1,2-Dimethoxyethane → rac-(7aR,11aS)-11a-ethyl-2-methyl-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2'-[1,3]dioxolan]-3-amine

HRID 718829Notes

Reaction equation

HRID 718829 reaction equation
Br[C:2]1[C:22]([NH2:23])=[CH:21][C:5]2[O:6][CH2:7][CH2:8][CH:9]3[CH2:18][C:13]4([O:17][CH2:16][CH2:15][O:14]4)[CH2:12][CH2:11][C:10]3([CH2:19][CH3:20])[C:4]=2[CH:3]=1.[C:24]([O-])([O-])=O.[Cs+].[Cs+].COCCOC.CB1OB(C)OB(C)O1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:19]([C:10]12[CH2:11][CH2:12][C:13]3([O:14][CH2:15][CH2:16][O:17]3)[CH2:18][CH:9]1[CH2:8][CH2:7][O:6][C:5]1[CH:21]=[C:22]([NH2:23])[C:2]([CH3:24])=[CH:3][C:4]2=1)[CH3:20]

Participants

7

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 10796Cesium carbonateHCID 574072TrimethylboroxineHCID 86722436rac-(7aR,11aS)-2-bromo-11a-ethyl-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2'-[1,3]dioxolan]-3-amine

Product 1

HCID 86722437rac-(7aR,11aS)-11a-ethyl-2-methyl-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2'-[1,3]dioxolan]-3-amineYield 74.9%

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 962WaterSolvent

Conditions

Temperature
90 °C

Procedure

A 500 mL round-bottom flask equipped with air cooled reflux condenser outfitted with a nitrogen inlet adapter was charged with rac-(7aR,11aS)-2-bromo-11a-ethyl-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2′-[1,3]dioxolan]-3-amine (87, R2=Ethyl) (9.14 g, 23.9 mmol), bis(triphenylphosphine)palladium(II) chloride (0.839 g, 1.20 mmol) and Cs2CO3 (23.4 g, 71.7 mmol), and then DME (180 mL), water (60 mL) and trimethylboroxine (6.67 mL, 47.8 mmol) were added. The reaction mixture was heated to about 90° C. for about 15 h. The reaction was allowed to cool to rt and then it was partitioned between EtOAc (350 mL) and water (200 mL). After separating the layers, the aqueous phase was extracted with EtOAc (2×100 mL). The combined organic phases were then washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was purified on silica gel (330 g, eluted with 0% to 50% EtOAc in heptane). Collection and concentration of the appropriate fractions gave rac-(7aR,11aS)-11a-ethyl-2-methyl-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2′-[1,3]dioxolan]-3-amine (88, R2=Ethyl) (5.68 g, 74.8%) containing about 20% of a minor regioisomer. The material was used directly in Step #5 without further purification. LC/MS, method 3, 2.26 min, MS m/z 318 (M+H)+.

Workup

  1. customA 500 mL round-bottom flask equipped with air
  2. temperaturecooled
  3. temperaturereflux condenser
  4. customoutfitted with a nitrogen inlet adapter
  5. temperatureto cool to rt
  6. customit was partitioned between EtOAc (350 mL) and water (200 mL)
  7. customAfter separating the layers
  8. extractionthe aqueous phase was extracted with EtOAc (2×100 mL)
  9. washThe combined organic phases were then washed with brine (500 mL)
  10. dry with materialdried over Na2SO4
  11. filtrationfiltered
  12. concentrationconcentrated under reduced pressure
  13. customThe material was purified on silica gel (330 g, eluted with 0% to 50% EtOAc in heptane)
  14. customCollection and concentration of the appropriate fractions

Sources & evidence

ORD record
ord-840cb7c3d36d4e15b7baee5efdd16025
Source dataset
uspto-grants-2015_11
Patent number
US09193744B2

Reaction notes

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