* 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] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 11, p. 1211 - 1214
3
[ 100-54-9 ]
[ 100-55-0 ]
[ 108-99-6 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 1994, vol. 67, # 4, p. 1107 - 1112
4
[ 100-54-9 ]
[ 100-55-0 ]
Reference：
[1] Diss.<Berlin 1938> S.20,
5
[ 100-54-9 ]
[ 3731-52-0 ]
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[1] Synlett, 2001, # 10, p. 1623 - 1625
[2] Chemistry - A European Journal, 2016, vol. 22, # 14, p. 4991 - 5002
[3] Catalysis Science and Technology, 2018, vol. 8, # 2, p. 499 - 507
[4] Small, 2018, vol. 14, # 37,
[5] Journal of the American Chemical Society, 2015, vol. 137, # 28, p. 8888 - 8891
[6] Helvetica Chimica Acta, 1937, vol. 20, p. 690
[7] Journal fuer Praktische Chemie (Leipzig), 1936, vol. <2> 146, p. 88,102
[8] Journal of the American Chemical Society, 1956, vol. 78, p. 3693
[9] Journal of the American Chemical Society, 1944, vol. 66, p. 876,877
[10] Chemicke Listy, 1951, vol. 45, p. 451[11] Chem.Abstr., 1953, p. 8068
[12] Journal of the American Chemical Society, 1941, vol. 63, p. 490
[13] Journal of the American Chemical Society, 1944, vol. 66, p. 1293
[14] Patent: US2615896, 1950, ,
[15] Helvetica Chimica Acta, 1937, vol. 20, p. 690
[16] Journal fuer Praktische Chemie (Leipzig), 1936, vol. <2> 146, p. 88,102
[17] Chemistry - A European Journal, 2008, vol. 14, # 31, p. 9491 - 9494
[18] Medicinal Chemistry Research, 2011, vol. 20, # 7, p. 1091 - 1101
[19] Catalysis Science and Technology, 2014, vol. 4, # 3, p. 629 - 632
[20] Chemical Communications, 2016, vol. 52, # 9, p. 1812 - 1815
[21] Catalysis Science and Technology, 2016, vol. 6, # 13, p. 4768 - 4772
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[24] ChemSusChem, 2017, vol. 10, # 5, p. 842 - 846
[25] Journal of Medicinal Chemistry, 2017, vol. 60, # 19, p. 7965 - 7983
[26] Synlett, 2017, vol. 28, # 20, p. 2855 - 2858
[27] Patent: CH244837, 1945, ,
6
[ 100-54-9 ]
[ 3731-52-0 ]
[ 1656-94-6 ]
Reference：
[1] Journal of the American Chemical Society, 1944, vol. 66, p. 1293
[2] Journal of the American Chemical Society, 1944, vol. 66, p. 1293
[3] Chemicke Listy, 1951, vol. 45, p. 451[4] Chem.Abstr., 1953, p. 8068
Reference：
[1] Chemistry Letters, 1984, p. 769 - 772
13
[ 100-54-9 ]
[ 74-89-5 ]
[ 20173-04-0 ]
Reference：
[1] Patent: US2798077, 1955, ,
14
[ 100-54-9 ]
[ 67-56-1 ]
[ 3222-48-8 ]
[ 5444-01-9 ]
Reference：
[1] Chemistry Letters, 1984, p. 769 - 772
15
[ 100-54-9 ]
[ 927-77-5 ]
[ 1701-70-8 ]
Reference：
[1] Journal of the American Chemical Society, 1948, vol. 70, p. 3482
[2] Journal of pharmaceutical sciences, 1980, vol. 69, # 7, p. 850 - 851
16
[ 100-54-9 ]
[ 10557-57-0 ]
[ 1701-70-8 ]
Reference：
[1] Journal of the American Chemical Society, 1928, vol. 50, p. 2482
17
[ 100-54-9 ]
[ 141-43-5 ]
[ 40055-37-6 ]
Yield
Reaction Conditions
Operation in experiment
89%
With sulfur; cobalt(II) nitrate In neat (no solvent) at 90℃; for 0.05 h; Microwave irradiation
General procedure: A mixture of nitrile (0.5 mmol), 2-aminoethanol (4) (0.65 mmol, 0.040 g), Co(NO3)2 (0.02 mmol, 0.036 g), and sulfur (0.05 mmol, 0.0016 g) was stirred at 90 C or subjected to microwave irradiation (90 C, 800 W) for appropriate time. For the synthesis of monooxazolines, dicyanobenzene (0.5 mmol), 2-aminoethanol (4) (0.65 mmol, 0.040 g), Co(NO3)2 (0.02 mmol, 0.036 g), and sulfur(0.05 mmol, 0.0016 g) was stirred at 90 C for 3 h or subjected to microwave irradiation (90 C, 800 W) for 3 min. For the synthesis of bis-oxazoline, dicyanobenzene (0.5 mmol), 2-aminoethanol (4) (2.6 mmol, 0.159 g), Co(NO3)2 (0.02 mmol, 0.036 g), and sulfur (0.05 mmol, 0.0016 g) was stirred at 110 C for 10 h or subjected to microwave irradiation (110 C, 800 W) for 8 min. After completionof the reaction (detected by TLC), the reaction mixture was cooled to room temperature, ethyl acetate (6 mL) was added and the catalyst was separated by the filtration. Following concentration under reduced pressure, the residue was purified by silica gel chromatography to give pure product (5a-r).
85%
With sulfur In neat (no solvent) at 50 - 80℃; Green chemistry
General procedure: An equimolar mixture of 2-aminoethanol (1.0 mmol) and sulfur(1.0 mmol) was heated under solvent-free condition at 50°C. Nitrile (1.0 mmol) was then added to reaction mixture and refluxed at 80°C. The progress of the reaction was monitored through TLC (n-hexane: EtOAc, 8:2). After completion of the reaction, excess of water was added, and the product was filtered (for solid). Further chromatographic purification afforded pure product. All the compounds were characterizedby infrared (IR) and 1H NMR and 13C NMR spectroscopic data, as well as by comparison with data of reported compounds.
85%
With Cu(II) immobilized on Fe3O4-agarose nanomagnetic catalyst functionalized with ethanolamine phosphate-salicylaldehyde Schiff base In dimethyl sulfoxide at 100℃; for 3 h;
General procedure: Benzonitrile (0.1 g, 1 mmol), 2-aminoethanol (0.09 g, 1.5 mmol), and Fe3O4 Agarose/SAEPH2 /Cu(II) nanomagnetic catalyst (0.05 g, 14 molpercent) were added to DMSO (2 mL) at 100 °C. The resultant mixture was stirred and controlled by TLC. After completion of the reaction, the reaction mixture was cooled and the nanomagnetic catalyst was separated by an external magnetic field. Then water (2 x 10 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate (2 x 10 mL). The organic layer was evaporated and the residue was puried by thin layer chromatography using ethyl acetate/n-hexane (1/1) as eluent. The pure 2-phenyl-4,5-dihydro-1,3-oxazole was obtained with a 95percent yield (0.13 g).
78%
With sulfur In neat (no solvent) at 100℃; for 9 h;
0.5 mmol 3-cyanopyridine, 1.0 mmol aminoethanol and 0.05 mmol sulfur were added to a 25 mL round bottom flask and the reaction temperature was 100 ° C with stirring for 9 h. After the reaction was completed (TLC monitoring), cool to room temperature. Added 6mL ethyl acetate filtered sulfur. Evaporation The ethyl acetate was concentrated and subjected to silica gel column chromatography with ethyl acetate / petroleum ether (1: 1) to obtain 57.6 mg of a white solid with a yield of 78percent.
Reference：
[1] Synlett, 2005, # 18, p. 2747 - 2750
[2] Monatshefte fur Chemie, 2009, vol. 140, # 12, p. 1489 - 1494
[3] Journal of the Serbian Chemical Society, 2012, vol. 77, # 9, p. 1181 - 1189,9
[4] Tetrahedron, 2013, vol. 69, # 32, p. 6591 - 6597
[5] Phosphorus, Sulfur and Silicon and the Related Elements, 2016, vol. 191, # 7, p. 971 - 974
[6] Turkish Journal of Chemistry, 2018, vol. 42, # 1, p. 170 - 191
[7] Dalton Transactions, 2013, vol. 42, # 44, p. 15570 - 15580
[8] Journal of Organic Chemistry, 2014, vol. 79, # 18, p. 8668 - 8677
[9] Journal of Organic Chemistry, 2015, vol. 80, # 20, p. 9910 - 9914
[10] Patent: CN103664917, 2017, B, . Location in patent: Paragraph 0018; 0020; 0021; 0032;
[11] Green Chemistry, 2017, vol. 19, # 24, p. 5789 - 5793
18
[ 60573-68-4 ]
[ 100-54-9 ]
[ 35779-35-2 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1951, vol. 70, p. 1054,1061
[2] Journal of Organic Chemistry, 1954, vol. 19, p. 1127,1129
General procedure: A screw capped vial was charged with nitrile (2 mmol), NaN3(2.4 mmol, 1.2 equiv.) and tetrabutylammonium bromide (2.4 mmol,1.2 equiv.). The resulting mixture was stirred at 105 °C and monitoredby TLC. After completion of the reaction, the reaction mixture wascooled to room temperature and dissolved with water (5 mL). Then, theaqueous solution was acidified with 1M HCl to pH = 3. If a precipitatewas formed, the suspension was filtered and the filter cake was washedwith water to afford the pure product. Otherwise, the aqueous solutionwas extracted with EtOAc (3 × 4 mL). The organic phase was washedwith 1M HCl (3 × 4 mL), dried with anhydrous Na2SO4, filtered andevaporated under vacuum to afford the pure product.
94%
With sodium azide; Acetate de N,N-dimethylamino-4 pyridinium In neat (no solvent) at 100℃; for 1 h;
To a round-bottomed flask containing 4-(N,N-dimethylamino)pyridiniumacetate (0.15 mmol, 0.02 g) at 100 C, 3-cyanopyridine (1.0 mmol, 0.104 g) andsodium azide (1.0 mmol, 0.06 g) were added and the mixture was stirred. After1 h, the reaction was complete. The mixture was cooled and washed with coldEtOH (2 5 mL), each time it was permitted to stir for 1 h. Filtration followed bydrying of the precipitate gave the corresponding pure tetrazole as a white solid.Yield (0.14 g, 94percent); mp 242–244 C; 1H NMR (400 MHz, DMSO-d6) d (ppm): 9.10(s, 1H), 8.42 (d, J = 7.9 Hz, 1H), 8.22 (d, J = 7.9 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H); 13CNMR (100 MHz, DMSO-d6) d (ppm): 162.7, 151.9, 149.8, 137.1, 126.4, 125.3; IR(KBr) v (cm1): 3389, 2129, 2036, 1644, 1423, 1144, 1014, 754, 639, 410.
92%
With sodium azide In N,N-dimethyl-formamide at 110℃; for 5 h;
General procedure: A mixture of nitrile (1 mmol), sodium azide (1.5 mmol), Cu complex catalyst (0.4 molpercent) and DMF (3 mL) was taken in a round-bottomed flask and stirred at 110 °C temperature. After completion of the reaction the catalyst was separated from the reaction mixture with an external magnet and reaction mixture was treated with ethyl acetate (2 × 20 mL) and 1 N HCl (20 mL). The resultant organic layer was separated and the aqueous layer was again extracted with ethyl acetate (2 × 15 mL). The combined organic layers were washed with water, concentrated, and the crude material was chromatographed on silica gel (Hexane-EtoAc, 1:1) to afford the pure product.
92%
With sodium azide; silver(I) triflimide In toluene at 85℃; for 2 h;
General procedure: A mixture of the appropriate nitrile (1 mmol), NaN3 (1.5 mmol),toluene (2 mL) and AgNTf2 (5 molpercent) was placed in a round bottomed flask and heated at 85 oC. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was cooled and treated with ethyl acetate (15 mL) and 1M HCl (15 mL)and stirred vigorously. The resultant organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The combined organic layer was washed with water and concentrated to give the pure tetrazole. All the products are known compounds and the spectral data and melting points were identical to those reported in the literature. The disappearance of one strong and sharp absorption band (CN stretching band), and the appearance of an NH stretching band in the IR spectra, were characteristic of the formation of 5-substituted 1H-tetrazoles.
92%
at 100℃; for 1.3 h;
In a roundbottom flask in 100°C, consecutively, the catalyst (0.015mmol, 0.004 g), 3-cyanopyridine (1.0 mmol, 0.104 g) andsodium azide (1.0 mmol, 0.065 g) were added and the mixturewas stirred for 90 min until it was completed. Then, thereaction mixture was cooled to room temperature andwashed with ethanol (25 mL). After filtration, the white In a roundbottom flask in 100°C, consecutively, the catalyst (0.015mmol, 0.004 g), 3-cyanopyridine (1.0 mmol, 0.104 g) andsodium azide (1.0 mmol, 0.065 g) were added and the mixturewas stirred for 90 min until it was completed. Then, thereaction mixture was cooled to room temperature andwashed with ethanol (25 mL). After filtration, the white
90%
With sodium azide In N,N-dimethyl-formamide at 120℃; for 6 h;
General procedure: A mixture of nitrile (1 mmol), sodium azide (1.5 mmol) and catalyst (0.02 g, contains 0.4 molpercent of Cu(II)) in DMF (3 mL) was taken in a round-bottomed flask and stirred at 120 °C. The progress of the reaction was followed by thin-layer chromatography (TLC). After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (3×20 mL). The catalyst was removed by using magnetic field or filtration and then the resulting solution was washed with 1N HCl, dried over anhydrous Na2SO4 and then was evaporated. The crude products were obtained in excellent yields. All products were characterized by 1H, 13C NMR, FT-IR, and melting point which were in agreement with literature. We have reported the spectral data of some aromatic and heteroaromatic synthesized compounds
81%
With lithium tetraazidoborate; ammonium acetate In methanol; N,N-dimethyl-formamide at 110℃; for 8 h;
General procedure: NH4OAc (15 mg) was added to a mixture of benzonitrile(103 mg, 1 mmol) and LiB(N3)4(93 mg, 0.5 mmol) in DMF/MeOH (9/1) solution (5 mL) and stirred the mixture was at 100 oC for 8 h. After completion of reaction (monitored by TLC),the mixture was cooled to room temperature and diluted with ethyl acetate. The resulting solution was washed with 1 M HCl, dried over anhydrous Na2SO4, and concentrated. An aqueous solution of NaOH (1 M) was added to the residue, and the mixture was stirred for 30 min at room temperature. The resulting solution was washed with ethyl acetate, and then 2 M HCl was added until the pH value of the water layer became 1~2. The aqueous layer was extracted with ethyl acetate three times, and the combined organic layers were washed with 1M HCl.The organic layer was dried over anhydrous Na2SO4 and concentrated to furnish pure 5-phenyl-1-H-tetrazole 1b as a white solid (125 mg) in 86percent yield.
66%
With sodium azide; ammonium chloride In N,N-dimethyl-formamide for 24 h; Reflux
General procedure: In a typical procedure, 5-aryl-1H-tetrazoles (1–24) were synthesized by adding aryl nitriles (1 eq.), sodium azide (1.2 eq.), and ammonium chloride (1 eq.) in solvent, the mixture was refluxed for 24 h. Progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, 2.5 mL of 2M NaOH was added and the solution was stirred for half an hour. The reaction mixture was concentrated on reduced pressure, and dissolved in water. 3M HCl was added to the reaction mixture until precipitates formed. The precipitates were filtered and washed with distilled water. The yields of title compounds were found to be moderate to high.
46%
Stage #1: With sodium azide; ammonium chloride In DMF (N,N-dimethyl-formamide) at 90℃; for 15 h; Stage #2: With hydrogenchloride In water
[0342] 3-(1H-tetrazol-5-yl)pyridine (64). To a solution of 3-cyanopyridine (1. 1 g, 10.6 mmol) in DMF (15 mL) was added ammonium chloride (718 mg, 13.4 mmol) and sodium azide (824 mg, 12.7 mmol) and the resultant slurry was vigorously stirred at 90 °C for 15 h. The DMF was removed in vacuo, the residue was dissolved in aqueous potassium hydroxide (1 M, 20 mL), washed with EtOAc (2 x 25 mL), the aqueous layer was adjusted to pH No. 3 with aqueous HCl (6 N) and the solid was collected by filtration to afford the title compound 64 (904 mg, 46 percent yield) as a white solid: mp = 239-241 °C dec. ; 1H NMR (CDC13) b 9.21 (m, 1H), 8.76 (m, 1H), 8.39 (m, 1H), 7.64 (m, 1H) ; LRMS (ESI) m/z calcd for C6H6N5 [M + H] + 148, found 148; HRMS (ESI) m/z calcd for C6H6Ns [M + H] + 148.0623, found 148.0624 ; HPLC > 99percent (tR = 4. 88 min, 60 (A): 40 (B): 0.009 (C); tR = 3.74 min, 60 (A): 40 (B): 0.02 (C) ).
Reference：
[1] Journal of Heterocyclic Chemistry, 2010, vol. 47, # 4, p. 913 - 922
[2] Polyhedron, 2011, vol. 30, # 15, p. 2606 - 2610
[3] Mendeleev Communications, 2011, vol. 21, # 6, p. 334 - 336
[4] European Journal of Organic Chemistry, 2014, vol. 2014, # 2, p. 436 - 441
[5] European Journal of Organic Chemistry, 2014, vol. 2014, # 2, p. 436 - 441
[6] Applied Organometallic Chemistry, 2015, vol. 29, # 11, p. 730 - 735
[7] Journal of Chemical Research, 2013, vol. 37, # 11, p. 665 - 667
[8] Tetrahedron Letters, 2015, vol. 56, # 5, p. 739 - 742
[9] RSC Advances, 2016, vol. 6, # 79, p. 75227 - 75233
[10] Journal of Molecular Catalysis A: Chemical, 2014, vol. 393, p. 18 - 29
[11] Journal of Chemical Research, 2015, vol. 39, # 6, p. 321 - 323
[12] Letters in Organic Chemistry, 2016, vol. 13, # 2, p. 113 - 119
[13] Applied Organometallic Chemistry, 2016, vol. 30, # 11, p. 897 - 904
[14] Journal of Organometallic Chemistry, 2013, vol. 743, p. 87 - 96
[15] Journal of Organic Chemistry, 2004, vol. 69, # 8, p. 2896 - 2898
[16] Tetrahedron Letters, 2009, vol. 50, # 31, p. 4435 - 4438
[17] Tetrahedron Letters, 2013, vol. 54, # 49, p. 6779 - 6781
[18] Heteroatom Chemistry, 2011, vol. 22, # 2, p. 168 - 173
[19] Synthetic Communications, 2010, vol. 40, # 17, p. 2624 - 2632
[20] Angewandte Chemie - International Edition, 2010, vol. 49, # 39, p. 7101 - 7105
[21] European Journal of Organic Chemistry, 2008, # 23, p. 3928 - 3932
[22] Journal of Organic Chemistry, 2000, vol. 65, # 23, p. 7984 - 7989
[23] New Journal of Chemistry, 2015, vol. 39, # 6, p. 4814 - 4820
[24] RSC Advances, 2014, vol. 4, # 69, p. 36713 - 36720
[25] Bioorganic Chemistry, 2018, vol. 79, p. 201 - 211
[26] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1994, vol. 30, # 10, p. 1192 - 1194[27] Chimia, 1994, # 10, p. 1375 - 1377
[28] Russian Journal of Organic Chemistry, 2011, vol. 47, # 5, p. 728 - 730
[29] Russian Journal of Organic Chemistry, 2010, vol. 46, # 3, p. 417 - 421
[30] Journal of Agricultural and Food Chemistry, 2013, vol. 61, # 23, p. 5483 - 5493
[31] Journal of Medicinal Chemistry, 2005, vol. 48, # 1, p. 224 - 239
[32] Patent: WO2005/66162, 2005, A1, . Location in patent: Page/Page column 113
[33] Patent: WO2006/86229, 2006, A1, . Location in patent: Page/Page column 25
[34] Inorganica Chimica Acta, 2014, # PA, p. 87 - 94
[35] Australian Journal of Chemistry, 2015, vol. 68, # 6, p. 889 - 895
[36] Monatshefte fur Chemie, 2016, vol. 147, # 12, p. 2135 - 2142
21
[ 100-54-9 ]
[ 4648-54-8 ]
[ 3250-74-6 ]
Yield
Reaction Conditions
Operation in experiment
62%
With tetrabutyl ammonium fluoride In tetrahydrofuran at 25 - 80℃;
Step-1: To a mixture of 3-cyanopyridine (12 g, 115 mmol) and trimethylsilyl azide (20 ml, 150 mmol), was added a solution of 0.1 M tetra-n-butylammonium fluoride in THF (57 ml, 56 mmol) at 25-30° C. temperature. The resulting mixture was heated at 80° C. for overnight. The mixture is allowed to warm at 25-30° C. temperature and then quenched in ice-water mixture. Solid precipitated out was filtered and washed with water (2.x.25 ml) and dried under vacuum to provide step-1 compound in 62percent (10.5 g) yield. MS: 148 (M+1).
Stage #1: With ammonium peroxydisulfate; sulfuric acid; silver nitrate In dichloromethane; water at 0 - 40℃; for 1.5 h; Stage #2: With sodium hydroxide In dichloromethane; water at 0℃;
Method B; 1) 2-Acetyl-5-cyanopyridine; Ammonium peroxodisulfate (10.3 g) was gradually added to a solution of 3-cyanopyridine (3.12 g), pyruvic acid (6.23 ml), and silver nitrate (1.27 g) in a mixture of dichloromethane (150 ml) and water (150 ml) at room temperature. Sulfuric acid (3.2 ml) was gradually added to the reaction liquid under ice cooling, and the mixture was stirred at 40°C for 1.5 hours. To the reaction liquid was added 1N aqueous sodium hydroxide to make the solution basic under ice cooling, and the solution was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate-hexane) to give 2-acetyl-5-cyanopyridine (903 mg, 21percent) as a solid. 1H-NMR (400 MHz, CDCl3)δ: 2.75 (3H, s), 8.13-8.16 (2H, m), 8.95 (1H, d, J = 1.2 Hz).
21%
Stage #1: With ammonium peroxydisulfate; silver nitrate In dichloromethane; water Stage #2: With sulfuric acid In dichloromethane; water at 0 - 40℃; for 1.5 h; Stage #3: With sodium hydroxide In dichloromethane; water
1) 2-Acetyl-5-cyanopyridine At room temperature, ammonium peroxodisulfate (10.3 g) was gradually added to 3-cyanopyridine (3.12 g), pyruvic acid (6.23 mL), and silver nitrate (1.27 g) in a mixture of dichloromethane (150 mL) and water (150 mL). Sulfuric acid (3.2 mL) was gradually added to the reaction mixture under cooling on ice, followed by stirring at 40°C for 1.5 hours. Subsequently, the reaction mixture was alkalinized with 1M aqueous solution of sodium hydroxide under cooling on ice, and then the resultant mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate anhydrate. After a filtration step, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate - hexane), to thereby give 2-acetyl-5-cyanopyridine as a solid product (903 mg, 21percent). 1H-NMR(400MHz,CDCl3)δ:2.75(3H,s), 8.13-8.16(2H,m), 8.95(1H,d,J=1.2Hz).
