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Triphenylphosphine → Tert-butyl 4-(5-chloro-3-(methoxycarbonyl)-2-methylphenoxy)piperidine-1-carboxylate

HRID 1050463
Notes
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Reaction equation

HRID 1050463 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].O[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([CH3:12])=[C:4]([CH:3]=1)[O:13][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 11776TriphenylphosphineHCID 643502Tert-butyl 4-hydroxypiperidine-1-carboxylateHCID 5363146Diisopropyl azodicarboxylateHCID 70904667Methyl 5-chloro-3-hydroxy-2-methylbenzoate

Product 1

HCID 90273066Tert-butyl 4-(5-chloro-3-(methoxycarbonyl)-2-methylphenoxy)piperidine-1-carboxylateYield 80%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
55 °C

Procedure

A mixture of methyl 5-chloro-3-hydroxy-2-methylbenzoate (500 mg, 2.492 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (752 mg, 3.74 mmol) and triphenylphosphine (1307 mg, 4.98 mmol), stirred in THF (10 mL) until completely dissolved, then DIAD (1.530 mL, 7.48 mmol) was slowly added dropwise via syringe over 5 minutes. The reaction heated at 55° C. for 4 h under nitrogen. The reaction was cooled to room temperature and concentrated in vacuo. The orange oil residue was purified by flash column chromatography (30% EtOAc/hexanes). The desired fractions were combined, concentrated, then triturated with EtOAc to give tert-butyl 4-(5-chloro-3-(methoxycarbonyl)-2-methylphenoxy)piperidine-1-carboxylate (0.765 g, 1.99 mmol, 80% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.10-1.26 (m, 1 H) 1.41 (s, 9 H) 1.49-1.63 (m, 2 H) 1.79-1.92 (m, 2 H) 2.28 (s, 3 H) 3.15-3.30 (m, 2 H) 3.51-3.66 (m, 2 H) 3.83 (s, 3 H) 4.63-4.81 (m, 1 H) 7.31 (d, J=2.02 Hz, 1 H) 7.37 (d, J=2.02 Hz, 1 H) MS (ES) [M+H]+ 384.1.

Workup

  1. dissolutionuntil completely dissolved
  2. temperatureThe reaction was cooled to room temperature
  3. concentrationconcentrated in vacuo
  4. customThe orange oil residue was purified by flash column chromatography (30% EtOAc/hexanes)
  5. concentrationconcentrated
  6. customtriturated with EtOAc

Sources & evidence

ORD record
ord-f3161348f9b944cab1740fd8f13a6c63
Source dataset
uspto-grants-2016_07
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09382234B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes