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Sodium Hydroxide → Tert-butyl 4-(4-bromophenyl)-4-cyanopiperidine-1-carboxylate

HRID 1788278
Notes
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Reaction equation

HRID 1788278 reaction equation
[C:1]([O:5][C:6](=[O:14])[N:7]([CH2:11][CH2:12]Cl)[CH2:8][CH2:9]Cl)([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][CH:17]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O.[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC>[C:1]([O:5][C:6]([N:7]1[CH2:11][CH2:12][C:22]([C:19]2[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][CH:18]=2)([C:23]#[N:24])[CH2:9][CH2:8]1)=[O:14])([CH3:4])([CH3:3])[CH3:2]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 3

HCID 14798Sodium HydroxideHCID 27914Benzeneacetonitrile, 4-bromo-HCID 11230235N-BOC-N,N-Bis(2-chloroethyl)amine

Product 1

HCID 49760269Tert-butyl 4-(4-bromophenyl)-4-cyanopiperidine-1-carboxylateYield 51.7%

Reagents, catalysts & solvents 3

HCID 84716Hexadecyltributylphosphonium bromide
Catalyst
HCID 962WaterSolvent
HCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

To a mixture of bis-(2-chloro-ethyl)-carbamic acid tert-butyl ester from Step 1 (7.26 g, 30 mmol, 1 eq) and 4-bromophenylacetonitrile (5.88 g, 30 mmol, 1 eq) in 38 mL of toluene and 76 mL of H2O was added NaOH (45.6 g, 114 mmol, 10M solution) followed by hexadecyltributylphosphonium bromide (3.0 g, 6.0 mmol, 0.2 eq). The resulting dark mixture was heated to 110° C. for 2 h and then allowed to cool to ambient temperature. It was extracted with three 200 mL portions of ethyl acetate and the combined organic extracts were dried over Na2SO4, filtered and concentrated by rotary evaporation to give the crude product as a black oily residue. Purification by flash column chromatography eluting with a gradient of 5-10% ethyl acetate in hexane gave 5.67 g of 4-(4-bromo-phenyl)-4-cyano-piperidine-1-carboxylic acid tert-butyl ester as a pale yellow foam. 1H NMR (300 MHz, CDCl3): δ 7.56-7.48 (d, 2H), 7.36-7.30(d, 2H), 4.40-4.10 (br. s, 2H), 3.27-3.05 (t, 2H), 2.10-1.80 (m, 4H), 1.45 (s, 9H).

Workup

  1. temperatureto cool to ambient temperature
  2. extractionIt was extracted with three 200 mL portions of ethyl acetate
  3. dry with materialthe combined organic extracts were dried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated by rotary evaporation
  6. customto give the crude product as a black oily residue
  7. customPurification by flash column chromatography
  8. washeluting with a gradient of 5-10% ethyl acetate in hexane

Sources & evidence

ORD record
ord-68d18f1c220342eb93c6beaf327191d9
Source dataset
uspto-grants-2009_03
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07511146B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes