Toluene → Ethyl 2-methoxy-6-methylisonicotinate
Reaction equation
[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7](Cl)[CH:6]=1)[CH3:2].[C:15]1(C)C=CC=CC=1>O1CCOCC1.[CH3-].[CH3-].[Zn+2]>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:6]=[C:7]([CH3:15])[N:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH3:2]Participants
Reactant 2
Product 1
Reagents, catalysts & solvents 2
Conditions
- Temperature
- 75 °C
Procedure
Under argon, dimethyl zink (14.26 g, 149 mmol, 124 mL of a 1.2 M solution in toluene) is added dropwise to a solution of 2-chloro-6-methoxy-isonicotinic acid ethyl ester (5.37 g, 24.9 mmol) and Pd(dppf) (203 mg, 0.249 mmol) in dioxane (120 mL). The mixture is heated to 75° C. and stirred for 18 h before it is cooled again to rt. The reaction is quenched by carefully adding water. The mixture is diluted further with water, filtered over celite and the filtrate is extracted with EA (2×250 mL). The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 2-methoxy-6-methyl-isonicotinic acid ethyl ester (4.10 g) as a colourless oil; LC-MS: tR=0.92 min, [M+1]+=195.93. 1H NMR (CDCl3): δ 1.41 (t, J=7.3 Hz, 3H), 2.52 (s, 3H), 3.97 (s, 3H), 4.39 (q, J=7.3 Hz, 2H), 7.12 (s, 1H), 7.28 (s, 1H).
Workup
- temperatureis cooled again to rt
- customThe reaction is quenched by carefully adding water
- additionThe mixture is diluted further with water
- filtrationfiltered over celite
- extractionthe filtrate is extracted with EA (2×250 mL)
- dry with materialextracts are dried over MgSO4
- filtrationfiltered
- concentrationconcentrated
- customThe crude product is purified by CC on silica gel eluting with heptane:EA 4:1
Sources & evidence
- ORD record
- ord-8ae5c2665ca54e788feacb3f3f061932
- Source dataset
- uspto-grants-2013_12
- Patent number
- US08598208B2
Reaction notes
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