| 83% |
With 3-chloro-benzenecarboperoxoic acid; In chloroform; at 0℃; for 16h; |
To a stirred solution of 2,3-lutidine (5.00 g, 46.7 mmol) in chloroform (100 mL) at 0C was added m- chloroperbenzoic acid (12.0 g of a 77% max reagent) portionwise over 5 min. The reaction mixture was stirred for an additional 30 min at 0C and then allowed to warm to room temperature. After 16 h, the reaction mixture was concentrated to dryness, water (20 mL) was added and the pH of the mixture was adjusted to 8 (saturated NaHCO3). The mixture was concentrated and the residue was extracted with dichloromethane/methanol (4: 1). The extracts were concentrated to a white solid. Subsequent column purification (Si02 ; dichloromethane/methanol, 9: 1) gave 2, 3-lutidine-N-oxide as a white solid (4.80 g, 83%). A stirred solution of 2,3-lutidine-N-oxide (4.80 g, 39.0 mmol) in acetic anhydride (50 mL) was heated under reflux overnight, cooled and then concentrated to dryness providing (2-acetoxymethyl) -3-methylpyridine as a brown oil (6.34 g). A mixture of the crude (2-acetoxymethyl)-3- methylpyridine and K2CO3 (10. 0 g, 72.4 mmol), methanol (60 mL) and water (30 mL) was stirred at room temperature overnight. The solid was filtered off and the filtrate was concentrated to dryness. The residue, after column chromatography (Si02 ; dichloromethane/methanol, 9: 1), gave (2-hydroxymethyl) -3-methylpyridine as a light brown oil (2.86 g, 59% over 2 steps). (2-Hydroxymethyl) -3-methylpyridine: 1H NMR (CDC13) : 5 8.41 (d, J = 4.9, 1 H), 7.48 (d, J = 7.5, 1 H), 7.16 (dd, J = 4.9 and 7.5, 1 H), 4.69 (s, 2 H), 4.00 (br, 1 H), 2.22 (s, 3 H). |
| 78% |
With 1,2-diphenyl-1,1,2,2-tetrahydroperoxyethane; In acetonitrile; at 20℃; for 0.25h; |
General procedure: To a solution of pyridine derivative 1 or tertiary amine 2(1 mmol) in acetonitrile (5 mL) was added 1,2-diphenyl-1,1,2,2-tetrahydroperoxyethane (1 g, 3 mmol). The resulting mixture was stirred at room temperature for an appropriate time (Table 2). After completion of the reaction as monitored by TLC, the reaction mixture was diluted with toluene (10 mL) and water (6 mL). The aqueous layer which contained the product was separated from theorganic layer and evaporated under reduced pressure toleave the product. The products were characterized on the basis of their melting points, elemental analysis and IR, 1HNMR and 13C NMR spectral analysis. |
| 65.3% |
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; |
To a solution of 2,3-dimethylpyridine (20.0 g, 186.65 mmol) in DCM (400.0 mL) was added 3-chlorobenzoperoxoic acid (m-CPBA) (46.7 g, 270.64 mmol). The solution was stirred at room temperature overnight. An aqueous solution of sodium sulfite was added and the resulting mixture was extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, the filtrate was concentrated and the residue was purified by chromatography on a silica gel column to give X4-348-2 (15.0 g, 65.3% yield) as white solid. ?H NIVIR (CDC13) 2.34(s, 3H), 2.5 1(s, 3H), 7.03-7.05 (m, 2H), 8.16 (s, 1H). |
|
With dihydrogen peroxide; In acetic acid;Heating / reflux; |
5,6-dimethylpicolinonitrile: 2,3-lutidine (13.25 mmol) was refluxed overnight with 18 ml of glacial AcOH and 6 ml of hydrogen peroxide. The solvent was evaporated and the residue was co-evaporated two times with water, basified with Na2CO3 and extracted with chloroform. The organic layer was dried over Na2SO4 and evaporated to give 1.45 g of a crystalline product. The product (615 mg, 5 mmol) was reacted with trimethylsilane carbonitrile (5.5 mmol) in dichloromethane (10 mL) at room temperature for 5 min followed by addition of dimethylcarbamoyl chloride (5 mmol) and the solution was stirred at room temperature for 3 days. The reaction mixture was treated with 10% potassium carbonate (10 mL), the organic layer was separated and the aqueous layer was extracted 2 times with dichloromethane. The organic phase was dried over Na2SO4 and evaporated to give 495 mg of 5,6-dimethylpicolinonitrile (75%). 1H NMR (500 MHz, CDCl3): delta 2.35 (s, 3H), 2.53 (s, 3H), 7.43-7.45 (d, 1H), 7.51-7.52 (d, 1H); 13C: delta 19.71, 22.80, 117.87, 126.36, 130.60, 136.58, 137.66, 159.84). MS (M+H, 133.1). |
| 97 - 98%Chromat. |
With magnesium bis(monoperoxyphthalate)hexahydrate; potassium carbonate; In water; at 20 - 30℃; for 3h;pH 6.5 - 7.0; |