21%
Stage #1: With ammonium peroxydisulfate; sulfuric acid; silver nitrate In dichloromethane; water at 0 - 40℃; for 1.5 h; Stage #2: With sodium hydroxide In dichloromethane; water at 0℃;
1) 2-Acetyl-5-cyanopyridine Ammonium peroxodisulfate (10.3 g) was slowly added to a mixture of 3-cyanopyridine (3.12 g), pyruvic acid (6.23 mL) and silver nitrate (1.27 g) in dichloromethane (150 mL) and water (150 mL) at room temperature. Under ice cooling, sulfuric acid (3.2 mL) was slowly added to the reaction solution, and then the mixture was stirred for 1.5 hours at 40°C. Under ice cooling, the reaction solution was alkalinized by adding an aqueous 1 M sodium hydroxide solution, and then extracted with dichloromethane. The organic solvent was dried over anhydrous sodium sulfate. After separation by filtration, a residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate), to obtain 2-acetyl-5-cyanopyridine (903 mg, 21percent) as a solid. 1H-NMR(400MHz, CDCl3)δ: 2.75(3H, s), 8.13-8.16(2H, m), 8.95(1H, d, J=1.2Hz).
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1986, vol. 25, p. 194 - 195
31
[ 19424-11-4 ]
[ 74-89-5 ]
[ 100-54-9 ]
[ 32399-08-9 ]
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1986, vol. 25, p. 194 - 195
[2] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1986, vol. 25, p. 194 - 195
32
[ 106058-62-2 ]
[ 74-89-5 ]
[ 100-54-9 ]
[ 32399-08-9 ]
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1986, vol. 25, p. 194 - 195
[2] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1986, vol. 25, p. 194 - 195
33
[ 1004-16-6 ]
[ 100-54-9 ]
[ 7521-41-7 ]
[ 32399-08-9 ]
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1986, vol. 25, p. 194 - 195
34
[ 1004-16-6 ]
[ 100-54-9 ]
[ 32399-08-9 ]
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1986, vol. 25, p. 194 - 195
Reference：
[1] Journal of the American Chemical Society, 2016, vol. 138, # 19, p. 6103 - 6106
37
[ 100-54-9 ]
[ 65141-46-0 ]
Reference：
[1] Green Chemistry, 2017, vol. 19, # 24, p. 5789 - 5793
38
[ 100-54-9 ]
[ 7356-60-7 ]
Yield
Reaction Conditions
Operation in experiment
74%
Stage #1: With sodium methylate In methanol at 20℃; Stage #2: With ammonium chloride In methanol for 4 h; Reflux
General procedure B 1.B : Nicotinimidamide hydrochloride 3-Cyanopyridine (20 g, 0.2 mol) was dissolved in MeOH (200 mL). Powdered NaOMe (1.1 g, 20 mmol) was added in one portion. The solution was stirred overnight at room temperature. After adding NH4C1 (16.5 g, 0.31 mol), the mixture was heated at reflux for 4 h and then cooled. The solvent was removed in vacuo. Absolute EtOH (300 mL) was added and the mixture was heated to reflux. After 15 min, the solids were filtered off and the mixture was allowed to cool to room temperature and stand overnight. Additional inorganic salts were filtered off, and the reaction mixture was concentrated to approximately volume and filtered to afford title compound (22.4, 74percent). FontWeight="Bold" FontSize="10" H NMR (500 MHz, DMSO-d6) a 9.5 (bs, 4H); 9.02 (dd, 1H, J= 2.5 Hz, J= 0.9 Hz); 8.86 (dd, 1H, J= 4.9 Hz, J= 1.6 Hz); 8.27 (ddd, 1H, J= 8.0 Hz, J= 2.5 Hz, J = 1.6 Hz); 7.64 (ddd, 1H, J = 8.0 Hz, J= 4.9 Hz, J= 0.9 Hz). 13C (125 MHz, DMSO-d6) 5 164.4; 154.2; 148.9; 136.5; 124.7; 123.9. HRMS: calcd for C6H7N3, 121.0640; found, 121.0644.
74%
Stage #1: With sodium methylate In methanol at 20℃; Stage #2: With ammonium chloride In methanol for 4 h; Reflux
3-Cyanopyridine (20.0 g, 0.2 mol) was dissolved in dry MeOH (200 mL) andpowdered sodium methoxide (1.1 g, 20 mmol) was added in one portion. Thesolution was stirred overnight at room temperature. After addition of NH4Cl (16.5 g,0.31 mol), the reaction mixture was heated at reflux for 4 h and then cooled to ambienttemperature. The solvent was evaporated and absolute EtOH (300 mL) was added. Then themixture was heated to reflux. After 15 min, the solids were filtered off and the filtrate wasallowed to cool to room temperature and stand overnight. Additional inorganic salts werefiltered off, and the reaction mixture was concentrated to approximately volume andfiltered to afford 22.4 g (74percent) of the title compound.
78%
With ammonium chloride In methanol; sodium methylate
EXAMPLE 28 3-Pyridinecarboxamidine hydrochloride To a solution of 3-cyanopyridine (208 g, 2.0 mol) in methanol (100 ml) in an ice-bath was added sodium methoxide (11.2 g, 0.2 mol). The reaction mixture was stirred until all of the sodium methoxide had dissolved and was subsequently stoppered and placed in the refrigerator for 96 hours. Ammonium chloride (118 g, 2.2 mol) was then added and the reaction mixture was stirred in an ice-bath for 8 hours, followed by room temperature for 24 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was taken up in boiling ethanol (2 l), the solution was filtered and cooled to cause precipitation. The solid was collected by filtration and recrystallized in boiling n-propanol (1.4 l) to afford 153 g of a white solid. The filtrates were combined, concentrated in vacuo and the residue was recrystallized from n-propanol to afford 17.5 g of a white solid. The filtrate was once again concentrated in vacuo and the residue was recrystallized from n-propanol (500 ml) to afford 73 g of a white solid. The three crops were combined to afford 243.5 g (78percent) of 3-pyridinecarboxamidine hydrochloride, m.p. 185°-190° C. when dried at 60° C. in high vacuum.
Reference：
[1] Patent: WO2014/128213, 2014, A1, . Location in patent: Page/Page column 29
[2] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 15, p. 3487 - 3490
[3] Journal of Medicinal Chemistry, 1990, vol. 33, # 4, p. 1230 - 1241
[4] Patent: US5294612, 1994, A,
[5] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 1, p. 299 - 301
[6] Bioorganic and Medicinal Chemistry, 2009, vol. 17, # 1, p. 111 - 118
[7] Chemical Communications, 2016, vol. 52, # 78, p. 11653 - 11656
39
[ 100-54-9 ]
[ 67-56-1 ]
[ 31795-61-6 ]
Reference：
[1] Chemistry Letters, 1984, p. 769 - 772
40
[ 100-54-9 ]
[ 216431-85-5 ]
Reference：
[1] Journal of Organic Chemistry, 2007, vol. 72, # 15, p. 5574 - 5580
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[ 100-54-9 ]
[ 13600-43-6 ]
[ 216431-85-5 ]
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[1] Journal of the American Chemical Society, 2016, vol. 138, # 19, p. 6103 - 6106
42
[ 100-54-9 ]
[ 76-09-5 ]
[ 878194-92-4 ]
Yield
Reaction Conditions
Operation in experiment
18%
Stage #1: With Triisopropyl borate; 2,2,6,6-tetramethylpiperidinyl-lithium In tetrahydrofuran; hexane at -78 - 20℃; Inert atmosphere Stage #2: With acetic acid In tetrahydrofuran; hexane at 20℃; Inert atmosphere Stage #3: at 20℃; for 2 h; Inert atmosphere
In a dry 500 mL flask under N2 2,2,6,6-tetramethylpiperidine (57.6 mmol) was dissolved in dry THF (200 mL) and the mixture was cooled to -10 °C before n-BuLi (57.6 mmol, 2.5 M in n-hexane) was added over 2 min. The mixture was stirred for 10 min before cooling to -78 °C. At -78 °C, B(O-i-Pr)3 (65.3 mmol) was added over 2 min and stirred for 5 min at -78 °C before 3-cyanopyridine (48 mmol) dissolved in dry THF (50 mL) was added dropwise over 5 min. The reaction was left in the dry ice bath, allowed to reach room temperature overnight and quenched with glacial acetic acid (67.2 mmol) followed by addition of pinacol (72 mmol). The mixture was stirred for 2 h at room temperature and then transferred to a separating funnel with CH2Cl2 (75 mL) and washed with aqueous KH2PO4 (10 w/v percent) (4.x.60 mL). The combined aqueous layers was back-extracted once with CH2Cl2 (15 mL), the combined organic phase was dried over MgSO4, and the solvents were evaporated to give cyanopyridineboronic ester 3b as a yellow solid with 18percent yield; mp 88 °C; IR (KBr) ν 3097, 2968, 2930, 2238 (CN), 1618, 1522, 1476, 1464, 1421, 1385, 1373, 1337, 1201, 1113, 1046, 963, 882, 849, 778, 765, 714, 655, 578 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H, H2), 8.74 (d, J=4.6 Hz, 1H, H6), 7.70 (d, J=4.6 Hz, 1H, H5), 1.34 (s, 12H); 13C NMR (100 MHz, CDCl3) δ 153.3, 152.1, 129.3, 117.1, 114.2, 85.8, 83.1, 25.0.
Stage #1: With n-butyllithium In tetrahydrofuran at -30℃; for 0.5 h; Inert atmosphere Stage #2: With 1,4,7,10-tetramethyl-1,4, 7,10-tetraazacyclododecane In tetrahydrofuran at -30 - 20℃; for 4 h; Stage #3: With hydrogenchloride In tetrahydrofuran; water for 1 h;
Under a nitrogen atmosphere, 300 g of anhydrous tetrahydrofuran was added to the reaction flask, stirring was continued, 12 g of 3-cyano-pyridine was added and cooled to -30C.N-BuLi was slowly added dropwise to 70 mL of 2.0 M, and after stirring for 30 minutes, a solution of 1,4,7,10-tetramethyl-1,4,7,10-tetraazacyclododecane was slowly added dropwise.After 2 hours of incubation, 41 mL of triisopropyl borate was slowly added dropwise at -30 ° C, stirred for 1 hr, slowly raised to room temperature and stirred for 1 hour.And 400 g of concentrated hydrochloric acid was added thereto, followed by stirring for 1 hour to carry out a hydrolysis reaction.The layers were allowed to stand, and the organic layer was washed three times with water (3 x 100 g).The aqueous layers were combined and the aqueous layer was extracted once with 100 ml of petroleum ether. The combined organic layers were dried over 50 g of anhydrous sodium sulfate and filtered.The filtrate was concentrated to dryness to give 3-cyano-4-pyridine boronic acid 14 g,
Stage #1: With n-butyllithium In tetrahydrofuran at -30℃; for 0.5 h; Inert atmosphere Stage #2: With N,N',N''-trimethyl-1,4,7-triazacyclononane In tetrahydrofuran at -30 - 20℃; for 4 h; Stage #3: With hydrogenchloride In tetrahydrofuran; water for 1 h;
Under a nitrogen atmosphere, 300 g of anhydrous tetrahydrofuran was added to the reaction flask, stirring was continued, 12 g of 3-cyano-pyridine was added and cooled to -30C.N-BuLi was slowly added dropwise to 70 mL of 2.0 M, and after stirring for 30 minutes, 26 g of 1,4,7-trimethyl-1,4,7-triazacyclononane was slowly added dropwise.After incubation for 2 hours, 26 mL of trimethyl borate was slowly added dropwise at -30 ° C, stirred for 1 hr, slowly warmed to room temperature and stirred for 1 hour.And 400 g of concentrated hydrochloric acid was added thereto, followed by stirring for 1 hour to carry out a hydrolysis reaction.The layers were allowed to stand, and the organic layer was washed three times with water (3 x 100 g).The aqueous layers were combined and the aqueous layer was extracted once with 100 ml of petroleum ether. The combined organic layers were dried over 50 g of anhydrous sodium sulfate and filtered.The filtrate was concentrated to dryness to give 13 g of 3-cyano-4-pyridine boronic acid.
With hydroxylamine hydrochloride; sodium hydrogencarbonate; In isopropyl alcohol; at 80 - 85℃;
To a solution of 5.012 g (72.1 mmol) of hydroxylamine hydrochloride in 55 mL of isopropyl alcohol, 8.8 g (105.7 mmol) of sodium bicarbonate was added. The resulting mixture was stirred at 25 C to 30 C for 10 - 15 min. 5.0 g (48 mmol) of 3- cyanopyridine was added and stirred at 80 C to 85 C for 3 - 4 h. After completion of the the reaction, the reaction mixture was cooled to 25 C to 30 C, filtered and washed with 10 mL of isopropyl alcohol. The filtrate was collected and distilled to obtain a crude residue, which was chased with 5 mL of toluene to yield the title compound.Yield: 6.0 g (91 %).
86%
With hydroxylamine hydrochloride; sodium hydrogencarbonate; In ethanol; for 6h;Reflux;
General procedure: To a stirred suspension of corresponding nitrile and hydroxylamine hydrochloride (1.5 equiv.) in EtOH (10 mL per gram of nitrile) a NaHCO3 (1.5 equiv.) was added. The reaction mixture was stirred under reflux for a 6 h. After the reaction had completed, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with cold water (200 mL). The resulting precipitate was filtered off and washed with cold water (50 mL).
86.56%
With hydroxylamine hydrochloride; triethylamine; In ethanol; for 4h;
To a 250 mL three-necked flask was added 0.19 mol (13.21 g) of hydroxylamine hydrochloride, 0.2 mol (20.2 g) of triethylamine.100mL of ethanol as a solvent,Heat and reflux for half an hour,Then add 0.1 mol (10.4 g) of 3-cyanopyridine.Stirring for 4 h,TLC SupervisorThe reaction was completed, the ethanol was removed by rotary evaporation, 200 g of water was added, triethylamine was removed, and filtered to give a white solid, 11.86 g, yield.86.56%.
86%
With hydroxylamine hydrochloride; sodium hydrogencarbonate; In ethanol; for 6h;Reflux;
General procedure: To a stirred suspension of corresponding nitrile and hydroxylamine hydrochloride (1.5 equiv.) in EtOH (10 mL per gram of nitrile) a NaHCO3 (1.5 equiv.) was added. The reaction mixture was stirred under reflux for a 6 h. After the reaction had completed, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with cold water (200 mL). The resulting precipitate was filtered off and washed with cold water (50 mL). N'-Hydroxynicotinimidamide (AM-3). Compound was synthesized by following GP1 starting from nicotinonitrile (1 g, 0.01 mol) in 86% (1.13 g) yield
86%
With hydroxylamine hydrochloride; sodium hydrogencarbonate; In ethanol; for 6h;Reflux;
General procedure: To a stirred suspension of corresponding nitrile and hydroxylamine hydrochloride (1.5 equiv.) in EtOH (10 mL per gram of nitrile) a NaHCO3 (1.5 equiv.) was added. The reaction mixture was stirred under reflux for a 6 h. After the reaction had completed, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with cold water (200 mL). The resulting precipitate was filtered off and washed with cold water (50 mL).
62%
With hydroxylamine hydrochloride; triethylamine; In methanol; at 20℃;Reflux;
General procedure: A solution of the appropriate cyanophenyl 1a-1k (0.1 mol), hydroxylamine hydrochloride (0.2 mol), and TEA (0.2 mol) in methanol was left under stirring at room temperature for 1 h, then heated under reflux until the disappearance of the starting materials (TLC analysis). After cooling, the solvent was evaporated to dryness under reduced pressure to give the crude, which was dissolved in ethyl acetate (400 mL) and washed with brine (3 100 mL) and dried with Na2SO4. The ethyl acetate was evaporated under reduced pressure to yield the compounds 2a-2k.
62%
With hydroxylamine hydrochloride; triethylamine; In methanol; at 20 - 65℃;
General procedure: A solution of the appropriate cyanophenyl 1a-1j (0.1mol), hydroxylamine hydrochloride (0.2 mol), and TEA (0.2 mol) in methanol was stirred at room temperature for 1 h, then heated under reflux until the disappearance of the starting materials (TLC analysis). After cooling, the solvent was evaporated to dryness under reduced pressure to give the crude, which was dissolved in ethyl acetate (400 mL) and washed with brine (3×100 mL) and dried with Na2SO4. Ethyl acetate was evaporated under reduced pressure to yield the compounds 2a-2j.
With hydroxylamine hydrochloride; sodium carbonate; In methanol; water; at 100℃; for 2.5h;
Hydroxylamine hydrochloride (1.3 g) and sodium carbonate (2.0 g) were added to a mixed solution of 3-cyanopyridine in methanol (10 ml)/water (10 ml) and the mixture was stirred at 100 C. for 2.5 hours. After distilling off the solvent under reduced pressure, water was added to the residue and extracted with tetrahydrofuran, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure to obtain N'-hydroxypyridine-3-carboximidamide (1.3 g) as a colorless oily substance.
With hydroxylamine hydrochloride; sodium hydrogencarbonate; In ethanol; water; for 6h;Reflux;
General procedure: Sodium bicarbonate (5.88 g, 70 mmol) was added in portionsto a solution of 4.79 g hydroxylamine hydrochloride(70 mmol) in 20 cm3 of water. A solution of aryl nitriles(35 mmol) in 50 cm3 of ethanol was then added, and themixture stirred under reflux for 6 h. The precipitate formedwas filtered off and purified by crystallization from ethanol.Melting points of compounds 1b-1f were in agreementwith the literature values [23, 25-28].
With hydroxylamine hydrochloride; sodium hydroxide; In ethanol; water; for 8h;Reflux;
General procedure: All solvents and reagents were obtained from commercialsources. All synthesized compounds were purified by chromatography and analyzed by IR, HRMS, and NMR. Purity of synthesizedcompounds was verified prior to biological tests by chromatographic analyses and NMR (see supplementary material) and in allthe cases purity was higher than 95%. IR spectra have been registered (in Nujol) with a Shimadzu FTIR-8300 spectrophotometer;melting points have been determined on a Reichart-Thermovarhotstage Kofler and are uncorrected. NMR spectra have beenregistered on a Bruker AVANCE DMX 300 using CDCl3 and DMSO assolvent. HRMS spectra were recorded by analyzing a 50 ppm solution of the compound in a 6540 UHD Accurate-Mass Q-TOF LC/MS(Agilent Technologies) equipped with a Dual AJS ESI source. GC-MSspectra have been registered by using either an Agilent 7890B/7000C GC-MS-TQ or a GC-MS Shimadzu QP-2010 Instrument. Flashchromatography was performed by using silica gel (Merck,0.040e0.063 mm) and mixtures of ethyl acetate and petroleumether (fraction boiling in the range of 40e60 C) in various ratios. 3-Methyl-benzamidoxime [31], 2-picolin-amidoxime [32],isonicotin-amidoxime [33], nicotin-amidoxime [33], and benzamidoxime [34] were synthesized as reported. Generally, an acqueous solution of hydroxylamine was prepared by mixingNH2OH*HCl (36 mmol) and NaOH (36 mmol) in water (20 mL). Thehydroxylamine solution was then added to an alcoholic solution ofthe corresponding nitrile (30 mmol) dissolved in ethanol (100 mL)in a 250 mL round bottomed flask. The mixture was refluxed for 8 h.The solvent was then removed under vacuum and 100 mL waterwere added to the residue. The amidoxime was filtered as a whitesolid and re-crystallized from ethanol.
With hydroxylamine hydrochloride; sodium carbonate; In ethanol; water; for 5h;Reflux;
General procedure: Solutions of 50 mmol of hydroxylamine hydrochloride,25 mmol of anhydrous sodium carbonate and 20 mL ofwater were added to a round-bottomed flask. The mixturewas homogenized until no effervescence occurred. Then,33 mmol of a nitrile derivative (1-4) and 20 mL of ethanolwere added to the reaction medium, which was keptunder stirring and refluxed for 5 h. After this period, theproduct, an amidoxime (5-8), was recrystallized from water(Scheme 1).19
With hydroxylamine monohydrate; In ethanol; at 90℃; for 1h;Sealed tube;
General procedure: In a pressurized sealed vial, aqueous hydroxylamine 50% w/w (4equiv) was added to a stirred solution of the appropriate carbonitrile(1 equiv) in absolute ethanol. The resulting mixture washeated at 90 C for 1 h. The solvent was then evaporated to drynessproviding the desired amidoxime quantitatively, which was usedwithout further purification.
With hydroxylamine hydrochloride; sodium acetate; In ethanol; water; at 50 - 60℃; for 8h;
General procedure: 0.01mol nitrile dissolved in 10 ml ethanol. After that, 0.011 mol hydroxylamine hydrochloride, 10 ml water and 1.23g sodium acetate was added as followed, stirred in room temperature for 0.5 h then refluxed in 50-60 for 8 h. The ethanol was mostly evaporated in vacuum and then the aqueous residue was extracted with CH2Cl2 three times. The combined organic layer was dried over MgSO4 and evaporated to dryness to afford the desired product.
With hydroxylamine hydrochloride; triethylamine; In ethanol; for 3h;Reflux;
Combine 3-cyanopyridine (2mmol), hydroxylamine hydrochloride (153mg, 2.2mmol) andTriethylamine (305 muL, 2.2 mmol) was added to absolute ethanol (10 mL) in sequence, heated to reflux for 3 h, and monitored by TLC. When the reaction is complete, evaporate the solvent, add distilled water (20mL),Extract with ethyl acetate (20mL×3), combine the organic layers, wash with saturated NaCl (60mL),Anhydrous Na2SO4 is dried, the desiccant is filtered off, and the solution is concentrated under reduced pressure to obtain F-3,Used directly in the next reaction.
With sodium azide; tetrabutylammomium bromide; at 105℃; for 12h;Sealed tube; Green chemistry;
General procedure: A screw capped vial was charged with nitrile (2 mmol), NaN3(2.4 mmol, 1.2 equiv.) and tetrabutylammonium bromide (2.4 mmol,1.2 equiv.). The resulting mixture was stirred at 105 C and monitoredby TLC. After completion of the reaction, the reaction mixture wascooled to room temperature and dissolved with water (5 mL). Then, theaqueous solution was acidified with 1M HCl to pH = 3. If a precipitatewas formed, the suspension was filtered and the filter cake was washedwith water to afford the pure product. Otherwise, the aqueous solutionwas extracted with EtOAc (3 × 4 mL). The organic phase was washedwith 1M HCl (3 × 4 mL), dried with anhydrous Na2SO4, filtered andevaporated under vacuum to afford the pure product.
