Cesium carbonate → Methyl 4-chloro-6-methylpyridine-3-carboxylate

HRID 2369566Notes

Reaction equation

[Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.[CH3:13]B1OB(C)OB(C)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([CH3:13])[CH:3]=1

Participants

Conditions

Temperature: 110 °C

Procedure

A solution of methyl 4,6-dichloronicotinate (2.0 g, 9.71 mmol) in 1, 4-dioxane (30 mL) and water (1.5 mL), trimethylboroxine (0.731 g, 5.82 mmol), PdCl2(dppf)-CH2Cl2 (0.396 g, 0.485 mmol) and Cs2CO3 (9.49 g, 29.1 mmol) was degassed with argon for 15 min then heated to 110° C. for 16 h. After cooling, the solution was diluted with water (100 mL) and extracted with ethyl acetate (150 mL). The organic layer was 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-chloro-6-methylnicotinate (0.1 g, 0.539 mmol, 22% yield) as a yellow oil. LCMS (ESI) m/e 186.0 [(M+H)+, calcd for C8H9ClNO2 186.02]; LC/MS retention time (Method E): tR=1.75 min. 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 7.27 (s, 1H), 3.95 (s, 3H), 2.58 (s, 3H).

Workup

temperatureAfter cooling
extractionextracted with ethyl acetate (150 mL)
dry with materialThe organic layer was dried over Na2SO4
concentrationconcentrated under reduced pressure
customThe residue was purified by silica gel chromatography (20% EtOAc in pet. ether)

Sources & evidence

ORD record: ord-cb97d54c3e7c4ababb1db61565492b65
Source dataset: uspto-grants-2014_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08703953B2

Reaction notes

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