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Structure of 539-44-6 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of the American Chemical Society, 1951, vol. 73, p. 2756,2758
[2] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1935, vol. 235, p. 201,213
2
[ 539-44-6 ]
[ 16382-15-3 ]
Reference：
[1] Journal of Biological Chemistry, 1925, vol. 62, p. 507
3
[ 141-97-9 ]
[ 539-44-6 ]
[ 74-88-4 ]
[ 56430-08-1 ]
Reference：
[1] Beilstein Journal of Organic Chemistry, 2013, vol. 9, p. 2033 - 2039
4
[ 539-44-6 ]
[ 56430-08-1 ]
Reference：
[1] Chemische Berichte, 1884, vol. 17, p. 542[2] Justus Liebigs Annalen der Chemie, 1888, vol. 245, p. 368
[3] European Journal of Organic Chemistry, 2013, # 24, p. 5276 - 5281
5
[ 533-60-8 ]
[ 539-44-6 ]
[ 3449-48-7 ]
Reference：
[1] Journal of the Chemical Society, 1950, p. 1328,1330
6
[ 123-06-8 ]
[ 539-44-6 ]
[ 103646-82-8 ]
Yield
Reaction Conditions
Operation in experiment
80%
for 2 h; Reflux
General procedure: A mixture of the appropriate phenylhydrazine (0.001 mol)and 10 mL of ethanol was stirred and allowed to reflux.Then, 2-(ethoxymethylene)malononitrile (0.001 mol) dissolvedin 10 mL of ethanol was slowly added. The reactionmixture was refluxed for 2 h. The reaction mixture waspoured into 50 mL of ice-cold water. The precipitate wascollected by filtration and washed with water to provide10a–c in 61–80percent yield.
Reference：
[1] Medicinal Chemistry Research, 2018, vol. 27, # 8, p. 1876 - 1884
[2] Heterocyclic Communications, 2005, vol. 11, # 5, p. 385 - 388
[3] European Journal of Medicinal Chemistry, 2008, vol. 43, # 4, p. 771 - 780
[4] Journal of Organic Chemistry, 1956, vol. 21, p. 1240,1242
[5] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 9, p. 2121 - 2125
[6] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2009, vol. 64, # 7, p. 840 - 846
[7] Molecules, 2015, vol. 20, # 1, p. 807 - 821
[8] RSC Advances, 2015, vol. 5, # 68, p. 55179 - 55185
[9] RSC Advances, 2016, vol. 6, # 29, p. 24491 - 24500
[10] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 7, p. 1732 - 1737
Reference：
[1] Patent: CN107814748, 2018, A, . Location in patent: Paragraph 0017; 0025; 0026; 0036; 0046
9
[ 59997-51-2 ]
[ 539-44-6 ]
[ 285984-25-0 ]
Yield
Reaction Conditions
Operation in experiment
80.3%
With hydrogenchloride In ethanol for 8 h; Reflux
In a 250 mL pre-flask was added 100 mL of ethanol,(30 mmol) of pivaloylacetonitrile,(33. 63 mmol) of 4-methylphenylhydrazine,3. 6 mL of concentrated hydrochloric acid was added dropwise with stirring, heated under reflux for 8 hours,Cooled, concentrated, the residue adjusted with dilute sodium hydroxide PH10-11,Extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, concentrated,The resulting solid was recrystallized from ethyl acetate / petroleum ether to give white crystals C,Yield 80.3percent. 5-tert-butyl-2-p-methylphenyl-3-aminopyrazole (3. 5 mmolC) was placed in 100 ml three-necked flask and dissolved in 30 ml of tetrahydrofuran. The three-necked flask was allowed to cool to -20 ° C, stirring in batches by adding 2. 9g sodium bicarbonate, 15min, dropwise dropwise chloroformic acid trichloroethyl ester(3. 5 mmol),Control solution temperature does not exceed ° C,After completion of the dropwise addition, the mixture was stirred for 30 min and then heated to 0 ° C for 12 h. After completion of the reaction, the mixture was filtered and the residue was rinsed with ethyl acetate and the filtrate was concentrated to yield 85percent.
80.3%
With hydrogenchloride In ethanol; water for 8 h; Reflux
In a 250 mL round botom flask, 100 mL of ethanol was added, (30 mmol) of pivaloylacetonitrile, (33.63 mmol) of 4-methylphenylhydrazine, A solution of 3.6 mL of concentrated hydrochloric acid was added dropwise with stirring,Heated to reflux for 8 hours, cool down, concentrate, The residue was adjusted to pH 10-11 with dilute sodium hydroxide, Extracted three times with ethyl acetate, Dried over anhydrous sodium sulfate, concentrate, The resulting solid was recrystallized from ethyl acetate / petroleum ether to give white crystals C, Yield 80.3percent. 5-tert-butyl-2-p-methylphenyl-3-aminopyrazole (3.5 mmolC) was placed in a 100 ml three-Dissolved in 30 ml of tetrahydrofuran, Place the three-necked flask in a cryogenic tank to cool to -20 ° C, 2.9 g of sodium bicarbonate was added in portions with stirring, After 15 min, A solution of trichloroethyl chloroformate (3.5 mmol) was added dropwise, Control the solution temperature does not exceed 0 deg C, After dripping, Continue stirring for 30min, And then heated to 0 ° C for 12 h. After completion of the reaction, The mixture is filtered, The residue was washed with ethyl acetate, The filtrate was concentrated, Yield 85percent.
80.3%
for 8 h; Reflux
In 250 ml bottle eggplant adding 100 ml ethanol, (30mmol) special fifth heavenly stem acyl acetonitrile, (33.63mmol) 4 - methyl phenyl hydrazine, stirring next adds by drops 3.6 ml concentrated hydrochloric acid, heating reflux for 8 hours, cooling, concentrated, the residue with dilute sodium hydroxide to adjust the pH 10 - 11, ethyl acetate extraction three times, dried with anhydrous sodium sulfate, concentrated, the obtained solid ethyl acetate/petroleum ether recrystallization to obtain white crystal C, yield 80.3percent. 5 - tert-butyl -2 - methylphenyl -3 - amino pyrazole (3.5mmolC) in 100 ml in three-necked bottle, to 30 ml tetrahydrofuran is dissolved, the low temperature troughthree-necked bottle is lowering the temperature to -20 °C, stirring in batches under the adding 2.9g sodium bicarbonate, 15min after, little by chlorination formic acid trichloroethyl (3.5mmol), control solution at a temperature of not more than 0 °C, after dropping, continuing to stir 30min, then heating up to 0 °C reaction 12h. The completion of the reaction, the mixture filtration, the filter residue washed ethyl acetate, the filtrate is concentrated, yield 85percent.
Reference：
[1] Patent: CN106518767, 2017, A, . Location in patent: Paragraph 0075; 0076; 0115
[2] Patent: CN106518766, 2017, A, . Location in patent: Paragraph 0098
[3] Patent: CN106518858, 2017, A, . Location in patent: Paragraph 0076
[4] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 6, p. 1772 - 1777
[5] Patent: US2009/131437, 2009, A1, . Location in patent: Page/Page column 15
[6] Patent: EP1698335, 2006, A1, . Location in patent: Page/Page column 42
[7] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 19, p. 5401 - 5409
[8] MedChemComm, 2016, vol. 7, # 7, p. 1421 - 1428
General procedure: A mixture of the appropriate phenylhydrazine (0.001 mol)and 10 mL of ethanol was stirred and allowed to reflux.Then, 2-(ethoxymethylene)malononitrile (0.001 mol) dissolvedin 10 mL of ethanol was slowly added. The reactionmixture was refluxed for 2 h. The reaction mixture waspoured into 50 mL of ice-cold water. The precipitate wascollected by filtration and washed with water to provide10a-c in 61-80% yield.
80%
In ethanol; for 2h;Reflux;
General procedure: A mixture of the appropriate phenylhydrazine (0.001 mol) and10 mL of ethanol was stirred and allowed to reflux. Then, 2-(ethoxymethylene)malononitrile (0.001 mol) dissolved in 10 mL of ethanol was slowly added. The reaction mixture was refluxed for 2 h. The reaction mixture was poured into 50 mL of ice-cold water. The precipitate was collected by filtration and washed with water to produce 7-12 in 48-90% yield.
In ethanol; for 3h;Reflux;
General procedure: A stirred mixture of para-substituted phenylhydrazine hydrochloride (0.025 mol) was dissolved inH2O (30 mL), then the pH of the mixture was adjusted to pH 7-8 by the dropwise addition of 10% NaOHsolution to form the free para-substituted phenyl hydrazines, which were then refluxed for 3 h withethoxymethylene malononitrile in an ethanol medium. After completion of the reaction, the reactionmixture was allowed to cool at room temperature, and the solid 2a-2d were filtered under vacuum. Thecrude products obtained were recrystallized from DMF to afford the pure products.
General procedure: To a neat solution containing 1,3-ketoester (2.84 mmol) and hydrazines (2.84mmol) was added glacialacetic acid (0.05 mL). The reaction mixture was stirred at 100 oil-bath for 1h. After the reaction was completed, the solution was cooled down to room temperature and then diluted with Et2O (2 mL)and stirred vigorously for 2h. The resultant solid was filtrated off, washed with Et2O (1 mL), driedunder vacuum at 50 for 6h to give pure pyrazolones 2 as white to light yellow crystal or powder in70-97.7% yield
In ethanol; water; at 60℃;
General procedure: The intermediate 5-chloro-1-aryl-3-methyl-1H-pyrazole-4-carboxylic acids 1a-1d were synthesized as the following: para-substituted phenylhydrazines (0.025 mol) were reacted with ethyl acetoacetate (0.025 mol) in anhydrous ethanol to form a solid, which was then dissolved in a cold mixed solution of DMF (20 mL) and POCl3 (16 mL), and stirred at 50-60 C. The resulting mixture was poured into ice-cold water, a saturated solution of sodium hydroxide was added to neutralize the mixture, and the solid precipitate was filtered, and washed with water. Then above product was oxidized by KMnO4 solution, stirred at 70-80 C. After cooling to room temperature the pH of the reaction mixture wasadjusted to pH 7-8 by the dropwise addition of KOH solution, and the solution was filtered, HCl solution was added to the solution and solid 1a-1d eventually separated out. The crude product obtained was recrystallized from DMF to afford the pure product. All the reactions were monitored by TLC.
61 mg
With acetic acid; at 120℃; for 0.75h;Inert atmosphere; Glovebox;
General procedure: In an inert atmosphere glovebox, [Pd(cinnamyl)Cl]2 (typically 2.5 mol%) and Mor-DalPhos(typically 7.5 mol%) were added to a vial sealed with a cap containing a PTFE septum and stirred in toluene for 5 min, then NaOtBu (2.1 equiv.) was added along with the aryl chloride substrate (1 equiv., [ArCl] = 0.1 M) if it was a solid. After removing the vial from the glovebox the aryl chloride was added via a syringe if it was a liquid, along with hydrazine hydrate (2.0 equiv.). The reaction was stirred at the desired temperature for 0.5-2 h. Generally, after a short period of time, reactions were observed to darken and considerable black precipitate was formed.After completion of the reaction was observed by thin layer chromatography (TLC) or GC methods, the solution was allowed to cool and filtered through a short plug of neutral alumina, which was washed with CH2Cl2/MeOH (25:1). The resulting eluent solution was concentrated and charged with ethyl acetoacetate (1 equiv., [ethyl acetoacetate] = 0.125 M) and glacial acetic acid. The solution was heated at reflux for 0.5-3 h, and the reaction progress was monitored by use of TLC or GC methods. After complete consumption of the aryl hydrazine, the reaction was cooled, diluted with EtOAc (40 mL) and washed with H2O (60 mL) followed by 1:1 water/brine (60 mL). The organic fractions were dried over Na2SO4, filtered and concentrated to afford crude product which was purified by column chromatography. Typical reaction scales were 0.4 -1.0 mmol. Aryl hydrazines were stored at -4 C for no longer than 12 hours before reacting with ethyl acetate.
In ethanol; at 70 - 80℃; for 5h;
General procedure: Para-substituted phenyl hydrazine (0.025 mol)was dissolved in anhydrous ethanol, ethyl acetoacetate(0.025 mol) was slowly added and stirred at 70-80 8C for 5 h,then the anhydrous ethanol was removed under reduced pressureto form a solid, which was dissolved in DMF (20 mL) andphosphorus oxychloride (16 mL) of cold mixed solution andstirred at 80-85 8C for 5 h. The resulting mixture was poured intoice-cold water, the resulting solid was separated by filtration togive the light yellow solid.
In ethanol; water; for 5h;Heating;
General procedure: para-Substituted phenyl hydrazine (25 mmol) was dissolved inanhydrous ethanol, ethyl acetoacetate (25 mmol) was slowlyadded and stirred at 70-80C for 5 h, then the anhydrousethanol was removed under reduced pressure to form a solid,which was dissolved in DMF (20 mL) and phosphorus oxychloride(16 mL) of cold mixed solution and stirred at 90Cfor 1h. The resulting mixture was poured into ice-cold water,the resulting solid was separated by filtration to give the lightyellow solid. Then above product was oxidized by 5.0 mol/LKMnO4 solution, stirred at 70-80C. After cooling to roomtemperature the pH of the reaction mixture was adjusted topH 7-8 by the dropwise addition of 3.0 mol/L KOH solution,and the solution was filtered, 6.0 mol/L HCl solution wasadded to the solution and solid 2a-2d eventually separatedout. The crude product obtained was recrystallized from anhydrousethanol to afford the pure product.
The hydrazine is then condensed with a beta-keto ester such as ethyl acetoacetate, compound (h), in an appropriate solvent such as acetic acid or ethanol at an appropriate temperature typically 0-100 to give the corresponding pyrazole, compound (I) as described herein.
In ethanol; water; at 60℃; for 5h;
General procedure: Intermediates 2a-d were obtained from Reference [30]. Dissolve para-substituted phenylhydrazine (0.025 mol) with anhydrous ethanol ethyl acetoacetate (0.025 mol) was added portionwise, stirred, and refluxed for 5 h, then the solution was rotary evaporated to form a solid, whichwas dissolved in DMF (25 mL) and phosphorus oxychloride (20 mL) of cold mixed solution andstirred at 85 C for 2 h. The resulting product was poured into ice-cold water and the solid wasisolated by filtration to give a yellow solid, which was oxidized by KMnO4 solution and stirred at70-80 C. After cooling to room temperature, the pH was adjusted to alkaline by the addition of 10%NaOH solution, and the solution was filtered, HCl solution was added to the solution and solid 2a-deventually separated out. The resulting crude product was recrystallized from anhydrous ethanol togive the pure product.
1.a Example 1; [3-[(4-CHLOROPHENVL) SULFONYLL-2N5-DIMEMVL-1H-INDOL-1-ACETIC ACID]; (a) [3- ( (4-CHLOROPHENYL, THIOL-2, 5-DIMETHYL-LH-INDOLE]
To a solution of methylphenylhydrazine (7 g) in acetonitrile (100 ml) was added [1- [ (4-] chlorophenyl) thio] acetone (8.84 g) and water (10 ml). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue dissolved in dichloromethane. The solution was washed with sodium hydrogen carbonate, brine, dried [(MGSO¢)] and concentrated in vacuo. The residue was recrystallised (methanol) to give the sub-title compound (6 g). MS: APCI+ [M+H] [288]
4 Preparation of 3,5-Dimethyl-1-p-tolyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester
EXAMPLE 4 Preparation of 3,5-Dimethyl-1-p-tolyl-1H-pyrazole-4-carboxylic Acid Ethyl Ester Similar to Example 1, p-tolylhydrazine (10 mmol, 1.8 g) and 2-acetyl-3-oxo-butyric acid ethyl ester (10 mmol, 1.7 g) were mixed in a solution of 50% pyridine in ethanol. The solvents were removed under vacuum. The named product was purified over silica gel (m.p. 47° C.-49° C.).
