven compounds of pyrazolyl based anilines bearing the electron donating methoxy and methyl groups demonstrated significant antibacterial and antifungal activity against the tested microbial strains and dermatophyte fungi, respectively.

Graphical Abstract

Keywords:

• Multicomponent reaction approach
• Knoevenagel condensation
• domino cyclization
• fluorescent property
• antimicrobial activity

Acknowledgements

JV acknowledges SERB, DST, New Delhi, India for their financial support and DST-FIST for the laboratory facilities. VB is grateful to UGC, New Delhi for the research fellowship [Ref: 22/12/2013 (ii) EU-V].

Disclosure statement

No potential conflict of interest was reported by the author(s).

Experimental section

Ethyl 3-amino-2-cyano-5-(1,3-diphenyl-1H-pyrazol-4-yl)-[1,1′-biphenyl]-4-carboxylate (4a) Ethyl 2-cyanoacetate 1 (99 mg, 1 mmol), pyrazole aldehyde 3 (249 mg, 1 mmol), and nitro styrene 2a (150 mg, 1 mmol) were dissolved in ethanol (6 mL). The reaction mixture was treated with the organic catalyst Et₃N (5 mol%) and refluxed at 70 °C for 1 h. After complete conversion of the starting materials (followed by thin layer chromatography), the reaction mixture was cooled to room temperature and diluted with EtOAc (50 mL) and water (30 mL). The organic layer was separated, washed with brine solution, dried over sodium sulfate, and evaporated under reduced pressure. The crude product was purified by column chromatography with EtOAc/n-hexane (3:1 v/v) as the eluent to afford 4a (438 mg) as a pale-yellow solid. mp 158–159 °C, 90% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.98 (s, 1H), 7.80 (s, 1H), 7.67–7.58 (m, 5H), 7.56–7.39 (m, 10H), 5.51 (s, 2H), 4.37 (q, J = 6.2 Hz, 2H), 1.41 (t, J = 6.0 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃+DMSO-d₆) δ 170.56, 154.74, 152.10, 147.43, 146.96, 144.16, 140.83, 137.75, 132.43, 131.88, 130.17, 129.88, 128.89, 127.42, 126.00, 124.63, 123.82, 123.57, 120.95, 118.85, 117.79, 115.50, 94.79, 61.12, 15.08; HRMS (ESI, m/z): Calcd. for C₃₁H₂₄N₄O₂ [M + H]⁺ 485.1972, found 485.1935; IR (KBr, cm⁻¹): ν_max 3461, 2980, 2250, 1730, 1665, 1590, 1511, 1344, 976, 748.