4-Cyanophenylboronic acid → 4'-Methoxy-3'-methyl-5'-(((4-phenylpiperidin-4-yl)methoxy)methyl)biphenyl-4-carbonitrile

HRID 391479Notes

Reaction equation

HRID 391479 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH3:32])[C:5]([O:30][CH3:31])=[C:6]([CH:29]=1)[CH2:7][O:8][CH2:9][C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1.[C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)#[N:34]>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:31][O:30][C:5]1[C:6]([CH2:7][O:8][CH2:9][C:10]2([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[CH:29][C:2]([C:38]2[CH:39]=[CH:40][C:35]([C:33]#[N:34])=[CH:36][CH:37]=2)=[CH:3][C:4]=1[CH3:32]

Participants

5

Reactant 2

HCID 27343264-Cyanophenylboronic acidHCID 58993511tert-Butyl 4-((5-bromo-2-methoxy-3-methylbenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate

Product 1

HCID 589934854'-Methoxy-3'-methyl-5'-(((4-phenylpiperidin-4-yl)methoxy)methyl)biphenyl-4-carbonitrile

Reagents, catalysts & solvents 2

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
120 °C

Procedure

tert-Butyl 4-((5-bromo-2-methoxy-3-methylbenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate (65 mg, 0.13 mmol), 4-cyanophenylboronic acid (76.4 mg, 0.52 mmol), and tetrakis(triphenylphosphine) palladium(0) (20 mg, 0.01 mmol) were combined in dry tetrahydrofuran (2 mL) in a microwave tube and sealed. After flushing with nitrogen, 0.46 mL of a 1 N potassium hydroxide aqueous solution was introduced. The mixture was heated at 120° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated and treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol and concentrated to afford 28 mg (51%). 1H-NMR (CDCl3, 500 MHz) δ 7.69 (s, 1H), 7.68 (s, 1H), 7.55 (s, 1H), 7.53 (s, 1H), 7.37 (s, 1H), 7.36 (s, 1H), 7.27-7.30 (m, 3H), 7.17-7.20 (m, 2H), 4.46 (s, 2H), 3.61 (s, 3H), 3.50 (s, 2H), 2.89-2.92 (m, 2H), 2.72-2.76 (m, 2H), 2.31 (s, 3H), 2.16-2.19 (m, 2H), 1.88-1.93 (m, 2H). 13C-NMR (CDCl3, 126 MHz) δ 157.1, 145.4, 144.4, 134.7, 132.5, 132.4, 131.7, 129.2, 128.3, 127.6, 127.4, 126.1, 125.8, 119.1, 110.6, 80.2, 68.2, 60.9, 42.7, 41.9, 33.6, 16.2. Mass spec.: 427.42 (MH)+. Accurate mass spec.: m/z 427.2378 [MH]+, Δ=1.8 ppm.

Workup

  1. customsealed
  2. customAfter flushing with nitrogen, 0.46 mL of a 1 N potassium hydroxide aqueous solution
  3. additionwas introduced
  4. temperatureAfter cooling to room temperature
  5. concentrationthe reaction mixture was concentrated
  6. additiontreated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h
  7. customThe solvent was removed in vacuo
  8. washAfter washing the column with several volumes of methanol
  9. washthe product was eluted
  10. washby washing the column with 2 M ammonia in methanol
  11. concentrationconcentrated
  12. customto afford 28 mg (51%)

Sources & evidence

ORD record
ord-01f3a4d12c284b5ea7186cade4a53573
Source dataset
uspto-grants-2013_02
Patent number
US08383821B2

Reaction notes

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