Reaction #44237

Reaction equation

methyl 4-chloro-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate

2-fluoro-4-methylthioaniline

BINAP

Cs2CO3

N2

→

desired product

Yield 42.4%

methyl 4-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate

Yield 42.4%

Solvents

EtOAc

toluene

Conditions

Workup

1. 1
   Temperatureheated at 80° C. for 16 hours
2. 2
   workup.STIRRINGwith stirring
3. 3
   TemperatureThe reaction mixture was cooled to room temperature
4. 4
   FiltrationThe precipitate was filtered off
5. 5
   Washwashed with EtOAc
6. 6
   WashThe filtrate was washed with water
7. 7
   OtherThe organic layer was separated
8. 8
   Extractionthe aqueous layer was extracted with EtOAc
9. 9
   DryingThe combined organic layers were dried over MgSO4
10. 10
    Filtrationfiltered
11. 11
    Concentrationconcentrated
12. 12
    Otherto give the crude material that
13. 13
    Otherwas purified by silica gel flash column chromatography (100% CH2Cl2 to 1% MeOH in CH2Cl2)

Procedure

A mixture solution of methyl 4-chloro-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylate (72 mg, 0.35 mmol), 2-fluoro-4-methylthioaniline (69 mg, 0.44 mmol), Pd(OAc)2 (10 mg, 0.044 mmol), BINAP (40 mg, 0.064 mmol), and Cs2CO3 (197 mg, 0.60 mmol) in toluene (1.5 mL) was sealed in a vial under N2 atmosphere. It was stirred for 10 minutes at room temperature and then heated at 80° C. for 16 hours with stirring. The reaction mixture was cooled to room temperature and diluted with EtOAc. The precipitate was filtered off and washed with EtOAc. The filtrate was washed with water. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, concentrated to give the crude material that was purified by silica gel flash column chromatography (100% CH2Cl2 to 1% MeOH in CH2Cl2) followed by additional silica gel flash column chromatography (10 to 15 to 20% EtOAc in CH2Cl2) to afford 48 mg (42%) of the desired product.

Source