* 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.
Reference：
[1] Chemistry - A European Journal, 2006, vol. 12, # 4, p. 1097 - 1113
[2] Roczniki Chemii, 1959, vol. 33, p. 387,392[3] Chem.Abstr., 1959, p. 18954
[4] Patent: US2004/92726, 2004, A1, . Location in patent: Page 7
[5] Patent: JP2004/509075, 2004, A, . Location in patent: Page 22-23
2
[ 557-21-1 ]
[ 5093-70-9 ]
[ 39965-81-6 ]
Yield
Reaction Conditions
Operation in experiment
77%
With tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl-formamide at 120℃; for 5.5 h; Inert atmosphere
Scheme 4, step A: Zinc cyanide (3.82g, 31.9 mmol) is added to a mixture of 4- bromo-2,6-dimethylpyridine (5.09 g, 26.5 mmol) and DMF (40 mL) stirring under nitrogen at RT. Nitrogen is bubbled through the stirred suspension for 15 min, and tetrakis(triphenylphoshpine) palladium(O) (1.54 g, 1.33 mmol) is added. After heating the reaction mixture at 120 °C for 5.5 hr, the mixture is cooled to RT and diluted with EtOAc (150 mL). The solids are removed via paper filtration and the filter cake is washed with EtOAc (50 mL). The combined organic filtrate and wash is washed sequentially with 15percent aqueous NH3 (2 x 50 mL), water (50 mL) and saturated aqueous NaCl, dried over Na2S04, filtered, and concentrated under reduced pressure to give a ellow solid. The crude product is purified by flash chromatography on silica, eluting with hexanes/ethyl acetate (gradient from 9: 1 to 1 : 1). The pure chromatography fractions are combined and concentrated under reduced pressure to give the title compound (2.79 g, 77percent yield). fH NMR (CDCI3): δ 2,61 (s. 6H), 7,21 (s. 2H).
77%
With tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl-formamide at 120℃; for 5.5 h; Inert atmosphere
Zinc cyanide (3.82g, 31.9 mmol) is added to a mixture of 4- bromo-2,6-dimethylpyndine (5.09 g, 26.5 mmol) and DMF (40 mL) stirring under nitrogen at RT. Nitrogen is bubbled through the stirred suspension for 15 min, and tetrakis(triphenylphosphine) palladium(O) (1 ,54 g, 1.33 mmol) is added. After heating th reaction mixture at 120 °C for 5.5 hr, the mixture is cooled to RT and diluted with EtOAc (150 mL). The solids are removed via paper filtration and the filter cake is washed with EtOAc (50 mL). The combined organic filtrate and wash is washed sequentially with 15percent aqueous NH3 (2 x 50 mL), water (50 mL) and saturated aqueous NaCl, dried over Na2S04, filtered, and concentrated under reduced pressure to give a yellow solid. The crude product is purified flash chromatography on silica, eluting with hexanes/ethyl acetate (gradient from 9: 1 to 1 : 1 ). The pure chromatography fractions are combined and concentrated under reduced pressure to give the title compound (2,79 g, 77percent). lH NMR (CDCI3): δ 2.61 (s, 6H), 7.21 (s, 2H).
2, 6-DimethylisonicotinonitrileTo a stirred quantity of 2, 6-lutidine-l -oxide (12.3 g, lOOmmol) was slowly added dimethyl sulphate (12.6 g, lOOmmol) at such a rate that the temperature of the reaction mixture was maintained at 8O0C throughout the addition. When the addition was complete (about one hour) the solution was stirred at that temperature for an additional 2 h. The salt crystallised upon cooling and was recrystallised from anhydrous acetone giving white prisms; m.p 96 - 970C. Yield 18 g (73 percent). To a solution of this 1- methoxy-2,6-dimethylpyridinium methyl sulphate (11.65 g, 50 mmol) dissolved in water (50 ml) , under nitrogen, was added a solution of potassium cyanide (10 g, 150 mmol) dissolved in 50 ml of water. The solution was allowed to stand at room temperature for 2 days at which time the nitrile , which had separated from the solution as long white needles, was removed by filtration, yielding 2.8 g of pure product ( 42percent) δH (CDCl3, 500 MHz) 2.44 (6 H, s, 2 x CH3), 4.2 (2 H, d, J 5, NHCH2), 6.78 (2 H, s, <n="62"/>ArH); δc (CDCl3, 500 MHz) 157.83 (2 x C), , 122.71 (C), 118.2 (2 x CH), 24.28 (2 x CH3)
Example 4; Synthesis of4-cyano-2, 6-dimethylpyddine; [0103] 2,6-Lutidine-N-oxide (25 g, 0.2 moles) and dimethylsulfate (25.3 g, . 2 moles) were combined and let sit until a solid precipitated, <1 hr. The salt was dissolved in water (100 ml) and potassium cyanide in water (150 ml) was added in one portion. After two days, in which the nitrile precipitated, the solution was filtered, washed with water and dried. 4-cyano-2, 6-dimethylpyridine was isolated as a tan solid in 13.7 percent yield.'H NMR (DMSO-d6) 2.48 (6 H, s), 7.51 (2H, s).