94%
With sodium azide; Acetate de N,N-dimethylamino-4 pyridinium; In neat (no solvent); at 100℃; for 1h;
To a round-bottomed flask containing 4-(N,N-dimethylamino)pyridiniumacetate (0.15 mmol, 0.02 g) at 100 C, 3-cyanopyridine (1.0 mmol, 0.104 g) andsodium azide (1.0 mmol, 0.06 g) were added and the mixture was stirred. After1 h, the reaction was complete. The mixture was cooled and washed with coldEtOH (2 5 mL), each time it was permitted to stir for 1 h. Filtration followed bydrying of the precipitate gave the corresponding pure tetrazole as a white solid.Yield (0.14 g, 94%); mp 242-244 C; 1H NMR (400 MHz, DMSO-d6) d (ppm): 9.10(s, 1H), 8.42 (d, J = 7.9 Hz, 1H), 8.22 (d, J = 7.9 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H); 13CNMR (100 MHz, DMSO-d6) d (ppm): 162.7, 151.9, 149.8, 137.1, 126.4, 125.3; IR(KBr) v (cm1): 3389, 2129, 2036, 1644, 1423, 1144, 1014, 754, 639, 410.
92%
With sodium azide; In N,N-dimethyl-formamide; at 110℃; for 5h;
General procedure: A mixture of nitrile (1 mmol), sodium azide (1.5 mmol), Cu complex catalyst (0.4 mol%) and DMF (3 mL) was taken in a round-bottomed flask and stirred at 110 C temperature. After completion of the reaction the catalyst was separated from the reaction mixture with an external magnet and reaction mixture was treated with ethyl acetate (2 × 20 mL) and 1 N HCl (20 mL). The resultant organic layer was separated and the aqueous layer was again extracted with ethyl acetate (2 × 15 mL). The combined organic layers were washed with water, concentrated, and the crude material was chromatographed on silica gel (Hexane-EtoAc, 1:1) to afford the pure product.
92%
With sodium azide; silver(I) triflimide; In toluene; at 85℃; for 2h;
General procedure: A mixture of the appropriate nitrile (1 mmol), NaN3 (1.5 mmol),toluene (2 mL) and AgNTf2 (5 mol%) was placed in a round bottomed flask and heated at 85 oC. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was cooled and treated with ethyl acetate (15 mL) and 1M HCl (15 mL)and stirred vigorously. The resultant organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 × 10 mL). The combined organic layer was washed with water and concentrated to give the pure tetrazole. All the products are known compounds and the spectral data and melting points were identical to those reported in the literature. The disappearance of one strong and sharp absorption band (CN stretching band), and the appearance of an NH stretching band in the IR spectra, were characteristic of the formation of 5-substituted 1H-tetrazoles.
92%
With sodium azide; piperazinium dihydrogen sulfate; at 100℃; for 1.3h;
In a roundbottom flask in 100C, consecutively, the catalyst (0.015mmol, 0.004 g), 3-cyanopyridine (1.0 mmol, 0.104 g) andsodium azide (1.0 mmol, 0.065 g) were added and the mixturewas stirred for 90 min until it was completed. Then, thereaction mixture was cooled to room temperature andwashed with ethanol (25 mL). After filtration, the white In a roundbottom flask in 100C, consecutively, the catalyst (0.015mmol, 0.004 g), 3-cyanopyridine (1.0 mmol, 0.104 g) andsodium azide (1.0 mmol, 0.065 g) were added and the mixturewas stirred for 90 min until it was completed. Then, thereaction mixture was cooled to room temperature andwashed with ethanol (25 mL). After filtration, the white
90%
With sodium azide; In N,N-dimethyl-formamide; at 120℃; for 6h;
General procedure: A mixture of nitrile (1 mmol), sodium azide (1.5 mmol) and catalyst (0.02 g, contains 0.4 mol% of Cu(II)) in DMF (3 mL) was taken in a round-bottomed flask and stirred at 120 C. The progress of the reaction was followed by thin-layer chromatography (TLC). After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (3×20 mL). The catalyst was removed by using magnetic field or filtration and then the resulting solution was washed with 1N HCl, dried over anhydrous Na2SO4 and then was evaporated. The crude products were obtained in excellent yields. All products were characterized by 1H, 13C NMR, FT-IR, and melting point which were in agreement with literature. We have reported the spectral data of some aromatic and heteroaromatic synthesized compounds
81%
With lithium tetraazidoborate; ammonium acetate; In methanol; N,N-dimethyl-formamide; at 110℃; for 8h;
General procedure: NH4OAc (15 mg) was added to a mixture of benzonitrile(103 mg, 1 mmol) and LiB(N3)4(93 mg, 0.5 mmol) in DMF/MeOH (9/1) solution (5 mL) and stirred the mixture was at 100 oC for 8 h. After completion of reaction (monitored by TLC),the mixture was cooled to room temperature and diluted with ethyl acetate. The resulting solution was washed with 1 M HCl, dried over anhydrous Na2SO4, and concentrated. An aqueous solution of NaOH (1 M) was added to the residue, and the mixture was stirred for 30 min at room temperature. The resulting solution was washed with ethyl acetate, and then 2 M HCl was added until the pH value of the water layer became 1~2. The aqueous layer was extracted with ethyl acetate three times, and the combined organic layers were washed with 1M HCl.The organic layer was dried over anhydrous Na2SO4 and concentrated to furnish pure 5-phenyl-1-H-tetrazole 1b as a white solid (125 mg) in 86% yield.
66%
With sodium azide; ammonium chloride; In N,N-dimethyl-formamide; for 24h;Reflux;
General procedure: In a typical procedure, 5-aryl-1H-tetrazoles (1-24) were synthesized by adding aryl nitriles (1 eq.), sodium azide (1.2 eq.), and ammonium chloride (1 eq.) in solvent, the mixture was refluxed for 24 h. Progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, 2.5 mL of 2M NaOH was added and the solution was stirred for half an hour. The reaction mixture was concentrated on reduced pressure, and dissolved in water. 3M HCl was added to the reaction mixture until precipitates formed. The precipitates were filtered and washed with distilled water. The yields of title compounds were found to be moderate to high.
46%
[0342] 3-(1H-tetrazol-5-yl)pyridine (64). To a solution of 3-cyanopyridine (1. 1 g, 10.6 mmol) in DMF (15 mL) was added ammonium chloride (718 mg, 13.4 mmol) and sodium azide (824 mg, 12.7 mmol) and the resultant slurry was vigorously stirred at 90 C for 15 h. The DMF was removed in vacuo, the residue was dissolved in aqueous potassium hydroxide (1 M, 20 mL), washed with EtOAc (2 x 25 mL), the aqueous layer was adjusted to pH No. 3 with aqueous HCl (6 N) and the solid was collected by filtration to afford the title compound 64 (904 mg, 46 % yield) as a white solid: mp = 239-241 C dec. ; 1H NMR (CDC13) b 9.21 (m, 1H), 8.76 (m, 1H), 8.39 (m, 1H), 7.64 (m, 1H) ; LRMS (ESI) m/z calcd for C6H6N5 [M + H] + 148, found 148; HRMS (ESI) m/z calcd for C6H6Ns [M + H] + 148.0623, found 148.0624 ; HPLC > 99% (tR = 4. 88 min, 60 (A): 40 (B): 0.009 (C); tR = 3.74 min, 60 (A): 40 (B): 0.02 (C) ).
With sodium azide; ammonium chloride; lithium chloride; In N,N-dimethyl-formamide; for 24h;Heating / reflux;
3-Cyanopyridine (1.0 g, 9.61 mmol), sodium azide (0.843 g, 12 mmol), ammonium chloride (0.694 g, 12 mmol), and lithium chloride (10 mg) were combined in DMF (10 mL) and heated at reflux behind a blast shield for 24 hours. The mixture was allowed to cool to ambient temperature, diluted with EtOAc, and washed with water. The title compound was recrystallized from EtOAc/hexanes. MS (DC]TNH3) m/z 148 (M+H)+; 1H NMR (DMSO-d6) delta 9.22 (d, IH, J=I .7 Hz), 8.77 (dd, IH, J=4.7, 1.7 Hz), 8.40 (dt, IH J=8.5, 2.0 Hz), 7.65 (ddd, IH, J=7.8, 4.8, 1.0 Hz).
With sodium azide; triethylamine hydrochloride; In toluene;
Synthesis and Characterization of Htzpya and Hpytza 5-(3-Pyridyl) tetrazole was prepared by [23] cycloadditionreactions by treating 3-cyanopyridine with NaN3 in toluene inthe presence of triethylammonium chloride.At 708C, the reaction of 5-(3-pyridyl) tetrazole with chloroacetic acid in methanolic potassium hydroxide solution gavemostly N(pyridine) products 3-(5-tetrazolyl)pyridine-1-acetatopotassium salt The reaction of 5-(3-pyridyl) tetrazole with ethylbromoacetate in methanolic potassium hydroxide solution gavemostly H(tetrazole)-substituted products 5-(3-pyridyl)tetrazole-2-acetato potassium salt.[8] Then, the pH of the solution wasadjusted to 2 with HCl (12 M). After cooling to room temperature, the precipitate was filtered off, washed with methanol(2 30 mL) and dried, forming the corresponding acid products(Htzpya or Hpytza). Htzpya: a 80 % yield was obtained based onHpytz consumed. nmax (KBr)/cm1 3426 (s), 1730 (s), 1570 (s),1420 (s), 1396 (m), 1257 (m), 1209 (m), 1146 (w), 1064 (m),1018 (w), 905 (w), 868 (w), 766 (w). Anal. Calc. for C8H7O2N5:C 46.83, H 3.44, N 34.13. Found: C 46.70, H 3.50, N 34.25 %.Hpytza: a 82 % yield was obtained based on Hpytz consumed.nmax (KBr)/cm1 3261 (s), 3102 (s), 1731 (w), 1544 (m), 1512(w), 1486 (w), 1457 (m), 1289 (m), 1229 (m), 1176 (w), 1094(w), 958 (w), 790 (w). Anal. Calc. for C8H7O2N5: C 46.83, H3.44, N 34.13. Found: C 46.75, H 3.40, N 34.18 %.
With sodium azide; In N,N-dimethyl-formamide; at 120℃; for 12h;Inert atmosphere; Green chemistry;Catalytic behavior;
General procedure: A mixture of aryl halide (1.0 mmol), K4[Fe(CN)6](0.22 mmol), 0.05 g [PS-ttet-Pd(II)], and sodium carbonate(1.0 mmol) was stirred in 5 cm3 DMF at 120 C for 1 h under an argon atmosphere. To the aryl nitrile compound generated in situ was added sodium azide (1.5 mmol) and the mixture was stirred at 120 C for appropriate time. After completion of the reaction (as indicated by TLC), the catalyst was centrifuged, washed with EtOH and the residue was diluted with 35 cm3 ethyl acetate and 20 cm3 HCl(4 N) and stirred vigorously. The resultant organic layer was separated and the aqueous layer was extracted with 25 cm3 ethyl acetate. The combined organic layer was washed with 8 cm3 water and concentrated to give a crude product. Column chromatography using silica gel gave thepure product. All products were characterized by 1H NMR and melting point which were in agreement with literature
With sulfur; cobalt(II) nitrate; In neat (no solvent); at 90℃; for 0.05h;Microwave irradiation;
General procedure: A mixture of nitrile (0.5 mmol), 2-aminoethanol (4) (0.65 mmol, 0.040 g), Co(NO3)2 (0.02 mmol, 0.036 g), and sulfur (0.05 mmol, 0.0016 g) was stirred at 90 C or subjected to microwave irradiation (90 C, 800 W) for appropriate time. For the synthesis of monooxazolines, dicyanobenzene (0.5 mmol), 2-aminoethanol (4) (0.65 mmol, 0.040 g), Co(NO3)2 (0.02 mmol, 0.036 g), and sulfur(0.05 mmol, 0.0016 g) was stirred at 90 C for 3 h or subjected to microwave irradiation (90 C, 800 W) for 3 min. For the synthesis of bis-oxazoline, dicyanobenzene (0.5 mmol), 2-aminoethanol (4) (2.6 mmol, 0.159 g), Co(NO3)2 (0.02 mmol, 0.036 g), and sulfur (0.05 mmol, 0.0016 g) was stirred at 110 C for 10 h or subjected to microwave irradiation (110 C, 800 W) for 8 min. After completionof the reaction (detected by TLC), the reaction mixture was cooled to room temperature, ethyl acetate (6 mL) was added and the catalyst was separated by the filtration. Following concentration under reduced pressure, the residue was purified by silica gel chromatography to give pure product (5a-r).
85%
With sulfur; In neat (no solvent); at 50 - 80℃;Green chemistry;
General procedure: An equimolar mixture of 2-aminoethanol (1.0 mmol) and sulfur(1.0 mmol) was heated under solvent-free condition at 50°C. Nitrile (1.0 mmol) was then added to reaction mixture and refluxed at 80°C. The progress of the reaction was monitored through TLC (n-hexane: EtOAc, 8:2). After completion of the reaction, excess of water was added, and the product was filtered (for solid). Further chromatographic purification afforded pure product. All the compounds were characterizedby infrared (IR) and 1H NMR and 13C NMR spectroscopic data, as well as by comparison with data of reported compounds.
85%
With Cu(II) immobilized on Fe3O4-agarose nanomagnetic catalyst functionalized with ethanolamine phosphate-salicylaldehyde Schiff base; In dimethyl sulfoxide; at 100℃; for 3h;
General procedure: Benzonitrile (0.1 g, 1 mmol), 2-aminoethanol (0.09 g, 1.5 mmol), and Fe3O4 Agarose/SAEPH2 /Cu(II) nanomagnetic catalyst (0.05 g, 14 molpercent) were added to DMSO (2 mL) at 100 °C. The resultant mixture was stirred and controlled by TLC. After completion of the reaction, the reaction mixture was cooled and the nanomagnetic catalyst was separated by an external magnetic field. Then water (2 x 10 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate (2 x 10 mL). The organic layer was evaporated and the residue was puried by thin layer chromatography using ethyl acetate/n-hexane (1/1) as eluent. The pure 2-phenyl-4,5-dihydro-1,3-oxazole was obtained with a 95percent yield (0.13 g).
78%
With sulfur; In neat (no solvent); at 100℃; for 9h;
0.5 mmol 3-cyanopyridine, 1.0 mmol aminoethanol and 0.05 mmol sulfur were added to a 25 mL round bottom flask and the reaction temperature was 100 ° C with stirring for 9 h. After the reaction was completed (TLC monitoring), cool to room temperature. Added 6mL ethyl acetate filtered sulfur. Evaporation The ethyl acetate was concentrated and subjected to silica gel column chromatography with ethyl acetate / petroleum ether (1: 1) to obtain 57.6 mg of a white solid with a yield of 78percent.
With tetrabutyl ammonium fluoride; In tetrahydrofuran; at 25 - 80℃;
Step-1: To a mixture of 3-cyanopyridine (12 g, 115 mmol) and trimethylsilyl azide (20 ml, 150 mmol), was added a solution of 0.1 M tetra-n-butylammonium fluoride in THF (57 ml, 56 mmol) at 25-30 C. temperature. The resulting mixture was heated at 80 C. for overnight. The mixture is allowed to warm at 25-30 C. temperature and then quenched in ice-water mixture. Solid precipitated out was filtered and washed with water (2×25 ml) and dried under vacuum to provide step-1 compound in 62% (10.5 g) yield. MS: 148 (M+1).
To a mixture of 3-cyanopyridine (12 g, 115 mmol) and trimethylsilyl azide (20 ml, 150 mmol), was added a solution of 0.1 M tetra-«-butylammonium fluoride in THF (57 ml, 56 mmol) at 25-30 C temperature . The resulting mixture was heated at 80 C for overnight. The mixture is allowed to warm at 25-30 C temperature and then quenched in ice-water mixture. Solid precipitated out was filtered and washed with water (2 x 25 ml) and dried under vacuum to provide step-1 compound in 62% (10.5 g) yield. MS: 148 (M+l).
Synthesis of XLVI:Cerium chloride (35.5 g, 144 mmol) was added to dry THF (250 mL). The reaction mixturewas stirred at room temperature for 2 h under a nitrogen atmosphere to allow the cerium chloride to form a suspension in the THF solution. This was cooled to -78C and then a 1.6 M methyl lithium solution in THF (48 mL, 144 mmol) was added. The reaction mixture was stirred for 30 minutes maintaining the same temperature and then a solution of 3-cyanopyridine (XLV, 5 g, 48 mmol) in THF (50 mL) was added through a cannula. The reaction mixture wasallowed to warm to room temperature and stirring continued for 12 h. The reaction mixture was diluted with a saturated aqueous solution of ammonium acetate solution and the stirring continued for a further 1 h at room temperature. The reaction mixture was filtered through a celite bed, concentrated and diluted with water. The resulting aqueous layer was extracted with ethyl acetate and the organic layer was dried (anhydrous Na2SO4), filtered and evaporatedunder reduced pressure to obtain the crude compound 2-(pyridin-3-yl)propan-2-amine (XLVI;2.0 g crude). MS (M+1): 137. The crude material was carried forward to the next step withoutpurification.
General procedure B 1.B : Nicotinimidamide hydrochloride 3-Cyanopyridine (20 g, 0.2 mol) was dissolved in MeOH (200 mL). Powdered NaOMe (1.1 g, 20 mmol) was added in one portion. The solution was stirred overnight at room temperature. After adding NH4C1 (16.5 g, 0.31 mol), the mixture was heated at reflux for 4 h and then cooled. The solvent was removed in vacuo. Absolute EtOH (300 mL) was added and the mixture was heated to reflux. After 15 min, the solids were filtered off and the mixture was allowed to cool to room temperature and stand overnight. Additional inorganic salts were filtered off, and the reaction mixture was concentrated to approximately volume and filtered to afford title compound (22.4, 74%). FontWeight="Bold" FontSize="10" H NMR (500 MHz, DMSO-d6) a 9.5 (bs, 4H); 9.02 (dd, 1H, J= 2.5 Hz, J= 0.9 Hz); 8.86 (dd, 1H, J= 4.9 Hz, J= 1.6 Hz); 8.27 (ddd, 1H, J= 8.0 Hz, J= 2.5 Hz, J = 1.6 Hz); 7.64 (ddd, 1H, J = 8.0 Hz, J= 4.9 Hz, J= 0.9 Hz). 13C (125 MHz, DMSO-d6) 5 164.4; 154.2; 148.9; 136.5; 124.7; 123.9. HRMS: calcd for C6H7N3, 121.0640; found, 121.0644.
74%
3-Cyanopyridine (20.0 g, 0.2 mol) was dissolved in dry MeOH (200 mL) andpowdered sodium methoxide (1.1 g, 20 mmol) was added in one portion. Thesolution was stirred overnight at room temperature. After addition of NH4Cl (16.5 g,0.31 mol), the reaction mixture was heated at reflux for 4 h and then cooled to ambienttemperature. The solvent was evaporated and absolute EtOH (300 mL) was added. Then themixture was heated to reflux. After 15 min, the solids were filtered off and the filtrate wasallowed to cool to room temperature and stand overnight. Additional inorganic salts werefiltered off, and the reaction mixture was concentrated to approximately volume andfiltered to afford 22.4 g (74%) of the title compound.
57%
3-Pyridylamidine hydrochloride (PTHP Precursor): Our procedure was similar to that describedby Schaefer and Peters [52] and Brown and Evans [53]. 3-cyanopyridine (35 g, 0.34 mol) was dissolvedin 300 mL MeOH containing sodium methoxide (1.82 g, 0.034 mol). The flask was fitted with acondenser equipped with a drying tube and the clear solution stirred at 25 C for 24 h. Ammoniumchloride (19.8 g, 0.37 mol), added according to and the mixture was reuxed and stirred for 24 h.Not all (~30%) of the ammonium chloride dissolved. After cooling the solution to room temperatureand removing excess NH4Cl by filtration the resulting solution was rotary evaporated and the productwas dissolved in 100 mL hot isopropanol and filtered hot, leaving the NH4Cl behind. After 24 h at 0 Cthe crystals were collected by filtration. Two more recrystallizations using isopropanol provided atotal of 30 g product (MP 187-190 C, 57% of theoretical yield). Elemental Analysis: Found, % C =45.60; % H = 5.17/ % N = 26.61; C6H8N3Cl requires: % C = 45.73; % H = 5.12; % N = 26.66). NMR Spectral data: In CD3OD, referenced to CD3OD at 3.34 ppm:delta (ppm): 9.0 (2H, m, H-2, H-5,6 couplingof 5 H observed); 8.38-8.63 (1H, dd, H-4), H-4,5 coupling of 8 Hz observed, as is H-2,4 coupling of1.5 Hz); 7.7-8.0 (1H, m, H-5); 5.3 (CD3OH, 4H, broad).
243.5 g (78%)
With ammonium chloride; In methanol; sodium methylate;
EXAMPLE 28 3-Pyridinecarboxamidine hydrochloride To a solution of 3-cyanopyridine (208 g, 2.0 mol) in methanol (100 ml) in an ice-bath was added sodium methoxide (11.2 g, 0.2 mol). The reaction mixture was stirred until all of the sodium methoxide had dissolved and was subsequently stoppered and placed in the refrigerator for 96 hours. Ammonium chloride (118 g, 2.2 mol) was then added and the reaction mixture was stirred in an ice-bath for 8 hours, followed by room temperature for 24 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was taken up in boiling ethanol (2 l), the solution was filtered and cooled to cause precipitation. The solid was collected by filtration and recrystallized in boiling n-propanol (1.4 l) to afford 153 g of a white solid. The filtrates were combined, concentrated in vacuo and the residue was recrystallized from n-propanol to afford 17.5 g of a white solid. The filtrate was once again concentrated in vacuo and the residue was recrystallized from n-propanol (500 ml) to afford 73 g of a white solid. The three crops were combined to afford 243.5 g (78%) of 3-pyridinecarboxamidine hydrochloride, m.p. 185-190 C. when dried at 60 C. in high vacuum.
3,4-dihydro-4-oxo-2-(pyridin-3-yl)-6-methyl-thieno[2,3-d]pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In 1,4-dioxane;
EXAMPLE 3 5 g of 2-amino-5-methyl-3-ethoxycarbonylthiophene together with 2.7 g of 3-cyanopyridine are dissolved in 40 ml of dioxane. Then, gaseous HCl is passed through the solution for 5 hours. After customary workup, 6 g of 3,4-dihydro-4-oxo-2-(pyridin-3-yl)-6-methylthieno[2,3-d]pyrimidine are obtained.
