There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.
Type
HazMat fee for 500 gram (Estimated)
Excepted Quantity
USD 0.00
Limited Quantity
USD 15-60
Inaccessible (Haz class 6.1), Domestic
USD 80+
Inaccessible (Haz class 6.1), International
USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic
USD 100+
Accessible (Haz class 3, 4, 5 or 8), International
USD 200+
Structure of 371-14-2 * 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] European Journal of Medicinal Chemistry, 2013, vol. 69, p. 125 - 138
[2] Tetrahedron, 2014, vol. 70, # 3, p. 702 - 707
[3] Australian Journal of Chemistry, 2015, vol. 68, # 10, p. 1603 - 1613
[4] Medicinal Chemistry Research, 2016, vol. 25, # 1, p. 135 - 148
5
[ 371-14-2 ]
[ 123-06-8 ]
[ 51516-70-2 ]
Yield
Reaction Conditions
Operation in experiment
61%
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.5-amino-1-(4-fluorophenyl)-1H-pyrazole-4-carbonitrile (10a)Yield: 61percent. MP: 173–174 °C. IR (cm−1): 3297–3183; 2225;1662; 1568; 1222. 1H NMR (400 MHz, DMSO-d6, TMS, δin p.p.m.): 7.31–7.25; (m; 2 H; H3′, H5′); 7.54–7.49; (m;2H; H2′, H6′); 7.67; (s; 1 H; H3). 13C NMR (100 MHz,DMSO-d6, TMS, δ in ppm): 73.2 (C4); 114.8 (CN); 116.3(d; J = 22.8 Hz; C3′, C5′); 126.9 (d; J = 8.9 Hz; C2′, C6′);133.7 (d; J = 2.8 Hz; C1′) 141.7 (C5); 151.4 (C3); 161.2 (d;J = 243.6 Hz; C4′). 19F NMR (376 MHz, DMSO-d6, TMS, δin p.p.m.): -114.26. EI [M + 1]+ 203.07.
Reference：
[1] European Journal of Organic Chemistry, 2018, vol. 2018, # 13, p. 1514 - 1524
[2] Tetrahedron Letters, 2008, vol. 49, # 2, p. 305 - 310
[3] Medicinal Chemistry Research, 2018, vol. 27, # 8, p. 1876 - 1884
[4] Journal of Medicinal Chemistry, 1991, vol. 34, # 9, p. 2892 - 2898
[5] Organic and Biomolecular Chemistry, 2007, vol. 5, # 17, p. 2758 - 2761
[6] Chemical Biology and Drug Design, 2014, vol. 83, # 3, p. 272 - 277
[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
[11] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 5, p. 2644 - 2649
[12] Journal of Enzyme Inhibition and Medicinal Chemistry, 2019, vol. 34, # 1, p. 87 - 96
6
[ 371-14-2 ]
[ 122-51-0 ]
[ 109-77-3 ]
[ 51516-70-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 1991, vol. 34, # 9, p. 2892 - 2898
7
[ 371-14-2 ]
[ 823-85-8 ]
Yield
Reaction Conditions
Operation in experiment
39.3%
With hydrogenchloride In water at 65℃;
(4) salt A mixture of 22. 4 g of 4-fluorophenylhydrazine was dissolved in 15.6 ml of 37percent hydrochloric acid and stirred at 65 ° C until the reaction solution was crystallized. The mixture was cooled to 20 ° C, filtered, and the filter cake was washed with acetone. That is 4-fluorophenylhydrazine hydrochloride finished product 24. 6g, content of 99. 1percent, the yield of 39. 3percent
Reference：
[1] Patent: CN106518711, 2017, A, . Location in patent: Paragraph 0017; 0025; 0026
[2] Die Pharmazie, 1985, vol. 40, # 1, p. 21 - 22
8
[ 80370-42-9 ]
[ 371-14-2 ]
[ 138907-73-0 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1993, vol. 30, # 4, p. 997 - 1002
9
[ 371-14-2 ]
[ 138907-73-0 ]
Reference：
[1] Patent: EP1176140, 2002, A1,
10
[ 371-14-2 ]
[ 187949-90-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 5, p. 1562 - 1575
11
[ 68350-76-5 ]
[ 371-14-2 ]
[ 138907-68-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 23, p. 6886 - 6889
12
[ 371-14-2 ]
[ 94-05-3 ]
[ 138907-68-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 5, p. 1562 - 1575
[2] Patent: EP1176140, 2002, A1, . Location in patent: Page 45 - 46
13
[ 371-14-2 ]
[ 946505-09-5 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2016, vol. 120, p. 37 - 50
Stage #1: 4-fluoroaniline With hydrogenchloride; sodium nitrite In water for 2h;
Stage #2: With hydrogenchloride; sodium sulfite In water at 0 - 100℃; for 4h;
5.1.12 General procedure for the preparation of substituted phenyl hydrazine hydrochloride (12a-e)
General procedure: Substituted aniline (0.17mol) and aqueous solution of NaNO2 (71.0mL, 1.24mol) were successively added to aqueous hydrochloric acid (115mL) maintaining the temperature between 0 and 5°C. The reaction mixture was stirred for 2h, alkalized to pH 6-7 with 12% w/v sodium carbonate solution, and the resulting diazonium salt solution was added drop-wise to sodium sulfite solution (443.0mL, 1.9mol) below 0°C. And then the mixture was stirred at room temperature for a future 1h, concentrated hydrochloric acid (277.0mL) was added slowly, and heated to 100°C for 3h. The mixture was then cooled and filtered, and dried to give compounds 12a-e.
50%
Stage #1: 4-fluoroaniline With hydrogenchloride; acetic acid; sodium nitrite In water at 0 - 20℃;
Stage #2: With hydrogenchloride; tin(II) dichloride dihydrate In water
With hydrogenchloride Diazotization.Reduzieren des Diazoniumsalzes mit Zinnchloruer und Salzsaeure;
With hydrogenchloride; sodium nitrite In water; acetic acid at 0℃; for 1h;
With hydrogenchloride; tin(ll) chloride; sodium nitrite at -5 - 20℃;
Multi-step reaction with 2 steps
1: hydrogenchloride; sodium nitrite / water / 0.25 h / 0 °C
2: hydrogenchloride; tin(ll) chloride / water / 4 h / Cooling with ice
Stage #1: 4-fluoroaniline With hydrogenchloride; sodium nitrite
Stage #2: With tin(ll) chloride
Stage #1: 4-fluoroaniline With hydrogenchloride; sodium nitrite In water at 0℃; for 0.75h;
Stage #2: With tin(ll) chloride In water at 0 - 20℃; for 1h;
Stage #3: With potassium hydroxide In water
Stage #1: 4-fluoroaniline With hydrogenchloride; sodium nitrite In water at 0℃; for 1h;
Stage #2: With hydrogenchloride; tin(ll) chloride In water at 0 - 20℃; for 2h;
3.2.3. Synthesis and Purification of Compound 5a-5s
General procedure: Substituted aniline 4a-4s (50 mmol) was dissolved in the 50 mL HCl (18%, aqueous) in the icebath. NaNO2 (50 mmol) dissolved in 50 mL water was added dropwise. The reaction mixture wasstirred for 1 h to obtain a clear solution. Then the solution of SnCl2 (0.1 mol) in 30 mL of concentratedHCl was added dropwise at 0 C. The mixture was stirred at room temperature for 2 h. Afterwards,the mixture was extracted with 50 mL EtOAc and the organic impurities were discarded. Then thesolution was basified with NaOH (40%, aqueous) until it reached pH 7.0. The reaction mass wasextracted with EtOAc three times. Finally, substituted phenylhydrzine 5a-5s was afforded after beingvapored under reduced pressure (in 55%-80% yield) [12].
22.4 g
Stage #1: 4-fluoroaniline With hydrogenchloride; sodium nitrite In water at 2℃; for 1h;
Stage #2: With zinc In water at 18℃;
1
diazotization 50 g of 4-fluoroaniline and 150 ml of 37% concentrated hydrochloric acid were added to a 1 L three-necked flask and cooled to 2 ° C with ice salt. 85% of a 35% aqueous solution of sodium nitrite was added with stirring to keep the temperature at 2 ° C The reaction was carried out for 1 hour. reduction To the reaction solution, 37 ml of concentrated hydrochloric acid (450 ml), 450 ml of water and 120 g of zinc powder were added, and the reaction was carried out at a temperature of 18 ° C until the reaction was complete. The reaction solution became gray and then added 20% sodium hydroxide solution to the reaction solution PH value of 10,5 ° C for 1 hour, precipitation of crystals, filtered 26. 9g 4-fluorophenylhydrazine crude. purification The crude product of 26. 9g 4-fluorophenylhydrazine dissolved in 538g water, heated to 60 ° C to completely dissolve, then add the appropriate amount of activated carbon decolorization for 20 minutes, heat filtration was a colorless filtrate, 5 ° C insulation 1 hour, precipitation of crystals, Filtration was made of22. 4 g of 4-fluorophenylhydrazine.
272 g
Stage #1: 4-fluoroaniline With hydrogenchloride; sodium nitrite In water at 2℃; for 1.5h;
Stage #2: With zinc In water at 18℃;
3
A process for the preparation of 4-fluorophenylhydrazine phosphate, comprising the steps of: diazotization500 g of 4-fluoroaniline and 1500 ml of 37% concentrated hydrochloric acid were added to 10 L of a three-necked flask, and the mixture was cooled to 2 ° C with ice salt. 650 g of a 35% aqueous solution of sodium nitrite was added while stirring, and the temperature was maintained at 2 ° C for 1.5 hours. reductionTo the reaction solution, 37% concentrated hydrochloric acid (730 ml, 730 ml of water and 480 g of zinc powder) were added thereto, and the reaction was carried out at a temperature of 18 ° C until the reaction was complete. The reaction solution became gray and a solution of 30% sodium hydroxide solution until the reaction solution had a pH of 10 , 5 for 2 hours, precipitation of crystals, filtered 272g 4-fluorophenylhydrazine crude. purificationThe crude product of 272 g of 4-fluorophenylhydrazine was dissolved in 5420 g of water, heated to 60 ° C to completely dissolve it. Then, the amount of the activated charcoal was decolored for 20 minutes. The colorless filtrate was filtered off at 5 ° C for 2 hours to precipitate crystals. 4- Fluorophenylhydrazine.
240 g
Stage #1: 4-fluoroaniline With hydrogenchloride; sodium nitrite In water at 2℃; for 1.5h;
Stage #2: With hydrogenchloride; zinc In water at 18℃;
3.1; 3.2; 3.3 Example 3A method for preparing 4-fluorophenyl hydrazine oxalate comprises the following steps:
diazotizationA 10 L three-necked flask was charged with 500 g of 4-fluoroaniline and 1500 ml of 37% concentrated hydrochloric acid. The mixture was cooled to 2 ° C with ice salt and 650 g of a 35% aqueous solution of sodium nitrite was added thereto while stirring, and the reaction was maintained at 2 ° C for 1.5 hours. reductionAdd 37% concentrated hydrochloric acid 730ml, 730ml water and 480g zinc powder to the reaction solution, keep the reaction temperature at 18 until the reaction is completed, the reaction solution turns gray white, then add 30% sodium hydroxide solution to the reaction solution PH value is 10 , Incubated at 5 ° C for 2 hours, precipitated crystal, filtered to give crude 272g 4-fluorophenylhydrazine. purification272g of 4-fluorophenylhydrazine crude was dissolved in 5420g of water, heated to 60 to completely dissolve, and then add the appropriate amount of activated carbon decolorization for 20 minutes, the filtrate was filtered hot colorless, incubated at 5 for 2 hours, precipitated crystals were filtered to obtain 240g 4 - Fluprazide pure product.
