* 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.
A. Preparation of 3-(4-pyridyl)acrylic acid 4-Pyridinecarboxaldehyde (18.96 g, 0.177 mol) and malonic acid (55.3 g, 0.53 mol) were placed in 200 ml of pyridine. Piperidine (5.25 ml, 0.053 mol) was added and the reaction was refluxed for 6 hours. The reaction mixture was cooled in an ice bath and then the white solid was filtered off and rinsed with ether and dried to afford 20.1 g of the subtitle compound. Concentration of the filtrate and then filtration and rinsing with ether resulted in recovery of another 2.2 g of product (84percent total yield).
Reference：
[1] Patent: EP846687, 1998, A1,
[2] Patent: US5972972, 1999, A,
[3] Patent: US5618939, 1997, A,
2
[ 872-85-5 ]
[ 141-82-2 ]
[ 84228-93-3 ]
Yield
Reaction Conditions
Operation in experiment
6.9 g
at 80 - 115℃; for 4 h;
pyridine-4-carbaldehyde (5 g, 0.047 mol), malonic acid (2.2 g (0.094 mol)), pyridine (30 mL), and piperidine (850 ul, 8.5 mmol) were mixed well, heated to 80-85° C. for 1 h and finally refluxed (110-115° C.) for an additional 3 h. The reaction mixture was poured into water and acidified with concentrated HCl. The precipitate obtained was filtered, and washed with cold water repeatedly. The residue was dissolved in NaOH, diluted, again acidified, the precipitate was collected washed with cold water and dried under high vacuum over P2O5 and used without further purifications. Yield=6.9 g.
Reference：
[1] Russian Journal of General Chemistry, 2005, vol. 75, # 7, p. 1113 - 1124
[2] Journal of Organic Chemistry, 1955, vol. 20, p. 1785,1790
[3] Synthesis, 1992, # 4, p. 395 - 398
[4] Heterocycles, 1994, vol. 37, # 3, p. 1495 - 1502
[5] Journal of Molecular Structure, 2015, vol. 1090, p. 25 - 33
[6] MedChemComm, 2015, vol. 6, # 6, p. 1036 - 1042
[7] Patent: US2016/168100, 2016, A1, . Location in patent: Paragraph 0374
3
[ 872-85-5 ]
[ 84228-93-3 ]
Reference：
[1] Patent: US6538007, 2003, B1,
[2] Patent: US5463067, 1995, A,
[3] Patent: EP1104754, 2001, A1,
[4] Patent: US2004/92598, 2004, A1,
[5] European Journal of Medicinal Chemistry, 2017, vol. 138, p. 313 - 319
4
[ 108-89-4 ]
[ 872-85-5 ]
[ 13362-78-2 ]
Yield
Reaction Conditions
Operation in experiment
49%
With acetic acid; lithium diisopropyl amide In tetrahydrofuran at -70℃; for 24 h; Darkness; Reflux
400μL (4.12mmol) of 4-picoline reacted with 3.0mL (4.32mmol) of LDA in THF (5mL) at −70°C. In the absence of light, 465mL (4.12mmol) of 4-piridincarboxyaldehyde was dropwise added with continuous stirring. After 24h of reflux in the presence of 10mL of acetic acid, the reaction mixture led to a yellow solution, from which a pale-yellow solid was separated by rotatory evaporation. The solid was purified employing column chromatography in analogous conditions to the ones previously mentioned (368mg, 49percent). 1H RMN (400MHz, CDCl3, δ): 8.62 (d, J=4Hz, 4H, Ar−H), 7.61 (d, J=4Hz, 4H, Ar−H), 7.55 (s, 2H, −CH=CH−).
Reference：
[1] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2017, vol. 183, p. 45 - 52
[2] Journal of the American Chemical Society, 1948, vol. 70, p. 2330,2333
Reference：
[1] Archiv der Pharmazie (Weinheim, Germany), 1987, vol. 320, # 7, p. 647 - 654
[2] Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 972 - 986
7
[ 872-85-5 ]
[ 6971-44-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 1995, vol. 38, # 11, p. 1892 - 1903
[2] CrystEngComm, 2011, vol. 13, # 22, p. 6817 - 6826
8
[ 872-85-5 ]
[ 94170-15-7 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1958, vol. 6, p. 615,617
9
[ 872-85-5 ]
[ 1099-45-2 ]
[ 5337-79-1 ]
Reference：
[1] Patent: US4638000, 1987, A,
10
[ 872-85-5 ]
[ 141-82-2 ]
[ 5337-79-1 ]
Reference：
[1] European Journal of Medicinal Chemistry, 1989, vol. 24, p. 65 - 72
[2] Journal of Medicinal Chemistry, 2014, vol. 57, # 19, p. 8140 - 8151
11
[ 872-85-5 ]
[ 67-56-1 ]
[ 2459-09-8 ]
Yield
Reaction Conditions
Operation in experiment
89%
With potassium carbonate In water at 20℃; for 2 h;
General procedure: A mixture of bromine chloride resin and K2CO3 in MeOH–H2O (8:2) 3 mL was placed in a round-bottom flask fitted with amagnetic stirrer. To this, the aldehyde (1 mmol, 1 equiv) was added dropwise, and the reaction mixture stirred at r.t. The progress of the reaction was monitored by TLC. After completionof the reaction the mixture was filtered, and the filtrate was extracted with Et2O. The ether layer was washed with H2O, brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography, if required, over silicagel (60–120 mesh) using a mixture of PE and EtOAc (9:1) as eluent.
