1-(1H-Indazol-5-YL)propan-1-one → 4-(1-(4-(2-chloroethoxy)phenyl)-2-(1H-indazol-5-yl)but-1-enyl)-phenol

HRID 626214Notes

Reaction equation

HRID 626214 reaction equation
[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](=O)[CH2:11][CH3:12])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[Cl:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=O)=[CH:20][CH:19]=1>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Cl:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)[CH2:11][CH3:12])=[CH:20][CH:19]=1

Participants

6

Reactant 2

HCID 391039921-(1H-Indazol-5-YL)propan-1-oneHCID 89656364[4-(2-Chloroethoxy)phenyl](4-hydroxyphenyl)methanone

Product 1

HCID 1212667324-(1-(4-(2-chloroethoxy)phenyl)-2-(1H-indazol-5-yl)but-1-enyl)-phenolYield 70%

Reagents, catalysts & solvents 3

HCID 23994ZincCatalystHCID 24193Titanium TetrachlorideCatalystHCID 8028TetrahydrofuranSolvent2×

Procedure

To a stirred mixture of Zn power (1.65 g, 10.0 eq) in dry THF at rt under N2 was slowly added TiCl4 (4.0 eq, 1.1 mL). The resulting mixture was heated at reflux for 1 h and cooled to rt. A mixture of 1-(1H-indazol-5-yl)propan-1-one (1.3 g, 3.0 eq) and (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (0.7 g, 1.0 eq) in dry THF was added, warmed to 80° C., refluxed for additional 1 h, quenched with Na2CO3 (aq), and extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give the title product (0.3 g, 70%, Z/E=1/1). 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.53 (s, 1H), 7.18 (d, J=8.8 Hz, 2H), 7.12 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 6.71-6.88 (m, 1H), 6.72 (d, J=8.8 Hz, 2H), 6.43 (d, J=8.8 Hz, 1H), 4.35 (t, J=7.2 Hz, 1H), 4.24 (t, J=7.2 Hz, 1H), 3.83 (t, J=6.0 Hz, 1H), 3.70 (t, J=6.0 Hz, 1H), 2.47-2.54 (m, 2H), 0.93 (t, J=7.2 Hz, 3H).

Workup

  1. temperatureThe resulting mixture was heated
  2. temperatureat reflux for 1 h
  3. additionwas added
  4. temperaturewarmed to 80° C.
  5. temperaturerefluxed for additional 1 h
  6. customquenched with Na2CO3 (aq)
  7. extractionextracted with EtOAc
  8. customThe extract was dried
  9. concentrationconcentrated
  10. custompurified by column chromatography

Sources & evidence

ORD record
ord-43ef09686f264b848c4a535688a9c066
Source dataset
uspto-grants-2016_04
Patent number
US09309211B2

Reaction notes

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