103 g
Stage #1: 4-fluoroaniline With hydrogenchloride; sodium nitrite In water at 2℃; for 1.5h;
Stage #2: With hydrogenchloride; zinc In water at 18℃;
2.1; 2.2; 2.3 Example 2A method for preparing 4-fluorophenylhydrazine sulfate, comprising the following steps:
diazotizationIn a 5 L three-necked flask, 200 g of 4-fluoroaniline and 600 ml of 37% concentrated hydrochloric acid were added, cooled to 2 ° C with ice salt, and 343 g of a 35% aqueous solution of sodium nitrite was added while stirring, and the reaction was maintained at 2 ° C for 1.5 hours. reductionThe reaction solution was added 37% concentrated hydrochloric acid 730ml, 730ml of water and 195g of zinc powder, the reaction temperature was maintained at 18 until the reaction was completed, the reaction was gray-white, then add 25% sodium hydroxide solution to the reaction solution PH value of 10 , 5 incubated for 1.5 hours, precipitated crystals, filtered 122g 4-fluorophenylhydrazine crude. purification122g of 4-fluorophenylhydrazine crude was dissolved in 2440g of water, heated to 60 ° C to completely dissolve, and then add the appropriate amount of activated carbon decolorization for 20 minutes, the filtrate was filtered hot colorless, 1.5 ° C for 1.5 hours, precipitated crystals were filtered 103g 4 - Fluprazide pure product.
Stage #1: 4-fluoroaniline With hydrogenchloride; sodium nitrite In water at -5℃; for 1h;
Stage #2: With hydrogenchloride; tin(ll) chloride In water at -5℃; for 4h;
Stage #1: 4-fluoroaniline With hydrogenchloride; sodium nitrite In water Cooling with ice;
Stage #2: With sodium chloride; tin(ll) chloride In water for 2h; Cooling with ice;
Into a 200 mL flask, tungsten metal (400 mg) and water (2 g) was added and warmed to 40C with stirring. Then, 30% by weight hydrogen peroxide solution in water (2.5 g) was added dropwise over 30 minutes and the mixture was stirred and retained at the same temperature for 0.5 hours to prepare an aqueous solution of tungsten metal oxide. The inner temperature of the aqueous solution was adjusted to 30C and benzene (90 g) and trimethyloctylammonium hydrogen sulfate salt (600 mg) were added thereto. Then, 30% by weight hydrogen peroxide solution in water (33.0 g) was added dropwise over 5 minutes. After the inner temperature of the mixture was increased to 80C, a mixture of 4-fluorophenylhydrazine (7.56 g) and benzene (20 g) was added dropwise over 5 hours and the mixture was then stirred and retained at the same temperature for another 1 hour to be reacted. After cooled to room temperature, water (20 g x 2) was added and the mixture was stirred and then allowed to stand to separate layers. The obtained organic layer containing 4-fluorobiphenyl was analyzed by gas chromatography. As a result, the yield of 4-fluorobiphenyl was found to be 90%. From this solution, the solvent was distilled off to obtain a yellow crystal (7.5 g). The purity of the crystal was found to be 97.0% (GC area percentage).