83%
at 20℃; for 1 h;
General procedure: To a solution of alcohol(1 mmol) in a mixture of MeCN and MeOH (5:1, 2.4 mL) was added TsNBr2(2.5 mmol) and K2CO3 (5 mmol) and stirred at room temperature. After completion of the reaction (TLC) sodium thiosulfate was added and the reaction mixture was stirred for 10 min. The reaction mixture was extracted indiethyl ether and hexane (1:1), dried, (Na2SO4) and concentrated. Purification of the crude product by flash chromatography on silica gel (230–400 mesh)with petroleum ether–EtOAc as eluent gave the pure product.In case of ester synthesis from aldehydes, reaction was carried out using1.5 mmol of TsNBr2 and 2 mmol of K2CO3 for 1 mmol of substrate. For methylester synthesis, methanol (5 mL) was used as a solvent and for other alkyl ester synthesis 5:1 mixture of MeCN–ROH (2.4 mL) was used as the reaction medium. Work-up procedure remains the same.
Reference：
[1] Synthesis, 2010, # 2, p. 276 - 282
[2] Synlett, 2016, vol. 27, # 9, p. 1344 - 1348
[3] Tetrahedron Letters, 2014, vol. 55, # 39, p. 5358 - 5360
[4] Synthetic Communications, 2010, vol. 40, # 2, p. 186 - 195
[5] Synthesis, 2009, # 9, p. 1578 - 1581
[6] Organic Letters, 2018, vol. 20, # 17, p. 5172 - 5176
[7] European Journal of Medicinal Chemistry, 2002, vol. 37, # 2, p. 163 - 170
[8] Green Chemistry, 2014, vol. 16, # 4, p. 2164 - 2173
[9] Chemical Science, 2016, vol. 7, # 7, p. 4428 - 4434
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 17, p. 6040 - 6049
[2] Patent: US2013/203754, 2013, A1,
20
[ 872-85-5 ]
[ 87-41-2 ]
[ 67592-40-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 2000, vol. 43, # 12, p. 2310 - 2323
[2] European Journal of Medicinal Chemistry, 2010, vol. 45, # 8, p. 3504 - 3510
[3] Archiv der Pharmazie, 2012, vol. 345, # 4, p. 287 - 293
[4] Chinese Chemical Letters, 2010, vol. 21, # 9, p. 1071 - 1074
21
[ 872-85-5 ]
[ 2107-69-9 ]
[ 4803-74-1 ]
Yield
Reaction Conditions
Operation in experiment
98%
With potassium hydroxide In water at 25 - 30℃; for 3 h;
Example 1: Process for preparation of 5,6-dimethoxy-2-(4-pyridylmethylene)-l- indanone of formula IVTo a 1 liter round bottom flask equipped with a mechanical stirrer, thermometer pocket, addition funnel and a condenser, charged demineralized water (250ml), 5,6- dimethoxy-l-indanone (25g) and pyridine-4-carboxaldehyde (19.5g). The reaction mixture was stirred for 5 minutes at a temperature of 25°C to 30°C. To the reaction mixture then charged a solution of potassium hydroxide (5.2g) dissolved in demineralized water (125ml) slowly over period of 2 hours at a temperature of 25 °C to 30°C. The reaction mixture was further maintained at a temperature of 25°C to 30°C for 1 hour to obtain the product, 5,6-dimethoxy-2-(4-pyridylmethylene)-l- indanone. The product obtained was then filtered and washed with demineralized water. Dry the product under vacuum at a temperature of 50°C to 55°C for 10 hours. Yield: 98percentPurity: 99.71percent
95.8%
Stage #1: With toluene-4-sulfonic acid In toluene for 6 h; Heating / reflux Stage #2: With sodium carbonate In water for 0.5 - 1 h;
5, 6 Dimethoxy indanone (100 grams), Pyridine-4-carboxaldehyde (78.0 grams) and p-toluene sulfonic acid (138.4 grams) were suspended in toluene (1250 ml) and heated to reflux using water separator for 6 hours. The resulting mass was cooled to 25-40° C. and the solid was filtered off under suction. Further the wet solid was suspended in aqueous 10percent sodium carbonate solution (1200 ml) and stirred for 30-60 minutes. The resulting pale yellow precipitate solid was filtered off under suction, washed with water (1000 ml) and dried at a temperature of 80° C. to afford 5,6 Dimethoxy-2-(pyridin-4yl)-methylene-indan-lone (Weight: 140 grams, 95.8percent).
