Cesium carbonate → rac-(7aR,11aR)-N-(diphenylmethylene)-11a-vinyl-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2'-[1,3]dioxolan]-3-amine

HRID 718826Notes

Reaction equation

HRID 718826 reaction equation
C([O-])([O-])=O.[Cs+].[Cs+].[C:7](=[NH:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[C:22]1[CH:23]=[CH:24][C:25]2[C:31]3([CH:40]=[CH2:41])[CH2:32][CH2:33][C:34]4([CH2:39][CH:30]3[CH2:29][CH2:28][O:27][C:26]=2[CH:42]=1)[O:38][CH2:37][CH2:36][O:35]4>O1CCOCC1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[C:8]1([C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:20][C:22]2[CH:23]=[CH:24][C:25]3[C:31]4([CH:40]=[CH2:41])[CH2:32][CH2:33][C:34]5([CH2:39][CH:30]4[CH2:29][CH2:28][O:27][C:26]=3[CH:42]=2)[O:35][CH2:36][CH2:37][O:38]5)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1

Participants

8

Reactant 3

HCID 10796Cesium carbonateHCID 136809Benzophenone imineHCID 77430720rac-(7aS,11aS)-3-bromo-11a-vinyl-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2'-[1,3]dioxolane]

Product 1

HCID 86722435rac-(7aR,11aR)-N-(diphenylmethylene)-11a-vinyl-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2'-[1,3]dioxolan]-3-amineYield 78%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

A 1 L round-bottom flask equipped with an air cooled reflux condenser outfitted with a nitrogen inlet adapter was charged with palladium(II) acetate (0.441 g, 1.97 mmol), Xantphos (1.71 g, 2.95 mmol), Cs2CO3 (22.4 g, 68.8 mmol), evacuated and filled with nitrogen (three cycles), and then 1,4-dioxane (131 mL) was added followed by an additional three cycles of evacuation and nitrogen backfilling. The suspension was stirred at rt for about 15 min and then TEA (0.41 mL, 3.0 mmol) was added. After an additional 15 min of stirring at rt, a solution of benzophenone imine (9.90 mL, 59.0 mmol) and rac-(7aS,11aS)-3-bromo-11a-vinyl-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2′-[1,3]dioxolane] (18.0 g, 49.1 mmol) (prepared as described in WO 2012125797) in dioxane (65 mL) was added and the reaction mixture was heated to about 100° C. for about 18 h. The reaction mixture was diluted with EtOAc (300 mL) and filtered. The filtered solid was washed with EtOAc (2×50 mL) and the combined filtrate was concentrated under reduced pressure. The crude material was purified on silica gel (330 g, eluted with 0 to 30% EtOAc in heptane). Collection and concentration of the appropriate fractions gave rac-(7aR,11aR)—N-(diphenylmethylene)-11a-vinyl-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2′-[1,3]dioxolan]-3-amine (85, R2=Vinyl) (17.8 g, 78%). LC/MS, method 3, 2.98 min, MS m/z 466 (M+H)+. 1H NMR (400 MHz, CDCL3) δ 7.86-7.79 (m, 2H), 7.58-7.50 (m, 1H), 7.49-7.40 (m, 2H), 7.38-7.26 (m, 3H), 7.19-7.13 (m, 2H), 7.10-7.04 (m, 1H), 6.73-6.58 (m, 1H), 6.49-6.44 (m, 1H), 5.97-5.85 (m, 1H), 4.96-4.88 (m, 1H), 4.42-4.32 (m, 1H), 4.08-3.98 (m, 1H), 3.99-3.86 (m, 4H), 3.71-3.59 (m, 1H), 2.41-2.30 (m, 1H), 2.29-2.19 (m, 1H), 2.16-2.08 (m, 1H), 1.88-1.60 (m, 4H), 1.61-1.46 (m, 1H), 1.44-1.35 (m, 1H).

Workup

  1. customA 1 L round-bottom flask equipped with an air
  2. temperaturecooled
  3. temperaturereflux condenser
  4. customoutfitted with a nitrogen inlet adapter
  5. customevacuated
  6. additionfilled with nitrogen (three cycles)
  7. addition1,4-dioxane (131 mL) was added
  8. stirringAfter an additional 15 min of stirring at rt
  9. temperaturethe reaction mixture was heated to about 100° C. for about 18 h
  10. filtrationfiltered
  11. washThe filtered solid was washed with EtOAc (2×50 mL)
  12. concentrationthe combined filtrate was concentrated under reduced pressure
  13. customThe crude material was purified on silica gel (330 g, eluted with 0 to 30% EtOAc in heptane)
  14. customCollection and concentration of the appropriate fractions

Sources & evidence

ORD record
ord-e6c15f1e0d974584a4d3ee9b4a13a789
Source dataset
uspto-grants-2015_11
Patent number
US09193744B2

Reaction notes

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