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.5-amino-1-(4-fluorophenyl)-1H-pyrazole-4-carbonitrile (10a)Yield: 61%. MP: 173-174 C. IR (cm-1): 3297-3183; 2225;1662; 1568; 1222. 1H NMR (400 MHz, DMSO-d6, TMS, deltain p.p.m.): 7.31-7.25; (m; 2 H; H3?, H5?); 7.54-7.49; (m;2H; H2?, H6?); 7.67; (s; 1 H; H3). 13C NMR (100 MHz,DMSO-d6, TMS, delta in ppm): 73.2 (C4); 114.8 (CN); 116.3(d; J = 22.8 Hz; C3?, C5?); 126.9 (d; J = 8.9 Hz; C2?, C6?);133.7 (d; J = 2.8 Hz; C1?) 141.7 (C5); 151.4 (C3); 161.2 (d;J = 243.6 Hz; C4?). 19F NMR (376 MHz, DMSO-d6, TMS, deltain p.p.m.): -114.26. EI [M + 1]+ 203.07.
61%
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.
5-Fluoro-6,7,8,9,10,11-hexahydro-7,11-iminocyclooct[b]indole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
12 5-Fluoro-6,7,8,9,10,11-hexahydro-7,11-iminocyclooct[b]indole
EXAMPLE 12 5-Fluoro-6,7,8,9,10,11-hexahydro-7,11-iminocyclooct[b]indole This compound was prepared from 9-azabicyclo[3.3.1]nonan-3-one hydrochloride and 4-fluorophenylhydrazine by the Fischer indole synthesis as described in Example 1, Method A. The product was obtained as yellow crystals (74% yield), mp 200°-201° C. (from methylene chloride).
Example 1: N-[(6-fluoro-2,3,4,9-tetrahydro-lH-carbazol-2-yl)methyl]-N-[(2S)-8- methyl-2,3-dihy dro [1 ,4] dioxino [2,3-fJ quinoIin-2-yI] methyl} amine6-Fluoro-2.3 A9-te1tauahvdro-l/f-carbazole-2-carboxylic acid (T) [0092] 4-fluorophenyhydrazine (0.90 g, 7.14 mmol) was dissolved in glacial acetic acid (25 mL) under a nitrogen atmosphere and added dropwise to a refluxing solution of 3- cyclohexanonecarboxylic acid ethyl ester (1.73 g , 10 mmol) dissolved in glacial acetic acid (15 mL). After the addition was complete, the solution was heated under reflux for 1 hr, cooled to room temperature and allowed to stir overnight. The orange solution was evaporated under reduced pressure to give a yellow-brown solid. The solid was suspended in 10% sulfuric acid and heated under reflux for 5 hrs, cooled to room temperature and allowed to stir overnight. The EPO <DP n="34"/>brovp ||sm:i|p ipyv^t|| g ||fpd.-iotaiQ j t°p °E)jnan . recrysta ze om acet c acid and water to give the compound I (1.21 g), mp: >200C. MS [M-H] "m/z 232.
With hydrogenchloride In ethanol; water at 20℃; for 2h; Reflux;
4 Preparation of ethyl 8-fluoro-1 ,3,4,5-tetrahydro-1 H-pyrido[4,3-b]indole-2(5H)-carboxylate
N-carbethoxy-4-piperidone 2.2 (1 eq) and appropriate phenylhydroxylamine or phenylhydrazine 2.1 (1 eq) were dissolved in absolute ethanol at room temperature, and 12N HCI solution can be added. The reaction mixture was stirred at reflux for 2h or overnight then cooled to room temperature. Treatment of resulting mixture according a suitable procedure gave the corresponding products. Compound 2.3d was synthesized according to the procedure described by using Ncarbethoxy-4-piperidone and 4-fluorophenyihydrazine at reflux for 2h. After evaporation of solvent, the residue was hydrolysed by water and extracted with ethyl acetate. The organic layer was dried with MgSO4 and evaporated and purified by preparative TLC(CH2CI2/MeOH:98/2). Yield 75%. LCMS m/z263.23 [M+H]
A flask containing tetrahydrofuran (6.0 niL; Aldrich) was charged with sodium amide (0.488 g, 11.89 mmol; Acros) and chilled to 0 0C. (4-Fluorophenyl)hydrazine (1.0 g, 7.9 mmol; Aldrich) was added in portions. After 5 minutes the solid had completely dissolved. The ice bath was removed and stirring was continued for 1 hour. The solution was chilled again in an ice bath and l-<strong>[332-42-3](2-bromoethyl)-4-fluorobenzene</strong> (1.731 ml, 8.72 mmol; Aldrich) was added dropwise. After 10 minutes the ice bath was removed and stirring was continued for 1.5 hours. The mixture was poured into water (5 mL). The tetrahydrofuran was removed under reduce pressure and the residue was diluted with water (20 mL). The aqueous layer was extracted with diisopropyl ether (2x25 mL) and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title product which was carried on without further purification: MS (DCI/NH3) m/z 248.9 (M+H)+.
