Efficient and selective synthesis of quinoline derivatives

Abstract

The bromination reaction of 1,2,3,4-tetrahydroquinoline (7) was investigated by NBS and molecular bromine. One-pot synthesis is described for synthetically valuable 4,6,8-tribromoquinoline (3) and 6,8-dibromo-1,2,3,4-tetrahydroquinoline (6) on bromination of 1,2,3,4-tetrahydroquinoline (7) in efficient yields (75 and 90%, respectively). 6-Bromo- (4) and 6,8-dibromo-1,2,3,4-tetrahydroquinolines (6) were converted to 6-bromo- (1) and 6,8-dibromo quinolines (2), respectively, by aromatization with DDQ in 83 anti 77% yields, respectively. Several novel trisubstituted quinoline derivatives were efficiently prepared via lithium-halogen exchange reactions of tribromide 3. Treatment of 4,6,8-tribromoquinoline with BuLi followed by quenching with electrophiles [Si(CH3)(3)Cl, S-2(CH3)(2), I-2] regioselectively proceeded at C-4 and C-8 sites and afforded corresponding 4,8-disubstituted-6-bromoquinolines. Similarly, lithiation oh tribromide 3 followed by addition of water to the intermediate produced 6-bromoquinoline in 65% yield. Copper induced nucleophile substitution of tribromide 3 with NaOMe afforded 4,6,8-trimethoxyquinoline (17) in 60% yield. (C) 2008 Elsevier Ltd. All rights reserved.