Potassium Phosphate, Tribasic → 3-Chloro-5-(4-phenoxyphenyl)isonicotinonitrile

HRID 81033Notes

Reaction equation

HRID 81033 reaction equation
Cl[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].[O:11]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].O1CCOCC1>[Cl:10][C:6]1[CH:7]=[N:8][CH:9]=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:19][CH:20]=2)[C:3]=1[C:4]#[N:5]

Participants

7

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 27343774-Phenoxyphenylboronic acidHCID 111375993,5-Dichloropyridine-4-carbonitrile

Product 1

HCID 669269133-Chloro-5-(4-phenoxyphenyl)isonicotinonitrileYield 55%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 12976736Bis(ditert-butyl(cyclopenta-2,4-dien-1-yl)phosphane);iron(2+)CatalystHCID 312751,4-DioxaneSolvent

Procedure

A mixture of 3,5-dichloroisonicotinonitrile (10.00 g, 57.8 mmol), 4-phenoxyphenylboronic acid (12.37 g, 57.8 mmol), palladium(II) acetate (0.389 g, 1.734 mmol), potassium phosphate (30.7 g, 145 mmol) and 1,1′-bis(di-t-butylphosphino)ferrocene (0.833 g, 1.734 mmol) was pumped and backfilled with nitrogen 3 times. Dioxane (200 mL) was added. The reaction vial was again pumped and backfilled with nitrogen 3 times, sealed and heated to gentle reflux for 20 h. The dioxane solvent was evaporated in vacuo. The residue was diluted with water (150 mL) and brine (150 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts were washed with brine (25 mL), dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 0-15% ethyl acetate in dichloromethane-hexanes (1:2), gave 3-chloro-5-(4-phenoxyphenyl)isonicotinonitrile as tan liquid (9.71 g, 55% yield). 1H NMR (500 CDCl3) δ ppm 8.74 (1H, s), 8.70 (1H, s), 7.50-7.59 (2H, m), 7.35-7.46 (2H, m), 7.20 (1H, t, J=7.42 Hz), 7.06-7.16 (4H, m); MS (ES+) m/z: 307 (M+H); LC retention time: 4.298 min (analytical HPLC Method A).

Workup

  1. customThe reaction
  2. customsealed
  3. temperatureheated
  4. temperatureto gentle reflux for 20 h
  5. customThe dioxane solvent was evaporated in vacuo
  6. additionThe residue was diluted with water (150 mL) and brine (150 mL)
  7. extractionextracted with ethyl acetate (3×100 mL)
  8. washThe combined extracts were washed with brine (25 mL)
  9. dry with materialdried (MgSO4)
  10. concentrationconcentrated
  11. washSilica gel chromatography, eluting with 0-15% ethyl acetate in dichloromethane-hexanes (1:2)

Sources & evidence

ORD record
ord-200c62f12535436abf0e038c889c3582
Source dataset
uspto-grants-2014_09
Patent number
US08846673B2

Reaction notes

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