Reference：
[1] Patent: WO2012/131540, 2012, A1, . Location in patent: Page/Page column 16
[2] Patent: US2004/143121, 2004, A1, . Location in patent: Page 3
[3] Patent: WO2004/82685, 2004, A1, . Location in patent: Page/Page column 9
[4] European Journal of Medicinal Chemistry, 2011, vol. 46, # 11, p. 5694 - 5697
[5] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 23, p. 7029 - 7035,7
[6] Journal of Enzyme Inhibition and Medicinal Chemistry, 2013, vol. 28, # 3, p. 644 - 650
[7] Journal of Enzyme Inhibition and Medicinal Chemistry, 2014, vol. 28, # 3, p. 644 - 650
22
[ 872-85-5 ]
[ 2747-08-2 ]
[ 4803-74-1 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2010, vol. 58, # 9, p. 1157 - 1160
23
[ 872-85-5 ]
[ 2747-08-2 ]
[ 4803-74-1 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2010, vol. 58, # 9, p. 1157 - 1160
24
[ 586-95-8 ]
[ 75-91-2 ]
[ 872-85-5 ]
[ 81660-73-3 ]
Reference：
[1] Journal of Organic Chemistry, 1996, vol. 61, # 4, p. 1467 - 1472
25
[ 872-85-5 ]
[ 138517-18-7 ]
[ 73564-69-9 ]
Reference：
[1] Journal of Organic Chemistry, 1992, vol. 57, # 5, p. 1622 - 1625
26
[ 872-85-5 ]
[ 73564-69-9 ]
Reference：
[1] Chemistry - A European Journal, 2011, vol. 17, # 25, p. 7032 - 7040
27
[ 872-85-5 ]
[ 109-97-7 ]
[ 123-08-0 ]
[ 51094-17-8 ]
[ 127822-97-3 ]
[ 127801-02-9 ]
[ 16834-13-2 ]
Reference：
[1] Dyes and Pigments, 2010, vol. 84, # 1, p. 140 - 147
28
[ 872-85-5 ]
[ 1122-62-9 ]
[ 112881-51-3 ]
Reference：
[1] Dalton Transactions, 2012, vol. 41, # 14, p. 4255 - 4261
[2] Synlett, 2005, # 8, p. 1251 - 1254
[3] Organic and Biomolecular Chemistry, 2016, vol. 14, # 15, p. 3793 - 3808
[4] Polyhedron, 2016, vol. 103, p. 241 - 247
[5] Inorganica Chimica Acta, 2011, vol. 366, # 1, p. 134 - 140
[6] Crystal Growth and Design, 2012, vol. 12, # 8, p. 4264 - 4274
[7] Canadian Journal of Chemistry, 1991, vol. 69, # 2, p. 315 - 321
[8] Dalton Transactions, 2008, # 3, p. 386 - 396
[9] Journal of the American Chemical Society, 2011, vol. 133, # 19, p. 7509 - 7516
[10] New Journal of Chemistry, 2014, vol. 38, # 6, p. 2679 - 2685
[11] ChemPlusChem, 2014, vol. 79, # 7, p. 985 - 994
[12] New Journal of Chemistry, 2016, vol. 40, # 7, p. 5906 - 5913
[13] Monatshefte fur Chemie, 2017, vol. 148, # 5, p. 893 - 900
[14] Australian Journal of Chemistry, 2017, vol. 70, # 5, p. 494 - 498
[15] Supramolecular Chemistry, 2018, vol. 30, # 8, p. 706 - 712
29
[ 872-85-5 ]
[ 112881-51-3 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 10, p. 3566 - 3570
[2] New Journal of Chemistry, 2016, vol. 40, # 7, p. 5775 - 5781
General procedure: Appropriate aldehyde (10.5 mmol) was added to the solution of <strong>[603-81-6]2,3-<strong>[603-81-6]diaminobenzoic acid</strong></strong> 6 (1.52 g, 10 mmol) in DMF (15 mL). The solution was heated to 80 C and then stirred for about 120 h. Then, the solution was cooled to room temperature. The precipitates were filtered, washed with ethanol and dried.
With p-benzoquinone; In 1,4-dioxane; at 80℃;
General procedure: Appropriate aldehyde 3 (1.5 mmol) was added to the solution of 2,3/3,4-<strong>[603-81-6]diaminobenzoic acid</strong> 2 (1.0 mmol) in dioxane (10 mL). 1,4-Benzoquinone was added and the solution was heated to 80 C and stirred for about 6-9 h.Then, the solution was cooled to room temperature. The separated solid crystals were filtered, washed with ethanol and ether, dried. The products were used in the next step without further purification.
800 mg (73%)
In nitrobenzene;
2-(Pyrid-4-yl)-1H-benzimidazole-4-carboxylic acid (1d) 700 mg (4.6 mmol) of <strong>[603-81-6]2,3-<strong>[603-81-6]diaminobenzoic acid</strong></strong> (1c) and 0.47 ml (4.95 mmol) of 4-pyridylaldehyde were dissolved in 40 ml of nitrobenzene and heated at 145 C. for 2 h with stirring. The mixture was then cooled and the precipitate was filtered off with suction. The precipitate was washed with ethyl acetate and dried in a desiccator. Yield: 800 mg (73%).
7-bromo-2-pyridin-4-yl[1,2,4]triazolo[1,5-a]pyridin-5-ylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydroxide; mesitylenesulfonylhydroxylamine;
EXAMPLE 75 7-Bromo-2-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine The title compound, MS m/e (%): 292 (M++2, 100), was prepared in accordance with the general method of example 63 from <strong>[329974-09-6]4-bromo-pyridine-2,6-diamine</strong>, O-mesitylene-sulfonylhydroxylamine, and 4-pyridinecarboxaldehyde. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
(c) wherein W = -(CH2)2-N (CH3)-CH2-; Step I: Preparation of methylpyridin-4-ylmethylamine40% methyl amine (68.7 mmol) was added to a solution of pyridine 4- carbaldehyde (57.3 mmol) in methanol (90 mL) at 0-5 0C and stirred for about 15minutes, followed by adding sodium borohydride (57.3 mmol). The reaction mixture was refluxed for about 1 hour, cooled to ambient temperature and solvent was removed under reduced pressure. Water was added to the resulting residue the mixture was extracted with dichloromethane. The dichloromethane layers were combined, mixed and washed successively with water and then brine, and dried over anhydrous sodium sulfate. Solvent was evaporated under reduced pressure to yield a crude product.