4-[(3-Cyano-pyridin-2-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethyl acetate;
Example 44 4-[(3-Cyano-pyridin-2-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester A mixture of <strong>[157023-34-2]benzyl 4-(aminomethyl)piperidine-1-carboxylate</strong> (EXAMPLE 13, Step 1) (1 g, 4.03 mmol) and 3-cyanopyridine (0.25 g) was heated to 100 C. for 30 min. The reaction mixture was partitioned between EtOAc and pH5.2 citrate buffer. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent evaporated to give a solid which was stirred with 5 mL ether and 0.5 mL EtOAc for 1 h and filtered to give the title compound as a solid. M. S (M+1): 351.
EXAMPLE 2 Synthesis of 2,3'-dipyridyl (A-2) The same synthesis procedures as in Example 1 were conducted except for using 3-cyanopyridine in place of 4-cyanopyridine and, after completion of the reaction, the organic layer was distilled under reduced pressure of 4.9 to 5.0 Torr to obtain a 90 to 93 C. fraction. Thus, there was obtained 127.9 g (yield: 85.3%) of the end product as pale yellow crystals. HPLC analysis revealed that purity of the product was 98.9%.
With hydrogenchloride; sodium methylate; sodium; In methanol; tert-Amyl alcohol; water; acetic acid;
The following Examples illustrate the invention. Example 1 6.90 g of sodium are stirred in 120 ml of tert-amyl alcohol at reflux temperature until the reaction is complete. After cooling to 90 C., 24.02 g of 4-cyano-pyridine-N-oxide are added, followed by the dropwise addition of 20.23 g of <strong>[924-88-9]diisopropyl succinate</strong> over 4 hours. The reaction mixture is stirred for 4 hours at 80 C. and then cooled to 30 C. A mixture of 29.56 g of hydrochloric acid and 240 ml of methanol/water (1:2) is run in and stirring is continued for a further 1 hour at room temperature. The precipitated pigment is isolated by filtration, washed with water and extracted hot with methanol. After filtration, the resultant crystals are washed with methanol and water and dried under vacuum, affording 6.80 g (21% of theory) of the compound of formula STR19 in the form of dark-red crystals with a melting point >250 C. Example 2 6.81 g of sodium methylate are stirred in 70 ml of methanol at reflux temperature until the reaction is complete. Then 6.05 g of 4-cyanopyridine-N-oxide are added, followed by the addition in small portions of 9.71 g of the compound of formula STR20 over 2 hours. The mixture is refluxed for 4 hours and then cooled to 40 C. A mixture of 12.4 g of hydrochloric acid and 140 ml of water is added dropwise and stirring is continued for a further 1 hour. The precipitated pigment is isolated by filtration, washed with water and extracted hot with methanol. After filtration, the resultant crystals are washed with methanol and then with water and dried under vacuum at 80 C., affording 3.65 g (28.4 % of theory) of a pigment of formula Example 3A 5.21 g of 3-cyanopyridine are completely dissolved in 50 ml of glacial acetic acid at 40 C., with stirring. Then 9.8 ml of a 30% aqueous solution of H2 O2 are added and the mixture is heated, with stirring, to 100 C. for 2 hours. Thin-layer chromatography shows that the reaction is complete. The solvent is cautiously removed by evaporation and the beige solid is treated with 25 ml of ethanol, cooled and and filtered. The residue is dried at 35 C. under vacuum, affording 3.5 g (58.3% of theory) of 3-cyanopyridine-N-oxide as a white solid with a melting point of 172-174 C.
REFERENCE EXAMPLE 1 A reaction was conducted for 12 hours in the same manner as in Example 1 except that <strong>[69045-78-9]2-chloro-5-trichloromethylpyridine</strong> (0.2 mole) was replaced by 3-trichloromethylpyridine (0.2 mole). The resulting reaction mixture was analyzed by gas chromatography, which indicated that the amount of 3-cyanopyridine formed was 1% or less.
With cupric indole-3-acetate; at 80℃; for 0.0833333h;Neat (no solvent); Microwave irradiation;
The typical reaction procedure under MW irradiation. A mixture of nitrile (10 mmol), EDA (40 mmol) and Cu(II)-(IAA)2 (2.0 mmol) was irradiated with microwave (1000 W) for 5-20 min by pulsed irradiation. At the end of the reaction (monitored by TLC, eluent: EtOAc/MeOH, 3:1), the mixture was cooled to room temperature, CH2Cl2 was then added and the catalyst was filtered. Evaporation of the solvent gave the almost pure product. Further purification was performed as for the procedure used in the synthesis of imidazolines under reflux condition. The identities of products were confirmed by mp, 1H NMR, MS and IR data.
General procedure: To a solution of N,N-dimethyl benzamide (298 mg, 2 mmol) in dry THF (4 mL) was added DIBAL-H (1.04 M in hexane, 2.3 mL, 1.2 equiv) at -78 C. The mixture was stirred for 1.5 h under an argon atmosphere at from -70 C to -40 C slowly. Then, aq NH3 (concentration: 28.0-30.0%, 4 mL) and I2 (762 mg, 3.0 equiv) were added at 0 C, and the reaction mixture was stirred for 2 h at room temperature. Reaction mixture was poured into saturated aq Na2SO3 solution (10 mL) and extracted with ethyl acetate (15 mL×3). The organic layer was dried over Na2SO4. After removal of the solvent under reduced pressure, the residue was purified by short column chromatography on silica gel (eluent: hexane/ethyl acetate=4:1) to afford benzonitrile in 67% yield (138 mg).Most of the present prepared nitriles are commercially available and they are identified with authentic nitrile compounds.
In a dry 500 mL flask under N2 2,2,6,6-tetramethylpiperidine (57.6 mmol) was dissolved in dry THF (200 mL) and the mixture was cooled to -10 C before n-BuLi (57.6 mmol, 2.5 M in n-hexane) was added over 2 min. The mixture was stirred for 10 min before cooling to -78 C. At -78 C, B(O-i-Pr)3 (65.3 mmol) was added over 2 min and stirred for 5 min at -78 C before 3-cyanopyridine (48 mmol) dissolved in dry THF (50 mL) was added dropwise over 5 min. The reaction was left in the dry ice bath, allowed to reach room temperature overnight and quenched with glacial acetic acid (67.2 mmol) followed by addition of pinacol (72 mmol). The mixture was stirred for 2 h at room temperature and then transferred to a separating funnel with CH2Cl2 (75 mL) and washed with aqueous KH2PO4 (10 w/v %) (4×60 mL). The combined aqueous layers was back-extracted once with CH2Cl2 (15 mL), the combined organic phase was dried over MgSO4, and the solvents were evaporated to give cyanopyridineboronic ester 3b as a yellow solid with 18% yield; mp 88 C; IR (KBr) nu 3097, 2968, 2930, 2238 (CN), 1618, 1522, 1476, 1464, 1421, 1385, 1373, 1337, 1201, 1113, 1046, 963, 882, 849, 778, 765, 714, 655, 578 cm-1; 1H NMR (400 MHz, CDCl3) delta 8.86 (s, 1H, H2), 8.74 (d, J=4.6 Hz, 1H, H6), 7.70 (d, J=4.6 Hz, 1H, H5), 1.34 (s, 12H); 13C NMR (100 MHz, CDCl3) delta 153.3, 152.1, 129.3, 117.1, 114.2, 85.8, 83.1, 25.0.
General procedure: The respective heteroarylcarbonitrile (5 mmol) wasrefluxed with 0.6 cm3 DBU (4 mmol) in 10 cm3 of methanolfor 0.5 h. Then 0.77 g <strong>[33263-43-3]4-chloropyridine-3-sulfonamide</strong>(4 mmol) were added and the mixture was refluxed foranother 3 h. Methanol was removed under vacuum and30 cm3 of water were added to the residue. The clearsolution was acidified with glacial acetic acid. The precipitatewas filtered off and recrystallized from a suitablesolvent.
With Pd(2+)*2C5F9O2(1-); trifluoroacetic acid; 6-methyl-2,2'-bipyridine; In tetrahydrofuran; water; at 130℃; for 0.5h;Microwave irradiation;
General procedure: A 5 mL microwave vial was charged with 6-methyl-2,2'-bipyridine(16.3 mg, 0.096 mmol), Pd(O2CCF3)2 (26.6 mg,0.08 mmol) and 2 mL THF. After stirring at room temperature for 5 minutes,<strong>[1466-76-8]2,6-dimethoxy benzoic acid</strong> (182.2 mg, 1 mmol), nitrile (2 mmol), water (200 muL) and TFA (77 muL, 1 mmol) were added and the mixture heated in the microwave for 30minutes at 130 C. Themixture was diluted with DCM (15 mL) and 0.1 M NaOH (15 mL, 3d, 3g, 3i and 3l) or 1% HCl (15 mL, 3b, 3e, 3f, 3h, 3j and 3k), the phaseswere separated and extracted with DCM (2 × 15mL), dried with Na2SO4, filtered and concentrated underreduced pressure. Purification by flash chromatography afforded ketones 3b,3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k or 3l in the yields stated in Tables 1and 2.
With Pd(2+)*2C5F9O2(1-); trifluoroacetic acid; 6-methyl-2,2'-bipyridine; In tetrahydrofuran; water; at 130℃; for 1h;Microwave irradiation;
General procedure: A 2 mL microwave vialwas charged with 6-methyl-2,2'-bipyridine (16.3 mg, 0.096 mmol), Pd(O2CCF3)2(26.6 mg, 0.08 mmol) and 500 muL THF. After stirring at room temperature for 5minutes, <strong>[123843-65-2]2,6-difluoro-4-methoxybenzoic acid</strong> (188.1 mg, 1 mmol), nitrile (5mmol), water (50 muL) and TFA (77 muL, 1 mmol) were added and the mixture heated inthe microwave for 1 hour at 130 C. Themixture was diluted with DCM (15 mL) and 0.1 M NaOH (15 mL), the phases wereseparated and extracted with DCM (2 ×15 mL), dried with Na2SO4, filtered and concentratedunder reduced pressure. Purification by flash chromatography afforded ketones 3p,3x or 3ac in the yields statedin Table 3.
With hydrogenchloride; In 1,4-dioxane; at 100℃; for 16h;
General procedure: The appropriate aminoester (30 mmol), and the appropriate nitrile (30 mmol), were placed in 150 ml flask, and saturated HCl solution in dioxane (30 ml) was added dropwise. The reaction mixture was heated with stirring at 100 C for 16 h. After it was cooled to rt, the reaction mixture was poured into water (100 mL). The formed precipitate was filtered and washed with a small amount of EtOH to give the title compound.
32%
With hydrogenchloride; In 1,4-dioxane; at 100℃; for 16h;
General procedure: The appropriate aminoester (30 mmol), and the appropriate nitrile (30 mmol), were placed in 150 ml flask, and saturated HC1 solution in dioxane (30 ml) was added dropwise. The reaction mixture was heated with stirring at 100 C for 16 h. After it was cooled to rt, the reaction mixture was poured into water (100 mL). The formed precipitate was filtered and washed with a small amount of EtOH to give the title compound.
