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4-Cyanobenzaldehyde → 4-((4-Chloro-3-(4-cyanobenzyl)-2-methoxyquinolin-6-yl)(hydroxy)methyl)benzonitrile

HRID 1507320
Notes
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Reaction equation

HRID 1507320 reaction equation
[Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([O:17][CH3:18])[C:11]([CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1)=[C:10]2[Cl:28].[CH:29]([C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1)=[O:30]>C1COCC1>[Cl:28][C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([CH:29]([OH:30])[C:31]3[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=3)[CH:8]=2)[N:13]=[C:12]([O:17][CH3:18])[C:11]=1[CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 3

HCID 660424-CyanobenzaldehydeHCID 867156234-((6-Bromo-4-chloro-2-methoxyquinolin-3-yl)methyl)benzonitrile2×HCID 178418339Butyllithium

Product 1

HCID 1180060204-((4-Chloro-3-(4-cyanobenzyl)-2-methoxyquinolin-6-yl)(hydroxy)methyl)benzonitrile

Reagents, catalysts & solvents 1

HCID 8028Tetrahydrofuran
Solvent
2×

Procedure

A solution of n-BuLi (2.5 M in hexanes, 1.25 mL. 3.12 mmol) was added dropwise by syringe to a solution of 4-((6-bromo-4-chloro-2-methoxyquinolin-3-yl)methyl)benzonitrile (1.211 g, 3.125 mmol, Intermediate 8: step d) in dry THF (15 mL) in a dry ice-acetone bath. After 1-2 minutes, a solution of 4-formylbenzonitrile (498.8 mg, 3.804 mmol) in dry THF (2 mL) was added dropwise. The reaction was stirred for 5 minutes and then removed from the cold bath and allowed to warm to room temperature. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was partitioned between water and dichloromethane. The separated aqueous phase was further extracted with dichloromethane. The combined organic phase was dried (Na2SO4), filtered, and concentrated. Crude product was purified by flash column chromatography (silica gel, 100% EtOAc, followed by 0-5% MeOH-DCM), to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 8.13-8.11 (m, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.63-7.59 (m, 2H), 7.56-7.51 (m, 5H), 7.38-7.34 (m, 2H), 6.03 (d, J=3.2 Hz, 1H), 4.33 (s, 2H), 4.05 (s, 3H); MS m/e 440.0 [M+H]+.

Workup

  1. customremoved from the cold bath
  2. customThe reaction was quenched with saturated aqueous ammonium chloride
  3. customThe mixture was partitioned between water and dichloromethane
  4. extractionThe separated aqueous phase was further extracted with dichloromethane
  5. dry with materialThe combined organic phase was dried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customCrude product was purified by flash column chromatography (silica gel, 100% EtOAc, followed by 0-5% MeOH-DCM)

Sources & evidence

ORD record
ord-43a3e746cea648a1a9fa13e50de14470
Source dataset
uspto-grants-2015_12
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09221804B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes