Dichloromethane → 4-[5-Chloro-4-(1-hydroxy-ethyl)-pyridin-3-yl]-2-methoxy-benzonitrile

HRID 1897601Notes

Reaction equation

HRID 1897601 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]=[C:25]([Cl:30])[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]>[Cl:30][C:25]1[C:26]([CH:27]([OH:29])[CH3:28])=[C:21]([C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([O:2][CH3:1])[CH:10]=2)[CH:22]=[N:23][CH:24]=1

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 595783882-methoxy-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrileHCID 671550211-(3-Bromo-5-chloro-pyridin-4-yl)-ethanol

Product 1

HCID 699381464-[5-Chloro-4-(1-hydroxy-ethyl)-pyridin-3-yl]-2-methoxy-benzonitrileYield 50.4%

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 (570 mg, 2.20 mmol), 1-(3-Bromo-5-chloro-pyridin-4-yl)-ethanol (520 mg, 2.20 mmol) and PdCl2(dppf). CH2Cl2 adduct (65 mg, 0.08 mmol) in DMF (10 mL) was added Na2CO3 solution (2M in eater, 2.75 ml, 5.50 mmol) under Nitrogen atmosphere. The mixture was stirred and heated at 100° C. for 6 hrs. After letting cool to room temperature, solvent was removed in vacuo. The residue was dissolved in DCM and saturated NH4Cl solution. After extraction with DCM and separation, the combined extracts were concentrated and purified by ISCO 40 g (10% MeOH/DCM, v/v, 0-25%) to give 4-[5-Chloro-4-(1-hydroxy-ethyl)-pyridin-3-yl]-2-methoxy-benzonitrile (320 mg, 50%) as colorless solid; ESI-MS m/z: 289 [M+1]+, Retention time: 1.30 min; 1H-NMR (MeOD, 400 MHz) δ 1.55 (d, J=6.8 Hz, 3H), 4.01 (s, 3H), 5.13 (q, J=6.8 Hz, 1H), 7.07 (dd, J=8.0, 2.0 Hz, 1H), 7.19 (d, J=2.0 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 8.31 (s, 1H), 8.61 (s, 1H).

Workup

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

Sources & evidence

ORD record
ord-3fa03133694e40d499bd0f26a30eba5d
Source dataset
uspto-grants-2013_08
Patent number
US08519134B2

Reaction notes

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