With sodium methylate; In methanol; Ethyl propionate; at 0 - 20℃; for 2.25h;Heating / reflux;
To a suspension of 20.27 g (150 mmol) furo[3,4-b]pyridin-5(7h)-one (for preparation see Synthesis 1997,113) and 14.13 ml (150 mmol) 4- pyridinecarbaldehyde in 120 ml methanol and 75 ml ethyl propionate, 27.8 ml (150 mmol) of a 5.4M solution of sodium methylate in methanol is added dropwise under ice cooling (and N2 atmosphere). The mixture is heated for 15 min to RT and then for 2 h to reflux temperature. The suspension temporarily goes into solution before a solid forms again. After cooling, 120 ml water is added, before stirring, filtering and washing the product with water. Further product is obtainable from the filtrate by acidification with acetic acid: FAB MS (M+H) +=225.
7-fluoro-2-(4-pyridyl)hydroxymethyl-1-tetralone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; In methanol;
7-Fluoro-2-(4-pyridyl)hydroxymethyl-1-tetralone may be prepared in the following manner: 4-pyridinecarbaldehyde (59.2 g) is added to a mixture of <strong>[2840-44-0]7-fluoro-1-tetralone</strong> (45.4 g), methanol (140 cc) and 2N sodium hydroxide (41.5 cc) at a temperature of 5° C. The mixture is stirred at a temperature in the vicinity of 25° C. for 3 hours. The expected compound (68.8 g), m.p. 133° C., is isolated directly. 7-Fluoro-1-tetralone may be prepared according to the method described by G. A. THIAULT, Bull. Soc. Chim. France, 1308 (1965).
6-Methoxy-3-(pyridin-4-yl)methylene-4-chromanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 272 6-Methoxy-3-(4-pyridyl)methylene-4-chromanone By the method of Example 1, <strong>[5802-17-5]6-methoxy-4-chromanone</strong> (26.7 g, 0.15 mol) and pyridine-4-carbaldehyde were converted to present title product, 13.5 g; m.p. 170-171.5 C.; IR (KBr) 1675, 1616, 1598, 1552 cm-1. Analysis calculated for C16 H13 NO3: C, 71.90; H, 4.90; N, 5.24%. Found: C, 71.76; H, 4.90; N, 5.29%.
With sodium hydroxide; In ethanol; water; at 20℃; for 24h;
An aqueous sodium hydroxide solution (6N, 2 mL) is added to a solution of 2- phenyl - 2, 3 - dihydroquinolin-4(lH)-one (223 mg, lmmol) in ethanol (5mL). Pyridine -4- carboxaldehyde (126 mg, 1.2 mmol) is then added to the reaction mixture, which is stirred at room temperature for 24 hours. Subsequently, it is evaporated under reduced pressure. The residue is dissolved into chloroform and the organic layer washed with water, dried over Na2SO4 and evaporated to dryness. Crude product further purified by column chromatography on silica gel using ethyl acetate: acetone (97:03 v/v) as eluent. Yield 130 mg (42percent); mp 222-224°C; IR (KBR) 3435, 1627 cm"1; 13C NMR (DMSO-d6) delta 30.84 (CH2), 116.04 (C-8), 118.40 (C-6), 123.16 (C-3), 123.39 (C-2" and C-6"), 123.76 (C-4'), 125.09 (C-4a), 128.61 (C-2' and C-6'), 128.66 (C-3' and C-5'), 129.67 (C-5), 131.73 (C-7), 134.58 (C-I'), 139.65 (C-2), 149.16 (C-3" and C-5"), 149.64 (C-I"), 150.49 (C-8a), 176.21 (C=O).
20 g (89 mmol) of T-BUTYL-P, P-dimethylphosphonoacetate in 50 ml of THF is added in drops at 0°C to a suspension of 3.9 g (98 mmol) of sodium hydride (60 percent in mineral oil) in 250 ml of THF. After 1 hour of stirring at 0°C, a solution of 10 g (93 mmol) of pyridine-4- carbaldehyde in 50 ml of tetrahydrofuran is added in drops, and the reaction mixture is stirred for 1 hour at 0°C and for 18 hours at room temperature. The precipitated solid is removed by filtration, and the solution is concentrated by evaporation. The residue is dissolved in isopro- panol while being heated, non-soluble portions are filtered off, and the solution is cooled to 0°C for crystallization. The solid that is produced is filtered off, stirred with hexane, filtered and dried. The intermediate product (15.3 g) is hydrogenated in 150 ml of ethanol with 0.15 g of 10percent palladium/activated carbon for 6 hours. The catalyst is filtered off, the solution is concentrated by evaporation, and the residue is filtered on silica gel (mobile solvent diethyl ether). 13.0 g of a light yellow oil (71percent of theory) is obtained.
20 g (89 mmol) of t-butyl-P,P-dimethylphosphonoacetate in 50 ml of THF is added in drops at O0C to a suspension of 3.9 g (98 mmol) of sodium hydride (60 percent in mineral oil) in 250 ml of THF. After 1 hour of stirring at 00C, a solution of 10 g (93 mmol) of pyridine-4- carbaldehyde in 50 ml of tetrahydrofuran is added in drops, and the reaction mixture is stirred for 1 hour at O0C and for 18 hours at room temperature. The precipitated solid is removed by filtration, and the solution is concentrated by evaporation. The residue is dissolved in isopropanol while being heated, non-soluble portions are filtered off, and the solution is cooled to 0°C for crystallization. The solid that is produced is filtered off, stirred with hexane, filtered and dried. The intermediate product (15.3 g) is hydrogenated in 150 ml of ethanol with 0.15 g of 10percent palladium/activated carbon for 6 hours. The catalyst is filtered off, the solution is concentrated by evaporation, and the residue is filtered on silica gel (mobile solvent diethyl ether). 13.0 g of a light yellow oil (71percent of theory) is obtained.