With pyridine; hydrogenchloride; sulfuric acid; sodium methylate; zinc; In ethanol; 2-methoxy-ethanol; water; acetic acid; N,N-dimethyl-formamide;
EXAMPLE 2 The procedure of Example 1 is repeated using 25.6 g of the phosphonate of the formula (101), 23.7 g of sodium benzaldehyde-2-sulphonate (content: 96.7%) and 7.6 g of sodium methylate (content: 92.7%) in 100 ml of anhydrous dimethyl formamide. When the reaction is complete, 200 ml of water are slowly added dropwise to the resultant red liquid, which is then neutralised with a small amount of formic acid and cooled. The crystallized product is collected with suction, washed with 500 ml of cold water and dried in vacuo at 100 to 110 C., affording 23.4 g of the compound of the formula STR24 which, after two recrystallisations from a mixture of 7 parts by volume of alcohol and 3 parts by volume of water, is obtained as a pale yellow powder with blue fluorescence. Melting point:>320 C. The following compounds can be obtained in a manner similar to that described above from the diphosphonate of the formula (101) using the corresponding aldehydes: STR25 The diphosphonate of the formula (101) can be obtained as follows: 73.5 g of 4-methyl-isonitrosoacetophenone and 65.5 g of p-tolylhydrazine are dissolved in 190 ml of methyl cellosolve with the addition of 3.5 ml of glacial acetic acid and the solution is heated, with stirring, to 80 C. and kept at 80 to 85 C. for 15 minutes. The reaction mixture is then allowed to cool to room temperature with stirring and then further stirred for 15 hours at room temperature. The dark, clear solution is added to a warm mixture of 38 C. of 215 g of crystalline copper sulphate, 270 ml of water and 1000 ml of pyridine. The batch is then heated to 50 C. and kept for 24 hours at 50 to 55 C. After cooling to room temperature, the solution is poured onto a mixture of 2400 ml of conc. hydrochloric acid and 2400 g of ice. The precipitated product is collected with suction, homogenised with 500 ml of filtrate, filtered off by suction once more, washed neutral with water and dried in vacuo at 50 to 60 C., giving 101.8 g of the compound of the formula STR32 Melting point: 111-113 C. To a warm solution (70 C.) of 101.5 g of the compound of the formula (210) in 500 ml of ethanol are added 50.1 g of zinc dust. Then a mixture of 208 ml of water, 191.2 g of 98% sulphuric acid and 600 ml of ethanol is added dropwise and the batch is stirred for 2 hours at 70 to 77 C. The reaction product is then filtered off hot by suction through a vacuum filter and the residue is washed with 200 ml of boiling ethanol. After cooling, the crystallized product is collected with suction, washed neutral firstly with 200 ml of cold ethanol and then with water and dried in vacuo at 50 to 60 C., giving 69.6 g of 2,4-bis-(p-tolyl)-2H-1,2,3-triazole with a melting point of 98-99 C.
In a 250 mL pre-flask was added 100 mL of ethanol,(30 mmol) of pivaloylacetonitrile,(33. 63 mmol) of 4-methylphenylhydrazine,3. 6 mL of concentrated hydrochloric acid was added dropwise with stirring, heated under reflux for 8 hours,Cooled, concentrated, the residue adjusted with dilute sodium hydroxide PH10-11,Extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, concentrated,The resulting solid was recrystallized from ethyl acetate / petroleum ether to give white crystals C,Yield 80.3%. 5-tert-butyl-2-p-methylphenyl-3-aminopyrazole (3. 5 mmolC) was placed in 100 ml three-necked flask and dissolved in 30 ml of tetrahydrofuran. The three-necked flask was allowed to cool to -20 C, stirring in batches by adding 2. 9g sodium bicarbonate, 15min, dropwise dropwise chloroformic acid trichloroethyl ester(3. 5 mmol),Control solution temperature does not exceed C,After completion of the dropwise addition, the mixture was stirred for 30 min and then heated to 0 C for 12 h. After completion of the reaction, the mixture was filtered and the residue was rinsed with ethyl acetate and the filtrate was concentrated to yield 85%.
80.3%
With hydrogenchloride; In ethanol; water; for 8h;Reflux;
In a 250 mL round botom flask, 100 mL of ethanol was added, (30 mmol) of pivaloylacetonitrile, (33.63 mmol) of 4-methylphenylhydrazine, A solution of 3.6 mL of concentrated hydrochloric acid was added dropwise with stirring,Heated to reflux for 8 hours, cool down, concentrate, The residue was adjusted to pH 10-11 with dilute sodium hydroxide, Extracted three times with ethyl acetate, Dried over anhydrous sodium sulfate, concentrate, The resulting solid was recrystallized from ethyl acetate / petroleum ether to give white crystals C, Yield 80.3%. 5-tert-butyl-2-p-methylphenyl-3-aminopyrazole (3.5 mmolC) was placed in a 100 ml three-Dissolved in 30 ml of tetrahydrofuran, Place the three-necked flask in a cryogenic tank to cool to -20 C, 2.9 g of sodium bicarbonate was added in portions with stirring, After 15 min, A solution of trichloroethyl chloroformate (3.5 mmol) was added dropwise, Control the solution temperature does not exceed 0 deg C, After dripping, Continue stirring for 30min, And then heated to 0 C for 12 h. After completion of the reaction, The mixture is filtered, The residue was washed with ethyl acetate, The filtrate was concentrated, Yield 85%.
80.3%
With hydrogenchloride; for 8h;Reflux;
In 250 ml bottle eggplant adding 100 ml ethanol, (30mmol) special fifth heavenly stem acyl acetonitrile, (33.63mmol) 4 - methyl phenyl hydrazine, stirring next adds by drops 3.6 ml concentrated hydrochloric acid, heating reflux for 8 hours, cooling, concentrated, the residue with dilute sodium hydroxide to adjust the pH 10 - 11, ethyl acetate extraction three times, dried with anhydrous sodium sulfate, concentrated, the obtained solid ethyl acetate/petroleum ether recrystallization to obtain white crystal C, yield 80.3%. 5 - tert-butyl -2 - methylphenyl -3 - amino pyrazole (3.5mmolC) in 100 ml in three-necked bottle, to 30 ml tetrahydrofuran is dissolved, the low temperature troughthree-necked bottle is lowering the temperature to -20 C, stirring in batches under the adding 2.9g sodium bicarbonate, 15min after, little by chlorination formic acid trichloroethyl (3.5mmol), control solution at a temperature of not more than 0 C, after dropping, continuing to stir 30min, then heating up to 0 C reaction 12h. The completion of the reaction, the mixture filtration, the filter residue washed ethyl acetate, the filtrate is concentrated, yield 85%.
In toluene; at 20℃; for 12h;Heating / reflux;
The title compound is prepared according to a published literature procedure (see J. Med. Chem. 2002, 45, 2994-3008.) 3.5 g (27.8 mMol) of pivaloylacetonitrile are added to a solution of 3.4 g (27.8 mMol) p-tolylhydrazine in 50 mL of toluene at rt, and the resulting yellow solution is heated to and kept under reflux for 12 h. After completion, the reaction mixture is concentrated, and the resulting crude product is purified by flash chromatography (SiO2, 100% CH2Cl2) to give the title compound as a yellow solid.
