Potassium Carbonate → Ethyl 4-(4-((2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)piperidin-1-yl)benzoate

HRID 1184502Notes

Reaction equation

HRID 1184502 reaction equation
[CH2:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.B1C2CCCC1CCC2.Br[C:29]1[CH:40]=[CH:39][C:32]2[O:33][CH:34]([CH3:38])[C:35](=[O:37])[NH:36][C:31]=2[CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.C1COCC1>[CH3:38][CH:34]1[O:33][C:32]2[CH:39]=[CH:40][C:29]([CH2:1][CH:2]3[CH2:7][CH2:6][N:5]([C:8]4[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=4)[CH2:4][CH2:3]3)=[CH:30][C:31]=2[NH:36][C:35]1=[O:37]

Participants

10

Reactant 4

HCID 11430Potassium CarbonateHCID 789669-Borabicyclo(3.3.1)nonaneHCID 16109082Ethyl 4-(4-methylenepiperidin-1-yl)benzoateHCID 226229036-bromo-2-methyl-3,4-dihydro-2H-1,4-benzoxazin-3-one

Product 1

HCID 67283662Ethyl 4-(4-((2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)piperidin-1-yl)benzoateYield 25.6%

Reagents, catalysts & solvents 5

HCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolvent2×HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
75 °C

Procedure

Ethyl 4-(4-methylenepiperidin-1-yl)benzoate 390C (145.8 mg, 0.594 mmol) was taken up with 0.5M THF solution of 9-BBN (1.189 mL, 0.594 mmol) under nitrogen and stirred at 75° C. for 1 h. The reaction mixture was then added to a suspension of 6-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one 19 (144 mg, 0.594 mmol), PdCl2(dppf)-CH2Cl2 adduct (14.56 mg, 0.018 mmol) and potassium carbonate (164 mg, 1.189 mmol) in DMF (2.0 mL) and water (0.2 mL) and stirred at 60° C. The reaction was pulled, cooled to RT, and diluted with water (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL); the organic layer was separated and washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Flash column chromatography (10%-20%-30% EA/Hex) provided the desired product as an off-white solid (62 mg, 25% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09-1.32 (m, 6H) 1.35-1.46 (m, 2H) 1.56-1.76 (m, 3H) 2.43 (d, J=6.82 Hz, 2H) 2.77 (t, J=11.75 Hz, 2H) 3.82-3.96 (m, 2H) 4.22 (q, J=7.07 Hz, 2H) 4.56-4.66 (m, 1H) 6.63-6.77 (m, 2H) 6.86 (d, J=8.08 Hz, 1H) 6.94 (d, J=9.09 Hz, 2H) 7.69-7.82 (m, 2H) 10.59 (s, 1H). ESI-MS: m/z 409.4 (M+H)+.

Workup

  1. stirringstirred at 60° C
  2. temperaturecooled to RT
  3. extractionThe aqueous layer was extracted with ethyl acetate (2×20 mL)
  4. customthe organic layer was separated
  5. washwashed with brine
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-d478c1e6ba4f487381ce60ca411bad03
Source dataset
uspto-grants-2014_03
Patent number
US08669249B2

Reaction notes

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