A mixture of 1 g (7.56 mmol) of (1) and 5 ml of concentrated sulfuric acid is heated at 100 C. for 5 hours. The resulting solution is then cooled on an ice bath, brought to pH 3.5 with 10 N sodium hydroxide and then concentrated to dryness. Extraction with ether for 48 hours (soxhlet) of a portion of the residue obtained gives 50 mg of 2,6-dimethylisonicotinic acid (2) for analysis. The remaining crude reaction product, not treated with ether, is used in its present form in the esterification reaction without further purification. [0133] NMR: 1H (D20); internal reference tBuOH 1.29 ppm. [0134] 2.82 (s, 6H, CH3); 8.05 (s, 2H, Py). [0135] MS (EI): 151 (M+, 100); 134 (M+-OH, 7.2); 106 (M+-CO2H, 16.4) [0136] MA: C8H9NO2+0.1 NaHSO4 (163.16) [0137] calculated: C 58.89H 5.62 N 8.58 O 23.53 [0138] found: C 58.73H 5.90 N 8.37 O 23.7
Example 5; Synthesis of2, 6-dimmethyl-4-acetylpvridine (General Procedure A); [0104] Methylmagnesium Iodide (3. 0M) (18.4 ml, 0.054 moles) and dry ether were cooled to 0-5C in an ice bath. 4-cyano-2, 6-dimethylpyridine from Example 4 in ether (30 ml) was added dropwise while stirring, under a nitrogen atmosphere. After 1 hour at 0-5C the reaction was refluxed for an additional hour. The reaction mixture was then cooled to 0-5C, quenched with saturated ammonium chloride (15 ml) and hydrolyzed with hydrochloric acid (15 ml) for at least one hour. Saturated sodium bicarbonate was then added until the solution became basic. The solution was then extracted with ethyl acetate. The organic portion was dried over magnesium sulfate, filtered and stripped to a brown oil. The oil was purified on a Biotage 40S silica gel column with ethyl acetate: heptane (1: 1) to give 2,6-dimethyl-4-acetylpyridine in an 11 % yield 1H NMR (CDC13) 2.57 (3H, s), 2.60 (6H, s), 7.36 (2H, s).
With 3-chloro-benzenecarboperoxoic acid; In chloroform; at 0 - 20℃;
87.6 g (663 mmol) of <strong>[39965-81-6]4-cyano-2,6-dimethylpyridine</strong> was dissolved in 200 ml of chloroform. To the solution was added 148 g (580 mmol) of m-chloroperbenzoic acid (70% equivalent) while cooling in an ice bath, and the solution was stirred over night at room temperature. The reaction mixture was diluted with chloroform. The organic layer was washed with an aqueous solution of sodium hydrogen carbonate, water and saturated salt water in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography [eluted with chloroform:methanol = 20:1 (v/v)] to give 19 g of the target compound.
t-Butyl (2,6-dimethylpyridin-4-yl)methyl carbamate<strong>[39965-81-6]2,6-dimethylisonicotinonitrile</strong> (2g, 15.15mmol) was dissolved in 10% acetic acid/ ethanol (30ml). 10% palladium over charcoal catalyst (0.5g) was added and the reaction stirred under an atmosphere of hydrogen for 24h.at 6O0C. The mixture was filtered through a pad of celite, Volatiles were removed and the crude residue dissolved in dichloromethane (30ml). To the stirred solution was then added triethylamine (5ml) followed by di-ter/-butyldicarbonate (3.3 g, 15.15mmol). After 3h, the solvent was removed and the residue dissolved in ethyl acetate. It was washed with water (50ml), saturated bicarbonate (50ml), dried and evaporated. The crude product was purified by silica gel flash column chromatography (ethyl acetate: hexane 1 :2) to provide 0.6 g of pure title compound (17.24% yield). deltaH (CDCl3, 500 MHz) 1.42 (9 H, s, 3 x CH3), 2.44 (6 H, s, 2 x CH3), 4.2 ( 2 H, d, J 5, NHCH2), 5.25 (1 H, s, b, NH), 6.81 ( 2 H, s, ArH); deltac (CDCl3, 500 MHz) 157.83 (C), 156.01 (CO), 148.71 (C), 118.58 (2 x CH), 79.77 (C), 43.41 (CH2), 28.34 (3 x CH3), 24.28 (2 x CH3); m/z 237.2 (M + H)
2, 6-DimethylisonicotinonitrileTo a stirred quantity of 2, 6-lutidine-l -oxide (12.3 g, lOOmmol) was slowly added dimethyl sulphate (12.6 g, lOOmmol) at such a rate that the temperature of the reaction mixture was maintained at 8O0C throughout the addition. When the addition was complete (about one hour) the solution was stirred at that temperature for an additional 2 h. The salt crystallised upon cooling and was recrystallised from anhydrous acetone giving white prisms; m.p 96 - 970C. Yield 18 g (73 %). To a solution of this 1- methoxy-2,6-dimethylpyridinium methyl sulphate (11.65 g, 50 mmol) dissolved in water (50 ml) , under nitrogen, was added a solution of potassium cyanide (10 g, 150 mmol) dissolved in 50 ml of water. The solution was allowed to stand at room temperature for 2 days at which time the nitrile , which had separated from the solution as long white needles, was removed by filtration, yielding 2.8 g of pure product ( 42%) deltaH (CDCl3, 500 MHz) 2.44 (6 H, s, 2 x CH3), 4.2 (2 H, d, J 5, NHCH2), 6.78 (2 H, s, <n="62"/>ArH); deltac (CDCl3, 500 MHz) 157.83 (2 x C), , 122.71 (C), 118.2 (2 x CH), 24.28 (2 x CH3)
With hydroxylamine hydrochloride; potassium tert-butylate; In methanol; at 0 - 60℃; for 15.5h;
To an ice-cooled solution of potassium tert.-butylate (1.25 g, 11.1 mmol) in methanol (20 mL), hydroxylamine hydrochloride (773 mg, 11.1 mmol) is added. The suspension is stirred for 30 min before 2,6-dimethyl-4-cyano-pyhdine (490 mg, 3.71 mmol) is added. The mixture is stirred at 60C for 15 h before it is filtered. The filtrate is evaporated to dryness and the resulting solid is washed with water and <n="87"/>then dried under HV to give N-hydroxy-2,6-dimethyl-isonicotinamidine (503 mg) as a white powder; LC-MS: tR = 0.23 min; [IVM]+ = 166.01 ; 1H NMR (D6-DMSO): delta 2.43 (s, 6 H), 5.88 (s, 2 H), 7.30 (s, 2 H), 9.90 (s, 1 H).
With hydroxylamine hydrochloride; potassium tert-butylate; In methanol; at 60℃; for 15h;
c) To an ice-cooled solution of potassium tert.-butylate (1.25 g, 11.1 mmol) in MeOH (20 mL), hydroxylamine hydrochloride (773 mg, 11.1 mmol) is added. The suspension is stirred for 30 min before <strong>[39965-81-6]2,6-dimethyl-isonicotinonitrile</strong> (490 mg, 3.71 mmol) is added. The mixture is stirred at 60 C. for 15 h before it is filtered. The filtrate is evaporated to dryness and the resulting solid is washed with water and then dried under HV to give N-hydroxy-2,6-dimethyl-isonicotinamidine (503 mg) as a white powder; LC-MS: tR=0.23 min; [M+1]+=166.01; 1H NMR (D6-DMSO): delta 2.43 (s, 6H), 5.88 (s, 2H), 7.30 (s, 2H), 9.90 (s, 1H).
