Cesium carbonate → 2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-4-(1H-pyrazol-5-yl)-1H-benzimidazole

HRID 1749580

Reaction equation

HRID 1749580 reaction equation
Br[C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:3]=1.[NH:29]1[C:33](B(O)O)=[CH:32][CH:31]=[N:30]1.C([O-])([O-])=O.[Cs+].[Cs+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:11][C:8]1[N:7]([CH2:12][C:13]2[C:22]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:16]=[CH:15][CH:14]=2)[C:6]2[CH:5]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:3]=[C:2]([C:31]3[NH:30][N:29]=[CH:33][CH:32]=3)[C:10]=2[N:9]=1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 83681Tris(1,1-dimethylethyl)phosphineHCID 112519791H-Pyrazole-5-boronic acidHCID 669770504-bromo-2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole

Product 1

HCID 569595332-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-4-(1H-pyrazol-5-yl)-1H-benzimidazole

Reagents, catalysts & solvents 3

HCID 6505921(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 4-bromo-2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole (200 mg, 0.46 mmol), 1H-pyrazol-5-ylboronic acid (100 mg, 0.92 mmol), Pd(dba)2 (40 mg, 0.046 mmol), Cs2CO3 (300 mg, 0.92 mmol) and P(t-Bu)3 (10 wt % in hexane, 20 mg, 0.092 mmol) in dioxane (20 mL) and water (10 mL), was stirred at 100° C. for 18 h under a nitrogen atmosphere. The reaction mixture was cooled and then concentrated. The resulting residue was purified by silica gel chromatography eluted with EtOAc to give the product (140 mg 72%), as a white solid. 1H NMR showed this compound is in a form of tautomeric mixture (major tautomer/minor tautomer=5/3)1H NMR of the major tautomer (300 MHz, DMSO-d6) δ ppm 2.45 (s, 3H), 3.08 (s, 4H), 3.71 (s, 4H), 6.00 (s, 2H), 6.37 (d, 1H, J=7.2 Hz), 6.96 (s, 1H), 7.24-7.72 (m, 6H), 7.83-7.87 (m, 1H), 8.01 (d, 1H, J=7.2 Hz), 8.25 (d, 1H, J=4.2 Hz), 13.24 (br s, 1H); LC-MS: m/e=424 [M+1]+

Workup

  1. temperatureThe reaction mixture was cooled
  2. concentrationconcentrated
  3. customThe resulting residue was purified by silica gel chromatography
  4. washeluted with EtOAc
  5. customto give the product (140 mg 72%)

Sources & evidence

ORD record
ord-2e5f1dd5cd7f4f2e94035eafd53c4238
Source dataset
uspto-grants-2015_10
Patent number
US09156797B2

Linked notes

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