A mixture of <strong>[59434-19-4]4-aminoisobenzofuran-1(3H)-one</strong> (894 mg, 6 mmol), isonicotinaldehyde (2.568 g, 24 mmol) and anhydrous sodium sulfate (3.6 g) in anhydrous ethanol (70 mL) was heated to reflux for two days. The mixture was cooled to room temperature and filtered. The filtrate was concentrated to give the crude product. The crude product was washed with petroleum ether to give (E)-4-(pyridin-4-ylmethyleneamino)isobenzofuran-1(3H)-one (1.1 g, yield 77%) as a white solid. 1H-NMR (400 MHz, CDCl3) delta (ppm): 5.44 (s, 1H), 7.40-7.42 (d, J=7.6 Hz, 1H), 7.59-7.63 (t, J=7.6 Hz, 1H), 7.77-7.79 (d, J=5.6 Hz, 2H), 7.84-7.86 (d, J=7.6 Hz, 1H), 8.54 (s, 1H), 8.81-8.82 (d, J=4.8 Hz, 1H); LC-MS (ESI) m/z: 239(M+1)+
77%
With sodium sulfate; In ethanol; at 20℃; for 144h;Reflux;
Example 3 IB(£')-4-(Pyridin-4-ylmethyleneamino)isobenzofuran- 1 (3H)-one[00562] A mixture of 4-aminoisobenzofuran- l(3H)-one (894 mg, 6 mmol), isonicotinaldehyde (2.568 g, 24 mmol) and anhydrous sodium sulfate (3.6 g) in anhydrous ethanol (70 mL) was heated to reflux for two days. The mixture was cooled to room temperature and filtered. The filtrate was concentrated to give the crude product. The crude product was washed with petroleum ether to give (£)-4-(pyridin-4- ylmethyleneamino)isobenzofuran- 1 (3H)-one (1.1 g, yield 77%) as a white solid. ^-NMR (400 MHz, CDCI3) delta (ppm): 5.44 (s, 1H), 7.40-7.42 (d, J= 7.6 Hz, 1H), 7.59-7.63 (t, J= 7.6 Hz, 1H), 7.77-7.79 (d, J = 5.6 Hz, 2H), 7.84-7.86 (d, J= 7.6 Hz, 1H), 8.54 (s, 1H), 8.81-8.82 (d, J= 4.8 Hz, 1H); LC-MS (ESI) m/z: 239(M+1)+.
A mixture of <strong>[59434-19-4]4-aminoisobenzofuran-1(3H)-one</strong> (149 mg, 1 mmol) and nicotinaldehyde (268 mg, 2.5 mmol) in ethyl propionate (10 mL) was cooled to 0 C. Then a solution of sodium methoxide in methanol [sodium (93 mg, 4 mmol) in methanol (3 mL)] was added dropwise. After the addition, the mixture was stirred at 25 C. for 16 hr. The mixture was quenched with water (5 mL) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by prep-HPLC to give methyl 4-oxo-2,3-di(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (60 mg, yield 17%) and ethyl 4-oxo-2,3-di(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (4 mg, yield 1%) as a light yellow solid. LC-MS (ESI) m/z: 360(M+1)+ (methyl 4-oxo-2,3-di(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate), 374(M+1)+(ethyl 4-oxo-2,3-di(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate)
tert-butyl 5-(pyridin-4-ylmethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 15h;
Amine F-26: 2-(Pyridin-4-ylmethyl)-2,5-diazabicyclo[2.2.1]heptane dihydrochloride(i): Tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (5 g, 25.214 mmol) and pyridine-4-carbaldehyde (2.97 g, 27.74 mmol) were placed in dichloromethane (650 ml); sodium triacetoxyborohydride (10.6 g, 50.43 mmol) and glacial acetic acid (0.14 ml, 2.521 mmol) were added, and the reaction mixture was stirred for 15 hours at room temperature. Hydrolysis was then carried out with saturated sodium hydrogen carbonate solution, the phases were separated, and the aqueous phase was extracted 2x with diethyl ether. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel; dichloromethane/methanol).Yield: 5.8 g, 79percent.
With potassium hydroxide; In ethanol; water; at 20℃; for 2h;
To a solution of 2-12 (100 mg, 0.62 mmol) in anhydrous acetic acid (4.9 ml/mmol) was added the pyridine-4-carbaldehyde (0.62 mmol), followed by dropwise addition of concentrated HCl (0.3 ml/mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with distilled water (100 ml) and adjusted to pH 9 with 50% KOH. The mixture was stirred for 15 min. The precipitate formed was filtered under suction to yield orange solid of 2-6 which was purified by column chromatography by using hexane:ethyl acetate (6:4). Yield: 38.2%.
With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 15h;
tert-Butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (5 g, 25.214 mmol) and pyridine-4-carbaldehyde (2.97 g, 27.74 mmol) were introduced into dichloromethane (650 ml), mixed with sodium triacetoxyboron hydride (10.6 g, 50.43 mmol) and glacial acetic acid (0.14 ml, 2.521 mmol) and the reaction mixture was stirred at room temperature for 15 h. The mixture was then hydrolysed with saturated sodium hydrogen carbonate solution, the phases were separated and the aqueous phase was extracted twice with diethyl ether. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by column chromatography (silica gel; dichloromethane/methanol). Yield: 5.8 g, 79%
With sodium dithionite; In ethanol; water; at 160℃; for 0.166667h;Microwave irradiation;
Example 1 : Preparation of compounds of general formula f I) ^pyridi ^-y -S^ASjS^etramethyl-I.S^^ioxaborolan^- ^-IH^enzoIdJimidaaoIe (Intermediate A)To a stirred solution of 2-nitro-4-(4>4.5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline {1.58 g, 6.0 mmol) and 4-pyridinecarboxaldehyde (0.622 mL» 6.6 mmol) in ethanol (7.5 mL) and H20 (7.5 mL), was added sodium dithionite (2.09 g, 12.0 mmol). The suspension was heated to 160 C for 10 minutes in the CEM microwave. The resulting dark coloured suspension was absorbed onto silica and purified by flash chromatography eluting with (0:100 EtOAc-Hexane to 100:0 (EtOAc-Hexane) to yield title compound as a yellow solid (0.82 g, 2.5 mmol, 42%).LCMS RT=1.79 min, MH* 322.1; 1H NMR (CDCI3): 8.68-8 58 (2 H, m), 8.13 (1 H, s), 8.07- 8.00 (2 H, m), 7.78-7.66 (2 H, m) and 1.30 (12 H, s).
42%
With sodium dithionite; In ethanol; water; at 160℃; for 0.166667h;Microwave irradiation;
Example 1: Preparation of compounds of general formula (I)2Kpyridln^-yl)-5^4,4,5l5-te amethyl-1,3,2-dioxaborolan-2-yl)-1 H-benzo[d]imidazole (Intermediate A)To a stirred solution of 2-nitro-4-(4,4,5,5-tetramethyl-1 ,3l2-dioxaborolan-2-yl)aniline (1.58 g, 6.0 mmol) and 4-pyridinecarboxaldehyde (0.622 mL, 6.6 mmol) in ethanol (7.5 mL) and H20 (7.5 mL), was added sodium dithionite (2.09 g, 12.0 mmol). The suspension was heated to 160 C for 10 minutes in the CEM microwave. The resulting dark coloured suspension was absorbed onto silica and purified by flash chromatography eluting with (0:1 EtOAc-Hexane to 1:0 (EtOAc-Hexane) to yield title compound as a yellow solid (0.82 g, 2.5 mmol, 42%).LCMS RT=1.79 min, MhT 322.1 ; H NMR (CDCI3): 8.68-8.58 (2 H, m), 8.13 (1 H, s), 8.07- 8.00 (2 H, m), 7.78-7.66 (2 H, m) and 1.30 (12 H, s).
General procedure: The proton acceptors viz., (4-pyridyl)-benzylidene-40-n-alkylanilines (PyBnAs0 , for n = 10, 14 and 16) are prepared as reported [10] earlier. To 4-pyridine carboxaldehyde (0.1 mmol) in an absolute ethanol, an equimolar ethanolic solution of 4-n-alkylaniline i.e., 0.1 mmol of decyl or tetradecyl or hexadecylaniline is added under constant stirring conditions. To the above mixture, 3-4 drops of glacial acetic acid is added as a catalyst and refluxed for 3 h. After refluxing the contents, the volume of the solvent is recovered by distillation. The resulting solution is kept in an ice bath for few minutes. A white shiny product is obtained. It is recrystallized with ethanol several times. The average yield is found to be 79%.
With acetic acid; In ethanol; for 3h;Reflux;
General procedure: The proton acceptors (4-pyridyl)-benzylidene-4?-n-alkyl anilines(PyBnA; n = 10, 14 and 16) are prepared as per the procedure reported [18-20] earlier. The 4-pyridine carboxaldehyde and the corresponding anilines (decyl, tetradecyl and hexadecyl) are dissolved stoichiometrically (1:1) in ethanol and then mixed together. The resulting solution is refluxed for 3 h with acetic acid as catalyst. The solvent is distilled to obtain the corresponding Schiff's base. The synthetic method is presented in Scheme1. The final Schiff's base products are recrystallized three times with ethyl acetate. The melting points of the proton acceptors,PyB10A, PyB14A and PyB16A are found to be 50.4 C, 66.1 C and67.6 C respectively. The reported 1H NMR spectra of PyB14A andPyB16A infer the purity of the products
General procedure: A mixture of appropriate heterocyclic amine (1.0 mmol) (3) and aromatic aldehyde (1.2 mmol) (4) were stirred in tetrahydrofuran under ice-cold condition for 5 min, followed by addition of the thioglycolic acid (2.0 mmol). After 5 min, dicyclohexylcarbodiimide(1.2 mmol) was added to the reaction mixture at 0 C and the reaction mixture was stirred for an additional 3-5 h at room temperature to complete the reaction. Progresses of the reactions were monitored by TLC using acetone:chloroform (7:3) as mobile phase. The precipitated dicyclohexylurea was filtered off; the filtrate was concentrated to drynessunder reduced pressure. Deionized water was added to the residueand extracted with ethylacetate. The organic layer was successively washed with 5% aqueous sodium hydrogen carbonate and sodium chloride. Finally organic layer was dried over anhydrous sodium sulfate. The crude solid obtained on evaporation of the solvent under reduced pressure was subjected for column chromatography using silica gel 100-200 mesh using n-hexane:ethyl acetate (7:3) as the solvent system and further recrystallized in acetone to yield white/yellowish-white products[42].
General procedure: Appropriate aldehyde 3 (1.5 mmol) was added to the solution of 2,3/3,4-diaminobenzoic acid 2 (1.0 mmol) in dioxane (10 mL). 1,4-Benzoquinone was added and the solution was heated to 80 C and stirred for about 6-9 h.Then, the solution was cooled to room temperature. The separated solid crystals were filtered, washed with ethanol and ether, dried. The products were used in the next step without further purification.
