Methane → Ethyl 7-(4-(tert-butoxycarbonyl)phenoxy)-6-chlorochroman-4-carboxylate

HRID 1047965Notes

Reaction equation

HRID 1047965 reaction equation
Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[OH:26])[O:22][CH2:21][CH2:20][CH:19]2[C:27]([O:29][CH2:30][CH3:31])=[O:28].Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].C>O1CCOCC1.C(OCC)(=O)C>[C:9]([O:8][C:6]([C:5]1[CH:13]=[CH:14][C:2]([O:26][C:25]2[CH:24]=[C:23]3[C:18]([CH:19]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:20][CH2:21][O:22]3)=[CH:17][C:16]=2[Cl:15])=[CH:3][CH:4]=1)=[O:7])([CH3:12])([CH3:11])[CH3:10]

Participants

8

Reactant 5

HCID 297MethaneHCID 10796Cesium carbonateHCID 75605N,N-Dimethylglycine hydrochlorideHCID 11334366Tert-butyl 4-bromobenzoateHCID 53393319Ethyl-6-chloro-7-hydroxy-3,4-dihydro-2H-chromene-4-carboxylate

Product 1

HCID 67080248Ethyl 7-(4-(tert-butoxycarbonyl)phenoxy)-6-chlorochroman-4-carboxylateYield 102.2%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
96 °C

Procedure

Tert-butyl 4-bromobenzoate (210.4 g, 818.2 mmol) was dissolved in 1 L of dioxane, which was previously degassed with argon, in a 4-neck 5 L round bottom flask equipped with a mechanical stirrer and a reflux condenser. Under argon flow and with stirring, ethyl 6-chloro-7-hydroxychroman-4-carboxylate (176.4 g, 687.2 mmol), N,N-dimethyl glycine hydrochloride (35.7 g, 346.2 mmol) and cuprous chloride (34.0 g, 342.9 mmol) were added via a funnel. Cesium carbonate then added and an additional 0.5 L of dioxane was added to the reaction mixture. The mixture was then heated at 95-97° C. for 20 hours. After cooling to ambient temperature, the reaction mixture was poured into 3 L of a 3:1 mixture of hexanes:ethyl acetate and activated charcoal (300 g) was added. After stirring periodically for 1 hour, the mixture was filtered thru GF/F paper, washing the filter cake with 2 L of a 3:1 mixture of hexanes:ethyl acetate. The resulting golden brown solution was concentrated to provide 304 g of crude ethyl 7-(4-(tert-butoxycarbonyl)-phenoxy)-6-chlorochroman-4-carboxylate. The crude product was dissolved in dichloromethane, concentrated onto silica gel and purified by flash column chromatography, eluting with a gradient of 10 to 25% ethyl acetate in hexanes to give ethyl 7-(4-(tert-butoxycarbonyl)phenoxy)-6-chlorochroman-4-carboxylate as a colorless, viscous oil (221 g, 74.3% yield). 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=8.8 Hz, 2H), 7.37 (s, 1H), 6.94 (d, J=8.8 Hz, 2H), 6.54 (s, 1H), 4.21-4.29 (m, 4H), 3.74 (t, J=5.3 Hz, 1H), 2.30-2.36 (m, 1H), 2.05-2.14 (m, 1H), 1.58 (s, 9H), 1.31 (t, J=7.0 Hz, 3H).

Workup

  1. customwhich was previously degassed with argon, in a 4-neck 5 L round bottom flask
  2. customequipped with a mechanical stirrer and a reflux condenser
  3. temperatureAfter cooling to ambient temperature
  4. stirringAfter stirring periodically for 1 hour
  5. filtrationthe mixture was filtered
  6. washwashing the filter cake
  7. additionwith 2 L of a 3:1 mixture of hexanes
  8. concentrationThe resulting golden brown solution was concentrated

Sources & evidence

ORD record
ord-8522dc05235f4ea3ade26cb238bf05a5
Source dataset
uspto-grants-2013_10
Patent number
US08569522B2

Reaction notes

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