In toluene;Heating / reflux;
A solution of 4-methylphenylhydrazine (0.90mL) and 4,4-dimethyl-3-oxopentanenitrile (1.0g) in toluene (3mL) was refluxed overnight. The reaction mixture was concentrated and the residue was purified by column to give the title compound (1.53g).
With silica-gel-supported sulfuric acid at 20℃; for 0.0833333h; Neat (no solvent); chemoselective reaction;
89%
With phosphotungstic acid In water at 20℃; for 0.1h; regioselective reaction;
83%
With 1-butyl-3-methylimidazolium tetrachloridoferrate(III) at 20℃; for 4h;
2.4 General reaction procedure for pyrazolesynthesis
General procedure: In a round bottom flask, a mixture of hydrazine derivative(1 mmol) and 1,3-diketone (1.2 mmol) and [C4mim][FeCl4](1.5 mL) was added and then allowed to stir at room temperaturefor the given time period as mentioned in Table 2.The progress of the reaction was monitored by TLC. Aftercompletion of the reaction, it was extracted with ethyl acetate (3 x 20 mL), washed with distilled water and brinesolution, dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The resulting residue waspurified through silica gel column chromatography(15-20% EtOAc/hexane) to get the desired product.
80%
With tetrafluoroboric acid; water In acetonitrile at 20℃; for 3h;
General experimental procedure for synthesis of pyrazoles using HBF4 as catalyst room temperature
General procedure: In a round bottom flask a mixture of hydrazine derivative (1 mmol) and 1,3-diketone (1.2 mmol) was taken and Fluoroboric acid (20 mol%) was added to it and then allowed to stir at room temperature for the given time period as mentioned in Table 3. The progress of the reaction was monitored by TLC. After completion of the reaction it was extracted with ethyl acetate (3×10 mL), washed with distilled water and brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified through silica gel column chromatography to get the desired product.
With potassium phosphate In ISOPROPYLAMIDE at 100℃; for 22h;
9
Example 9. Alternate synthetic route proceeding via tolylhydrazine [00111] p-Tolylhydrazine free-base (3.5 g) was stirred in DMAC (9.7 vol) with MVP(2 equiv) and K3PO4 (5.7 equiv) at 100 0C. The reaction was followed by HPLC and clean conversion was observed to one product. After 22 hrs, the reaction was diluted with water to dissolve the phosphate and separated. The bi-phasic toluene/DMAC layers were then separated and the DMAC was back-extracted with toluene. The combined organics were washed with water to remove residual DMAC and concentrated to an oil. Upon addition of heptane, solids crystallized and were isolated by filtration to afford 3.16 g of the hydrazine analog Int-1.
General procedure: A reaction mixture containing aryl hydrazine (2 mmol), ethyl acetoacetate (2 mmol), molecular sieves (4 A) and toluene (4 mL) was stirred in the dark in a sealed tube maintained at 120 C in an oil bath. After 17 h, the reaction mixture was cooled to room temperature. To this mixture, acetonitrile (2 mL) and iodomethane (6 mmol) were added successively and stirred in the dark in the sealed tube maintained at 120 C for additional 17 h, After the reaction was completed, the mixture was cooled to room temperature. The solvent was then evaporated in vacuo. The resulting residue was purified by flash column chromatography (ethyl acetate) to yield 1b-l.
With palladium diacetate; triphenylphosphine; Trimethylacetic acid In 1-methyl-pyrrolidin-2-one at 90℃; for 4h;
61%
With [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride; potassium carbonate In methanol at 50℃; for 3h;
General procedure for Suzuki-Miyaura reaction
General procedure: To a round bottle with a magnetic stir bar, catalyst, arylhydrazine (0.5 mmol), (hetero)arylboronic acid (0.75 mmol), Base (1.0 mmol) and 3 ml of solvent were added. The reaction mixture was conducted at 50 °C for the required time, and then the solvent was removed under reduced pressure. The residual was diluted with Et2O (5 mL), followed by extraction twice (2×5 mL) with Et2O. The organic layer was dried with anhydrous MgSO4, filtered and evaporated under vacuum. The conversions rates were analyzed by gas chromatography, based on the peak area normalization method. The corrected factor was determined by samples against a standard of n-heptane. The crude products were purified by silica-gel column chromatography using petroleum ether as an eluent, and the isolated yield was then calculated based on the feeding of the aryl halide. The isolated corresponding products were characterized by 1H NMR and 13C NMR.
With acetic acid; for 2h;Reflux; Inert atmosphere;
General procedure: A mixture of 3-keto lupeol (2, 0.19 mmol), phenylhydrazine hydrochloride (1.05 eq.) in acetic acid (10 mL) was refluxed for 2 h under nitrogen atmosphere. The reaction mixture was pipetted into distilled water (50 mL) and then extracted with Et2O (4×25 mL). After removing Et2O, the residue was purified by column chromatography (silica gel; EtOAc/petroleum ether) to provide indole derivative 9. Compounds 10-16 were prepared following the same protocol.
With bis(benzonitrile)palladium(II) dichloride; camphor-10-sulfonic acid; tetrabutyl ammonium fluoride In tetrahydrofuran at 50℃; for 3h;
Typical procedure forthe product
General procedure: A mixture of arylhydrazine (1 mmol), triethoxy(phenyl)silane (1.2 mmol), Pd(PhCN)2Cl2 (5 mol%) and CSA (camphorsulfonic acid, 1 mmol) was stirred in thesolvent of TBAF (1 M in THF, 1.0 ml) at 50oC for 3 hours under air. After cooling down to room temperature, the insoluble was firstremoved by filtration and then the solvent was removed undera reduced pressure. The cross-coupling products were purified by silica gelchromatography with a mixture of petroleum ether and ethyl acetate. Thecross-coupling products were confirmed by melting point and spectroscopic (1HNMR, 13C NMR and HRMS-EI) analysis, which wereall consistent with the literature results.
