* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With ammonium peroxydisulfate; sulfuric acid; silver nitrate In dichloromethane; waterReflux
Step 1 : 2-Acetylisonicotinonitrile To a solution of isonicotinonitrile (52 g, 0.5 mol) in dichloromethane (1300 mL) and water (1 100 mL) were added ammonium persulfate ((NH4)2S208) (170 g, 0.75 mol), silver nitrate (6.8 g, 0.04 mol) and aqueous sulfuric acid (40 mL, 98percent sulfuric acid in 400 mL). A solution of 3-oxo-butyric acid (1 10 g, 1.25 mol) in dichloromethane (100 mL) was added dropwise while keeping the mixture refluxing. The reaction mixture was refluxed for 2 h. The resulting mixture was basified to pH -8-9 using sodium carbonate powder. The mixture was filtered and the filtrate was extracted with dichloromethane (500 mL x 3). The combined organics were dried over sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol to afford 2-acetylisonicotinonitrile (52.0 g, 71.9percent).
Reference:
[1] Journal of Organic Chemistry, 1994, vol. 59, # 8, p. 2125 - 2131
6
[ 100-48-1 ]
[ 431-03-8 ]
[ 37398-49-5 ]
Reference:
[1] Journal of Chemical Research, Miniprint, 1982, # 10, p. 2801 - 2815
[2] Journal of Chemical Research, Miniprint, 1982, # 10, p. 2801 - 2815
7
[ 155806-66-9 ]
[ 37398-49-5 ]
Reference:
[1] Journal of Organic Chemistry, 1994, vol. 59, # 8, p. 2125 - 2131
With tert.-butylhydroperoxide; ferrous(II) sulfate heptahydrate; trifluoroacetic acid; In acetonitrile; for 3h;Reflux;
General procedure: 4.5 g (33 mmol) of methyl isonicotinate (Aldrich, Cat No. M52950-IOOG) and 18 g (66mmol) of ferrous sulfate heptahydrate were dissolved in 100 mL of ACN and 2.8 mL (36 mmol) of TEA. 9.1 mL (66 mmol) of 70% tert-butyl hydroperoxyde and and 3.7 mL (66 mmol) of acetaldehyde were added. The mixture was heated at reflux with stirring for about 3 h. The mixture was allowed to cool down to r.t. and the volatiles were removed under vacuum. The residue was taken up in I M aqueous NaOH and extracted withEtOAc. The organic phase was dried over Na2504, concentrated and the residue was purified by column chromatography (eluent n-hexane:EtOAc 9:1) providing methyl 2- acetylpyridine-4-carboxylate (Intermediate 1) as a beige solid (3.61 g, 61%).
7
[ 110-86-1 ]
[ 37398-49-5 ]
1-[2-(4-cyano-2-pyridyl)-2-oxoethyl]pyridinium iodide[ No CAS ]
2-(2-hydroxypropan-2-yl)isonicotinonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44.3%
In tetrahydrofuran; toluene; at -40℃; for 4.5h;
Step 2: 2-(2-Hydroxypropan-2-yl)isonicotinonitrile To a solution of <strong>[37398-49-5]2-acetylisonicotinonitrile</strong> (67.1 g, 0.457 mol) in tetrahydrofuran (2400 mL) was added dropwise a solution of methylmagnesium bromide (3.0 M, 167.6 mL, 0.503 mol) in toluene/tetrahydrofuran mixture (3:1 ) at -40C over a period of 2.5 h. The reaction mixture was stirred at -40C for another 2 h. A saturated aqueous solution of ammonium chloride (50 mL) was added. The resulting mixture was warmed to room temperature and another 400 mL of a saturated aqueous solution of ammonium chloride was added. The layers were separated and the aqueous layer was extracted with dichloromethane (400 mL x 2). The combined organics were dried over sodium carbonate and sodium sulfate and concentrated. The residue was purified via flash chromatography (ethyl acetate/petroleum ether 1 :20, 0.3% triethylamine) to afford 2-(2- hydroxypropan-2-yl)isonicotinonitrile (33.0 g, 44.3%).
With ammonium peroxydisulfate; sulfuric acid; silver nitrate; In dichloromethane; water;Reflux;
Step 1 : 2-Acetylisonicotinonitrile To a solution of isonicotinonitrile (52 g, 0.5 mol) in dichloromethane (1300 mL) and water (1 100 mL) were added ammonium persulfate ((NH4)2S208) (170 g, 0.75 mol), silver nitrate (6.8 g, 0.04 mol) and aqueous sulfuric acid (40 mL, 98% sulfuric acid in 400 mL). A solution of 3-oxo-butyric acid (1 10 g, 1.25 mol) in dichloromethane (100 mL) was added dropwise while keeping the mixture refluxing. The reaction mixture was refluxed for 2 h. The resulting mixture was basified to pH -8-9 using sodium carbonate powder. The mixture was filtered and the filtrate was extracted with dichloromethane (500 mL x 3). The combined organics were dried over sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol to afford 2-acetylisonicotinonitrile (52.0 g, 71.9%).
2-[(E)-N-hydroxy-C-methylcarbonimidoyl]pyridine-4-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With hydroxylamine hydrochloride; sodium acetate; In ethanol; water; at 55℃; for 1.5h;
A mixture of 0.10 g (0.68 mmol) of <strong>[37398-49-5]2-acetylpyridine-4-carbonitrile</strong> (Intermediate 3), 0.055g (0.78 mmol) of hydroxylamine hydrochloride and 0.065 g (0.78 mmol) of AcONa in 1.0mL of EtCH and 0.5 mL of water was stirred at 55C for about 1.5 h. The reaction mixturewas allowed to cool down to r.t. and about I mL of water was added while cooling in anice/water bath. The resulting solid was filtered off, washed with little water and dried togive 0.073 g (66%) of 2-[(E)-N-hydroxy-C-methyl-carbonimidoyl]pyridine-4-carbonitrile (Example 35) as a colourless solid. 1H NMR (DMSO-d6) (ppm): 11.87 (5, 1 H), 8.92- 8.73 (m, I H), 8.19-8.08 (m, I H), 7.83 (dd, J=1.2, 5.1 Hz, I H), 2.21 (5, 3 H); MS (ESI):m/z: 162 [M-?-H].