Hexahydro-1,4-diazepine → Ethyl 5-(4-ethylpiperazin-1-yl)thiophene-2-carboxylate

HRID 1092162Notes

Reaction equation

HRID 1092162 reaction equation
C[C:2]([CH3:5])([O-])C.[Na+].Br[C:8]1[S:12][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][CH:9]=1.[NH:18]1[CH2:24][CH2:23]C[NH:21][CH2:20][CH2:19]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:24]([N:18]1[CH2:5][CH2:2][N:21]([C:8]2[S:12][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][CH:9]=2)[CH2:20][CH2:19]1)[CH3:23]

Participants

8

Reactant 4

HCID 68163Hexahydro-1,4-diazepineHCID 605723Ethyl 5-bromothiophene-2-carboxylateHCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxide

Product 1

HCID 66589785Ethyl 5-(4-ethylpiperazin-1-yl)thiophene-2-carboxylateYield 17%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 887MethanolSolventHCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

Palladium(II) acetate (52.1 mg, 0.23 mmol) followed by sodium tert-butoxide (624 mg, 6.49 mmol) was added to a stirred solution of ethyl 5-bromothiophene-2-carboxylate (1090 mg, 4.64 mmol), homopiperazine (511 mg, 5.10 mmol) and (rac)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (289 mg, 0.46 mmol) in toluene (20 mL) at 25° C. under nitrogen. The resulting suspension was stirred at 110° C. for 3 h. The cooled reaction mixture was diluted with MeOH and the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions containing the desired product were evaporated to dryness to afford impure product as a brown oil. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% 7N NH3/MeOH in DCM and then 0 to 3% NH3/MeOH in DCM. Pure fractions were evaporated to dryness to afford ethyl 5-(4-ethylpiperazin-1-yl)thiophene-2-carboxylate (195 mg, 17%) as a yellow oil.

Workup

  1. customThe cooled reaction mixture
  2. customthe crude product was purified by ion exchange chromatography
  3. washThe desired product was eluted from the column
  4. additioncontaining the desired product
  5. customwere evaporated to dryness
  6. customto afford impure product as a brown oil
  7. customThe crude product was purified by silica column chromatography
  8. washeluting with a gradient of 0 to 5% 7N NH3/MeOH in DCM
  9. customPure fractions were evaporated to dryness

Sources & evidence

ORD record
ord-a082be8572b14706bbce54c9de86077e
Source dataset
uspto-grants-2012_03
Patent number
US08129391B2

Reaction notes

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