With hydroxylamine hydrochloride; potassium tert-butylate; In methanol; at 60℃; for 15h;
N-Hydroxy-2,6-dimethyl-isonicotinamidine To an ice-cooled solution of potassium tert.-butylate (1.25 g, 11.1 mmol) in methanol (20 mL), hydroxylamine hydrochloride (773 mg, 11.1 mmol) is added. The suspension is stirred for 30 min before 2,6-dimethyl-4-cyano-pyridine (490 mg, 3.71 mmol) is added. The mixture is stirred at 60 C. for 15 h before it is filtered. The filtrate is evaporated to dryness and the resulting solid is washed with water and then dried under HV to give N-hydroxy-2,6-dimethyl-isonicotinamidine (503 mg) as a white powder; LC-MS: tR=0.23 min; [M+1]+=166.01; 1H NMR (D6-DMSO): delta 2.43 (s, 6H), 5.88 (s, 2H), 7.30 (s, 2H), 9.90 (s, 1H).
With hydroxylamine hydrochloride; potassium tert-butylate; In methanol; at 60℃;Cooling with ice;
To an ice-cooled solution of potassium tert.-butylate (1.25 g, 1 1.1 mmol) in MeOH (20 mL), hydroxylamine hydrochloride (773 mg, 11.1 mmol) is added. The suspension is stirred for 30 min before <strong>[39965-81-6]2,6-dimethyl-isonicotinonitrile</strong> (490 mg, 3.71 mmol) is added. The mixture is stirred at 60C for 15 h before it is filtered. The filtrate is evaporated to dryness and the <n="53"/>resulting solid is washed with water and then dried under HV to give N-hydroxy-2,6- dimethyl-isonicotinamidine (503 mg) as a white powder; LC-MS: tR = 0.23 min; [M+1]+ = 166.01 ; 1H NMR (D6-DMSO): £2.43 (s, 6 H), 5.88 (s, 2 H), 7.30 (s, 2 H), 9.90 (s, 1 H).
b) To a suspension of crude 2,6-dimethyl-isonicotinamide (2.45 g, 16.31 mmol) in DCM (40 mL), pyridine (6.4 mL, 65.2 mmol) is added. The mixture is cooled to 0 C. before trifluoroacetic anhydride (6.91 mL, 48.9 mmol) is added portionwise. Stirring is continued at 0 C. for 24 h before the reaction is quenched with water. The mixture is diluted with DCM, and the org. phase is separated and washed with 5% aq. citric acid solution followed by sat. aq. NaHCO3 solution. The washings are extracted back twice with DCM. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluding with heptane:EA 9:1 to give 2,6-dimethyl-isonicotinonitrile (1.58 g) as a yellow powder; LC-MS: tR=0.53 min, [M+1]+=133.40. 1H NMR (CDCl3): delta 2.61 (s, 6H), 7.21 (s, 2H).
With pyridine; trifluoroacetic anhydride; In dichloromethane; at 0℃; for 24h;
To a suspension of crude 2,6-dimethyl-isonicotinamide (2.45 g, 16.31 mmol) in DCM (40 mL), pyridine (6.4 mL, 65.2 mmol) is added. The mixture is cooled to 00C before trifluoroacetic anhydride (6.91 mL, 48.9 mmol) is added portionwise. Stirring is continued at 00C for 24 h before the reaction is quenched with water. The mixture is diluted with DCM, and the org. phase is separated and washed with 5% aq. citric acid solution followed by sat. aq. NaHCO3 solution. The washings are extracted back twice with DCM. The combined org. extracts are dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 2,6-dimethyl-isonicotinonitrile (1.58 g) as a yellow powder; LC-MS: tR = 0.53 min, [M+1]+ = 133.40. 1H NMR (CDCI3): £2.61 (s, 6 H), 7.21 (s, 2 H).