a) <strong>[583-61-9]2,3-Dimethylpyridine</strong> N-oxide 46.2 g of magnesium monoperoxyphthalate hexahydrate in 150 ml of water were slowly added at room temperature to a solution of 11.32 ml (0.100 mole) of 2,3-dimethylpyridine and 11.2 g of potassium carbonate in 50 ml of water. The reaction was carried out at a pH of 6.5-7.0, adjusted by a solution of potassium carbonate, and the reaction mixture was stirred for three hours at a temperature of from 25 to 30C. At the end of the reaction, the pH was adjusted to 7.5-8.0, 40 g of sodium chloride were added and the 2,3-dimethylpyridine N-oxide was extracted with methylene chloride. The extraction was repeated from saturated reaction solution. The combined organic phases were dried with sodium sulphate and concentrated to a volume of 60 ml. The yield was 97-98%, determined by HPLC. |
|
With dihydrogen peroxide; In water; acetic acid; |
Reference Example 1 (see Reaction Scheme 1) 71.79 g of 2,3-dimethylpyridine (II) was dissolved in 240 ml of acetic acid, to which 40 ml of 30% hydrogen peroxide solution was added and the resulting mixture was heated at 95 C. for 3 hours. Furthermore, 18 ml of a 30% hydrogen peroxide solution was added to the mixture and heated at 95 C. for 13 hours, and thereafter, 700 ml of water was added thereto and the resulting mixture was neutralized with sodium carbonate and extracted with chloroform. The resulting organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting precipitation was recrystallized from diisopropylether to obtain 71.34 g of 2,3-dimethylpyridine N-oxide (III). 1H-NMR(CDCl3) delta: 2.35(3H, s), 2.51(3H, s), 6.95-7.10(2H, m), 8.10-8.17(1H, m) |
|
With calcium hydroxide; 3-chloro-benzenecarboperoxoic acid; In diethyl ether; chloroform; |
Step 1 <strong>[583-61-9]2,3-Dimethylpyridine</strong> N-oxide To the 2,3-dimethylpyridine (15.0 g, 140 mmol) in CHCl3 (40 mL) at 0 C. was slowly added a CHCl3 (200 mL) solution of m-chloroperbenzoic acid (21.5 g, 154 mmol). The mixture was stirred 1 hour at 0 C., the ice bath was removed and stirring continued another hour. Calcium hydroxide (26 g, 350 mmol) was added and the slurry was vigorously stirred 4.5 hours before filtering through celite. The cake was thoroughly washed with CH2 Cl2. Evaporation of the solvents left an oily solid that was swished in Et2 O giving 8.71 g of desired product which was used without further purification. |
|
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; |
(a) A solution of 24 g of 2,3-dimethylpyridine in 100 ml of methylene chloride was treated while cooling with ice with a solution of 46.6 g of m-chloroperbenzoic acid in 100 ml of methylene chloride. The reaction mixture was heated under reflux for 2 hours and concentrated in a rotary evaporator. The residue was chromatographed on silica gel with ethyl acetate/methylene chloride (3:1) as the elution agent, the medium pressure flash chromatography method being used and the pressure being produced with nitrogen gas. By recrystallization from ether there was obtained 2,3-dimethylpyridine 1-oxide of melting point 56. |
|
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; |
(a) A solution of 24 g (0.22 mol) of 2,3-dimethylpyridine in 100 ml of methylene chloride is treated while cooling with ice with a solution of 46.6 g (0.27 mol) of m-chloroperbenzoic acid in 100 ml of methylene chloride. The reaction mixture is heated under reflux for 2 hours and concentrated in a rotary evaporator. The residue is chromatographed on silica gel with ethyl acetate/methylene chloride (3:1) as the elution agent, the medium pressure flash chromatography method being used and the pressure being produced with nitrogen gas. By recrystallization from ether there is obtained 2,3-dimethylpyridine 1-oxide of melting point 56. |
|
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃; for 2h; |
Commercially available 2,3-lutidine (5.00 g) was dissolved in methylene chloride (50 ml), and the solution was cooled to 0C. Subsequently, mCPBA (12.1 g) was added, followed by stirring at room temperature for 2 hours. After completion of reaction, methylene chloride was added to the solution, and the resultant solution was washed with 1 mol/l sodium hydroxide aqueous solution and brine and dried with anhydrous sodium sulfate. The solvent was distilled off to obtain crude 2,3-lutidine-N-oxide (3.16 g). |
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|
