Cesium carbonate → Methyl 4-(4-chloro-2-fluorophenyl)-6-methylnicotinate

HRID 870975Notes

Reaction equation

Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([CH3:12])[CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([F:23])[CH:15]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C(OCC)(=O)C.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>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([CH3:12])[CH:3]=2)=[C:16]([F:23])[CH:15]=1

Participants

Conditions

Temperature: 80 °C

Procedure

A mixture of methyl 4-chloro-6-methylnicotinate (0.1 g, 0.539 mmol), (4-chloro-2-fluorophenyl) boronic acid (0.094 g, 0.539 mmol), Pd(PPh3)4 (0.031 g, 0.027 mmol) and Cs2CO3 (0.527 g, 1.616 mmol) in 1,4-dioxane (10 mL) was heated at 80° C. for 16 h. After cooling, the mixture was diluted with water (30 mL) and ethyl acetate (50 mL). The organic phase was collected, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20% EtOAc in pet. ether) to afford methyl 4-(4-chloro-2-fluorophenyl)-6-methylnicotinate (0.045 g, 0.161 mmol, 30% yield) as a yellow liquid. LCMS (ESI) m/e 280.0 [(M+H)+, calcd for C14H12ClFNO2 280.04]; LC/MS retention time (Method H): tR=2.51 min. 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.13-7.29 (m, 3H), 6.44 (s, 1H), 3.94 (s, 3H), 2.49 (s, 3H).

Workup

temperatureAfter cooling
customThe organic phase was collected
dry with materialdried over Na2SO4
concentrationconcentrated under reduced pressure
customThe residue was purified by silica gel chromatography (20% EtOAc in pet. ether)

Sources & evidence

ORD record: ord-d246b50e82674a51b31eb0932cd447d6
Source dataset: uspto-grants-2015_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08969564B2

Reaction notes

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