91%
With bis(benzonitrile)palladium(II) dichloride; camphor-10-sulfonic acid; tetrabutyl ammonium fluoride In tetrahydrofuran at 50℃; for 3h;
1-6 Examples 1 to 12
General procedure: 1 mmol of aromatic hydrazine, 1.2 mmol of aryl silicone ether,0.05 mmol of divalent palladium catalyst and 1 mmol of camphorsulfonic acid (CSA)A round bottom flask containing 1 ml of TBAF (1 M) in tetrahydrofuran was added and stirred at 50 ° C for 3 hours.After the reaction is completed, the temperature is lowered to room temperature, and the solid is filtered off. After the solvent is dried, the column is separated to obtain a product.The raw materials, catalysts and reaction results used are shown in Table 1.
(E)-1-(p-tolyl)-2-(4-(2,6,6-trimethylcyclohex-1-en-1-yl)butan-2-ylidene)hydrazine[ No CAS ]
(Z)-1-(p-tolyl)-2-(4-(2,6,6-trimethylcyclohex-1-en-1-yl)butan-2-ylidene)hydrazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61.29 % de
In dichloromethane at 20℃; for 3h; Molecular sieve; Inert atmosphere; Overall yield = 76 %; Overall yield = 227 mg;
4.2 General experimental procedure 1: preparation of aryl hydrazones
General procedure: A ketone (1.0equiv, 1.0 mmol) was added to a room temperature solution of aryl hydrazine (1.2equiv, 1.2mmol) in CH2Cl2 (8mL) containing 4 molecular sieves under a nitrogen atmosphere. After stirring at room temperature for three hours, the solution was filtered and the filtrate was concentrated. The residue was dissolved in hexane (12mL), was passed through a plug of basic alumina and was concentrated in vacuo to provide a diastereomeric mixture of the hydrazone as a yellow oil.
With copper phthalocyanine; copper diacetate In methanol at 30℃;
19 Synthesis of 4-methyldiphenylamine
Aniline reaction flask was added 0.093 g (1 mmol), 4- methyl-phenylhydrazine 0.159g (1.3 mmol), CuPc 0.058 Ke (0.1 mmol), Cu (OAc) 2 0.02 g (0.1 mmol) and 10 ml ofmethanol, 30 °C reaction; TLC until complete reaction was followed over; After thereaction, the crude product obtained was purified by column chromatography (petroleum ether: ethyl acetate = 100: 1) to give the desired product (90% yield).
83%
With tetrabenzoporphyrinatocobalt(II); copper diacetate In acetonitrile at 0℃; for 13h; chemoselective reaction;
3.23 4.2.1. General procedure for N-arylation of amines (2) with arylhydrazines (1).
General procedure: Into a 25 mL round-bottom flask, amine (2) (1 mmol), Cu(OAc)2 (0.02 g, 0.1 mmol) and acetonitrile (4 mL) were added, the mixture was stirred and cooled to 0 °C. Then, CoPc (0.057 g, 0.1 mmol) was added, the solution of arylhydrazine (1) (2 mmol) in acetonitrile (2 mL) was added successively at a rate of 0.2 mmol per hour while stirring for 13 h in air. After completion of the reaction monitored by TLC analysis (developing solvent: ethyl acetate/petroleum ether (1:8)), the mixture was filtered, concentrated, and the residue was further purified by column chromatography using ethyl acetate/petroleum ether (1:100) as eluent to afford N-aryl amine 3.
With potassium permanganate In acetonitrile at 80℃; for 3h; Schlenk technique; regioselective reaction;
4.2 General experimental procedure for thesynthesis of 3-arylcoumarins (3) and3-arylquinolinone derivatives (5)
General procedure: In a 50 mL Schlenk tube, a solution of coumarins 1 (orquinolinone derivatives 4) (0.5 mmol), arylhydrazines 2(1.0 mmol), and KMnO4 (1.5 mmol, 237 mg) in CH3CN (10mL) was stirred at 80°C for 3.0 h. After the reaction wasfinished, the mixture was diluted with saturated NaClsolution (50 mL). Then the aqueous layer was extractedwith EtOAc (3 × 15 mL). The organic phase was dried overanhydrous Na2SO4 and concentrated under vacuum. Thecrude product was purified by silica gel column chromatographyusing ethyl acetate/petroleum ether (1:5 to 2:1) aseluant to obtain the desired product 3 (or 5).
With 5,10,15,20-tetraphenyl-21H,23H-porphine; copper chromite; trifluorormethanesulfonic acid; nitratobis(triphenyl phosphine)copper(I); silver(I) triflimide; In 1,4-dioxane; dimethyl sulfoxide; at 70℃; for 12h;
To a suitable amount of an organic solvent (a mixture of 1,4-dioxane and dimethylsulfoxide (DMSO) in a volume ratio of 1: 3) at room temperature,100 mmol of the compound of the above formula (I)150 mmol of the compound of the above formula (II)10 mmol of catalyst (a mixture of 3.3 mmol of bis (triphenylphosphine) cuprous nitrate (Cu (PPh3) 2NO3) and 6.7 mmol of tetraphenylporphyrin)180 mmol of oxidizer copper chromite,5 mmol of accelerator AgNTf2 and 40 mmol of trifluoromethanesulfonic acid as an acid promoter were added and the temperature was raised to 70C and the reaction was stirred at that temperature for 12 hours.After completion of the reaction, the pH of the filtrate was adjusted to neutral by filtration while hot, and saturatedSodium carbonate aqueous solution to wash the full 2-3 times, then add acetone extraction 2-3 times, combine the organic phase,Dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography through 300-400 mesh,Was washed with an equal volume ratio of chloroform-ethyl acetate mixture to give the compound of formula (III) aboveThe yield was 97.2%.
