1,3-Difluorobenzene → 6-(2,6-Difluorophenyl)pyridin-3-amine

HRID 42033

Reaction equation

[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Li]CCCC.Br[C:15]1[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1>C1COCC1.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:15]1[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1

Participants

Conditions

Temperature: -78 °C

Procedure

In a three neck round bottle flask, to a mixture of 1,3-difluorobenzene (23.24 mmol, 2.29 ml) in THF (30 ml) at −78° C. under argon atmosphere, a solution of n-BuLi (10.2 ml) in THF (2.5M) was added. The mixture was stirred at −78° C. for 30 minutes and then it was heated to −50° C. A solution of ZnCl2 (51 ml) in THF (0.5M) was added drop wise and the mixture was stirred at this temperature for 20 minutes. A solution of 6-bromopyridin-3-amine (11.56 mmol, 2.0 g) in THF (20 ml) and Pd(PPh3)4 (1.16 mmol, 1.3 g) were added respectively and the crude mixture was heated at 40° C. overnight. The solvent was evaporated and the crude mixture was purified by reverse phase chromatography eluting with a water-MeOH/AcN system affording 0.72 g (yield 30%) of the expected product.

Workup

temperatureit was heated to −50° C
stirringthe mixture was stirred at this temperature for 20 minutes
customThe solvent was evaporated
customthe crude mixture was purified by reverse phase chromatography
washeluting with a water-MeOH/AcN system

Sources & evidence

ORD record: ord-887e871e69e540029f5e78fea7682c0c
Source dataset: uspto-grants-2013_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08536165B2

Linked notes

Loading…