General procedure: A mixture of 17 (2.00 g, 7.99 mmol) and 2-pyridinecarboxaldehyde (18a) (910 mg, 9.59 mmol) in toluene(20 mL) was heated to reflux under azeotropic reaction conditions using a Dean-Stark apparatus for 2 h. After cooling, the toluene was removed under reduced pressure. The residue was dissolved in MeOH (20mL), then sodium borohydride (360 mg, 9.59 mmol) was added in small portions over 10 min in the icebath. After removing an ice bath, the mixture was stirred at rt for 4 h. Acetone (10 mL) was then added tothe mixture to quench the reaction and the solvent was removed under reduced pressure. The residue was dissolved in AcOEt and washed with saturated aqueous NaHCO3 and brine. After drying the mixture(Na2SO4), the solvent was removed under reduced pressure and the residue was chromatographed(AcOEt/hexane/NH4OH = 20/1/0.2, v/v) to afford 19a 2.53 g (93%) as a pale yellow oil.
7,7-dimethyl-10-(pyridin-4-yl)-1,5,6,7,8,10-hexahydropyrimido[5,4-b]quinoline-2,4,9(3H)-trione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With copper(I) iodide; In water; at 20℃; for 3.5h;Green chemistry;
A mixture of aromatic aldehydes 1 (1 mmol), dimedone (2, 1 mmol), 5-aminouracil (3, 1 mmol), and CuI NPs (2.9 mg, 15 mol%) was stirred at room temperature in water (10 mL) for the appropriate times. After completion of the reaction (TLC), the reaction mixture filtered and the solid mass was then diluted with DMF (5 mL), and the mixture was centrifuged at 2000-3000 rpm for 5 min to recover the catalyst and then the catalyst was dried in a vacuum oven at 100 C for several hours. The organic solution was the npoured into cold water (15 mL) and filtered. The resulting solid was recrystallized from EtOH to afford the pure product 4.
With ZnBr2/SiO2; In neat (no solvent); for 0.0666667h;Microwave irradiation; Green chemistry;
General procedure: The mixture of 4-(4-chlorophenoxy)aniline (2) (220 mg,1.0 mmol), 3-nitrobenzaldehyde (3e) (155mg, 1.03 mmol),diethyl phosphite (4) (0.13 mL, 1.0 mmol) and SiO2-ZnBr2 (17.1 mg, 6 molpercent) were taken into a flask. Thereaction mass was irradiated with microwave radiationsfor 4 min using Catalyst systems (CATA-4R,), percentpower is 65percent and 465Watts. Ethyl acetate (10 mL) wasadded to the reaction mixture and stirred for 10 min,after completion of the reaction as checked by TLC.The catalyst, SiO2-ZnBr2 was separated by filtrationas residue, washed with ethyl acetate (2×5mL) andcollected residue was dried under vacuum at 100°C toutilize in further reactions. The combined organic layerwas washed with water (10 mL), dried over anhydrousNa2SO4 and concentrated under vacuum at 50°C toobtain crude mass. The pure compound, diethyl (4-(4-chlorophenoxy)phenylamino)(3-nitrophenyl)methylphosphonate (5e) was isolated by column chromatographyusing 20?60percent ethyl acetate:n-hexane as a mobilephase.
The 1gN ', ", N" N' -tri (4-nitrophenyl) amine with 10 ml of hydrazine hydrate is added to the container, by adding 30 ml anhydrous ethanol as solvent, adding 300 mg of Pb/C as catalyst, the reaction in 80 C, reaction under stirring speed of the 40r/min 10 hours, filtering to obtain strawcoloured crystal intermediate product N ', ", N" N' -tri (4-aminophenyl) amine. The 190mgN ', ", N" N' -tri (4-aminophenyl) amine with 210 mu l4-pyridylaldehyde in according to the into the container, by adding 30 ml anhydrous ethanol as solvent, through nitrogen for a period of time after the air, reaction in 80 C lower, 40r/min reaction under stirring speed of 12 hours, to filter out solid matter, dichloromethane is used for recrystallization, target product shall be red brown crystal, yield 98%.
With sodium methylate; In butan-1-ol; at 120℃; for 3h;
To a solution of <strong>[353-07-1]3-hydrazinylpropanenitrile</strong> (3.1 g, 0.037 mol) in BuOH (20 mL) was added isonicotinaldehyde (4.0 g, 0.037 mol). After stirring overnight, NaOMe (2 g, 0.074 mmol) was added and the mixture was stirred at 120 C for 3 hrs. The mixture was poured into ice water (100 mL) and extracted with EtOAc (100 mL x2). The extracts were washed with 1 N HC1 (100 mL). The aqueous pahse was neutralized with 5 N NaOH (100 mL) and extracted with DCM (100 mL x2). The solution was dried over Na2SO4 and concentrated in vacuum to give 4.5 g of crude 1-(pyridin-4-ylmethyl)-1H-pyrazol-5-amine as brown oil. MS:m/z 175.1 (M+H).
ethyl 2-(dibenzylamino)-3-hydroxy-3-(4-pyridyl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
8.72 g
To a cooled solution of <strong>[77385-90-1]ethyl 2-(dibenzylamino)acetate</strong> (10 g, 35.3 mmol) in dry THF(200 mL) was added dropwise lithium bis(trimethylsilyl)amide (100 mL, 1 M in THF,100 mmol) at -70 C. The solution was stirred for 1 hour. Then4-pyridinecarboxaldehyde (6.6 mL, 1.137 g/mL, 70.6 mmol) was added slowly. After complete addition the reaction mixture was warmed to 0 C over 1 hour. NH4C1- solution (aq., sat., 150 mL) was added and the product was extracted with EtOAc (3200 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified on silica using a DCM to EtOAc gradient yielding ethyl 2-(dibenzylamino)-3-hydroxy-3-(4-pyridyl)propanoate (8.72 g) as a yellow oil.