With dichloro [1,1'-bis(diphenylphosphino)propane]palladium(II); triethylamine; In water; tert-butyl alcohol; at 60℃; under 11251.1 Torr; for 16h;Autoclave; Inert atmosphere;
A 185 ml stirred autoclave was charged under argon with PdC12(dppp) (213 mg, 0.36 1 mmol), 6- chloro-nicotinonitrile (10 g, 72.2 mmol), dioxane (50 ml), deionized water (50 ml) and sodium, bicarbonate (15.2 g, 0.18 mol, 2.5 molar equivalents). The reaction vessel was closed, purged three times with carbon monoxide (15 bar) and finally charged with carbon monoxide to 60 bar. The mixture was stirred vigorously at 60C under constant pressure for 22 h; after this time no more carbon monoxide absorption was observed. The reaction mixture was transferred to a5 round-bottomed flask with aid of water and, after having removed the organic volatilecomponents on a rotary evaporator, the reaction mixture was worked-up as reported in Example1. Crystallization afforded 5-cyano-pyridine-2-carboxylic acid (9.55 g) as a white solid with 99.6a% purity by HPLC.Example 5a-h5-Cyano-pyridine-2-carboxylic acid A series of reaction conditions was tested using the same procedure described in Example 4. The results are included in the following table.Ex.PbarTCBase ImolarequivalentsSolvent Ivol/volratio2-Cl,5-CN-Py[a%]3-CN-Py-2-C0211[a % I3-CN-Py[a%]Isol.Yield(%)5a6060Na2CO31.25Water 1Dioxane 10.293.51.6895b6060NaOAc2.5Water 1Acetone 13.683.57.9n.d.5c4060Et3N2.5Water 1 t-BuOH 10.795.91.0895d1560Et3N2.5Water 1t-BuOH 4<0.195.41.992Se70100Et3N2.2Water 1THF40.453.825n.d.Sf3580Et3N2.5Water 1 CH3CN 4<0.193.54.9n.d.Sg3580Et3N2.5Water 1CH3CN 4MeOH 1<0.191.51.5n.d.5h4050Et3N2.5Water 1t-BuOH 110.586.60.5n.d.Example no. Sc: reaction time S h; example no. Sd and Sh: reaction time 16 h; example no. Sf:reaction time 12 h.Examples no. Se and Sf: S g of 2-Cl,S-CN-Py, S/C 330.Example no. Sg: crude mixture contains 3.7 a% of the methyl ester 3-CN-Py-2-CO2Me. a% S values are obtained by HPLC analysis.
potassium(pyridin-3-yl((trimethylsilyl)oxy)methylene)amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In toluene; for 4h;Reflux;
General procedure: To an oven dried round-bottomedflask containing <strong>[10519-96-7]potassium trimethylsilanolate</strong> (257 mg, 2 mmol, 2 equiv.) was addedeither anhydrous THF or toluene (5 mL) and benzonitrile (103 muL, 1 mmol, 1 equiv.).The reaction mixture was heated to reflux for 16 h (THF) or 4 h (toluene). The solidprecipitate was then filtered off, washed with anhydrous solvent and allowed to dryvia vacuum.
3-cyanopyridine (3-CNpy, 26.8mg, 0.20mmol) was dissolved in 5mL of EtOH, and H2tfBDC (23.8mg, 0.10mmol) was dissolved in 5mL of chloroform. Both the solutions were mixed and stirred at room temperature. About 30min later, the obtained homogeneous solution was allowed to stand at room temperature for slow evaporation. Three weeks later crystals started to form and the yield was about 63.38% (21.69mg), which is based on the H2tfBDC, m.p.: 176C. These were further washed with EtOH-chloroform (v/v=1: 1), and dried in vacuum desiccators. Elemental Anal. Calcd for C13H10F4N2O4: C, 45.59; H, 2.92; N, 8.18. Found: C, 46.45; H, 2.45; N, 7.52. IR data (KBr disc, cm-1): 3436m, 3087w, 3065w, 2484w, 2235m, 1891w, 1709m, 1638w, 1594m, 1575w, 1486s, 1417m, 1339s, 1325s, 1225s, 1188m, 1124m, 1067m, 1044m, 996s, 947w, 812m, 785w, 711s, 697m, 647m, 557w, 404w.
3-(1,5-diphenyl-1H-1,2,4-triazol-3-yl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With copper(l) iodide; 1,10-Phenanthroline; zinc(II) iodide; In chlorobenzene; at 130.0℃; for 36.0h;Sealed tube;
General procedure: A sealed tube equipped with a stirrer bar was charged with <strong>[1527-91-9]N-phenylbenzamidine</strong>(1a; 0.0393 g, 0.2 mmol), benzonitrile (2a; 41 muL, 0.40mmol), CuI (0.0190 g, 0.10 mmol), ZnI2 (0.0063 g, 0.02 mmol),phenanthroline (0.0040 g, 0.02 mmol) and chlorobenzene (1 mL). The resulting mixture was stirred at 130 C for 36 h. After reaction completion,the residue was directly purified by flash column chromatography(EtOAc-petroleum ether) to afford pure product 3aa.
5-(6-bromoimidazo[1,2-a]pyridin-2-yl)-3-(pyridin-3-yl)-1,2,4-oxadiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
General procedure: The first reaction, the formation of imidazo[1,2-a]pyridine-2-carboxylic acid, was carried out in a 1000 muL reactor (glasschip) at 100 C. The acid exiting the first reactor was combinedwith EDC/HOBt/DIPEA (1:1:1, 0.5 M, DMA) in a T-mixer.The synthesis of amidoxime (ArCN/NH2OH·HCl/DIPEA(1.1:1:3), 0.4 M, DMA) was achieved by placing a secondreactor (250 muL glass chip) in a heated silicone oil bath at100 C. This stream was next introduced into a third reactor andmixed with the stream exiting from the T-mixer at 150 C. Thestream exiting the third chip was collected after passing throughthe back pressure regulator. This reaction was carried out with aback pressure of 4.0 bar. The reaction mixture was mixed withexcess water and extracted three times with dichloromethane.The combined organic layers were washed with brine, driedover magnesium sulfate, filtered, and concentrated and the residue was purified via automated flash chromatography(SiO2) to afford the desired product (CombiFlash Rf, 12g flashcolumn). The solvent gradient was 90% hexane to 50% ethylacetate over 15 min at a flow rate of 15 mL/min.
Under a nitrogen atmosphere, 300 g of anhydrous tetrahydrofuran was added to the reaction flask, stirring was continued, 12 g of 3-cyano-pyridine was added and cooled to -30C.N-BuLi was slowly added dropwise to 70 mL of 2.0 M, and after stirring for 30 minutes, a solution of 1,4,7,10-tetramethyl-1,4,7,10-tetraazacyclododecane was slowly added dropwise.After 2 hours of incubation, 41 mL of triisopropyl borate was slowly added dropwise at -30 C, stirred for 1 hr, slowly raised to room temperature and stirred for 1 hour.And 400 g of concentrated hydrochloric acid was added thereto, followed by stirring for 1 hour to carry out a hydrolysis reaction.The layers were allowed to stand, and the organic layer was washed three times with water (3 x 100 g).The aqueous layers were combined and the aqueous layer was extracted once with 100 ml of petroleum ether. The combined organic layers were dried over 50 g of anhydrous sodium sulfate and filtered.The filtrate was concentrated to dryness to give 3-cyano-4-pyridine boronic acid 14 g,
Under a nitrogen atmosphere, 300 g of anhydrous tetrahydrofuran was added to the reaction flask, stirring was continued, 12 g of 3-cyano-pyridine was added and cooled to -30C.N-BuLi was slowly added dropwise to 70 mL of 2.0 M, and after stirring for 30 minutes, 26 g of 1,4,7-trimethyl-1,4,7-triazacyclononane was slowly added dropwise.After incubation for 2 hours, 26 mL of trimethyl borate was slowly added dropwise at -30 C, stirred for 1 hr, slowly warmed to room temperature and stirred for 1 hour.And 400 g of concentrated hydrochloric acid was added thereto, followed by stirring for 1 hour to carry out a hydrolysis reaction.The layers were allowed to stand, and the organic layer was washed three times with water (3 x 100 g).The aqueous layers were combined and the aqueous layer was extracted once with 100 ml of petroleum ether. The combined organic layers were dried over 50 g of anhydrous sodium sulfate and filtered.The filtrate was concentrated to dryness to give 13 g of 3-cyano-4-pyridine boronic acid.
With tert.-butylhydroperoxide; iodine; zinc(II) iodide; In water; N,N-dimethyl-formamide; at 20℃; for 8h;
General procedure: To an oven dried rb flask with a magnetic stir bar were added 2-amiobenzyl alcohol 1 (123.0 mg, 1.0 mmol), nitrile derivative (108.0 mg, 1.0 mmol) 2, anhydrous zinc iodide (0.3 equiv, 96 mg) and the mixture was stirred in 5 mL DMF at room temperature for 1h. Then iodine (127 mg, 0.5 mmol) and aq. TBHP (70% solution in water, 0.66 mL, 5.0 mmol) were added successively and stirring continued for another 7h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched by aq. Na2S2O3 solution (10%, 20 ml), extracted with EtOAc (10 mL × 3), and the combined organic part was dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure left a crude mass which was purified by column chromatography using silica gel (60-120 mesh size) (25% EtOAc/hexane) to afford pure 3a (140 mg; 72% yield).
With tert.-butylhydroperoxide; iodine; zinc(II) iodide; In water; acetonitrile; at 20℃; for 3h;
General procedure: To an oven dried rb flask with a magnetic stir bar were added 2-amiobenzamide 1a (136.0 mg, 1.0 mmol), nitrile derivative 2 (108.0 mg, 1.0 mmol), anhydrous zinc iodide (0.3 equiv, 96 mg) and the mixture were stirred in 5 mL acetonitrile for 1h at room temperature. Then iodine (51 mg, 0.2 mmol) and aq. TBHP (70% solution in water, 0.26 mL, 2.0 mmol) were added successively and the mixture stirred at rt for another 2 h. After completion of the reaction (TLC monitoring), the reaction mixture was quenched by aq. Na2S2O3 solution (5%, 20 mL), extracted with ethyl acetate (10 mL × 3), and the combined organic part was dried over anhydrous sodium sulphate. Removal of the solvent under reduced pressure left a crude mass which was purified by column chromatography using silica gel (25% EtOAc/hexane) to afford 3a (155 mg; 80% yield).
2-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one dihydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57 mg
A mixture of 3-aminopyridine-4-carboxylic acid (137 mg, 1.0 mmol), nicotinonitrile (125 mg, 1.2 mmol), sodium methoxide (54 mg, 0.25 mmol) in methanol (6 mL) was heated at reflux for 3 days. The mixture was concentrated and dissolved into dimethylformamide and purified by reverse phase-HPLC to give the desired product that was converted to an HCl salt (57 mg) using 4N HCl in dioxane. LC/MS: RT = 1.86 minutes, purity > 95percent, (M+l)+ = 224.98.
With lanthanum(III) fluoride; potassium hexamethylsilazane; In di-isopropyl ether; at 110℃; for 12h;Green chemistry;
General procedure: Lithium bis(trimethylsilyl)amide (66.8 mg, 0.4 mmol) and cesium fluoride (30.4 mg, 0.2 mmol) were placed in a microwave tube in a glove box. Add 0.4 mL of cyclopentyl methyl ether, Then <strong>[95-52-3]2-fluorotoluene</strong> (66 muL, 0.60 mmol) and benzonitrile (20 muL, 0.20 mmol) were added separately using a micro syringe. which was taken out from the glove box and refluxed at 110 C for 12 hours. After cooling to room temperature, the reaction was capped and three drops of water were added to quench the reaction. The solvent was removed under reduced pressure and the crude product was purified by column chromatography ( petroleum ether: ethyl acetate = 20:1) to give 2-phenylindole (34.7 mg) , 90% yield).
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