Application of a Regioselective Mannich Reaction on Naringenin and its Use in Fluorescent Labeling

Abstract

A novel strategy for site-specific fluorescent labeling on naringenin (1) was established by a new direct Mannich reaction in combination with a Huisgen [3+2]-cycloaddition reaction. High ­regioselectivity was observed for direct Mannich reactions on ­naringenin and several other flavonones using a variety of amines and aldehydes.

Key words

naringenin - Mannich reaction - Huisgen cycloaddition - regioselectivity - fluorescent labeling

References and Notes

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• 19 Data for 10: IR (KBr): 2937, 1759, 1637, 1616, 1505, 1459, 1364, 1250, 1174, 1110, 1085, 834 cm^-1. ¹H NMR (DMSO-d ₆, 300 MHz): δ = 8.24 (1 H, s), 8.00 (1 H, d, J = 7.5 Hz), 7.79-7.69 (2 H, m), 7.32 (1 H, s), 7.28 (2 H, d, J = 8.4 Hz), 7.09 (1 H, d, J = 2.7 Hz), 6.81-6.74 (4 H, m), 6.65 (1 H, d, J = 9.3 Hz), 6.59 (2 H, d, J = 1.2 Hz), 5.66 (1 H, s), 5.35 (1 H, dd, J = 12.6, 2.4 Hz), 5.22 (2 H, s), 4.36 (2 H, t, J = 6.6 Hz), 3.83 (2 H, s), 3.15 (1 H, dd, J = 17.1, 12.6 Hz), 2.69 (2 H, t, J = 7.2 Hz), 2.61 (1 H, dd, J = 17.1, 2.4 Hz), 2.40 (3 H, s), 1.82 (2 H, t, J = 6.6 Hz), 1.56 (2 H, br m), 1.27 (4 H, br m). ¹³C NMR (CDCl₃, 75 MHz): δ = 194.8, 173.4, 169.1, 162.6, 161.7, 160.2, 158.1, 152.8, 152.3, 142.6, 136.1, 130.6, 129.7, 129.5, 129.4, 128.7, 126.6, 125.1, 125.0, 124,5, 115.6, 113.4, 112.9, 111.9, 109.8, 102.7, 102.2, 100.0, 99.8, 96.6, 83.4, 78.5, 62.1, 55.7, 52.1, 49.8, 42.3, 40.4, 29.9, 26.1, 25.9, 25.3. HRMS: m/z calcd for C₄₆H₄₃N₄O₁₀ (M + H⁺): 811.2974; found: 811.2993
• 20 General Procedure: To a solution of naringenin (1 mmol) and paraformaldehyde or acetaldehyde (1.5 mmol) in EtOH (4 mL) was added the secondary amine (1.5 mmol) at r.t. The mixture was then heated to 40-65 °C, depending on the secondary amine (see Table 1), and the reaction was monitored by TLC. After the reactants were consumed, EtOAc (30 mL) and diluted HCl (30 mL, pH 3) were added to the mixture. Then the pH of the aqueous phase was adjusted to 7. The aqueous phase was extracted with EtOAc (3 × 15 mL). The combined extracts were dried over anhyd Na₂SO₄. The crude product was purified by silica gel chromatography