Diethoxymethane → 2-Methoxy-5-(pyridin-4-yl)benzaldehyde

HRID 2389729Notes

Reaction equation

HRID 2389729 reaction equation
[CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])=[O:2].Cl.Cl[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCOCC)C>CC([O-])=O.CC([O-])=O.[Pd+2].C([O-])([O-])=O.[K+].[K+]>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:4][C:3]=1[CH:1]=[O:2]

Participants

7

Reactant 4

HCID 10024DiethoxymethaneHCID 11776TriphenylphosphineHCID 818524-Chloropyridine hydrochlorideHCID 2759225(3-Formyl-4-methoxyphenyl)boronic acid

Product 1

HCID 105605352-Methoxy-5-(pyridin-4-yl)benzaldehyde

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 11430Potassium CarbonateSolvent

Conditions

Temperature
80 °C

Procedure

To a 1 L 3-neck RB flask equipped with a N2 inlet, condenser and temperature probe is added 3-formyl-4-methoxyphenylboronic acid P15 (25.62 g, 142.38 mmol), 4-chloropyridine hydrochloride (23.65 g, 157.66 mmol), triphenylphosphine (3.77 g, 14.37 mmol), diethoxymethane (140 mL), and a solution of K2CO3 (2.7M, 150 mL). The yellow slurry is degassed with N2 for 10 minutes and Pd(OAc)2 (840.9 mg, 3.74 mmol) is added. The mixture is heated to 80° C. for 19 h. The layers are separated and the aqueous layer is extracted with EtOAc. The combined organic extracts are concentrated in vacuo and purified by filter chromatography on SiO2 eluting with EtOAc/hexanes (30 to 100%) followed by 3% MeOH/EtOAc, to give 2-methoxy-5-(pyridin-4-yl)benzaldehyde P9 (29.97 g, 99%) as a yellow solid. (L30464-208, 266146). To remove excess palladium 2-methoxy-5-(pyridin-4-yl)benzaldehyde P9 (28.26 g, 132.53 mmol) in EtOAc (500 mL) is treated with N-acetylcysteine (2.22 g, 13.58 mmol) in H2O (100 mL). The mixture is stirred for 4 h diluted with H2O and the layers are separated. The aqueous layer is extracted with EtOAc (5×200 mL) and the combined organic extracts are concentrated in vacuo and filtered through a Magnesol pad to give 2-methoxy-5-(pyridin-4-yl)benzaldehyde P9 (25.33 g, 90%) as a yellow solid.

Workup

  1. customTo a 1 L 3-neck RB flask equipped with a N2 inlet, condenser
  2. customThe yellow slurry is degassed with N2 for 10 minutes
  3. customThe layers are separated
  4. extractionthe aqueous layer is extracted with EtOAc
  5. concentrationThe combined organic extracts are concentrated in vacuo
  6. custompurified
  7. filtrationby filter chromatography on SiO2 eluting with EtOAc/hexanes (30 to 100%)

Sources & evidence

ORD record
ord-6f808661f5324775805e5896823760fd
Source dataset
uspto-grants-2012_09
Patent number
US08273747B2

Reaction notes

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