2-Chloroquinoline 3-metallation

In an application of the Suzuki process, 2-chloroquinoline (141) has been converted into the condensed heterocycle 197 (Scheme 58) (89JHC1589). Thus, metalation, trimethyl borate quench, and hydrolysis affords the stable 3-boronic acid 195 which, upon subjection to cross coupling with ortho-iodo aniline in the presence of Pd(0) catalyst and base, affords the 3-arylquinoline 196. Acid catalysis converts this material into the in-dolo[2,3-f ]quinoline (197) in 35% overall yield. 

Although metalation of 5- and 8-ethoxyquinolines led, under a variety of temperatures, mainly to addition products, the 2-n-butyl derivatives 339 and 342, bearing DMGs in the benzene ring, respectively provided ring-(340) and ethoxy- (343) metalation directed results (Scheme 104) (83TH1). Application of the equilibrium shift procedure (combined LDA/TMSCl/ 0°C) on 8-ethoxy-5-chloroquinoline gave a low yield (6%) of product 341. 

Phospholide anions can undergo coupling reactions with sp -C-centers bearing halogens in the presence of metals. This method has been exploited with the 3,4-dimethylphospholide anion, which can be converted into l-(8-quinolyl)-phosphole 223 (52% yield) upon reaction with 8-chloroquinoline at 80 C in presence of Cul (Scheme 71) <1997JOM17>. In the presence of Ni in THF at reflux, the same P-anion reacts with 1,2-dibromobenzene to give the phosphole derivative 224 in 55% yield (Scheme 71) <19980M2996>. 

Metal-halogen exchange of 123 produced organozinc 124 [43]. This compound was then coupled with a chloroquinoline to afford 125, a key intermediate in the synthesis of camptothecin 126 vide infra). 

Yamamoto and Yanagi [24] have prepared iodoazines through iodo-destannation of trimethylstannylazines. Trimethylstannyl sodium was prepared in situ from chlorotrimethyl-stannane and metallic sodium. Subsequent treatment of 2-chloroquinoline 25 with trimethylstannyl sodium gave 2-trimethylstannylquinoline 41. Likewise, 3- and 4-trimethyl-stannyl quinolines 42 and 44 were converted to 3- and 4-iodoquinolines 43 and 45 in 96 and 91% yield, respectively via iodo-destannation. In the same fashion, 2,4-bis (trimethylstannyl)quinoline was synthesized from 4-bromo-2-chloroquinoline using two equivalents of trimethylstannyl sodium in 65% yield. 

Metal containing chloroquinolines Beyond hit and miss antimalarial efficacy to sohd science 13MRM597. 

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