Potassium Carbonate → 2-Methyl-6-((1-phenylpiperidin-4-yl)methyl)-2H-benzo[b][1,4]oxazin-3(4H)-one

HRID 1184498Notes

Reaction equation

HRID 1184498 reaction equation
[CH2:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.B1C2CCCC1CCC2.Br[C:24]1[CH:35]=[CH:34][C:27]2[O:28][CH:29]([CH3:33])[C:30](=[O:32])[NH:31][C:26]=2[CH:25]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C=O)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>[CH3:33][CH:29]1[O:28][C:27]2[CH:34]=[CH:35][C:24]([CH2:1][CH:2]3[CH2:3][CH2:4][N:5]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:6][CH2:7]3)=[CH:25][C:26]=2[NH:31][C:30]1=[O:32]

Participants

9

Reactant 4

HCID 11430Potassium CarbonateHCID 789669-Borabicyclo(3.3.1)nonaneHCID 226229036-bromo-2-methyl-3,4-dihydro-2H-1,4-benzoxazin-3-oneHCID 589027244-Methylene-1-phenylpiperidine

Product 1

HCID 667168272-Methyl-6-((1-phenylpiperidin-4-yl)methyl)-2H-benzo[b][1,4]oxazin-3(4H)-one

Reagents, catalysts & solvents 4

HCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolvent2×HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
75 °C

Procedure

To a 20 mL screw cap vial, under N2, 4-methylene-1-phenylpiperidine (0.0906 g, 0.523 mmol) was diluted with 0.5M THF solution of 9-BBN (1.046 mL, 0.523 mmol) and stirred at 75° C. for 1 hr. The reaction mixture was then added to a suspension of 6-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one 19 (0.127 g, 0.523 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.0128 g, 0.016 mmol) and K2CO3 (0.145 g, 1.046 mmol) in DMF (1.0 mL) and water (0.1 mL) and stirred at 60° C. for 4 hr. The mixture was cooled to RT, diluted with water (20 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers was washed with brine, dried with MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (10%-50% EA/Hex) provided the desired product as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21-1.32 (m, 2H) 1.40 (d, J=6.82 Hz, 3H) 1.47 (br. s., 1 H) 1.64 (d, J=13.14 Hz, 2H) 2.45 (d, J=6.82 Hz, 2H) 2.52-2.62 (m, 2H) 3.59-3.70 (m, 2H) 4.55-4.67 (m, 1H) 6.65-6.78 (m, 3H) 6.81-6.94 (m, 3H) 7.11-7.22 (m, 2H) 10.58 (s, 1 H). ESI-MS: m/z 337.3 (M+H)+.

Workup

  1. customTo a 20 mL screw cap vial, under N2
  2. stirringstirred at 60° C. for 4 hr
  3. temperatureThe mixture was cooled to RT
  4. extractionextracted with ethyl acetate (2×20 mL)
  5. washThe combined organic layers was washed with brine
  6. dry with materialdried with MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customPurification by flash column chromatography (10%-50% EA/Hex)

Sources & evidence

ORD record
ord-af23021923a1422aa5c40818d36d5304
Source dataset
uspto-grants-2014_03
Patent number
US08669249B2

Reaction notes

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