Reaction #45074

Reaction equation

ethyl 4-(3,5-dimethylpiperazin-1-yl)benzoate

paraformaldehyde

sodium borohydride

→

ethyl 4-(3,4,5-trimethylpiperazin-1-yl)benzoate

Yield 112.2%

Solvents

ethanol

acetonitrile

Conditions

Workup

1. 1
   TemperatureThis was cooled to 20° C.
2. 2
   TemperatureThe solution was heated at 60° C. for 24 h
3. 3
   OtherThe reaction mixture was quenched with 0.880 ammonia (0.5 mL)
4. 4
   Filtrationfiltered
5. 5
   Washwashed with diethyl ether (2×5 mL)
6. 6
   Otherthe organic extracts were evaporated
7. 7
   OtherThe crude product was purified by silica column chromatography
8. 8
   Washeluting with a gradient of 0-5% MeOH in DCM containing 0.1% ammonia
9. 9
   OtherFractions were evaporated to dryness
10. 10
    Otherto afford an oil
11. 11
    workup.ADDITIONwas added
12. 12
    workup.STIRRINGthe suspension was stirred overnight
13. 13
    FiltrationThe resin was filtered off
14. 14
    Otherthe solution evaporated to dryness

Procedure

Titanium(IV) isopropoxide (0.598 mL, 2.00 mmol) was added to ethyl 4-(3,5-dimethylpiperazin-1-yl)benzoate (0.262 g, 1 mmol), and paraformaldehyde (0.120 g, 4.00 mmol) in ethanol (5 mL). The resulting solution was stirred at 60° C. under nitrogen for 30 mins. This was cooled to 20° C. and sodium borohydride (0.095 g, 2.5 mmol) was added in one portion. The solution was heated at 60° C. for 24 h. The reaction mixture was quenched with 0.880 ammonia (0.5 mL), filtered, washed with diethyl ether (2×5 mL) and the organic extracts were evaporated. The crude product was purified by silica column chromatography, eluting with a gradient of 0-5% MeOH in DCM containing 0.1% ammonia. Fractions were evaporated to dryness to afford an oil. This was dissolved in acetonitrile (20 ml), polymer supported isocyante resin (1 mmol/g, 2 g) was added and the suspension was stirred overnight. The resin was filtered off and the solution evaporated to dryness to give ethyl 4-(3,4,5-trimethylpiperazin-1-yl)benzoate (0.310 g, 112%) as a white solid. MS: m/z 278 (MH+).

Source