Reaction #312627

Reaction equation

methyl boronic acid

5-(5-Bromo-pyrazin-2-yl)-2-(2,6-dimethyl-morpholin-4-yl)-3,4-difluoro-benzaldehyde

sodium carbonate

acetonitrile water

methyl boronic acid

→

product

Yield 41.8%

2-(2,6-Dimethyl-morpholin-4-yl)-3,4-difluoro-5-(5-methyl-pyrazin-2-yl)-benzaldehyde

Yield 41.8%

Solvents

EtOAc

water

Conditions

Workup

1. 1
   workup.ADDITIONwas added to the reaction
2. 2
   TemperatureThe mixture was cooled to room temperature
3. 3
   OtherThe phases were separated
4. 4
   Extractionthe aqueous phase was re-extracted with EtOAc (×2)
5. 5
   DryingThe combined organic layers were dried over MgSO4
6. 6
   Concentrationconcentrated
7. 7
   OtherPurified by column chromatography
8. 8
   Washeluting with ethyl acetate in hexanes (5-35%)

Procedure

To a suspension of 5-(5-Bromo-pyrazin-2-yl)-2-(2,6-dimethyl-morpholin-4-yl)-3,4-difluoro-benzaldehyde (0.375 g, 0.91 mmol) and sodium carbonate (0.29 g, 2.7 mmol) in previously degassed acetonitrile/water (1/1) mixture (4 mL) was added methyl boronic acid (0.11 g, 1.8 mmol) under nitrogen. Bis-(triphenylphosphine)-dichloro-palladium-(II) (0.026 g, 0.036 mmol) was added at room temperature and the reaction was heated for 5 hours at 85° C. Analysis indicated that starting material had not fully been consumed so an additional 1 equivalent of methyl boronic acid was added to the reaction and stirred overnight at 85° C. The mixture was cooled to room temperature, diluted with EtOAc and water then neutralized. The phases were separated and the aqueous phase was re-extracted with EtOAc (×2). The combined organic layers were dried over MgSO4 and concentrated. Purified by column chromatography eluting with ethyl acetate in hexanes (5-35%) to obtain 132 mgs of product. 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.28 (d, J=6.4 Hz, 6H), 2.61 (s, 3H), 3.00 (m, 2H), 3.38 (m, 2 H), 4.19 (m, 2H), 8.26 (dd, J=8.2, 2.1 Hz, 1H), 8.54 (d, J=1.2 Hz, 1H), 8.89 (dd, J=2.3, 1.6 Hz, 1H), 10.33 (s, 1H); MS(APCl+) m/z 348 (MH+).

Source