Hexamethylenetetramine → 6-Chloro-5-fluoropyridine-3-carbaldehyde

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Reaction Steps

A mixture of 5-(bromomethyl)-2-chloro-3-fluoropyridine (2.0 g, 8.91 mmol) and hexamethylenetetramine (2.75 g, 19.6 mmol) in 50% aqueous acetic acid (53 ml) was heated to reflux. After 1 hour, the mixture was cooled to room temperature, neutralized carefully with solid NaHCO3 (73.7 g), diluted with water (400 mL) and extracted with dichloromethane (2×100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, concentrated on a rotary evaporator and purified by silica gel column chromatography (hexane/ethyl acetate) to afford 6-chloro-5-fluoronicotinaldehyde as pale-yellow solid: 1H NMR (400 MHz, CDCl3) δ 10.12 (d, J=2.4 Hz, 1H), 8.72 (d, J=1.6 Hz, 1H), 7.94 (dd, J=2.0, 8.0 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −116.3.

Provenance & Evidence