With potassium permanganate In acetonitrile at 90℃; for 1h; Schlenk technique; regioselective reaction;
4.2. General experimental procedure for the synthesis of 2-arylquinoline N-oxides (3)
General procedure: Quinoline N-oxides 1 (0.3 mmol), arylhydrazines 2 (0.45 mmol), and KMnO4 (0.6 mmol, 94.8 mg) in acetonitrile (3.0 mL) were added to a 25 mL Schlenk tube. The mixture was heated at 90 °C for 60 min (monitored by TLC). After completion of the reaction, the solvent was distilled under vacuum. 10 mL ethylacetate was added to the residuum, and 30 mL saturated sodium chloride solution washed three times. The organic phase was dried over anhydrous NaSO4 and concentrated under vacuum. The crude product was purified by silica gel column chromatography to give the desired products 3 using ethyl acetate/petroleum ether (1:10 to 1:3) as eluant.
General procedure: A mixture of hydrazide (1 mmol) and aldehyde (1 mmol) was refluxed in PrOH (5 mL) for 1 h, cooled using rubbing with a rod and kept on ice. The precipitate that formed was filtered off, washed with cold PrOH and petroleum ether and dried. Yellowish crystals of compound 1 were obtained.
2-(2,6-dichloroquinolin-3-yl)-3-(p-tolylamino)-2,3-dihydroquinazolin-4(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
In propan-1-ol; for 1h;Reflux;
General procedure: A mixture of hydrazide (1 mmol) and aldehyde (1 mmol) was refluxed in PrOH (5 mL) for 1 h, cooled using rubbing with a rod and kept on ice. The precipitate that formed was filtered off, washed with cold PrOH and petroleum ether and dried. Yellowish crystals of compound 1 were obtained.
4-(3-(4-hydroxyphenyl)-1-(p-tolyl)-4,5-dihydropyrazol-5-yl)-5-methoxy-2-(2-methylbut-3-en-2-yl)phenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51.61%
With triethylamine; In ethanol; at 75.0℃; for 10.0h;
200 mg (1 mmol) of licorice Chalcone A and 93.87 mg (1.3 mmol) of p-methylphenylhydrazine were added to the reactor, and 50 ml of absolute ethanol was added as a reaction solvent. 0.5 mL of triethylamine was added as a catalyst and placed in a magnetic stirrer Stirred, heated to 75 C with a heat jacket, and refluxed for 10 hours. The solid solution was mixed with the above reaction system after the reaction was completed The residue was purified by column chromatography and dried to obtain brown crystalline powder (135 mg) in a total yield of 51.61%.
In a 100 mL four-port bottle, 4.2 g of diketene was added, and 10.08 g of 28% ammonia water was added dropwise under stirring.And keep the temperature at 0 C, keep the reaction for 2h; when the reaction is complete, heat up to 15 C,6.25g of 98% p-methylphenylhydrazine was added and the reaction was for 2.5h; after the reaction was complete, concentrated hydrochloric acid was added dropwise, the pH was adjusted to 1, stirred for 0.5h, and the reaction was detected by TLC (V. Petroleum ether: V. ethyl acetate = 3:1). end,Cool down to 25 C filter,Ethyl acetate washing gave dried 1-(4,-methylphenyl)-3-methyl-5-pyrazolone crystalline powder in 96.5% yield and 97.6% purity.
With palladium diacetate; potassium carbonate In 1-methyl-pyrrolidin-2-one at 60℃; for 3h;
86%
With sodium carbonate In ethanol; water at 70℃; for 4h; Green chemistry;
General procedure fordenitrogenative cross-coupling reaction
General procedure: Arylhydrazine (1.0mmol), aryl halide (1.1mmol) and Na 2 CO 3 (2.2 mmol) were added into the glass vial equipped with a cap and magnetic stir bar containing 10mL aqueous-ethanol (1:1) solvent in which dip catalyst (0.4mol.% Pd) was placed and stirred with a magnetic stir bar at 70°C for the required time of reaction, and the reac-tion progress was monitored by TLC. Once the reaction was completed, the dip catalyst was removed by tweezers, washed with water (2 × 10mL) and ethanol (2 × 10mL), dried and kept for further recycle studies. The crude prod-ucts were isolated by extracting with dichloromethane (2 × 10mL) followed by distilled water wash (2 × 10mL), and then dried over anhydrous Na 2 SO 4 to remove moisture and concentrated by rotary evaporator. All cross-coupled products were purified by column chromatography using hexane and ethyl acetate as eluent to get corresponding pure products and are confirmed by comparing the 1 H NMR spec-troscopic data with authentic samples. Also, some of the cross-coupled products were known molecules and were confirmed by comparing with our previous standards [28].
With sodium carbonate In ethanol; water at 70℃; for 3h; Green chemistry;
General procedure fordenitrogenative cross-coupling reaction
General procedure: Arylhydrazine (1.0mmol), aryl halide (1.1mmol) and Na 2 CO 3 (2.2 mmol) were added into the glass vial equipped with a cap and magnetic stir bar containing 10mL aqueous-ethanol (1:1) solvent in which dip catalyst (0.4mol.% Pd) was placed and stirred with a magnetic stir bar at 70°C for the required time of reaction, and the reac-tion progress was monitored by TLC. Once the reaction was completed, the dip catalyst was removed by tweezers, washed with water (2 × 10mL) and ethanol (2 × 10mL), dried and kept for further recycle studies. The crude prod-ucts were isolated by extracting with dichloromethane (2 × 10mL) followed by distilled water wash (2 × 10mL), and then dried over anhydrous Na 2 SO 4 to remove moisture and concentrated by rotary evaporator. All cross-coupled products were purified by column chromatography using hexane and ethyl acetate as eluent to get corresponding pure products and are confirmed by comparing the 1 H NMR spec-troscopic data with authentic samples. Also, some of the cross-coupled products were known molecules and were confirmed by comparing with our previous standards [28].
