Dichloromethane → 4-(4-(1-Hydroxyethyl)pyridin-3-yl)-2-methoxybenzonitrile

HRID 1897584Notes

Reaction equation

HRID 1897584 reaction equation
[CH3:1][O:2][C:3]1[CH:10]=[C:9](B2OC(C)(C)C(C)(C)O2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].Br[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[CH:27]([OH:29])[CH3:28].C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:29][CH:27]([C:26]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([O:2][CH3:1])[CH:10]=1)[CH3:28]

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 595783882-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrileHCID 667978531-(3-Bromopyridin-4-yl)ethanol

Product 1

HCID 532372824-(4-(1-Hydroxyethyl)pyridin-3-yl)-2-methoxybenzonitrileYield 67%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

To the solution of 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (3.53 g, 13.61 mmol), 1-(3-bromopyridin-4-yl)ethanol (2.50 g, 12.37 mmol) and PdCl2(dppf). CH2Cl2 adduct (505 mg, 0.62 mmol) in DMF (60 mL) was added 2M Na2CO3 solution (12.3 ml, 24.6 mmol) under Nitrogen atmosphere. The mixture was stirred and heated at 100° C. for 4 hrs. After letting cool to room temperature, solvent was removed in vacuo. The resulting residue was dissolved in DCM and saturated NH4Cl solution. After extraction and separation, the extracts were concentrated and purified by ISCO 40 g (10% MeOH/DCM=0-25%) to give 4-(4-(1-hydroxyethyl)pyridin-3-yl)-2-methoxybenzonitrile (2.1 g, 67%) as a white solid; ESI-MS m/z: 255 [M+1]+, Retention time 1.24 min. 1H-NMR (MeOD, 400 MHz) δ 1.36 (d, J=6.4 Hz, 3H), 3.98 (s, 3H), 4.88 (q, J=6.4 Hz, 1H), 7.06 (dd, J=8.0, 1.2 Hz, 1H), 7.18 (s, 1H), 7.71 (d, J=5.2 Hz, 1H), 7.73 (d, J=1.2 Hz, 1H), 8.36 (s, 1H), 8.58 (d, J=5.2 Hz, 1H). The racemate was separated by HPLC (ChiralPak IA-H, 5% MeOH/5% EtOH/Heptane) to give 4-[4-((R)-1-Hydroxy-ethyl)-pyridin-3-yl]-2-methoxy-benzonitrile 14-(enantiomer-1) retention time: 16.18 min) and 4-[4-((S)-1-Hydroxy-ethyl)-pyridin-3-yl]-2-methoxy-benzonitrile 14-(enantiomer-2), retention time: 19.07 min).

Workup

  1. temperatureAfter letting cool to room temperature
  2. customsolvent was removed in vacuo
  3. dissolutionThe resulting residue was dissolved in DCM
  4. extractionAfter extraction and separation
  5. concentrationthe extracts were concentrated
  6. custompurified by ISCO 40 g (10% MeOH/DCM=0-25%)

Sources & evidence

ORD record
ord-7af6b6c09063445d89c2d30e64b6b9bb
Source dataset
uspto-grants-2013_08
Patent number
US08519134B2

Reaction notes

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