General procedure for the synthesis of 5-fluoroquinoline from 5-aminoquinoline:
1. Preparation of 5-fluoro-1,2,3,4-tetrahydroquinoline: 5-aminoquinoline (50 g, 347 mmol) was suspended in 48% HBF4 (200 mL) at 0 °C. Sodium nitrite was added in batches and the reaction was stirred for 1 hour. The reaction mixture was poured into a 1:1 solvent mixture of ethyl acetate/ether (500 mL) and the resulting suspension was filtered and the solid was collected and dried.
2. The above dried solid (82.5 g, 338 mmol) was added to refluxed xylene (1 L) in batches, and the reaction was stirred for 2 hours and then cooled. The xylene was gently poured out and the residue was dissolved in 1N hydrochloric acid (600mL). After neutralization with sodium carbonate, the mixture was extracted with ethyl acetate (3 x 500 mL). The organic phases were combined, dried with sodium sulfate, filtered and the solvent was removed under reduced pressure.
3. The residue was purified by silica gel column chromatography using a 10-20% diethyl ether solution in hexane as eluent. The grades containing the target product were collected and concentrated under reduced pressure to give 5-fluoroquinoline 28.1 g (55% yield). MS (EI, m/z) C9H6FN (M+1) 148.0.
4. Reduction reaction: A methanolic solution of 5-fluoroquinoline (28.1 g) and 5% palladium carbon (5.6 g) was subjected to a hydrogen atmosphere (60 psi) and the reaction was shaken at 40 °C overnight. After completion of the reaction, the mixture was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure.
5. The residue was purified by silica gel column chromatography using a hexane solution of 5-10% ethyl acetate as eluent. The grades containing the target product were collected and concentrated under reduced pressure to give 5-fluoro-1,2,3,4-tetrahydroquinoline 22.5 g (78% yield). MS (EI, m/z) C9H10FN (M+1) 152.0.