(5-amino-4-(3-chlorobenzoyl)-3-(pyridin-4-yl)-1H-pyrrol-2-yl)(phenyl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
With potassium carbonate; In ethanol;Reflux;
General procedure: The synthesis of 2-aminopyrrole analogues was based on a multicomponent reaction by refluxing a solution of three reactants including a methylsulfonamidoacetophenone, an aldehydes and acyanoacetic acid with 0.6 equiv of K2CO3 in ethanol. This reaction results in three substituted 2-aminopyrroles [35]. Compounds1-30 in Tables 1 and 2, and Fig. 3 were synthesized as shown in Scheme 1.
2-amino-6-hydroxy-5,8-dioxo-4-(pyridin-4-yl)-7-undecyl-5,8-dihydro-4H-chromene-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With triethylamine; In ethanol;Reflux;
General procedure: To a mixture of 0.1mmol of malononitrile, 0.1mmol of the corresponding aldehyde, and 10mol % of Et3N in 5mL of EtOH were added 30mg of <strong>[550-24-3]embelin</strong> (0.1mmol). The reaction mixture was stirred and refluxed until disappearance of the starting benzoquinone. The solvent was removed under vacuum, and the crude product was purified by preparative-TLC to yield the corresponding dihydropyran derivative.
With toluene-4-sulfonic acid; sodium hydrogensulfite; In N,N-dimethyl-formamide; at 160℃; for 0.2h;Microwave irradiation;
In a 20 mL microwave vial was added <strong>[64188-97-2]3-aminoisonicotinamide</strong> (1a, 2 g, 14.58 mmol), isonicotinaldehyde (1 .521 mL, 16.04 mmol), sodium bisulfite (1 .821 g, 17.50 mmol) and 4-methylbenzenesulfonic acid hydrate (0.277 g, 1.458 mmol) in DMA (Volume: 5 mL) to give an orange suspension. The reaction was well stirred and heated in microwave at 160C for 12 min. The reaction mixture was diluted with water and filtered. The solid was washed with water, MeOH and ether to give 2.03g off white solid as the product 1 b (59%). 1 H NMR (400 MHz, DMSO-d6) delta 9.18 (d, J = 0.9 Hz, 1 H), 8.88 - 8.78 (m, 2H), 8.73 (d, J = 5.2 Hz, 1 H), 8.16 - 8.08 (m, 2H), 8.03 (dd, J = 5.2, 0.9 Hz, 1 H).
N-(2-(cyclohexylamino)-2-oxo-1-(pyridin-4-yl)ethyl)-3,5-dimethyl-N-(p-tolyl)isoxazole-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
General procedure: The aldehyde (0.8 equivalent) and amine (0.7 equivalent) were dissolved in methanol (2.0 mL) and stirred for two to 3 h depending upon the starting material. The acid (100 mg, 1 equivalent) and isocyanide (0.7 equivalent) were added in the reaction mixture and further stirred. The reaction mixture was monitored using TLC analysis.Water (4 mL) was added upon completion of the reaction.The resulted solid was filtered off and dissolved in ethyl acetate(10 mL), washed with water (2 3 mL) and dried over sodium sulphate. The crude product was purified using silica gel column chromatography. The ethyl acetate:hexane (6:4) solvent system was used for the purification of these compounds.
N-(2-(cyclohexylamino)-2-oxo-1-(pyridin-4-yl)ethyl)-N-(2,3-dimethylphenyl)-3,5-dimethylisoxazole-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
General procedure: The aldehyde (0.8 equivalent) and amine (0.7 equivalent) were dissolved in methanol (2.0 mL) and stirred for two to 3 h depending upon the starting material. The acid (100 mg, 1 equivalent) and isocyanide (0.7 equivalent) were added in the reaction mixture and further stirred. The reaction mixture was monitored using TLC analysis.Water (4 mL) was added upon completion of the reaction.The resulted solid was filtered off and dissolved in ethyl acetate(10 mL), washed with water (2 3 mL) and dried over sodium sulphate. The crude product was purified using silica gel column chromatography. The ethyl acetate:hexane (6:4) solvent system was used for the purification of these compounds.
With sodium cyanoborohydride; acetic acid; In methanol; at 20 - 50℃;pH 6-7;
General procedure: To a stirring solution of 8 (0.3 mmol) in MeOH (5 mL) was added the corresponding aldehyde (0.4 mmol) and NaCNBH3 (0.5 mmol)at room temperature. The mixture was adjusted to pH 6-7 by acetic acid, stirred overnight at room temperature, and quenched by 1M NaOH solution (5 mL). The mixture was diluted by H2O (15 mL), and extracted by DCM (10mL x 3). The combined organic layer waswashed by brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified over silica gel column(DCM: MeOH = 20 : 1) to yield oils 9b-s (70-93%).
General procedure: In a dark environment, a mixture of <strong>[711007-44-2]2,3-<strong>[711007-44-2]diaminobenzamide</strong></strong>(1.51 g, 10 mmol), PYTZ (20 mg), and ethanol (200 mL)was taken in an open pear-shaped bottle, stirred magneticallyat room temperature, and then aldehyde (10 mmol) wasadded slowly in 2 min. The bottle was exposed to visiblelight (Xenon, 10 A) under stirring condition. The reactionwas monitored by TLC. After the reaction completed, thereaction mixture was transferred to a three-neck bottle outsideof the photochemical reactor and air was introduced toensure that the intermediate was completely oxidized. Then,the solvent was evaporated in vacuum to 40 mL until thesolid appeared. The mixture was cooled down in an ice bathfor crystallization, filtration. The crude solid was recrystallizedfrom 25 mL ethanol (30 C) to get the target products.
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