Reaction #1973920

Reaction equation

2,4,5-trichloropyrimidine

N-cyclopropyl-1-(ethoxymethyl)-1H-indole-4-carboxamide

tri(isopropyl) borate

diisopropylamine

n-BuLi

→

title compound

Yield 32.2%

N-cyclopropyl-2-(2,5-dichloropyrimidin-4-yl)-1-(ethoxymethyl)-1H-indole-4-carboxamide

Yield 32.2%

Solvents

THF

THF

Conditions

Workup

1. 1
   workup.ADDITIONAfter the addition
2. 2
   Temperaturecooled to −70° C
3. 3
   workup.STIRRINGThe reaction mixture is stirred at −70° C. for 30 min
4. 4
   TemperatureThe reaction is slowly warmed up to ambient temperature
5. 5
   workup.STIRRINGstirred for 1 h
6. 6
   OtherThe crude reaction mixture
7. 7
   Otheris degassed
8. 8
   Otherpurged with N2 for three times
9. 9
   workup.STIRRINGstirred under nitrogen
10. 10
    Temperatureat refluxing temperature for 1.5 h
11. 11
    OtherThe volatiles are removed in vacuo
12. 12
    ExtractionThe residue is extracted with dichloromethane (DCM, 3×500 mL)
13. 13
    WashThe combined extracts are washed with aqueous saturated sodium chloride (3×100 mL)
14. 14
    Dryingdried over anhydrous Na2SO4
15. 15
    Filtrationfiltered
16. 16
    Concentrationconcentrated
17. 17
    OtherThe residue is purified by chromatography on silica gel

Procedure

To a solution of diisopropylamine (DIPA, 147 mL, 1.04 mol) in anhydrous THF (600 mL) is added n-BuLi (2.5 M in hexane, 420 mL, 1.04 mol) at −50 C. After the addition, the mixture is stirred at −20° C. for 30 minutes and then cooled to −70° C. A solution of N-cyclopropyl-1-(ethoxymethyl)-1H-indole-4-carboxamide (60 g, 0.23 mol) and tri(isopropyl) borate (56.4 mL, 0.25 mol) in anhydrous THF (300 mL) is added. The reaction mixture is stirred at −70° C. for 30 min. The reaction is slowly warmed up to ambient temperature, stirred for 1 h and then quenched with aqueous K3PO4.3H2O (195 g, 0.74 mol, in 700 mL of water). The crude reaction mixture is degassed and purged with N2 for three times. 2,4,5-trichloropyrimidine (51 g, 0.27 mol) and palladium diphenylphosphinoferrocene dichloride (PdCl2(dppf).CH2Cl2, 19.2 g, 0.023 mol) are added and stirred under nitrogen at refluxing temperature for 1.5 h. The volatiles are removed in vacuo. The residue is extracted with dichloromethane (DCM, 3×500 mL). The combined extracts are washed with aqueous saturated sodium chloride (3×100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified by chromatography on silica gel to give the title compound (30 g, 32%). MS (m/z): 405 [(M+1)+, 35Cl, 35Cl], 407 [(M+1)+, 35Cl, 37Cl] and 409 [(M+1)+, 37Cl, 37Cl].

Source