Commercially available 2,3-lutidine (5.00 g) was dissolved in dichloromethane (50 ml) and the solution was cooled to 0C. After that, the solution was added with meta-chloroperbenzoic acid (12.1 g) and then stirred at room temperature for 2 hours. After completion of the reaction, the solution was added with dichloromethane and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution, followed by drying with anhydrous sodium sulfate. Then, the solvent was distilled off, thereby obtaining crude 2,3-lutidin-N-oxide (3.16 g). A 2.00 g part thereof was dissolved in dichloromethane (40 ml) and then the solution was cooled to 0C. Subsequently, the solution was added with trifluoroacetic anhydride (4.49 ml), followed by stirring at room temperature for 4 hours and then at 45C for 3 hours. After completion of the reaction, the solvent was distilled off and the residue was dissolved in methanol (30 ml), followed by the addition of a sodium methoxide/methanol solution until the pH of the solution would reach pH = 10. After the solution had been stirred at room temperature for 1 hour, the solvent was distilled off and extraction was then carried out with dichloromethane. The extract was dried with anhydrous sodium sulfate and the solvent was then distilled off, thereby obtaining 3-methyl-2-hydroxymethylpyridine (1.30 g). A 605.3 mg part thereof was dissolved in chloroform (30 ml) and then added with manganese dioxide (chemically processed product) (3.03 g), followed by stirring at 70C for 2 hours. After completion of the reaction, the catalyst was removed through Celite filtration and the solvent was then concentrated. Then, the residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (419.8 mg) as a pale-orange colored liquid. MS(FAB,Pos.):m/z=122[M+H]+1H-NMR(500MHz,CDCl3):delta=2.67(3H,s),7.40(1H,dd,J=7.8,4.6Hz),7.64(1 H,d,J=7.8Hz),8.67(1H,d,J=4.6Hz),10.2(1H,s). |
|
With dihydrogen peroxide; In water; acetic acid; at 100℃; for 13.5h; |
2,3-dimethylpyridine 1-oxide (B): A solution of A (5.00 ml, 0.0436 mol) and hydrogen peroxide (15% in water, 7.5 ml) in acetic acid (50.0 ml) was heated at 100 degree Celsius for 3.5 hours. TLC analysis showed some A remained. Hydrogen peroxide (30% in water, 3 ml) was added to the reaction solution, which was kept at 100 degree Celsius for another 10 hours. The solution was cooled to room temperature. The acetic acid was removed, and the residue was basified with sodium carbonate (aq) to pH around 7. The aqueous layer was extracted with a solution of chloroform/isopropanol (3:1) until all the UV active material was in the organic layers. The pooled organic layers were dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was purified by chromatography on silica gel (100% ethyl acetate, then 3-4% ammonia methanol in dichloromethane) to give 2,3-dimethylpyridine 1 -oxide (B) as a white solid. |
|
With dihydrogen peroxide; acetic acid; at 90℃; for 12h; |
30% hydrogen peroxide (100 ml) was added to a solution of 2,3-lutidine (2 g) in 50 ml of acetic acid, which was stirred for 12 hours at 900C, and then the reaction mixture was concentrated under reduced pressure. The resulting residue was added to a mixture (30 ml) of concentrated sulfuric acid and nitric acid (7:3). The reaction mixture was refluxed under stirring for 3.5 hours, cooled to room temperature, and then added to ice water. The reaction mixture was alkalized with a sodium hydroxide solution, extracted with methylene chloride, dried on anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was re-crystallized with ethyl alcohol to give 2.4 g of the titled compound as a pale yellow solid. |
|
With dihydrogen peroxide; In acetic acid; at 90℃; for 7h; |
2,3-dimethylpyridine (1 g, 9.33 mmol, Aldrich) and hydrogen peroxide (1.059 ml, 9.33 mmol) were dissolved in acetic acid (4.67 ml) in a 25 ml. round-bottomed flask open to the atmosphere and stirred at 90 0C for 7 hours. The reaction mixture was allowed to cool to room temperature and evaporated to dryness to give the title compound (1.440 g) as a colourless oil. The product was directly used in the following reaction, m/z [M+H]+ : 123.8. Retention time 0.35 min (LC/MS method 3). |
|
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; |
A solution of2 in Scheme 4-3, 3-dimethylpyridine (107 mg, 1 mmol) in DCM (10 mL) wastreated with m-CPBA (345 mg, 2 mmol) and stirred at room temperature overnight. The reactionmixture was concentrated and the resulting material was purified directly by combi-flash(MeOH/HzO (NH4HC03)) to give a white solid. LCMS (ESI) m/z=124(M+Ht. |
|
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃; |
Step A: 2, 3-dimethylpyridine 1-oxide (2)A solution of 2 in Scheme 4-3, 3-dimethylpyridine (107 mg, 1 mmol) in DCM (10 mL) was treated with m-CPBA (345 mg, 2 mmol) and stirred at room temperature overnight. The reaction mixture was concentrated and the resulting material was purified directly by combi-flash (MeOH/H20 ( H4HCO3)) to give a white solid. LCMS (ESI) m/z=124(M+H)+. |
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