Sodium Carbonate → 5-(Bromomethyl)-2-(difluoromethoxy)-3-(3-(oxetan-3-yloxy)phenyl)pyridine

HRID 578825Notes

Reaction equation

[F:1][CH:2]([F:18])[O:3][C:4]1[C:9]([C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)=[CH:8][C:7]([CH3:17])=[CH:6][N:5]=1.[Br:19]C1C(OC(F)F)=NC=C(CBr)C=1.[OH:32][C:33]1C=C(B(O)O)C=[CH:37][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[Br:19][CH2:17][C:7]1[CH:8]=[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH:38]3[CH2:33][O:32][CH2:37]3)[CH:11]=2)[C:4]([O:3][CH:2]([F:1])[F:18])=[N:5][CH:6]=1

Participants

Conditions

Temperature: 100 °C

Procedure

3-(2-(Difluoromethoxy)-5-methylpyridin-3-yl)phenol. A 20 mL microwave vial was charged with 3-bromo-2-(difluoromethoxy)-5-methylpyridine (intermediate 4, 1.90 g, 7.98 mmol), 3-hydroxyphenylboronic acid (1.32 g, 9.58 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (330 mg, 0.40 mmol), sodium carbonate (2.12 g, 19.96 mmol), water (4.0 mL), and ACN (12 mL). The vial was sealed, purged with nitrogen, and heated under microwave irradiation at 100° C. for 15 min. The reaction mixture was diluted with water and extracted with DCM (3×). The combined organic phase was dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification (FCC, SiO2, 0-40% EtOAc/hexanes) afforded the title compound (1.81 g, 91%) as a colorless waxy solid. [M+H]=252.12.

Workup

customThe vial was sealed
custompurged with nitrogen
additionThe reaction mixture was diluted with water
extractionextracted with DCM (3×)
dry with materialThe combined organic phase was dried (Na2SO4)
filtrationfiltered
concentrationconcentrated under reduced pressure
customPurification (FCC, SiO2, 0-40% EtOAc/hexanes)

Sources & evidence

ORD record: ord-3f0f4f4bcfb148058c43b0e669d8608f
Source dataset: uspto-grants-2015_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09040692B2

Reaction notes

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