tert-Butyl piperazine-1-carboxylate → 3-(4-BOC-piperazino)-2-chloropyridine

HRID 220444Notes

Reaction equation

HRID 220444 reaction equation
[Cl:1][C:2]1[C:7](I)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]

Participants

7

Reactant 4

HCID 143452tert-Butyl piperazine-1-carboxylateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 27357432-Chloro-3-iodopyridineHCID 23676156Sodium t-butoxide

Product 1

HCID 593218363-(4-BOC-piperazino)-2-chloropyridineYield 95%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

Dissolve 2-chloro-3-iodopyridine (2.0 g, 8.37 mmol) in toluene (7 mL). Add piperazine-1-carboxylic acid t-butyl ester (1.2 g, 6.4 mmol), followed by the addition of tris(dibenzylideneacetone)dipalladium(0) (0.12 g, 0.13 mmol), 4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene (0.23 g, 0.39 mmol), and sodium t-butoxide (0.93 g, 9.7 mmol). Heat at 100° C. for 3.5 hr. Concentrate and partition the residue between EtOAc and water. Extract the aqueous phase twice with ethyl acetate. Wash combined organic layers with brine. Dry the organic extracts (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 0:100 to 20:80 ethyl acetate:hexanes), to give 4-(2-Chloro-pyridin-3-yl)-piperazine-1-carboxylic acid t-butyl ester (95%). MS (ES): m/z=298 [M+H]+.

Workup

  1. concentrationConcentrate
  2. custompartition the residue between EtOAc and water
  3. extractionExtract the aqueous phase twice with ethyl acetate
  4. washWash
  5. dry with materialDry the organic extracts (sodium sulfate)
  6. filtrationfilter
  7. concentrationconcentrate
  8. custompurify
  9. wash(silica gel chromatography, eluting with 0:100 to 20:80 ethyl acetate:hexanes)

Sources & evidence

ORD record
ord-2e9211458d6741ceadb424b1a1087696
Source dataset
uspto-grants-2012_06
Patent number
US08202873B2

Reaction notes

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