Chloromethyl Methyl Ether → 2-Bromo-6-methoxy-1-(methoxymethoxy)-3-methylnaphthalene

HRID 1992820Notes

Reaction equation

HRID 1992820 reaction equation
[Br:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[C:3]=1[OH:15].C(N(CC)C(C)C)(C)C.Cl[CH2:26][O:27][CH3:28]>C1COCC1>[Br:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[C:3]=1[O:15][CH2:26][O:27][CH3:28]

Participants

5

Reactant 3

HCID 7864Chloromethyl Methyl EtherHCID 81531DiisopropylethylamineHCID 685367182-Bromo-3-methyl-6-(methyloxy)-1-naphthalenol

Product 1

HCID 685362562-Bromo-6-methoxy-1-(methoxymethoxy)-3-methylnaphthaleneYield 79.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To an ice-water cooled solution of 2-bromo-3-methyl-6-(methyloxy)-1-naphthalenol (13) (6.8 g, 25.5 mmol) in THF (70 mL) was slowly added N,N-diisopropylethylamine (7 mL, 5.19 g, 40 mmol, 1.58 eq) followed by the slow addition of chloromethylmethyl ether (3.2 mL, 3.39 g, 42.1 mmol, 1.65 eq) between 0-5° C. with stirring under N2. The ice-water bath was removed and the reaction mixture was allowed to stir at RT overnight. The reaction mixture was diluted with Et2O (400 mL), washed with H2O (2×250 mL) followed by 1 N HCl (2×250 mL), dried over MgSO4, filtered, and the filtrate was concentrated to give the crude product as a dark orange oil. The crude product was partially purified by flash chromatography over SiO2 with hexanes:EtOAc (12:1 to 9:1) to give 6.32 g of the impure title compound. The impure compound was purified by flash chromatography over SiO2 with hexanes:EtOAc (15:1) to give 4.8 g (60%) of compound 14 as a pale yellow oil. 1H NMR (400 MHz; DMSO-d6): δ 3.59 (s, 3H), 3.85 (s, 3H), 5.18 (s, 2H), 7.17 (dd, J=2.5 Hz, 9.3 Hz, 1H), 7.26 (d, J=2.4 Hz, 1H), 7.60 (s, 1H), 7.95 (d, J=9.2 Hz, 1H). 1H NMR (400 MHz; CDCl3): δ 2.54 (s, 3H), 3.72 (s, 3H), 3.90 (s, 3H), 5.24 (s, 2H), 7.02 (d, J=2.4 Hz, 1H), 7.12 (dd, J=2.6 Hz, 9.2 Hz, 1H), 7.42 (s, 1H), 8.03 (d, J=9.1 Hz, 1H). (Note: In DMSO-d6, the 3-methyl group is coincident with the DMSO peak.) HRMS (EI+) calcd for C14H15BrO3: 310.0205 (M•+). Found: 310.0196.

Workup

  1. customThe ice-water bath was removed
  2. stirringto stir at RT overnight
  3. additionThe reaction mixture was diluted with Et2O (400 mL)
  4. washwashed with H2O (2×250 mL)
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationthe filtrate was concentrated
  8. customto give the crude product as a dark orange oil
  9. customThe crude product was partially purified by flash chromatography over SiO2 with hexanes:EtOAc (12:1 to 9:1)

Sources & evidence

ORD record
ord-cf2a4f26ddf545eb94714112bf53d9b4
Source dataset
uspto-grants-2010_01
Patent number
US07649093B2

Reaction notes

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