Aza-Michael Addition of 2-Aminopyridine with 7-Aza-2-Indolone Chalconides: Synthesis of Functionalized α-Enaminones and One-Pot N-Alkenylation–Dearomatization of Pyridine Ring

Abstract

A facile, efficient, and catalyst-free synthetic route for the synthesis of α-enaminones, a motif found in synthetically and biologically active compounds has been developed by the reaction of 2-aminopyridine with 7-aza-2-indolone chalcone derivatives adopting aza-Michael addition as a key reaction. To demonstrate the substrate scope, an array of α-enaminones was synthesized from a number of N-alkylated-3-acylidene-7-aza-2-indolones and aromatic 2-amino azaheterocycles and carbocycles in excellent yields. The structure and relative stereochemistry of representative compounds were established by the single-crystal XRD. Based on control experiments, a plausible and alternate operating mechanism for the formation of the products is also provided. Significantly, the synthetic transformation of the aza-Michael products thus obtained was successfully demonstrated by an unusual heterocyclic functionalization via N-alkenylation and dearomatization of the pyridine ring has also been provided.

Keywords

3-Alkylidene-7-aza-2-indolones - 2-Aminopyridine - α-Enaminones - Aza-Michael addition - Dearomatization

Publication History

Received: 18 September 2025

Accepted after revision: 19 November 2025

Accepted Manuscript online:
20 November 2025

Article published online:
22 December 2025

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• 25 General procedure for the synthesis of compound 9. A 50 mL RB flask was charged with 100 mg of 5k (1.0 equiv) and 5 mL of ethanol and kept for stirring at RT. Once the compound was completely dissolved, potassium carbonate (2.0 equiv) was added. Followed by the addition of allyl bromide 8a/4-bromo-1-butene 8b/5-bromo-1-butene 8c (2.0 equiv). The reaction was monitored by TLC and found to be completed within 1.5–2 h. Then 50 mL of water were added to the reaction mixture, followed by ethyl acetate. The combined organic layer was evaporated and purified through silica gel column chromatography. The products 9a–c were isolated with 30–50% ethyl acetate in hexane as eluent.
• 26 Spectroscopic data for (E)-3-(1-(((E)-1-allylpyridin-2(1H)-ylidene) amino)-2-oxo-2-phenylethylidene)-5-bromo-1-methyl-1,3-dihydro-2H-pyrrolo[2,3-b] pyridin-2-one 9a: Nature: Red solid; Yield: 90%; R_f (30% EtOAc-Hexane): 0.20; FTIR (KBr) ν_max: 2919, 2842, 1652, 1576, 1423, 1308, 1227, 1093, 964, 859, 754, 673, 568 cm⁻¹¹H NMR (400 MHz, CDCl₃): δ 8.01 (dd, J = 11.7, 2.2 Hz, 2H), 7.97–7.92 (m, 1H), 7.45 (t, J = 7.4 Hz, 1H), 7.39–7.27 (m, 4H), 6.94 (d, J = 9.0 Hz, 1H), 6.39 (td, J = 6.8, 1.1 Hz, 1H), 5.97–5.88 (m, 1H), 5.30 (d, J = 10.4 Hz, 1H), 5.04–5.00 (m, 1H), 4.83 (d, J = 5.1 Hz, 1H), 3.16 (s, 1H) ppm;¹³C NMR (101 MHz, CDCl₃)): δ 193.9, 167.7, 157.9, 154.8, 152.5, 143.3, 140.1, 138.0, 135.2, 133.8, 131.6, 129.9, 129.5, 128.8, 120.7, 119.8, 119.4, 112.7, 111.2, 54.5, 24.9 ppm; DEPT-135 (101 MHz, CDCl₃): δ 143.4, 140.1, 138.0, 133.8, 131.6, 129.9, 129.5, 128.8, 119.8, 119.4, 111.1, 54.5, 24.9 ppm; HRMS (ESI): calcd for C₂₄H₁₉BrN₄O₂ (M+H) m/z: 475.0770; found: 475.0771.