N,N,N',N'-Tetramethylethylenediamine → (E)-4-(4-chlorostyryl)-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-2(1H)-one

HRID 2059850Notes

Reaction equation

HRID 2059850 reaction equation
[Cl:1][C:2]1[CH:16]=[CH:15][C:5](/[CH:6]=[CH:7]/[C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[N:9]=2)=[CH:4][CH:3]=1.[OH:17][C:18]([CH3:33])([CH3:32])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[O:30][CH3:31].CN(C)CCN(C)C.B(O)O.O.CO.FC(C(O)=O)(F)F>CO.O.C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.[Cu]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[C:8]2[CH:13]=[CH:12][N:11]([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH2:19][C:18]([OH:17])([CH3:33])[CH3:32])=[C:22]([O:30][CH3:31])[CH:23]=3)[C:10](=[O:14])[N:9]=2)=[CH:15][CH:16]=1

Participants

11

Reactant 5

HCID 8037N,N,N',N'-Tetramethylethylenediamine2×HCID 61668Boronic AcidHCID 21999908MeOH water TFAHCID 585798634-(2-Hydroxy-2-methylpropoxy)-3-methoxyphenylboronic acidHCID 178517729HCID 178517729, compound

Product 1

HCID 58579881(E)-4-(4-chlorostyryl)-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-2(1H)-one

Reagents, catalysts & solvents 5

HCID 8895Cupric acetateCatalystHCID 23978CopperCatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

To a stirred mixture of (E)-4-(4-chlorostyryl)pyrimidin-2(1H)-one Part A (21 mg, 0.09 mmol), 4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenylboronic acid Part D of Procedure 4 (43 mg, 0.18 mmol) and copper (II) acetate (16.39 mg, 0.090 mmol) in MeOH (2 mL) and H2O (0.5 mL) was added N1,N1,N2,N2-tetramethylethane-1,2-diamine (21 mg, 0.18 mmol) at RT. After stirring at RT for 45 min under oxygen, the reaction diluted with CH2Cl2 and washed sequentially with 5% aq. sulfuric acid and sat. NaHCO3. The organic phase was dried (MgSO4) and concentrated. LC/MS showed incomplete reaction (starting pyrimidinone:desired product=ca. 4:1). The crude product mixture was resubjected to the above reaction conditions using another 2 equivalents of the boronic acid, copper salt and N1,N1,N2,N2-tetramethylethane-1,2-diamine After the above described workup, the crude product mixture was subjected to preparative HPLC (ODS column/water-MeOH-TFA 90:10:0.1 to 10:90:0.1 gradient) to afford a brown solid. Further purification was achieved by dissolution of this solid in a few drops of MeOH followed by addition of MTBE (ca. 1 mL) which upon standing at RT induced the formation of a yellow precipitate. The precipitated yellow solid was isolated to afford the title compound (E)-4-(4-chlorostyryl)-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-2(1H)-one B-6 (8 mg, 0.018 mmol, 20% yield) as a yellow solid. LC/MS 427 (M+H)+, tR 0.84 min (method 5); 1H NMR (400 MHz, chloroform-D) δ 7.91 (1H, d, J=16.06 Hz), 7.69 (1H, d, J=6.78 Hz), 7.54 (2H, d, J=8.28 Hz), 7.39 (2H, d, J=8.53 Hz), 6.87-7.01 (4H, m), 6.49 (1H, d, J=6.78 Hz), 3.87 (3H, s), 3.85 (2H, s), 1.36 (6H, s).

Workup

  1. washwashed sequentially with 5% aq. sulfuric acid and sat. NaHCO3
  2. dry with materialThe organic phase was dried (MgSO4)
  3. concentrationconcentrated
  4. customreaction (starting pyrimidinone:desired product=ca. 4:1)
  5. customto afford a brown solid
  6. customFurther purification
  7. dissolutionwas achieved by dissolution of this solid in a few drops of MeOH
  8. additionfollowed by addition of MTBE (ca. 1 mL) which
  9. customupon standing at RT
  10. customThe precipitated yellow solid was isolated

Sources & evidence

ORD record
ord-41dfa91af7cf4613b0c95133faf912e2
Source dataset
uspto-grants-2012_10
Patent number
US08278316B2

Reaction notes

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