tert-Butyl Dimethylphosphonoacetate → 3-[3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-7-yl)-4-trifluoromethoxy-phenyl]-acrylic acid tert-butyl ester

HRID 2239252Notes

Reaction equation

HRID 2239252 reaction equation
[C:1]([O:5][C:6]([CH2:8]P(=O)(OC)OC)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH2:20]([N:22]1[C:27]2[CH:28]=[C:29]([C:33]3[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=3[O:41][C:42]([F:45])([F:44])[F:43])[CH:36]=O)[C:30]([CH3:32])=[CH:31][C:26]=2[C:25]([CH3:47])([CH3:46])[O:24][C:23]1=[O:48])[CH3:21]>C1COCC1.CN1C(=O)N(C)CCC1.C1COCC1>[C:1]([O:5][C:6](=[O:7])[CH:8]=[CH:36][C:35]1[CH:38]=[CH:39][C:40]([O:41][C:42]([F:45])([F:43])[F:44])=[C:33]([C:29]2[C:30]([CH3:32])=[CH:31][C:26]3[C:25]([CH3:46])([CH3:47])[O:24][C:23](=[O:48])[N:22]([CH2:20][CH3:21])[C:27]=3[CH:28]=2)[CH:34]=1)([CH3:2])([CH3:3])[CH3:4]

Participants

6

Reactant 3

HCID 4564495tert-Butyl DimethylphosphonoacetateHCID 866116793-(1-ethyl-4,4,6-trimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-7-yl)-4-trifluoromethoxy-benzaldehydeHCID 178418339Butyllithium

Product 1

HCID 685832523-[3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-7-yl)-4-trifluoromethoxy-phenyl]-acrylic acid tert-butyl esterYield 41%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 22565281tetrahydrofuran 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinoneSolvent

Conditions

Temperature
-78 °C

Procedure

A flask charged with 0.23 mL (2.5 mmol) of dimethyl t-butoxycarbonyl-methylphosphonate in 8.75 mL of dry THF/DMPU (10:1). The flask was cooled to −78° C. where 1.78 mL (0.9 mmol, 2.5M hexanes) of n-butyl lithium was added slowly via syringe. The reaction mixture was stirred at −78° C. for 10 minutes and then a solution of 0.35 g (0.86 mmol) of Compound 14E in 3 mL of dry THF was added. After warming to room temperature and an additional 20 minutes of stirring, the reaction was quenched with 3 mL of water and then partitioned with 10 mL of saturated ammonium chloride and 20 mL of ethyl acetate, The water layer was further extracted with ethyl acetate (2×15 mL) and the combined organic layers were then washed with brine (10 mL), dried over magnesium sulfate, filtered and excess solvent was removed on the rotary evaporator. The crude product was purified by flash chromatography (3.5:1 EtOAc/Hexanes) to give 0.16 g (41%) of the product as a white solid. MS (electrospray): mass calculated for C23H22F3NO5, 449.15; m/z found 450, [M+H]+.

Workup

  1. additionwas added slowly via syringe
  2. temperatureAfter warming to room temperature and an additional 20 minutes
  3. stirringof stirring
  4. customthe reaction was quenched with 3 mL of water
  5. custompartitioned with 10 mL of saturated ammonium chloride and 20 mL of ethyl acetate
  6. extractionThe water layer was further extracted with ethyl acetate (2×15 mL)
  7. washthe combined organic layers were then washed with brine (10 mL)
  8. dry with materialdried over magnesium sulfate
  9. filtrationfiltered
  10. customexcess solvent was removed on the rotary evaporator
  11. customThe crude product was purified by flash chromatography (3.5:1 EtOAc/Hexanes)

Sources & evidence

ORD record
ord-ba17807c991e447fa26d6e64eec62f48
Source dataset
uspto-grants-2010_05
Patent number
US07723326B2

Reaction notes

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