Hydrochloric Acid → 4-Hydroxy-4-[5-(methoxymethyl)-2-pyridinyl]cyclohexanone

HRID 1016007Notes

Reaction equation

HRID 1016007 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH3:10])=[CH:4][N:3]=1.C([Li])CCC.[O:16]1[C:20]2([CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)OCC1.Cl.C([O-])(O)=O.[Na+].O>C1COCC1.C(OCC)(=O)C.CCCCCC>[OH:26][C:23]1([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH3:10])=[CH:4][N:3]=2)[CH2:24][CH2:25][C:20](=[O:16])[CH2:21][CH2:22]1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 5674151,4-Dioxaspiro[4.5]decan-8-oneHCID 533855212-Bromo-5-(methoxymethyl)pyridineHCID 86585896Sodium bicarbonate waterHCID 178418339Butyllithium

Product 1

HCID 578034194-Hydroxy-4-[5-(methoxymethyl)-2-pyridinyl]cyclohexanone

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 21226206Ethyl acetate hexaneSolvent

Procedure

A solution of 2-bromo-5-(methoxymethyl)pyridine (2.61 g, 12.9 mmoles) was dissolved in dry THF (40 mL) under nitrogen and cooled to −78° C. n-Butyllithium (6.20 mL, 15.5 mmoles, 2.5 M in hexane) was added dropwise over 10 minutes to form a black solution. After 15 minutes, a solution of 1,4-dioxa-spiro[4.5]decan-8-one (2.21 g, 14.1 mmoles) in THF was added dropwise over 2 minutes and the mixture was gradually warmed to room temperature over 3 hours. TLC (50% ethyl acetate/hexane) and LC/MS indicated complete conversion. Aqueous HCl (14 mL, 6.0 M) was added and the mixture was stirred for 3 hours at room temperature and then neutralized with NaHCO3/H2O. The mixture was extracted 3 times with ethyl acetate and the combined extracts were adsorbed onto silica gel and chromatographed. The column was eluted with a gradient of hexane to 40% ethyl acetate/hexane. Pure fractions were combined and concentrated to provide the title compound as a pale yellow solid, 1.00 g (33%). LC/MS (positive ion) m/z=236.1 (M+H)+.

Workup

  1. additionwas added dropwise over 10 minutes
  2. customto form a black solution
  3. extractionThe mixture was extracted 3 times with ethyl acetate
  4. customchromatographed
  5. washThe column was eluted with a gradient of hexane to 40% ethyl acetate/hexane
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-f0bd27808b7042a7a2620e2410efdecc
Source dataset
uspto-grants-2011_07
Patent number
US07985730B2

Reaction notes

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