Cesium carbonate → Trans-8-(4-fluorophenyl)-2-methyl-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[3,4-c]azepin-6(10bH)-one

HRID 84939Notes

Reaction equation

HRID 84939 reaction equation
Cl[C:2]1[CH:17]=[CH:16][C:5]2[C@@H:6]3[CH2:14][N:13]([CH3:15])[CH2:12][C@H:7]3[CH2:8][NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.N12CCCN=C1CCCCC2>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:17]=[CH:16][C:5]3[C@@H:6]4[CH2:14][N:13]([CH3:15])[CH2:12][C@H:7]4[CH2:8][NH:9][C:10](=[O:11])[C:4]=3[CH:3]=2)=[CH:21][CH:20]=1

Participants

9

Reactant 5

HCID 10796Cesium carbonateHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 83681Tris(1,1-dimethylethyl)phosphineHCID 2856454-Fluorophenylboronic acidHCID 54673810trans-8-Chloro-2-methyl-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[3,4-c]azepin-6(10bh)-one

Product 1

HCID 66821412Trans-8-(4-fluorophenyl)-2-methyl-1,2,3,3a,4,5-hexahydrobenzo[e]pyrrolo[3,4-c]azepin-6(10bH)-one

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a microwave vial was added a mixture of Example 53 (750 mg, 2.99 mmol), 4-fluorophenylboronic acid (1674 mg, 11.97 mmol), Cs2CO3 (1170 mg, 3.59 mmol) and N,N-dimethylformamide (6.5 mL). Then tri-tert-butylphosphine (0.179 mL, 0.179 mmol, 1.0 M in toluene), palladium(II) acetate (20.15 mg, 0.09 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.067 mL, 0.449 mmol) subsequently were added under nitrogen. The vial was sealed, and this mixture was then irradiated in a Biotage Initiator™ 2.0 microwave instrument for 50 minutes at 150° C. Reaction completion was monitored by LC/MS. Another batch was done at same scale. After the reactions were cooled to room temperature, the two reaction mixtures were combined and diluted with ethyl acetate and then filtered through a pad of diatomaceous earth. The filtrate was washed with saturated brine (2×), and the combined aqueous phases were extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, then concentrated, and purified by flash column chromatography with methanol in dichloromethane (0-20%, 0.5% triethylamine). A solid was obtained, which was purified again by crystallization from ethyl acetate to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.07 (d, J=2.1, 1H), 8.03 (s, 1H), 7.74-7.66 (m, 3H), 7.34-7.22 (m, 3H), 3.34-3.21 (m, 2H), 3.19-3.04 (m, 2H), 2.93 (dd, J=8.9, 10.3, 1H), 2.71-2.59 (m, 2H), 2.39 (s, 3H), 2.30-2.14 (m, 1H); MS (ESI+) m/z 310.9 [M+H]+.

Workup

  1. customThe vial was sealed
  2. customthis mixture was then irradiated in a Biotage Initiator™ 2.0 microwave instrument for 50 minutes at 150° C
  3. customReaction completion
  4. customthe two reaction mixtures
  5. filtrationfiltered through a pad of diatomaceous earth
  6. washThe filtrate was washed with saturated brine (2×)
  7. extractionthe combined aqueous phases were extracted with ethyl acetate
  8. dry with materialThe combined organic layers were dried over Na2SO4
  9. concentrationconcentrated
  10. custompurified by flash column chromatography with methanol in dichloromethane (0-20%, 0.5% triethylamine)
  11. customA solid was obtained
  12. customwhich was purified again by crystallization from ethyl acetate

Sources & evidence

ORD record
ord-4a4b2754992742c6b74bc4af984f5980
Source dataset
uspto-grants-2014_09
Patent number
US08846951B2

Reaction notes

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