Water → 5-(4-fluorophenyl)-1-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole

HRID 2178395Notes

Reaction equation

HRID 2178395 reaction equation
I[C:2]1[CH:32]=[CH:31][C:5]2[N:6]([CH:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=4)=[C:13]([O:29][CH3:30])[CH:12]=3)[CH3:10])[CH:7]=[N:8][C:4]=2[CH:3]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCCC1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:2]2[CH:32]=[CH:31][C:5]3[N:6]([CH:9]([C:11]4[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]5[CH:20]=[N:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=5)=[C:13]([O:29][CH3:30])[CH:12]=4)[CH3:10])[CH:7]=[N:8][C:4]=3[CH:3]=2)=[CH:36][CH:35]=1

Participants

7

Reactant 4

HCID 962WaterHCID 62657Potassium Phosphate, TribasicHCID 2856454-Fluorophenylboronic acidHCID 1181140745-iodo-1-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole

Product 1

HCID 1180098375-(4-fluorophenyl)-1-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazoleYield 115.5%

Reagents, catalysts & solvents 2

HCID 54751079XPhos PalladacycleCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
75 °C

Procedure

To a stirred solution of 5-iodo-1-(1-(3-methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazole (0.248 g, 0.45 mmol), (4-fluorophenyl)boronic acid (0.088 g, 0.63 mmol), and potassium phosphate tribasic (0.485 g, 2.24 mmol) in tetrahydrofuran (7 mL)/water (5 mL) was added 2nd generation XPhos precatalyst (0.024 g, 0.031 mmol). The yellow solution was degassed under vacuum/backfilled with nitrogen (×3). The mixture was heated to 75° C. After 45 min, the brown reaction mixture was allowed to cool to room temperature and was diluted with water (30 mL). The mixture was extracted with dichloromethane (2×25 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 0.271 g of a brown oil. Chromatographic purification (CombiFlash, 12 g SiO2 gold column, 1-5% methanol/dichloromethane elute) afforded 0.200 g (86%) of the product as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J=2.0 Hz, 1H), 8.08 (s, 1H), 7.99-7.94 (m, 2H), 7.70 (dd, J=8.1, 0.8 Hz, 1H), 7.61-7.52 (m, 2H), 7.40 (dd, J=8.4, 1.7 Hz, 1H), 7.27-7.23 (m, 1H), 7.16-7.09 (m, 2H), 6.88-6.84 (m, 1H), 6.80-6.76 (m, 1H), 6.75-6.73 (m, 1H), 5.60 (q, J=7.0 Hz, 1H), 5.20 (s, 2H), 3.80 (s, 3H), 2.01 (d, J=7.0 Hz, 3H) ppm; (M+1)=522.

Workup

  1. customThe yellow solution was degassed under vacuum/backfilled with nitrogen (×3)
  2. temperatureto cool to room temperature
  3. additionwas diluted with water (30 mL)
  4. extractionThe mixture was extracted with dichloromethane (2×25 mL)
  5. dry with materialThe combined organic phases were dried over magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated

Sources & evidence

ORD record
ord-cb73734c44054f5bb460cf9f20e657e1
Source dataset
uspto-grants-2015_06
Patent number
US09067914B1

Reaction notes

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