Example 4; Synthesis of4-cyano-2, 6-dimethylpyddine; [0103] 2,6-Lutidine-N-oxide (25 g, 0.2 moles) and dimethylsulfate (25.3 g, . 2 moles) were combined and let sit until a solid precipitated, <1 hr. The salt was dissolved in water (100 ml) and potassium cyanide in water (150 ml) was added in one portion. After two days, in which the nitrile precipitated, the solution was filtered, washed with water and dried. 4-cyano-2, 6-dimethylpyridine was isolated as a tan solid in 13.7 % yield.'H NMR (DMSO-d6) 2.48 (6 H, s), 7.51 (2H, s).
N-[(2,6-dimethylpyridin-4-yl)methyl]-5-{(1R)-1-[(3R)-3-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-3-yl]ethyl}pyridine-2-carboxamide hydrochloride[ No CAS ]
N-[(2,6-dimethylpyridin-4-yl)methyl]-5-{(1R)-1-[(3R)-3-methyl-2-oxo-1-[2-(trimethylsilyl)ethoxy]methyl}-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-3-yl]ethyl}pyridine-2-carboxamide[ No CAS ]
1-(2,6-dimethylpyridin-4-yl)methanamine dihydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With hydrogenchloride; palladium 10% on activated carbon; hydrogen; In ethanol; water; at 20℃; under 2844.39 Torr; for 16h;
Scheme 4, step B: A solution of <strong>[39965-81-6]2,6-dimethylpyridine-4-carbonitrile</strong> (2.26 g, 16.7 mmol) in EtOH (40 mL) is added to a suspension of 10% Pd on carbon (405 mg), EtOH (10 mL), and concentrated aqueous HCI (6.9 mL). The reaction vessel is evacuated, filled with nitrogen, and IL (55 psi) is introduced, with stirring of the subsequent reaction mixture at RT for 16 hr. The reaction mixture is filtered through diatomaceous earth. The filter cake is washed with MeOH and the combined filtrate/wash is concentrated to give a yellow solid. The crude material is triturated with boiling 30% EtOH/EtOAc, cooled to RT, and collected via filtration to give the title compound (2,64 g, 75% yield). LC-ES/MS (m/z): 137.0 (M+H).
With hydrogenchloride; palladium 10% on activated carbon; hydrogen; In 1,4-dioxane; methanol; at 20℃; under 2844.39 Torr;Inert atmosphere; Autoclave;
The following may be run in two batches and the two batches combined after the complete hydrogenation reaction : 2,6-Dimethylpyridine-4- carbonitrile (77.39 g, 527.0 mmol) is added to a 2 L Parr autoclave, equipped with a mechanical stirrer, containing a mixture of 10% Pcl'C (45.8 g) in MeOH (800 mL) and a 4M solution of HCl in dioxane (500 mL). The autoclav e is sealed, the resulting mixture is purged thoroughly with N2 followed by H2, and pressurized with H2 to 60 psi with stirring at RT overnight. The reaction mixture is filtered and the filtrate is evaporated under reduced pressure. MeOH (~ 250 mL) is added to the resulting residue and stirred for 15 hr, and MTBE (2.5 L) is added slowly. The mixture is stirred at RT for Ihr, filtered, and the solids are washed with MTBE (1 L). The solids are dried in vacuo at RT overnight to obtain the title compound as a pale yellow solid (217.0 g, 91.6% yield, combination of two runs), suitable for use without additional purification. LC-ES/MS (m z): 137.2 (M+H), 92.5%) purity, with 7.5% triphenylphosphine impurity present ( 1 .57 min, m/z: 263.0),
With ammonia; hydrogen; In methanol; at 20 - 40℃; under 3105.31 Torr; for 18h;
A solution of <strong>[39965-81-6]2,6-dimethylpyridine-4-carbonitrile</strong> (2.0 g, 15.1 mmol) in 2.0 M NH3 in MeOH (75 mL) is added to a suspension of Raney nickel (0.5 g, 9 mmol) in 2.0 M NH3 in MeOH (75 mL) in a 500 mL Parr shaker. The Parr shaker is sealed, purged with N2, purged with H2, and pressurized to 414 kPa with H2. The reaction mixture is heated to 40 C and allowed to cool slowly to RT while being shaken for 18 hr. The reaction mixture is filtered and concentrated under reduced pressure to give a green residue. The residue is purified by flash chromatography over silica, eluting with hexanes/DCM IPArn (gradient from 9:0: 1 to 6:3: 1), The product-containing chromatography fractions are concentrated under reduced pressure and repurified by flash chromatography over silica, eluting with hexanes/DCM/IPAm (45:45: 10) to give the title compound (1.02 g, 49% yield), after solvent evaporation. LC-ES/MS (m/z): 137.0 (M+H).
With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 120℃; for 5.5h;Inert atmosphere;
Scheme 4, step A: Zinc cyanide (3.82g, 31.9 mmol) is added to a mixture of 4- bromo-2,6-dimethylpyridine (5.09 g, 26.5 mmol) and DMF (40 mL) stirring under nitrogen at RT. Nitrogen is bubbled through the stirred suspension for 15 min, and tetrakis(triphenylphoshpine) palladium(O) (1.54 g, 1.33 mmol) is added. After heating the reaction mixture at 120 °C for 5.5 hr, the mixture is cooled to RT and diluted with EtOAc (150 mL). The solids are removed via paper filtration and the filter cake is washed with EtOAc (50 mL). The combined organic filtrate and wash is washed sequentially with 15percent aqueous NH3 (2 x 50 mL), water (50 mL) and saturated aqueous NaCl, dried over Na2S04, filtered, and concentrated under reduced pressure to give a ellow solid. The crude product is purified by flash chromatography on silica, eluting with hexanes/ethyl acetate (gradient from 9: 1 to 1 : 1). The pure chromatography fractions are combined and concentrated under reduced pressure to give the title compound (2.79 g, 77percent yield). fH NMR (CDCI3): delta 2,61 (s. 6H), 7,21 (s. 2H).
77%
With tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 120℃; for 5.5h;Inert atmosphere;
Zinc cyanide (3.82g, 31.9 mmol) is added to a mixture of 4- bromo-2,6-dimethylpyndine (5.09 g, 26.5 mmol) and DMF (40 mL) stirring under nitrogen at RT. Nitrogen is bubbled through the stirred suspension for 15 min, and tetrakis(triphenylphosphine) palladium(O) (1 ,54 g, 1.33 mmol) is added. After heating th reaction mixture at 120 °C for 5.5 hr, the mixture is cooled to RT and diluted with EtOAc (150 mL). The solids are removed via paper filtration and the filter cake is washed with EtOAc (50 mL). The combined organic filtrate and wash is washed sequentially with 15percent aqueous NH3 (2 x 50 mL), water (50 mL) and saturated aqueous NaCl, dried over Na2S04, filtered, and concentrated under reduced pressure to give a yellow solid. The crude product is purified flash chromatography on silica, eluting with hexanes/ethyl acetate (gradient from 9: 1 to 1 : 1 ). The pure chromatography fractions are combined and concentrated under reduced pressure to give the title compound (2,79 g, 77percent). lH NMR (CDCI3): delta 2.61 (s, 6H), 7.21 (s, 2H).
(2,6-dimethylpyridin-4-yl)(phenyl)methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With fac-tris(2-phenylpyridinato-N,C2')iridium(III); N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 20℃; for 12h;Irradiation; Inert atmosphere; Sealed tube;
General procedure: A 10-mL Pyrex tube equipped with a magnetic stir bar wascharged with 1,4-DCB (25.6 mg, 0.2 mmol), fac-Ir(ppy)3 (2.6mg, 2 mol%) and DMSO (2 mL). The Pyrex tube was sealed with rubber plug and then deaerated by bubbling Ar for 15 min, then benzaldehyde (30.5 muL, 0.3 mmol) and DIPEA (52.4 muL, 0.3mmol) were added. The reaction system was irradiated with blue LEDs (lambda = 450 ± 10 nm) for 12 h at RT. When the reaction was complete, the aqueous solution was extracted with ethyl acetate (5 mL × 3). The organic extracts were combined, washed with brine and dried over anhydrous sodium sulfate.The solvent was removed under vacuum and the residue was purified by chromatography on silica gel (petroleum ether:ethyl acetate = 3:1) to afford the desired product.
With water-d2; benzoic acid; In 1,4-dioxane; at 100℃; for 96h;Sealed tube;
To a degassed solution of <strong>[39965-81-6]2,6-dimethylisonicotinonitrile</strong> (2 g, 14 mmol) and benzoic acid (0.9 g, 7 mmol) in dioxane (20 ml_) (sealed-tube) was added D20 (20 ml_). The resulting mixture was stirred at 100C for 4 days. The reaction mixture was allowed to cool to room temperature and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure and dried under vacuum to afford 2,6-bis(methyl-d3)isonicotinonitrile (1.8 g with -94% D, 86%). 1H NMR: 6H (400 MHz, CDC ) 7.21 (2H, s).
1-(2,6-dimethylpyridin-4-yl)cyclopropan-1-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
150 mg
To a solution of <strong>[39965-81-6]2,6-dimethylisonicotinonitrile</strong> (200 mg, 1.51 mmol) in diethyl ether (3 ml_), at -78C, were added ethyl magnesium bromide (3.33 ml_, 3.33 mmol) and titanium isopropoxide (0.47 ml_, 1.66 mmol). After 2 h at -78C, BF3.0Et2 (0.42 ml_, 3.03 mmol) was added and allowed to stir at room temperature for 14 h. The reaction was quenched with saturated ammonium chloride solution (3 ml_), NaOH solution was added to maintain pH I Q- 12 and the mixture was extracted with ethyl acetate (3 x 10 ml_). The combined organic filtrate was washed with water (30 ml_) and saturated aqueous NaCI, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography, eluting with 40% to 60% ethyl acetate in petroleum ether to afford 1-(2,6-dimethylpyridin-4-yl)cyclopropan-1-amine (150 mg). 1 H NMR: 6H (400 MHz, CDC ) 6.83 (2H, s), 2.57 (6H, s), 1.20 - 1.17 (2H, m), 1.08 - 1.05 (2H, m).
In dimethyl sulfoxide at 25℃; for 24h; Inert atmosphere; Irradiation;
5 Example 5
Add one by one to the 10mL reaction tube equipped with magnets2,6-Dimethyl-4-cyanopyridine (0.2mmol),Cesium carbonate (0.4mmol),Catalyst 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile (0.006mmol);Vacuum the reaction tube,Replace with nitrogen three times,Styrene (0.5mmol) was then added,2,2-diethoxyacetic acid (0.5mmol)And solvent anhydrous dimethyl sulfoxide (2mL),The reaction tube is a blue LED with a wavelength of 455nmLamp irradiation and stirring at a reaction temperature of 25°C for 24h.After the reaction,Add water to quench the reaction,The reaction solution was extracted with ethyl acetate,After combining the organic phases, dry with anhydrous sodium sulfate,Column chromatography to obtain the target product,The target product is a colorless oil.Based on the molar amount of 2,6-dimethyl-4-cyanopyridine as 100%,The yield of the target product was 94%.
With 2,4,5,6‐tetra‐9H‐carbazol‐9‐yl‐1,3‐benzenedicarbonitrile; caesium carbonate In dimethyl sulfoxide at 20℃; for 24h; Inert atmosphere; Irradiation;
2.2 General procedure for the synthesis of acetalation-pyridylation of alkenes
General procedure: In a 10 mL reaction vial with a stirring bar, 4-cyanopyridine 1 (0.2 mmol), Cs2CO3 (2.0 equiv.), and 1,2,3,5-tetrakis(carbazol- 9-yl)-4,6-dicyanobenzene (4CzIPN) (3 mol%) were added. The vial was then evacuated and backfilled three times with N2, followed by adding DMSO (2 mL), styrene 2 (2.5 equiv.), and 2,2-diethoxyacetic acid 3 (2.5 equiv.). The mixture was stirred at room temperature with 10 W blue LED irradiation for 24 h under a nitrogen atmosphere. After the reaction was completed, it was quenched with water (5 mL), and then the ethyl acetate (15 mL) was added three times for extraction. The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 5/1) to afford the desired product 4 or 5.
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