tert-Butyl piperazine-1-carboxylate → tert-Butyl 4-(2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yl)-2,3-dihydrobenzofuran-5-yl)piperazine-1-carboxylate

HRID 1025503Notes

Reaction equation

HRID 1025503 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)[CH2:7][C:6]=2[CH:25]=1.[N:26]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:22]([C:19]1[CH:18]=[N:17][C:16]([N:13]2[CH2:14][CH2:15][CH:10]([CH:8]3[CH2:7][C:6]4[CH:25]=[C:2]([N:29]5[CH2:28][CH2:27][N:26]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30]5)[CH:3]=[CH:4][C:5]=4[O:9]3)[CH2:11][CH2:12]2)=[N:21][CH:20]=1)[CH2:23][CH3:24]

Participants

8

Reactant 3

HCID 143452tert-Butyl piperazine-1-carboxylateHCID 674689342-(4-(5-Bromo-2,3-dihydrobenzofuran-2-yl)piperidin-1-yl)-5-propylpyrimidineHCID 178418730sodium 2-methylpropan-2-olate

Product 1

HCID 68211901tert-Butyl 4-(2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yl)-2,3-dihydrobenzofuran-5-yl)piperazine-1-carboxylateYield 76%

Reagents, catalysts & solvents 4

HCID 634876Binap, (A+-)-CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

To a degassed solution of 2-(4-(5-bromo-2,3-dihydrobenzofuran-2-yl)piperidin-1-yl)-5-propylpyrimidine (280 mg, 0.522 mmol), tert-butyl piperazine-1-carboxylate (389 mg, 2.088 mmol), t-BuONa (251 mg, 2.61 mmol), and BINAP (6.5 mg, 10.44 μmol) in toluene (5 mL) was added Pd2(dba)3 (28.7 mg, 0.031 mmol). Upon completion of addition, the reaction mixture was stirred in a sealed vial at 80° C. overnight. At the conclusion of this period, the reaction mixture was allowed to cool to room temperature. Once at the prescribed temperature, the reaction mixture was diluted with water (3 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with aqueous NaHCO3 (saturated, 5 mL) and then brine (5 mL). The organic layer was separated, dried (Na2SO4), filtered, and concentrated to yield a residue. The residue was purified by column chromatography (silica gel, CH2Cl2/EtOAc gradient 0 to 50% EtOAc) to afford Compound 9C as a light yellow solid (201 mg, 76% yield). 1H NMR (500 MHz, CDCl3) δ ppm 8.15 (s, 2 H), 6.83 (d, J=1.9 Hz, 1 H), 6.70-6.75 (m, 1 H), 6.66-6.69 (m, 1 H), 4.80 (dd, J=13.2, 2.5 Hz, 2 H), 4.48-4.56 (m, 1 H), 3.53-3.61 (m, 4 H), 3.18 (dd, J=15.5, 8.9 Hz, 1 H), 2.94-3.02 (m, 4 H), 2.80-2.90 (m, J=12.9, 12.9, 7.6, 2.8 Hz, 2 H), 2.40 (t, J=7.4 Hz, 2 H), 2.00-2.07 (m, 1 H), 1.91 (dddd, J=11.5, 8.0, 7.7, 3.6 Hz, 1 H), 1.74 (br. s., 1 H), 1.53-1.62 (m, 2 H), 1.47-1.51 (m, 9 H), 1.32-1.43 (m, 2 H), 0.94 (t, J=7.3 Hz, 3 H). LC/MS (m/z)=508 (M+H)+.

Workup

  1. additionUpon completion of addition
  2. temperatureto cool to room temperature
  3. extractionextracted with EtOAc (3×5 mL)
  4. washThe combined organic layers were washed with aqueous NaHCO3 (saturated, 5 mL)
  5. customThe organic layer was separated
  6. dry with materialdried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customto yield a residue
  10. customThe residue was purified by column chromatography (silica gel, CH2Cl2/EtOAc gradient 0 to 50% EtOAc)

Sources & evidence

ORD record
ord-a2c1a73f7738490a8ff10b8f5659a83a
Source dataset
uspto-grants-2014_05
Patent number
US08729084B2

Reaction notes

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