A Regioselective S_NAr Reaction of Poly-halo-quinoline-3-carboxylates with Phenol, Thiophenol, or N-Methylaniline

Abstract

By S_NAr reaction, poly-halo-quinoline-3-carboxylates such as ethyl 4-chloro-2-cyclopropyl-6,7-difluoro-quinoline-3-carboxylate and ethyl 4-chloro-2-cyclopropyl-5,6-difluoro-quinoline-3-carboxylate were transformed into the 4-phenoxy or 4-phenylthio or 4-(N-methyl)phenylamino-6,7 (or 5,6)-difluoro-quinoline-3-carboxylates or the 4,7-disubstituted, 4,5-disubstituted, 4,6,7-trisubstituted and 4,5,6-trisubstituted products under mild conditions in moderate to excellent yields. Highly regioselective mono- or multi-substitution was observed.

Keywords:

• N-Methylaniline
• phenol
• poly-halo-quinoline-3-carboxylates
• S_NAr reaction
• synthesis
• thiophenol

ACKNOWLEDGMENT

This work was supported by “New Drug Innovation 2009 × 9301–007” by Ministry of Science and Technology of China.

Notes

*The products 9a–10b were recrystallized from n-hexane; 10c–11e were isolated by flash chromatography.

*The products 12a–c were recrystallized from n-hexane; 13a–14b were isolated by flash chromatography.