Diisopropylamine → 3-(2-(1-(4-Fluorophenyl)cyclohexyl)ethyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole

HRID 1506372Notes

Reaction equation

HRID 1506372 reaction equation
C(NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[CH:21]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)/[C:29](=[N:33]/[OH:34])/[CH2:28][CH2:27][CH2:26]2)=[CH2:22].[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2([CH2:48][CH2:49][C:50](OCC)=O)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:38][CH:37]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C(OCC)(=O)C>[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2([CH2:48][CH2:49][C:50]3[O:34][N:33]=[C:29]4[C:30]5[C:25]([CH2:26][CH2:27][C:28]=34)=[CH:24][C:23]([CH:21]=[CH2:22])=[CH:32][CH:31]=5)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:38][CH:37]=1

Participants

9

Reactant 6

HCID 7912DiisopropylamineHCID 521998p-Toluenesulfonic acid monohydrateHCID 2724682Lithium diisopropylamideHCID 67168455Ethyl 3-(1-(4-fluorophenyl)cyclohexyl)propanoate2×HCID 121012766(NE)-N-(6-ethenyl-3,4-dihydro-2H-naphthalen-1-ylidene)hydroxylamine2×HCID 178418339Butyllithium

Product 1

HCID 671711303-(2-(1-(4-Fluorophenyl)cyclohexyl)ethyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazoleYield 41.6%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent3×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-20 °C

Procedure

To a stirring solution of the diisopropylamine (0.230 mL, 1.617 mmol) in 2.5 mL of THF at −60° C. was added 2.5 M n-butyl lithium in hexanes (0.657 mL, 1.644 mmol) dropwise. The solution was allowed to stir with a gradual warm up to about −20° C. This freshly generated LDA solution was slowly added to a stirring solution of the 6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (Intermediate 1, 0.151 g, 0.808 mmol) in 1 mL of THF at ice bath temperature and the reaction mixture was stirred at this temperature for 15 min. To this mixture was then slowly added a solution of ethyl 3-(1-(4-fluorophenyl)cyclohexyl)propanoate (Intermediate 7, 0.15 g, 0.539 mmol) in 2 ml of THF. The reaction was warmed to room temperature and stirred for 4 hrs. It was quenched with saturated aq ammonium chloride and partitioned between ethyl acetate and water. The organic layer was then dried over anhyd. magnesium sulfate, concentrated and dried in vacuo. The residue was taken in 3 ml of toluene and treated with p-toluenesulfonic acid monohydrate (0.205 g, 1.078 mmol) and the mixture was then heated at 60° C. for slightly over an hour. The reaction mixture was cooled and diluted with ethyl acetate and washed with saturated. aq. sodium bicarbonate and brine. It was dried over anhyd. magnesium sulfate, concentrated and chromatographed (40 g REDISEP® silica cartridge; eluted with 10% ethyl acetate-hexanes) to yield 3-(2-(1-(4-fluorophenyl)cyclohexyl)ethyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (89.8 mg, 0.224 mmol, 41.5% yield) as a pale oil. LC/MS M+1=402.22.

Workup

  1. stirringthe reaction mixture was stirred at this temperature for 15 min
  2. temperatureThe reaction was warmed to room temperature
  3. stirringstirred for 4 hrs
  4. customIt was quenched with saturated aq ammonium chloride
  5. custompartitioned between ethyl acetate and water
  6. customThe organic layer was then dried over anhyd
  7. concentrationmagnesium sulfate, concentrated
  8. customdried in vacuo
  9. temperaturethe mixture was then heated at 60° C. for slightly over an hour
  10. temperatureThe reaction mixture was cooled
  11. washwashed with saturated
  12. customIt was dried over anhyd
  13. concentrationmagnesium sulfate, concentrated
  14. customchromatographed
  15. wash(40 g REDISEP® silica cartridge; eluted with 10% ethyl acetate-hexanes)

Sources & evidence

ORD record
ord-596f345d9217472689910ba48c5aff68
Source dataset
uspto-grants-2015_12
Patent number
US09216972B2

Reaction notes

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