Dimethylformamide → 3-Hydroxymethyl-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid methyl ester

HRID 919008Notes

Reaction equation

HRID 919008 reaction equation
[OH:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].CC1C=CC(S([O:24][CH2:25][C@@H:26]2O[CH2:27]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOCC>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[O:12][CH2:27][CH:26]([CH2:25][OH:24])[O:1][C:2]=2[C:3]=1[CH3:13])=[O:6]

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 11430Potassium CarbonateHCID 154187Glycidyl tosylate, (R)-HCID 59016598Methyl 3,4-Dihydroxy-2-methylbenzoate

Product 1

HCID 687788313-Hydroxymethyl-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid methyl esterYield 78%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent

Conditions

Temperature
60 °C

Procedure

To a round bottom flask equipped with magnetic stirring and a nitrogen inlet was added methyl 3,4-dihydroxy-2-methylbenzoate (24.0 g, 132 mmol), (2R)-(−)-glycidyl tosylate (30.1 g, 132 mmol), potassium carbonate (21.8 g, 158 mmol), and DMF (264 mL). This mixture was heated to 60° C. for 5 hours. The mixture was cooled to room temperature, diluted with ether, and washed once with water. The aqueous wash was back extracted once with ether and the ethereal solutions combined. These organic solutions were then washed 3 times with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to give a brown oil. This oil was chromatographed on silica gel eluting with 25% ether in hexanes to give a yellow oil, 3-hydroxymethyl-5 methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid methyl ester, (24.6 g, 103 mmol) in 78% yield. 1H-NMR (300 MHz, CD3COCD3) δ (ppm): 2.42 (s, 2H), 3.80 (s, 3H), 3.83 (m, 1H), 4.12 (dd, 1H), 4.23 (m, 2H), 4.42 (dd, 1H), 6.75 (d, 1H), 7.42 (d, 1H); TLC Rf=0.40 (1:1 ethyl acetate/hexane).

Workup

  1. customTo a round bottom flask equipped
  2. temperatureThe mixture was cooled to room temperature
  3. washwashed once with water
  4. washThe aqueous wash
  5. extractionwas back extracted once with ether
  6. washThese organic solutions were then washed 3 times with saturated sodium chloride solution
  7. dry with materialdried over magnesium sulfate
  8. filtrationfiltered
  9. customevaporated
  10. customto give a brown oil
  11. customThis oil was chromatographed on silica gel eluting with 25% ether in hexanes

Sources & evidence

ORD record
ord-c43caef73d6b43caacb1bfe5481c0172
Source dataset
uspto-grants-2016_03
Patent number
US09272986B2

Reaction notes

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