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Potassium Carbonate → 4-(2-Cyclopropylmethyl-7-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ester

HRID 252067
Notes
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Reaction equation

HRID 252067 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B1C2CCCC1CCC2.Br[C:25]1[CH:26]=[C:27]2[C:31](=[C:32]([CH3:34])[CH:33]=1)[C:30](=[O:35])[N:29]([CH2:36][CH:37]1[CH2:39][CH2:38]1)[CH2:28]2.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:25]2[CH:26]=[C:27]3[C:31](=[C:32]([CH3:34])[CH:33]=2)[C:30](=[O:35])[N:29]([CH2:36][CH:37]2[CH2:39][CH2:38]2)[CH2:28]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 4

HCID 11430Potassium CarbonateHCID 789669-Borabicyclo(3.3.1)nonaneHCID 27568081-Boc-4-MethylenepiperidineHCID 579494565-Bromo-2-cyclopropylmethyl-7-methyl-2,3-dihydro-isoindol-1-one

Product 1

HCID 576722654-(2-Cyclopropylmethyl-7-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ester
Yield 68.9%

Reagents, catalysts & solvents 3

HCID 44119782Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolvent2×HCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

To a purged (Argon) sample of 4-Methylene-piperidine-1-carboxylic acid tert-butyl ester (727 mg, 3.68 mmol) was added 9-BBN (11.32 mL, 5.66 mmol). The mixture was stirred at 60° C. for two hours. After cooling to room temperature this solution was added to 5-Bromo-7-methyl-2-cyclopropylmethyl-2,3-dihydro-isoindol-1-one (794 mg, 2.83 mmol), Pd(dppf)Cl2 (115 mg, 0.142 mmol), DMF (25 mL), potassium carbonate (1.17 g, 8.49 mmol) and water (2.5 mL). The mixture was allowed to stir at 75° C. for 1.5 hours. The mixture was then cooled to room temperature and poured into water (3 mL). The product was extracted with ethyl acetate. The combined organic layers were washed with water three times, brine, dried over sodium sulphate, filtered and concentrated. Column chromatography (30% Ethyl acetate/hexanes) provided the title compound as a light yellow oil (777 mg, 53%). 1H NMR (300 MHz, CDCl3): δ 7.01 (s, 1H), 6.94 (s, 1H), 4.39 (s, 2H), 3.42 (d, 2H), 2.68 (s, 3H), 2.57 (s, 2H), 2.54 (d, 2H), 1.70-1.62 (m, 4H), 1.43 (s, 9H), 1.09 (d, 1H), 1.01 (m, 1H), 0.56-0.5 (m, 2H), 0.31-0.29 (m, 2H).

Workup

  1. temperatureAfter cooling to room temperature this solution
  2. stirringto stir at 75° C. for 1.5 hours
  3. temperatureThe mixture was then cooled to room temperature
  4. extractionThe product was extracted with ethyl acetate
  5. washThe combined organic layers were washed with water three times, brine
  6. dry with materialdried over sodium sulphate
  7. filtrationfiltered
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-11f05c0702c74801b13b8d5fafe1bb66
Source dataset
uspto-grants-2011_01
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07868008B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes