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Structure of 1620-76-4 * Storage: {[proInfo.prStorage]}
* 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] Journal of the American Chemical Society, 1990, vol. 112, # 17, p. 6248 - 6254
[2] Organic and Biomolecular Chemistry, 2011, vol. 9, # 8, p. 3026 - 3032
2
[ 1620-76-4 ]
[ 102854-88-6 ]
[ 53547-60-7 ]
Yield
Reaction Conditions
Operation in experiment
37%
at -78℃; for 2 h;
Reference Example 55 4-Methyl-2-pyridinecarbaldehyde diisobutyl aluminium hydride in toluene (1.5 M, 43.5 ml, 65 mmol) was added dropwise to a solution of 2-cyano-4-methylpyridine (7.0 g, 59 mmol) in dichloromethane (180 ml) at -78 °C, and the mixture was stirred at the same temperature for 2 hrs.. The reaction mixture was combined with concentrated hydrochloric acid (28 ml) and water (112 ml), and the water layer and the organic layer were separated.. The organic layer was extracted with 2 N hydrochloric acid.. The water layer was combined, neutralized with sodium hydrogen carbonate and extracted with diethyl ether.. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate.. The solvent was evaporated to give the titled compound (2.7 g, 37 percent).
Stage #1: at 0 - 20℃; for 2 h; Inert atmosphere Stage #2: With water; ammonium chloride In diethyl ether; benzeneInert atmosphere
To a stirred solution of 2-nitrile-4-methylpyridine {31.19 g, 229 mmol; that was prepared by us from the corresponding 4-methylpyridine 1-oxide according to the reported procedure [17] and [46], 1H NMR (270 MHz, CDCl3) δ 8.57 (1H, d, J = 5.1 Hz), 7.53-7.52 (1H, m), 7.35-7.32 (1H, m), 2.44 (3H, m)} in dry benzene (300 mL)-anhydrous Et2O (230 mL) was added dropwise 2 M solution of MeMgI/Et2O (149.0 mL, 298 mmol) at 0 °C under N2 over 1 h. The reaction mixture was warmed to room temperature, stirred under N2 for 1 h, and then cooled to 0 °C. After aqueous NH4Cl (120 mL) was added dropwise to the mixture at 0 °C, the resulting mixture was warmed to room temperature and stirred for 1 h. The aqueous layer was removed, and the organic layer was washed with water, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, hexane/AcOEt = 8:1) to afford 16.20 g of 1-(4-methylpyridin-2-yl)ethanone 41 as a yellow oil in 52percent yield. 1H NMR (CDCl3, 270 MHz) δ 8.54 (1H, d, J = 4.9 Hz), 7.88-7.87 (1H, m), 7.30-7.27 (1H, m), 2.72 (3H, s), 2.43 (3H, m).
Reference：
[1] European Journal of Medicinal Chemistry, 2012, vol. 50, p. 179 - 195
[2] Journal of the American Chemical Society, 1956, vol. 78, p. 5842
4
[ 1620-76-4 ]
[ 75-16-1 ]
[ 59576-26-0 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2015, vol. 13, # 36, p. 9418 - 9426
5
[ 1003-67-4 ]
[ 7677-24-9 ]
[ 1620-76-4 ]
Yield
Reaction Conditions
Operation in experiment
42%
With N,N-Dimethylcarbamoyl chloride In Nitroethane at 20℃; for 120 h;
Reference Example 35 2-Cyano-4-methylpyridine 4-Methylpyridine N-oxide (2. 0 g, 18.3 mmol) was dissolved in nitroethane (25 ml), and trimethylsilyl cyanide (2.0 g, 20.2 mmol) and N,N-dimethylcarbamoyl chloride (1.7 ml, 18.5 mmol) were added thereto.. The reaction mixture was stirred at room temperature for 5 days, concentrated under reduced pressure, combined with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate.. The extract was washed with saturated brine and dried.. The solvent was evaporated under reduced pressure.. The obtained crystals were collected by filtration, washed with diisopropyl ether and dried to give the titled compound (0.91 g, 42 percent).1H-NMR (CDCl3) δ: 2.43 (3H, s), 7.33 (1H, d, J = 5.1 Hz), 7.53 (1H, s), 8.57 (1H, d, J = 4.8 Hz).
Reference：
[1] Journal of Organic Chemistry, 1983, vol. 48, # 8, p. 1375 - 1377
[2] Journal of Organic Chemistry, 2013, vol. 78, # 16, p. 8054 - 8064
[3] Synthesis, 1983, # 4, p. 316 - 319
[4] Advanced Synthesis and Catalysis, 2013, vol. 355, # 5, p. 947 - 956
[5] Journal of the American Chemical Society, 1990, vol. 112, # 17, p. 6248 - 6254
[6] Patent: EP1193265, 2002, A2, . Location in patent: Page 68
[7] Journal of Medicinal Chemistry, 2000, vol. 43, # 16, p. 3168 - 3185
[8] Patent: EP1424336, 2004, A1, . Location in patent: Page 105
[9] Journal of Organic Chemistry, 1990, vol. 55, # 2, p. 738 - 741
[10] Patent: US6150379, 2000, A,
[11] Patent: US2003/229079, 2003, A1, . Location in patent: Page 30-31
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1984, p. 2013 - 2018
11
[ 1003-67-4 ]
[ 77-78-1 ]
[ 1620-76-4 ]
Reference：
[1] Patent: US5219847, 1993, A,
[2] Chemical and Pharmaceutical Bulletin, 1959, vol. 7, p. 925,928
12
[ 3678-62-4 ]
[ 1620-76-4 ]
Reference：
[1] Pharmaceutical Bulletin, 1957, vol. 5, p. 13
13
[ 108-89-4 ]
[ 1620-76-4 ]
Reference：
[1] Journal of Organic Chemistry, 2013, vol. 78, # 16, p. 8054 - 8064
14
[ 100-70-9 ]
[ 67-56-1 ]
[ 1620-76-4 ]
Reference：
[1] Chemistry Letters, 1984, p. 769 - 772
15
[ 1003-67-4 ]
[ 1620-76-4 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1984, p. 2013 - 2018
16
[ 1003-67-4 ]
[ 151-50-8 ]
[ 77-78-1 ]
[ 1620-76-4 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1993, vol. 30, # 3, p. 631 - 635
17
[ 460-19-5 ]
[ 78-79-5 ]
[ 1620-76-4 ]
Reference：
[1] Canadian Journal of Research, Section B: Chemical Sciences, 1947, vol. 25, p. 284
[2] Canadian Journal of Research, Section B: Chemical Sciences, 1947, vol. 25, p. 284
18
[ 1620-76-4 ]
[ 42508-74-7 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2013, vol. 355, # 5, p. 947 - 956
19
[ 1620-76-4 ]
[ 4021-08-3 ]
Yield
Reaction Conditions
Operation in experiment
85%
With hydrogenchloride In water for 24 h; Heating / reflux
A solution of 2-cyano-4-methyl pyridine (0.15 g, 1.27 mmol) in about 10 mL of 6 M HCl was heated under reflux for 24 h. During this time, the initially light yellow solution changed to a clear solution. The solution was evaporated to dryness to leave a white solid. The solid was recrystallized from a minimal amount of distilled water to give a yield of 148 mg (85 percent) . 1H NMR (DMSO-dff) : δ = 8.65 (IH, s), 8.06 (IH, s), 7.66 (IH, s) 2.05 (3H, s)
85%
With hydrogenchloride In water for 24 h; Heating / reflux
A solution of 2-cyano-4-methyl pyridine (0.15 g, 1.27 mmol) in about 10 mL of 6 M HCl was heated under reflux for 24 h. During this time, the initially light yellow solution changed to a clear solution. The solution was evaporated to dryness to leave a white solid. The solid was recrystallized from a minimal amount of distilled water to give a yield of 148 mg (85 percent) . 1H NMR (DMSO-dff) : δ = 8.65 (IH, s), 8.06 (IH, s), 7.66 (IH, s) 2.05 (3H, s)
53.8%
With sodium carbonate; sodium sulfite In sulfuric acid; water
II-3-2: Synthesis of 4-methylpicolinic acid A solution of 0.80 g (6.8 mmol) of 2-cyano-4-methylpyridine dissolved in 10.0 g of sulfuric acid was stirred under heating at 120° C. for 2 hours and then cooled to 20° C. A solution of 4.00 g of sodium sulfite in 8 ml of water was dropwise added at 20° to 25° C., and heated at the same temperature for 1.5 hours, and further, at 75° to 85° C. for 1.5 hours. After cooling, sodium carbonate was added to adjust the pH to about 3, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the extract was concentrated under a reduced pressure and the residue recrystallized from an ethyl acetate hexane mixture to give 0.50 g of crystals (yield 53.8percent). m.p.: 127°-128° C. IR (KBr): 3400, 3150, 2600, 2150, 1590, 1515 cm-1.
Reference：
[1] Patent: WO2008/17855, 2008, A1, . Location in patent: Page/Page column 49
[2] Patent: WO2008/17855, 2008, A1, . Location in patent: Page/Page column 49
[3] Patent: US5219847, 1993, A,
[4] Advanced Synthesis and Catalysis, 2013, vol. 355, # 5, p. 947 - 956
[5] Patent: US6251919, 2001, B1,
Reference：
[1] Advanced Synthesis and Catalysis, 2013, vol. 355, # 5, p. 947 - 956
[2] Patent: US6251919, 2001, B1,
22
[ 1620-76-4 ]
[ 71670-71-8 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2013, vol. 355, # 5, p. 947 - 956
23
[ 1620-76-4 ]
[ 129768-95-2 ]
Reference：
[1] Journal of the American Chemical Society, 2015, vol. 137, # 43, p. 13776 - 13779
[2] Patent: US2008/194650, 2008, A1, . Location in patent: Page/Page column 31
II-3-1: Synthesis of 2-cyano-4-methylpyridine A mixture of 10.9 g (0.1 mol) of 4-methylpyridine N-oxide and 12.6 g (0.1 mol) of dimethylsulfuric acid was stirred under heating at 70 to 75 C., and then, a solution of 12.6 g (0.2 mol) of potassium cyanide dissolved in 40 ml of water at 10 C. or lower was dropwise added while stirring. After stirring at the same temperature for one hour, and further, at room temperature for one hour, 150 ml of water was added and the mixture extracted with dichloromethane. After drying over anhydrous sodium sulfate, the extract was concentrated and separated by silica gel column chromatography (with ethyl acetate:hexane=2:8 to 3:7 for the first time, 2:8 for the second time), followed by recrystallization from hexane to give 0.80 g of a colorless solid (yield 6.78%). m.p 84.5-85.5 C. IR (KBr): 2240 1595 cm-1.
To a stirred solution of 2-nitrile-4-methylpyridine {31.19 g, 229 mmol; that was prepared by us from the corresponding 4-methylpyridine 1-oxide according to the reported procedure [17] and [46], 1H NMR (270 MHz, CDCl3) delta 8.57 (1H, d, J = 5.1 Hz), 7.53-7.52 (1H, m), 7.35-7.32 (1H, m), 2.44 (3H, m)} in dry benzene (300 mL)-anhydrous Et2O (230 mL) was added dropwise 2 M solution of MeMgI/Et2O (149.0 mL, 298 mmol) at 0 °C under N2 over 1 h. The reaction mixture was warmed to room temperature, stirred under N2 for 1 h, and then cooled to 0 °C. After aqueous NH4Cl (120 mL) was added dropwise to the mixture at 0 °C, the resulting mixture was warmed to room temperature and stirred for 1 h. The aqueous layer was removed, and the organic layer was washed with water, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, hexane/AcOEt = 8:1) to afford 16.20 g of 1-(4-methylpyridin-2-yl)ethanone 41 as a yellow oil in 52percent yield. 1H NMR (CDCl3, 270 MHz) delta 8.54 (1H, d, J = 4.9 Hz), 7.88-7.87 (1H, m), 7.30-7.27 (1H, m), 2.72 (3H, s), 2.43 (3H, m).
With tetrachloromethane; triethylamine; phosphonic acid diethyl ester; In acetonitrile; at 20℃; for 6h;
4-methyl-pyridine-N-oxide (0.109 g, 1 mmol), trimethyl cyanosilane (0.119 g, 1.2 mmol), diethyl H-phosphite (0.276 g, 2 mmol), carbon tetrachloride ( 0.308 g, 2 mmol), triethylamine (0.202 g, 2 mmol), 10 mL of acetonitrile in a 50 mL three-necked flask, and reacted at room temperature for 6 h. After the reaction was completed, the solvent was removed under reduced pressure and separated by column chromatography (petrol Ethyl acetate, V / V = 4: 1), the target compound is obtained as a colorless liquid with a yield of 80% and the structural formula is as follows:
42%
With N,N-Dimethylcarbamoyl chloride; In Nitroethane; at 20℃; for 120h;
Reference Example 35 2-Cyano-4-methylpyridine 4-Methylpyridine N-oxide (2. 0 g, 18.3 mmol) was dissolved in nitroethane (25 ml), and trimethylsilyl cyanide (2.0 g, 20.2 mmol) and N,N-dimethylcarbamoyl chloride (1.7 ml, 18.5 mmol) were added thereto.. The reaction mixture was stirred at room temperature for 5 days, concentrated under reduced pressure, combined with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate.. The extract was washed with saturated brine and dried.. The solvent was evaporated under reduced pressure.. The obtained crystals were collected by filtration, washed with diisopropyl ether and dried to give the titled compound (0.91 g, 42 %).1H-NMR (CDCl3) delta: 2.43 (3H, s), 7.33 (1H, d, J = 5.1 Hz), 7.53 (1H, s), 8.57 (1H, d, J = 4.8 Hz).
With sodium hydrogencarbonate; triethylamine; In acetonitrile;
Example 2 4-Methylpyridine-2-carbonitrile, a Compound of Formula 1 in which C Comprises 4-methylpyridin-2-yl and R8 is --CN Triethylamine (13.4 mL, 91.9 mmol) and trimethylsilyl cyanide (25 mL, 187.5 mmol) were added sequentially to a solution comprising 4-methylpyridine N-oxide (5 g, 45.8 mmol) and acetonitrile (20 mL). The mixture was heated at reflux for 24 hours, cooled and diluted with methylene chloride (150 mL). Saturated sodium bicarbonate solution (100 mL) was added slowly to the mixture and then the aqueous layer was separated and extracted with methylene chloride (100 mL). The combined organic layers were washed with water (2*150 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was crystallized from ethyl acetate/hexanes to provide 4-methylpyridine-2-carbonitrile (3.5 g, 29.6 mmol) as a dark solid, 1 H-NMR (300 Mhz, DMSO-d6): 2.4 (s, 3H), 7.6 (d, 1H, J=5 Hz), 7.8 (s, 1H), 8.6 (d, 1H, J=5 Hz), MS (ESI), Calculated for C7 H6 N2: 228.24, Found (MH+): 119.
2-Cyano-4-methylpyridine (3G). To a cold (0 C.) solution of 4-methyl-pyridine-1-oxide (3F) (10 g; commercially available) and trimethylsilyl cyanide (14.7 mL) in CH2Cl2 (150 mL) under an atmosphere of argon, N,N-dimethylcarbamoyl chloride (10.6 mL) was added dropwise with the temperature of the reaction maintained below 3 C. After the addition was complete, the resultant mixture was allowed to warm to room temperature and was stirred at room temperature overnight. The product mixture was treated with a 10% solution of K2CO3 (300 mL) and was stirred for 15 minutes. The aqueous layer was separated and extracted three times with CH2Cl2. The organic extracts were combined, washed with brine and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with 30% EtOAc in hexanes. Collection and concentration of appropriate fractions provided 2-cyano-4-methylpyridine (3G) as a white solid. 1H NMR (400 MHz, CDCl3) delta 8.58 (d, 1H), 7.5 (s, 1H), 7.32 (m, 1H), 7.25 (s, 1H), 2.4 (s, 3H).
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 77℃; for 4h;
10 mol of 2-cyano-4-methylpyridine was dissolved in 100 mL of carbon tetrachloride. 11 mol of benzoyl peroxide and 11 mol of bromosuccinimide were added and reacted at 77 C for 4 hours. The solvent was distilled off under reduced pressure. The pure product was purified by column chromatography on silica gel (200-300 mesh) with petroleum ether:ethyl acetate (3:1) in 67% yield.
0.146 ml of acetic acid is added to a solution of 0.236 g of 2-cyano-4-methylpyridine in 5 ml of carbon tetrachloride, under an inert atmosphere of argon at a temperature in the region of 20 C. The mixture is brought, with stirring, to a temperature of 50 C. 0.712 g of N-bromosuccinimide and 0.096 g of benzoyl peroxide are successively added at this temperature. The mixture is maintained at 80 C. for about 18 hours. After cooling, the reaction medium is placed on a cartridge 27 mm in diameter packed with 25 g of 20-40 mum silica not conditioned beforehand, and then eluted with dichloromethane at a flow rate of 10 ml/minute. The fractions between 140 and 175 ml are concentrated to dryness under reduced pressure. 0.097 g of 2-cyano-4-(bromomethyl)pyridine is thus obtained.
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃;Inert atmosphere;
Intermediate 11 : 4-(bromomethyl)-2-pyridinecarbonitrile 4-Methyl-2-pyridinecarbonitrile (1 g; Apollo) was dissolved in carbon tetrachloride (17 ml) in a 100 ml round-bottomed flask. This solution was treated with N-bromosuccinimide (1.507 g) followed by AIBN (0.139 g) then flushed with Argon, heated to 80 0C and stirred overnight. The reaction mixture was allowed to cool to room temperature, filtered through Kieselguhr, washed with DCM and evaporated to give the crude product (2.01 g) as a brown solid. The crude product was purified on a 40+M Biotage silica cartridge, eluting with a 0 to 50 % mixture of diethyl ether in hexane. This gave the target compound (345 mg) as a white solid, m/z [M+H]+: 197.1 / 199.1. Retention time 0.76 min (LC/MS method 3).
With hydrogenchloride; water; for 3h;Heating / reflux;
Methyl 4-methylpyridine-2-carboxylate (3H). A cold (0 C.) solution of 2-cyano-4-methylpyridine (3G) (7.2 g, 0.061 mol) and water (1.11 mL, 0.061 mol) in MeOH (150 mL) was saturated with HCl gas. The resultant mixture was refluxed under an atmosphere of argon for 3 hr. The reaction mixture was concentrated under vacuum, and the residue partitioned between saturated aqueous NaHCO3 and CHCl3. The organic extracts were combined, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with 5% Et2O/CHCl3. Collection and concentration of appropriate fractions gave methyl 4-methylpyridine-2-carboxylate (3H) as a clear oil. 1H NMR (400 MHz, CDCl3) delta8.6 (d, 1H), 8.0(s, 15H), 7.3(m, 1H), 4.0 (s, 3H), 2.43(s, 3H).
With triethylamine; In toluene; for 8h;Heating / reflux;
Example 138 2-(4-Methyl-2-pyridyl)-4H-1,3-benzothiazine-4-one A mixture of methyl thiosalicylate (1.15 g, 6.8 mmol), 2-cyano-4-methylpyridine (0.81 g, 6.8 mmol), triethylamine (1.50 ml, 10.8 mmol) and toluene (2.0 ml) was refluxed for 8 hrs.. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol to give the titled compound (1.11 g, 64 %). mp. 199.7-199.9 C IR (KBr): 1659, 1574, 1537, 1300, 1281 cm-11H-NMR (CDCl3) delta: 2.48 (3H, s), 7.36 (1H, d, J=4.2Hz), 7.60-7.72 (3H, m), 8.41 (1H, s), 8.54-8.60 (2H, m).
Reference Example 55 4-Methyl-2-pyridinecarbaldehyde diisobutyl aluminium hydride in toluene (1.5 M, 43.5 ml, 65 mmol) was added dropwise to a solution of 2-cyano-4-methylpyridine (7.0 g, 59 mmol) in dichloromethane (180 ml) at -78 C, and the mixture was stirred at the same temperature for 2 hrs.. The reaction mixture was combined with concentrated hydrochloric acid (28 ml) and water (112 ml), and the water layer and the organic layer were separated.. The organic layer was extracted with 2 N hydrochloric acid.. The water layer was combined, neutralized with sodium hydrogen carbonate and extracted with diethyl ether.. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate.. The solvent was evaporated to give the titled compound (2.7 g, 37 %).
Specific examples of compounds of Library 11; Synthesis of C- (5-METHYL-PYRIDIN-2-YL)-C-PHENYL-METHYLAMINE; 4-methyl-pyridine-2-carbonitrile (10.4g) was dissolved in dry Toluene (300ml) and cooled to 0-5C. Phenyl-magnesium chloride (55ML of 2M in tetrahydrofuran) was added dropwise over 30 minutes to give a thick creamy precipitate. The reaction was stirred for a further 30 minutes at 5C then iso butanol (120ML) was added dropwise keeping the temperature below 5C to give a clear brown solution. The reaction was then treated with sodium borohydride (5.3g) portionwise and the reaction was stirred at room temperature overnight. The reaction was quenched with methanol/water and concentrated in vacuo to remove the toluene. The mixture was extracted with dichloromethane and the organic phase was dried over magnesium sulphate before concentrating in vacuo. Purification was carried out by flash column chromatography on silica eluted with ethyl ACETATE/TRIETHYLAMINE to give (13. 6G ; 69% overall yield) of C- (4-METHYL-PYRIDIN-2-YL)-C-PHENYL methylamine as a brown oil ; 1H NMR (CDC13) : 8 = 2.1 (bs, 3H, NH3C1), 2.3 (s, 3H, CH3), 5.2 (s, 1H, CH), 6.9-7. 5 (m, 7H, ArH), 8.4 (m, 1H, ArH)
Preparation 15 To a stirred solution of 2-chloro-4-methylthiazole (6.35 g) in tetrahydrofuran (50 ml) was added a solution of n-butyllithium in n-hexane (1.66M, 34.35 ml) dropwise at -70 C. under a nitrogen atmosphere, and the mixture was stirred for 20 minutes at -70 C. To the resultant mixture was added a solution of 2-cyano-4-methylpyridine (3.74 g) in tetrahydrofuran (30 ml) dropwise at -70 C., and the mixture was stirred for 15 minutes. The mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography (silica gel 240 g, n-hexane:ethyl acetate=10:1) to give 2-chloro-4-methyl-5-(4-methylpyridin-2-ylcarbonyl)thiazole (1.64 g). 1H-NMR (CDCl3): delta2.47(3H,s), 2.86(3H,s), 7.34(1H,dd,J=4.9 Hz,0.9 Hz), 8.04(1H,d,J=0.9 Hz), 8.54(1H,d,J=4.9 Hz)
Preparation 23 To a stirred suspension of 2-cyano-4-methylpyridine (1.0 g) in tetrahydrofuran (10 ml) was added a solution of ethylmagnesium bromide in tetrahydrofuran (0.96M, 9.7 ml) dropwise at -55 C. The reaction mixture was stirred at -55 C. for 30 minutes and warmed to 0 C. Then the mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate twice. The combined organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 1-(4-methylpyridin-2-yl)-propan-1-one (1.21 g). 1H-NMR (CDCl13): delta; 1.21 (3H,t,J=7.3 Hz), 2.42(3H,s), 3.23(2H,q,J=7.3 Hz), 7.27(1H,d,J=5.0 Hz), 7.86(1H,s), 8.52(1H,d,J=5.0 Hz)
With hydrogenchloride; In water; for 24h;Heating / reflux;
A solution of 2-cyano-4-methyl pyridine (0.15 g, 1.27 mmol) in about 10 mL of 6 M HCl was heated under reflux for 24 h. During this time, the initially light yellow solution changed to a clear solution. The solution was evaporated to dryness to leave a white solid. The solid was recrystallized from a minimal amount of distilled water to give a yield of 148 mg (85 %) . 1H NMR (DMSO-dff) : delta = 8.65 (IH, s), 8.06 (IH, s), 7.66 (IH, s) 2.05 (3H, s)
53.8%
With sodium carbonate; sodium sulfite; In sulfuric acid; water;
II-3-2: Synthesis of 4-methylpicolinic acid A solution of 0.80 g (6.8 mmol) of 2-cyano-4-methylpyridine dissolved in 10.0 g of sulfuric acid was stirred under heating at 120 C. for 2 hours and then cooled to 20 C. A solution of 4.00 g of sodium sulfite in 8 ml of water was dropwise added at 20 to 25 C., and heated at the same temperature for 1.5 hours, and further, at 75 to 85 C. for 1.5 hours. After cooling, sodium carbonate was added to adjust the pH to about 3, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the extract was concentrated under a reduced pressure and the residue recrystallized from an ethyl acetate hexane mixture to give 0.50 g of crystals (yield 53.8%). m.p.: 127-128 C. IR (KBr): 3400, 3150, 2600, 2150, 1590, 1515 cm-1.
With hydrogenchloride;
Step 2. The preparation of 4-methyl-pyridine-2-carboxylic acid: 4-Methyl-2-cyano-pyridine (13.0 g, 110 mmol) was treated with 6N HCl and heated to reflux for twenty hours. The reaction was concentrated to give the desired product. MS: 138 (M+1 for C8H11N1O2); 1H-NMR (DMSO-d6)delta2.43 (s, 3 H), 7.61 (dd, 1 H, J=5.4, 1.0 Hz), 7.99 (d, 1 H, J=1.0 Hz), (8.57 (d, 1 H, J=5.4 Hz).
Step 2 Preparation of 4-methyl-N-[4-(methylsulfonyl)phenyl]-2-pyridinecarboximidamide To a solution of 4-methylsulfonyl aniline (7.62 g, 44.5 mmol) in 40 ml of 1,2-dichloroethane, was added 23.4 ml of a 1.9 H solution of triethylaluminum in toluene. After stirring for 1.5 hours at 0 C., 2-cyano-4-methyl-pyridine from step 1 (5.26 g, 44.5 mmol) was added. The reaction mixture was heated to reflux for 20 hours and poured onto a pad of silica gel, in a fritted filter funnel, pre-wetted with 50% methanol/methylene chloride. The filtrates were evaporated under reduced pressure to provide 11.05 g (85%) of the desired amidine as a light brown solid: mp 180-184 C. Anal. Calc'd. for C14 H15 N3 O2 S: C, 58.11; H, 5.23; N, 14.52. Found: C, 57.56; H, 5.15; N, 14.35.
1,8-Diazabicyclo[5.4.0]undec-7-ene [DBU][ No CAS ]
[ 7677-24-9 ]
[ 1620-76-4 ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran;
Step 1 Preparation of 2-cyano-4-methylpyridine To a suspension of 4-picoline N-oxide (13.64 g, 0.124 mole) in 82 ml of THF, under an inert atmosphere, was added trimethylsilyl cyanide (20.1 ml, 0.15 mole) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (4.4 ml, 0.028 mole). After stirring at 25 C. for 12 hours, the reaction mixture was heated to reflux. After 4.5 hours, the solvent was removed under reduced pressure and the crude sample was eluted with methylene chloride through a pad of Florisil. The solvent was removed under reduced pressure to provide (8.7 g, 60%) of 2-cyano-4-methyl pyridine, a white crystalline solid: mp 88-89 C. Anal. Calc'd. for C7 H6 N2: C, 71.17; H, 5.12; N, 23.71. Found: C, 70.71; H, 5.16; N, 23.44.
2-aminomethyl-4-methyl pyridine g 2 (0.0169 moles) of 2-cyano-4-methyl pyridine [J. Am. Chem. Soc. 78, 5842-5843 (1956)] dissolved in 400 ml of methanol containing 12% W/W of ammonia, were hydrogenated on 2 g of Ni-Raney at room temperature and 20 psi, until the theoretical amount of hydrogen was consumed. The catalyst was filtered off and the filtrate evaporated in vacuo. The obtained oily product, g 1.8, was sufficiently pure for the subsequent step.
Ni-Raney; In methanol;
2-aminomethyl-4-methyl pyridine g 2 (0.0169 moles) of 2-cyano-4-methyl pyridine [J. Am. Chem. Soc. 78 , 5842-5843 (1956)] dissolved in 400 ml of methanol containing 12% W/W of ammonia, were hydrogenated on 2 g of Ni-Raney at room temperature and 20 psi, until the theoretical amount of hydrogen was consumed. The catalyst was filtered off and the filtrate evaporated in vacuo . The obtained oily product, g 1.8, was sufficiently pure for the subsequent step.
With potassium carbonate; In dichloromethane; water;
Step 1. The preparation of 4-methyl-2-cyano-pyridine: 4-Picoline-N-oxide (10.0 g, 91.6 mmol) was dissolved in CH2Cl2 (92 mL) and dried over MgSO4. The drying agent was filtered away and the solution was added to trimetbylsilyl cyanide (11.5 g, 116 mmol). A solution of dimethylcarbamoyl chloride (12.5 g, 116 mmol) in CH2Cl2 (25 mL) was added dropwise over 45 minutes. The reaction was stirred overnight. A 10% solution of K2CO3 in water (100 mL) was added dropwise and stirred for ten minutes. The layers were separated, then the aqueous layer was washed with CH2Cl2 (2*100 mL). The organic layers were combined, dried over Na2SO4, and concentrated to give the desired product (13.18 g crude material). MS: 119 (M+1 for C7H6N2); 1H-NMR (CDCl3)delta2.28 (s, 3 H), 7.18 (d, 1 H, J=4.9 Hz), 7.37 (s,1 H), 8.41 (d, 1 H, J=5.1 Hz).
2-Cyano 4-methylpyridine in MeOH (35 ml) and concentrated HCl (1 ml) was stirred under a H2 balloon for 14 hours. The reaction mixture was filtered and concentrated. The pH was adjusted to 12 by the addition of aq sodium hydroxide. The resulting reaction mixture was extracted with dichloromethane several times. Concentration of the solvent gave the crude title compound, which was used in the next step without further purification.
[2-(2-dimethylaminoethyl)benzo[b]thiophen-3-yl]pyridin-2-ylmethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
EXAMPLE 5; [2-(3-Bromo-benzo[b]thiophen-2-yl)-ethyl]-dimethyl-amine (0.36 g, 1.28 mmol) was dissolved in 3.5 mL of anhydrous toluene. To the solution was added TMEDA (192 uL, 1.28 mmol) and the mixture was chilled to -78 C. To the mixture was carefully added sec-BuLi (1.0 mL, 1.41 mmol, 1.4M in cyclohexane) while keeping the internal temperature <-60 C. The mixture was stirred at -78 C. for 30 minutes. To the solution was added 4-Methyl-pyridine-2-carbonitrile (150 mg, 1.28 mmol). The mixture was stirred at -78 C. for 30 minutes. The reaction was quenched by careful dropwise addition of a mixture of 1 mL 6N HCl and 2 mL methanol. The mixture was allowed to warm to 0 C. and the organic phase was subsequently separated. The organic phase was extracted with 1N HCl. The combined aqueous phases were stirred at ambient temperature overnight. Following complete hydrolysis of the imine, the mixture was brought to pH 10 with the careful addition of 50% sodium hydroxide and extracted 3 times with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Silica gel chromatography (eluent: dichloromethane/methanol=98/2 with 0.2% NH4OH) generated 310 mg of [2-(2-Dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-pyridin-2-yl-methanone (Compound 5-1) (78%). ;
With lithium diisopropyl amide; In tetrahydrofuran; n-heptane; ethylbenzene; at -78 - 20℃; for 14.5h;
To a solution of 4-methylpyridine-2-carbonitrile (2.0 g) in THF (60 mL) was added 2.0 M LDA in heptane/THF/ethylbenzene (10.2 mL) at -78 C. The mixture was stirred at -78 C. for 2 hr. Allyl bromide (2.4 g) was added to the mixture at -78 C. The reaction mixture was stirred at -78 C. for 2.5 hr and at RT for 12 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (Developing solvent: hexane/ethyl acetate=9/1) to give the title compound (0.34 g, 12%).1H-NMR (400 MHz, CDCl3) delta: 8.59 (1H, dd, J=5.07, 0.66 Hz), 7.53 (1H, dd, J=1.54, 0.66 Hz), 7.33 (1H, dd, J=5.07, 1.76 Hz), 5.83-5.73 (1H, m), 5.06-5.01 (2H, m), 2.78 (2H, t, J=7.61 Hz), 2.44-2.38 (2H, m).
To 4-methyl-2*pyridinecarbonitrile (142 mg, 1.2 mmol) was added a solution of sodium methoxide in methanol (0.087 M, 1.4 ml, 0.1 eq) and the solution stirred under nitrogen in a 40 C oil-bath for 2 h. A suspension of 2-amino-4-(5'-(4"-methylpiperazin- 1 "-yl)benzimidazol-2'-yl)aniline(7) (264 mg, 0.82 mmol) in dry methanol (13 ml) was added, followed by glacial acetic acid (0.14 ml, 2.4 mmol) and the mixture gently refluxed under nitrogen for 21 h. After cooling the solvents were removed by rotary evaporator, the residue treated with dilute ammonia solution (2.7 M, 10 ml) and stirred for 45 min to give an even suspension of friable material. The suspension was centrifuged, the supernatant removed and the residue treated with additional dilute ammonia (2.7 M, 5 ml), followed by acetonitrile (2 5 ml), with centrifugation and removal of the supernatant between each treatment. The remaining solid was then applied to a short plug of alumina (basic, Act I, 30 x 70 mm) and eluted with 50:3:1 ethyl acetate/methanol/triethylamine to give 4-methyl- 2-(5'-(5"-(4" ^memylpiperazin- 1 ' ' ,-yl)ben7imida7ol-2"-yl)benzimida7ol-2,-yl)pyridine as a yellow powder (281 mg, 83%), mp 200 C (dec)..H nmr (400 MHz, dj-MeOH + 4 drops d-TFA) delta 2.58, s, 3H, 4-Me; 3.01, s, 3H,4"'-MeN; 3.21, m (obs), NCH2; 3.34, m (obs), NCH2; 3.68, d (J = 12.0 Hz), 2H, NCH2; 3.97, d (J = 12.4 Hz), 2H, NCH2; 7.34, d (J = 2.4 Hz), 1H, H4"; 7.43, dd (J = 2.2, 9.0 Hz), 1H, H6"; 7.58, d (J = 4.0 Hz), 1H, H5; 7.75, d (J = 9.2 Hz), 1H, H7"; 8.08, d ( J = 8.8 Hz), 1H, H7'; 8.20, dd (J = 1.6, 8.4 Hz), 1H, H6'; 8.29, s, 1H, H3; 8.60, d (J =1.6 Hz), 1H, H4'; 8.73, d (J = 4.8 Hz), 1H, H6. 13C nmr (125 MHz, d,-MeOH + 4 drops HOAc) delta 21.1, 4- Me*; 43.6, 4"'-MeN; 49.3, C2"76"'; 54.6, C3"75'"; 102.4, C4"; 115.1, C4'; 116.3, C7"; 116.9 (overlap), C6", C7'; 123.0, C6'; 123.5, C3; 123.9, C5'; 127.0, C5; 134.0, C7a"; 138.8, 140.3, 141.5, C3a C3a", C7a'; 148.4, 148.6, C2, C5"; 150.1, C4; 150.5, C6; 152.8, 154.2, C2 C2". MS (ESI +ve) m/z 847 (M2H+, 8%), 424 (MH+, 100), 213 (MH22+, 14). HRMS (ESI +ve) m/z 424.22433, C25H26N7 requires 424.22442 (Delta = 0.2 ppm).* Obscured by HOAc, observed indirectly by gHSQC experiment.Cytotoxicity and radioprotection resultsC50 = 130.5PF = 183.8DMFm = 2.55DMF10 = 2.36
4-(5-morpholin-4-yl-1(3)<i>H</i>-benzoimidazol-2-yl)-benzene-1,2-diamine[ No CAS ]
[ 1339045-14-5 ]
Yield
Reaction Conditions
Operation in experiment
73%
4-Methyl-2-pyridinecarbonitrile (105 mg, 0.89 mmol) was treated with a solution: of sodium methoxide in methanol (0.087 M, 1.1 ml, 0.09 mmol) and the mixture heated at 40 C under nitrogen for 90 min. A solution of 2-amino-4^5'-mo holmobenzirnidazol- 2'-yl)aniline (121 mg, 0.39 mmol) (for preparation see Example 19 part C(i)) in dry methanol (13 ml) and glacial acetic acid (0.11 ml, 1.9 mmol) was then added and the mixture gently refluxed under nitrogen for 18 h. The solvent was then removed under reduced pressure and dilute ammonia (3.0 M, 10 ml) was added before diluting with water (10 ml) and extraction with n-butanol (20 ml). The n-butanol extract was washed with water (2 x 15 ml) then evaporated to give an orange glassy solid. The material was triturated with acetonitrile (4 x 3 ml) to give a tan powder (90 mg) that was further purified by column chromatography (silica gel, 20 x 150 mm), eluting with 9:1 ethyl acetate/methanol to give 2-(5,-(5"-mo^holmoben2imidazol-2"-yl)ben7imida7ol-2,-yl)-4- methylpyridine as a pale yellow powder (67 mg, 42%), mp 214-230 C.Additional material was obtained by column chromatography of the acetonitrile soluble material to give a further 51 mg (total yield 73%).1H nmr (500 MHz, dj-MeOH + 4 drops d-TFA) delta 2.58, s, 3H, 4-Me; 3.30, m (obs),H3"75'"; 3.90, m, 4H, H2"76"'; 7.24, d (J = 2.0 Hz), 1H, H4"; 7.41, dd (J = 2.5, 9.0 Hz), 1H, H6"; 7.57, br d (J = 5.0 Hz), 1H, H5; 7.70, d (J = 9.0 Hz), 1H, H7"; 8.06, d (J = 8.5 Hz), 1H, H7'; 8.16, dd (J = 1.8, 8.8 Hz), 1H, H6'; 8.27, br s, 1H, H3; 8.55, d (J = 1.5 Hz), 1H, H4'; 8.72, d (J = 5.5 Hz), TH, H6. I3C nmr (125 MHz, dj-MeOH + 4 drops HOAc) delta 21.1, 4-Me; 51.3, C3"75"'; 67.8, C2"76"'; 100.1, C4"; 115.1, 115.7, 116.3, 116.9, C4', C6", C7 CT; 122.0, C5'; 122.6, 123.4, C3, C6'; 126.9, C5; 131.5, C7a"; 137.2, 140.1, 141.6, C3a C3a", C7a'; 150.0, C2", C4 or C5"; 150.4, C6; 150.5, 151.2, C2", C4 or C5"; 154.3, C2'. MS (ESI +ve) m/z 821 (M2H+, 8%), 411 (MH+, 100). HRMS (ESI +ve) m/z 411.19274, C24H23N60 requires 411.19279 (Delta = 0.1 ppm).Cytotoxicity and radioprotection resultsC50 = 213.4PF = 18.2DMFm = 1.77DMF10 = 1.47
To 4-methylpyridine-2-carbonitrile (135 mg, 1.14 mmol) was added a solution of sodium methoxide in methanol (0.1 M, 1.1 ml, 0.11 mmol) and the solution heated under nitrogen in a 40-45 C oil-bath for 110 min. A solution of 2-amino-4-(5'-(4"- hydroxypiperidm-l"-yl)benzimidazol-2'-yl)aniline (0.60 mmol) in dry methanol (10 ml) and glacial acetic acid (0.12 ml, 2.1 mmol) was added and the mixture gently refluxed under nitrogen for 19 h. After cooling the solvents were removed by rotary evaporator and the residue dissolved in water (9 ml) and basified to pH 8-9 with 3 M ammonia solution. Additional water was added (~10 ml) and the oily suspension extracted with n-butanol (20 ml). The butanol extract was washed with water (20 ml) and evaporated to give a brown oil. The oil was treated with acetonitrile (2 ml) and stirred for 40 min to give a friable olive solid that was further triturated with acetonitrile (2 x 2 ml). The solid was dissolved in methanol (3 ml) with heating and applied to a silica gel cartridge (Reveleris 12 g) and eluted with a ethyl acetate/methanol gradient to give 2-(5'-(5,' 4,''-hydroxypiperidin- ''- yljbeiTzimidayol^-yQbenT mida/ol^'-yl^-mem lpyridme as a yellow powder (155 mg, 61%), mp 204-209 C.lH nmr (500 MHz, d4-MeOH + 4 drops d-TFA) delta 2.00, m, 2H, H3",/H5'"; 2.25, m, 2H, H3"75"'; 2.58, s, 3H, 4-Me; 3.61, m, 2H, H2"76'"; 3.91, m, 2H, H2"76"'; 4.09, tt (J = 3.5, 7.0 Hz), 1H, H4'"; 7.58, dq (J = 5.0, 0.7 Hz), 1H, H5; 7.74, dd (J = 2.2, 8.8 Hz), 1H, H6"; 7.92, d (J = 8.5 Hz), 1H, H7"; 7.99, d (J = 2.0 Hz), 1H, H4"; 8.07, dd (J = 0.8, 8.8 Hz), 1H, H7'; 8.27, m, 2H, H3, H6'; 8.64, dd (J = 0.5, 1.5 Hz), 1H, H4'; 8.73, d (J = 5.0 Hz), 1H, H6. 13C nmr (125 MHz, drMeOH + 5 drops HOAc) delta 21.1, 4-Me; 34.8, C3"75"'; 49.7, C2"76"'; 68.0, C4'"; 101.0, C4"; 115.1, 115.5, 116.9, 117.6, C4 C6", C7', C7"; 121.5, C5'; 122.6, 123.4, 126.9, C3, C5, C6'; 130.9, C7a"; 136.9, C3a"; 140.0, C3a'; 141.6, C7a'; 148.0, C2; 149.9, 150.1, C4, C5"; 150.4, C6; 150.9, 154.3, C2', C2". MS (ESI +ve) m/z 425 (MH+, 100%). HRMS (ESI +ve) m/z 425.20844, C25H25N60 requires 425.20844 (Delta = 0.0 ppm).Cytotoxicity and radioprotection resultsC50 = 134.3PF = 23.5DMFm = 1.79DMF10 = 1.33
With NaOCH3; In methanol; water; N,N-dimethyl-formamide;
2-6. Preparation of 3-Trifluoromethyl-5-(4-methyl-2-pyridyl)-1,2,4-triazole (21) 2-Cyano-4-methylpyridine, 18 (1.3 g, 9.3 mmol), in N,N-dimethyl formamide (60.0 ml) was added to 20 (2.2 g, 17.2 mmol) and stirred at room temperature. After 30 min, 28% NaOCH3 solution in methanol (0.2 g) was added to the reaction mixture and refluxed at 153 C. for 2 days. The solution was evaporated in vacuo and water (50 ml) was added to the residue. This solution was extracted with ethyl acetate (50 ml*2). The organic solution was dried over sodium sulfate and the filtrate was evaporated in vacuo. The crude product was subjected to column chromatography on silica (solvent: ethyl acetate/chloroform=1/5) and white solid, 21 (0.6 g, 2.5 mmol, 27%), was obtained. 1H-NMR (CDCl3) delta 8.70 (d, 1H, J=5.4 Hz), 8.21 (s, 1H), 7.36 (s, 1H, J=5.4 Hz), 2.51 (s, 3H), 13C-NMR (CDCl3) delta 21.1, 117.2, 120.8, 123.6, 126.9, 149.1, 150.6, 155.1, HRMS (M+, 229.0703, Calcd, 229.0623).
Step 1: Preparation of 2-(4-methyl-2-pyridyl)propan-2-amine To a mechanically stirred solution of THF (180 mL) was added anhydrous CeCl3 (76.5 mmol, 18.8 g) and the mixture was aged at 65 C. for 3.5 h. The mixture was cooled to -78 C. and MeLi (1.6 M in Et2O, 76.5 mmol, 55 mL) was added dropwise over 25 min. The reaction was stirred an additional 30 min at -78 C. before addition of 4-methylpyridine-2-carbonitrile (15.3 mmol, 1.81 g) as a THF solution (25 mL). After addition the reaction was kept 1.5 h at -78 C. before being slowly brought back to RT abd stirred overnight. The reaction was quenched by addition of NH4Cl sat. aq. solution and ammonium hydroxide (25% in H2O, 50 mL) added. The reaction mixture was filtered over Celite to remove the precipitate and the filter pad washed with CH2Cl2. The combine organic phase were washed with brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by column chromatography over SiO2 (CH2Cl2/MeOH/NH4OH 95:4.5:0.5) to yield 2-(4-methyl-2-pyridyl)propan-2-amine as yellow oil. 1H NMR (CDCl3) delta ppm: 8.41 (1H, d), 7.25 (1H, s), 6.94 (1H, d), 2.36 (3H, s), 2.14 (2H, bs), 1.51 (6H, s).
To a mechanically stirred solution of THF (180 ml_) was added anhydrous CeCI3 (76.5 mmol, 18.8 g) and the mixture was aged at 65C for 3.5 h. The mixture was cooled to - 78C and MeLi (1.6 M in Et20, 76.5 mmol, 55 ml_) was added dropwise over 25 min. The reaction was stirred an additional 30 min at -78C before addition of 4- methylpyridine-2-carbonitrile (15.3 mmol, 1.81 g) as a THF solution (25 ml_). After addition the reaction was kept 1.5 h at -78C before being slowly brought back to RT abd stirred overnight. The reaction was quenched by addition of NH4CI sat. aq. solution and ammonium hydroxide (25% in H20, 50 ml_) added. The reaction mixture was filtered over Celite to remove the precipitate and the filter pad washed with CH2CI2. The combine organic phase were washed with brine, dried over Na2S04, filtered and evaporated. The crude product was purified by column chromatography over Si02 (CH2CI2/MeOH/NH4OH 95:4.5:0.5) to yield 2-(4-methyl-2-pyridyl)propan-2-amine as yellow oil.1 H NMR (CDCIa) delta ppm: 8.41 (1 H, d), 7.25 (1 H, s), 6.94 (1 H, d), 2.36 (3H, s), 2.14 (2H, bs), 1.51 (6H, s).
General procedure: Sodium (0.092g, 4.0 mmol) was added to dried methanol (25 mL), and stirred until complete dissolution was achieved. 2-Cyanopyridine or <strong>[1620-76-4]2-Cyano-4-methylpyridin</strong>e (24.9 mmol) wasthen added, the mixture was stirred for 30 min. The N(4)-disubstituted thiosemicarbazide (24.9mmol) was then added in small portions over a period of 1 h. A further quantity of methanol(25 mL) was added and the mixture was heated under reflux for a minimum of 4 h. Slow evaporation of the methanol produced the crystals of desired product
24%
General procedure: Sodium (0.092 g, 4.0 mmol) was added to dried methanol (25 mL), and stirred until complete dissolution was achieved. 2-Cyanopyridine or substituted 2-cyanopyridine (24.9 mmol) was then added. The mixture was stirred for 30 min. The N(4)-disubstituted thiosemicarbazide (24.9 mmol) was then added in small portions over a period of 1 h. A further quantity of methanol (25 mL) was added and the mixture was heated under reflux for a minimum of 4 h. Slow evaporation of the methanol produced the crystals of the desired product.(See Supplementary data)
General procedure: Sodium (0.092g, 4.0 mmol) was added to dried methanol (25 mL), and stirred until complete dissolution was achieved. 2-Cyanopyridine or <strong>[1620-76-4]2-Cyano-4-methylpyridin</strong>e (24.9 mmol) wasthen added, the mixture was stirred for 30 min. The N(4)-disubstituted thiosemicarbazide (24.9mmol) was then added in small portions over a period of 1 h. A further quantity of methanol(25 mL) was added and the mixture was heated under reflux for a minimum of 4 h. Slow evaporation of the methanol produced the crystals of desired product
29%
General procedure: Sodium (0.092 g, 4.0 mmol) was added to dried methanol (25 mL), and stirred until complete dissolution was achieved. 2-Cyanopyridine or substituted 2-cyanopyridine (24.9 mmol) was then added. The mixture was stirred for 30 min. The N(4)-disubstituted thiosemicarbazide (24.9 mmol) was then added in small portions over a period of 1 h. A further quantity of methanol (25 mL) was added and the mixture was heated under reflux for a minimum of 4 h. Slow evaporation of the methanol produced the crystals of the desired product.(See Supplementary data)
General procedure: Sodium (0.092g, 4.0 mmol) was added to dried methanol (25 mL), and stirred until complete dissolution was achieved. 2-Cyanopyridine or <strong>[1620-76-4]2-Cyano-4-methylpyridin</strong>e (24.9 mmol) wasthen added, the mixture was stirred for 30 min. The N(4)-disubstituted thiosemicarbazide (24.9mmol) was then added in small portions over a period of 1 h. A further quantity of methanol(25 mL) was added and the mixture was heated under reflux for a minimum of 4 h. Slow evaporation of the methanol produced the crystals of desired product
41%
General procedure: Sodium (0.092 g, 4.0 mmol) was added to dried methanol (25 mL), and stirred until complete dissolution was achieved. 2-Cyanopyridine or substituted 2-cyanopyridine (24.9 mmol) was then added. The mixture was stirred for 30 min. The N(4)-disubstituted thiosemicarbazide (24.9 mmol) was then added in small portions over a period of 1 h. A further quantity of methanol (25 mL) was added and the mixture was heated under reflux for a minimum of 4 h. Slow evaporation of the methanol produced the crystals of the desired product.(See Supplementary data)
General procedure: Sodium (0.092g, 4.0 mmol) was added to dried methanol (25 mL), and stirred until complete dissolution was achieved. 2-Cyanopyridine or <strong>[1620-76-4]2-Cyano-4-methylpyridin</strong>e (24.9 mmol) wasthen added, the mixture was stirred for 30 min. The N(4)-disubstituted thiosemicarbazide (24.9mmol) was then added in small portions over a period of 1 h. A further quantity of methanol(25 mL) was added and the mixture was heated under reflux for a minimum of 4 h. Slow evaporation of the methanol produced the crystals of desired product
32%
General procedure: Sodium (0.092 g, 4.0 mmol) was added to dried methanol (25 mL), and stirred until complete dissolution was achieved. 2-Cyanopyridine or substituted 2-cyanopyridine (24.9 mmol) was then added. The mixture was stirred for 30 min. The N(4)-disubstituted thiosemicarbazide (24.9 mmol) was then added in small portions over a period of 1 h. A further quantity of methanol (25 mL) was added and the mixture was heated under reflux for a minimum of 4 h. Slow evaporation of the methanol produced the crystals of the desired product.(See Supplementary data)
General procedure: Sodium (0.092g, 4.0 mmol) was added to dried methanol (25 mL), and stirred until complete dissolution was achieved. 2-Cyanopyridine or <strong>[1620-76-4]2-Cyano-4-methylpyridin</strong>e (24.9 mmol) wasthen added, the mixture was stirred for 30 min. The N(4)-disubstituted thiosemicarbazide (24.9mmol) was then added in small portions over a period of 1 h. A further quantity of methanol(25 mL) was added and the mixture was heated under reflux for a minimum of 4 h. Slow evaporation of the methanol produced the crystals of desired product
45%
General procedure: Sodium (0.092 g, 4.0 mmol) was added to dried methanol (25 mL), and stirred until complete dissolution was achieved. 2-Cyanopyridine or substituted 2-cyanopyridine (24.9 mmol) was then added. The mixture was stirred for 30 min. The N(4)-disubstituted thiosemicarbazide (24.9 mmol) was then added in small portions over a period of 1 h. A further quantity of methanol (25 mL) was added and the mixture was heated under reflux for a minimum of 4 h. Slow evaporation of the methanol produced the crystals of the desired product.(See Supplementary data)
Compound d-17-3 was synthesized according to the following reaction scheme. Then, exemplified dye D-1-36a was synthesized in the same manner as exemplified dye D-1-1a, except that compound d-1-3 was changed to compound d-17-3.
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