90%
With potassium carbonate; tris-(o-tolyl)phosphine; palladium dichloride In 1-methyl-pyrrolidin-2-one at 40℃; for 3h;
12 Example 12
3.17 g (20 mmol) of p-methylphenylhydrazine,3.23 g (21.5 mmol) of o-carboxybenzaldehyde was added to a 10 mL single-neck round bottom flask.Heat to 80 ° C,The reaction was kept under stirring for 240 minutes.TLC or gas phase monitoring reaction,After the reaction was completed, 3 mL of methanol and 1 mL of ethanol were added to the reaction system.After stirring for 0.5 hours, it was allowed to stand and filtered to give 5.45 g of an orange solid.Namely, the target compound 12 was obtained in a yield of 88.32%.
84%
With NiCl2·6H2O In lithium hydroxide monohydrate at 20℃; for 2h; Green chemistry;
General procedure for the synthesis of Phthalazin-1(2H)-ones:
General procedure: In a round bottom flask a mixture of 2-carboxybenzaldehyde (1 mmol), hydrazine derivative (1.2 mmol), NiCl2.6H2O (10 mol%) and 4 ml water was added and then allowed to stir at room temperature for the given time period as mentioned in Table 4. The progress of the reaction was monitored by TLC. After completion of the reaction, it was extracted with ethyl acetate (3x20 mL), washed with deionized water and brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified through silica gel column chromatography (20-25% EtOAc/hexane) to get the desired product.
General procedure: A mixture of a substituted phenylhydrazine i (3.0 mmol), 1,2-cyclohexanedione ii (6.0 mmol), and water (50 mL) was stirred at room temperature (23 C) in a 250 mL round bottom flask. After 16 h,10 mL of aqueous 1 M HCl was added and the reaction was heated to reflux. After 12 h, the reaction was refrigerated to induce crystallization. The resulting solid was filtered and air dried to provide the crude product. The desired product was purified by flash column chromatography (SiO2) using 20-30% ethyl acetate in hexanes as the eluent. NMR of products were compared to literature values to confirm structure.
10-methyl-12-phenylindolo[2,1-a]phthalazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
Stage #1: o-(phenylethynyl)benzaldehyde; N-4-methylphenylhydrazine In N,N-dimethyl acetamide for 0.5h;
Stage #2: With 1,4-diaza-bicyclo[2.2.2]octane In N,N-dimethyl acetamide at 100℃; for 15h;
11 Preparation of 10-methyl-12-phenylindolo[2,1-a]pyridazine
0.2 mmol of 2-(phenylethynyl)benzaldehyde and 0.4 mmol of 4-methylphenylhydrazine in a room temperature air atmosphere, and added to a reaction tube containing 1 mL of N,N-dimethylacetamide for 0.5 h. Then, 0.1 mmol of DABCO (triethylenediamine) and 1 mL of N,N-dimethylacetamide were added, and the mixture was placed in an oil bath at 100 ° C for 15 hours. The reaction was removed from the heat source and cooled to room temperature.The reaction mixture was extracted with water / ethyl acetate (50 mL / 50 mL)Purification by column chromatography gave 40.7 mg of the desired product.The yield was 66%.
Multi-step reaction with 2 steps
1: N,N-dimethyl acetamide / 0.5 h / 20 °C / Schlenk technique
2: 1,4-diaza-bicyclo[2.2.2]octane / N,N-dimethyl acetamide / 15 h / 100 °C / Schlenk technique
2-benzyl-4,4,8-trimethyl-3,5-dihydro-1H-pyrido[4,3-b]indole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
16%
With hydrogenchloride; In ethanol; water; at 80℃; for 16h;
General procedure: To a solution of [Int-1.1] (1 g, (0213) 1 eq., 4.21 mmol) and tert-butyl 4-oxopiperidine-l- carboxylate (0.8 g, 1 eq., 4.21 mmol) in EtOH (15 mL) , HC1 36% (4 mL)was added. The reaction mixture was heated at 80 C and stirred for 16 h. The suspension was filtered and washed with Et20 to furnish the title compound as brown solid (0.6 g, 50%) :
4.1.2 General procedure for the synthesis of 1-phenyl-1H-pyrazol-5-amine derivatives
General procedure: A round bottom flask were charged with P-substituted phenyl-hydrazine (1mmol) and 2-(ethoxymethyl) malononitrile/2-cyano-3-ethoxypropanoic acid (1.2mmol) in the ethanol and the mixture was heated to 80°C and refluxed for 4h. After the reaction was completed, the mixture was vacuum filtered and concentrated to obtain intermediate 7.
With [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride; potassium carbonate In methanol at 50℃; for 3h;
General procedure for Suzuki-Miyaura reaction
General procedure: To a round bottle with a magnetic stir bar, catalyst, arylhydrazine (0.5 mmol), (hetero)arylboronic acid (0.75 mmol), Base (1.0 mmol) and 3 ml of solvent were added. The reaction mixture was conducted at 50 °C for the required time, and then the solvent was removed under reduced pressure. The residual was diluted with Et2O (5 mL), followed by extraction twice (2×5 mL) with Et2O. The organic layer was dried with anhydrous MgSO4, filtered and evaporated under vacuum. The conversions rates were analyzed by gas chromatography, based on the peak area normalization method. The corrected factor was determined by samples against a standard of n-heptane. The crude products were purified by silica-gel column chromatography using petroleum ether as an eluent, and the isolated yield was then calculated based on the feeding of the aryl halide. The isolated corresponding products were characterized by 1H NMR and 13C NMR.
(E)-9-isopropyl-6-(p-tolyldiazenyl)-9H-purine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 6-chloro-9-(1-methylethyl)-9H-purine; N-4-methylphenylhydrazine With N-ethyl-N,N-diisopropylamine In butan-1-ol at 150℃; Microwave irradiation;
Stage #2: With oxygen In butan-1-ol
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