3,5-Difluoroanisole → 5-Bromo-2-(2,6-difluoro-4-methoxyphenyl)pyrimidine

HRID 42006Notes

Reaction equation

[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[CH:3]=1.[Li]CCCC.[Br:16][C:17]1[CH:18]=[N:19][C:20](I)=[N:21][CH:22]=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>[Br:16][C:17]1[CH:18]=[N:19][C:20]([C:3]2[C:2]([F:1])=[CH:7][C:6]([O:8][CH3:9])=[CH:5][C:4]=2[F:10])=[N:21][CH:22]=1

Participants

Conditions

Temperature: -78 °C

Procedure

In a three neck round bottle flask, to a mixture of 1,3-difluoro-5-methoxybenzene (8.39 mmol, 0.98 ml) in THF (40 ml) at −78° C. under argon atmosphere, a solution of n-BuLi (9.13 mmol, 3.65 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 (9.13 mmol, 18.3 ml) in THF (0.5M) was added dropwise and the mixture was stirred at this temperature for 20 minutes. A solution of 5-bromo-2-iodopyrimidine (7.02 mmol, 2.0 g) in THF (5 ml) and Pd(PPh3)4 (0.70 mmol, 0.81 g) were added respectively and the crude mixture was heated at 40° C. overnight. The solvent was evaporated and the crude mixture was purified over SiO2 eluting with mixtures of hexane/ethyl acetate affording 0.89 g (39% of yield) 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 over SiO2 eluting with mixtures of hexane/ethyl acetate affording 0.89 g (39% of yield) of the expected product

Sources & evidence

ORD record: ord-4d16c8f35f0c41efab5adb9498d52603
Source dataset: uspto-grants-2013_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08536165B2

Reaction notes

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