Reaction #1833254

Reaction equation

acetonitrile

2-(1,3-dihydroisobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

methyl 4-amino-3,6-dichloro-5-fluoropicolinate

sodium carbonate

→

title compound

Yield 22.1%

Methyl 4-amino-3-chloro-6-(1,3-dihydroisobenzofuran-5-yl)-5-fluoropicolinate

Yield 22.1%

Solvents

water

water

Conditions

Workup

1. 1
   Otherat 23° C
2. 2
   OtherThe cooled reaction mixture
3. 3
   Extractionextracted with dichloromethane (4×70 mL)
4. 4
   DryingThe combined organic layers were dried (magnesium sulfate), gravity
5. 5
   Filtrationfiltered
6. 6
   Concentrationconcentrated by rotary evaporation
7. 7
   OtherThe residue was purified by reverse phase column chromatography (5% acetonitrile to 100% acetonitrile gradient)

Procedure

To the crude 2-(1,3-dihydroisobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (estimated to be 570 mg, 2.3 mmol, 1.1 equiv) was added methyl 4-amino-3,6-dichloro-5-fluoropicolinate (500 mg, 2.1 mmol, 1.0 equiv), dichloro[bis(triphenylphosphino)]-palladium(II) (150 mg, 0.21 mmol, 0.10 equiv), and sodium carbonate (240 mg, 2.3 mmol, 1.1 equiv) followed by a 1:1 mixture of water:acetonitrile (7.0 mL) at 23° C. The resulting dark orange/brown mixture was heated to 85° C. and stirred for 4 h. The cooled reaction mixture was diluted with water (150 mL) and extracted with dichloromethane (4×70 mL). The combined organic layers were dried (magnesium sulfate), gravity filtered, and concentrated by rotary evaporation. The residue was purified by reverse phase column chromatography (5% acetonitrile to 100% acetonitrile gradient) to yield the title compound as an orange powder (150 mg, 22%): mp 153-156° C.; IR (neat film) 3468 (m), 3334 (s), 3205 (m), 2952 (m), 2856 (m), 1735 (s), 1623 (s), 1579 (w) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.81-7.86 (m, 2H), 7.33 (d, J=8 Hz, 1H), 5.16 (br d, J=4 Hz, 1H), 4.89 (br s, 2H), 3.97 (s, 3H); ESIMS m/z 323 [(M+H)+].

Source