3.1.3. General Procedure for the Preparation of M2
General procedure: To a solution of aryl-aldehydes (5.0 mmol) and the corresponding phenylhydrazines (5.0 mmol)in ethanol (25 mL), was added one drop of acetic acid. The reaction mixture was stirred at roomtemperature for 8 h. After removing of the solvent, the residue was dissolved in CH2Cl2 (DCM) (20 mL),washed by water (10 mL), dried over Na2SO4, filtered and concentrated to give the hydrazones M2that were used without further purification.
In methanol at 20℃;
In ethanol at 60℃; for 0.5h;
In ethanol; water at 80℃;
4.2. General process for the synthesis of the compounds (3a-aq)
General procedure: To a round-bottom flask (100 mL) was added commerciallyavailable phenylhydrazine 1a-p (10 mmoL) and 30 mL ethyl alcohol(20% in water), then stirred at room temperature, followed byadding aromatic aldehyde 2a-ac in portions. Then, the system wasrefluxed at 80 C for 6e8 h, monitored by TLC until completeconversion, cooled to room temperature, and filtered, the solid waswashed with cold ethyl alcohol (20% in water), dried in oven toproduce intermediate hydrazones 3a-aq with more than 90% yield.
With indium(III) chloride In water at 100℃; for 0.166667h;
4.3. General procedure for synthesis of 3-(5-amino-3-methyl-1-phenyl-1H-4-pyrazolyl)-3-hydroxy-2-indolinone (13)
General procedure: A mixture of phenylhydrazine (1 mmol), 3-aminocrotononitrile (1 mmol), and InCl3 (0.1 mmol) in water (10 ml) was added to isatin (1 mmol) and the reaction mixture heated under reflux at 100 °C for 10 min. After completion of the reaction (TLC), the reaction mixture was cooled to room temperature; the precipitate was filtered off and washed with methanol to obtain pure 13 as a colorless solid. Spectroscopic data for all the compounds are given below.
With indium(III) chloride; In water; at 100℃; for 0.166667h;
General procedure: A mixture of phenylhydrazine (1 mmol), 3-aminocrotononitrile (1 mmol), and InCl3 (0.1 mmol) in water (10 ml) was added to isatin (1 mmol) and the reaction mixture heated under reflux at 100 C for 10 min. After completion of the reaction (TLC), the reaction mixture was cooled to room temperature; the precipitate was filtered off and washed with methanol to obtain pure 13 as a colorless solid. Spectroscopic data for all the compounds are given below.
Stage #1: phenoxyacetic acid ethyl ester With lithium hexamethyldisilazane In tetrahydrofuran; toluene at -30℃; for 0.0333333h;
Stage #2: propionyl chloride In tetrahydrofuran; toluene for 0.166667h;
Stage #3: 4-fluorophenylhydrazine In tetrahydrofuran; ethanol; toluene Reflux;
Stage #1: phenoxyacetic acid ethyl ester With lithium hexamethyldisilazane In tetrahydrofuran; toluene at -30℃; for 0.0333333h;
Stage #2: acetyl chloride In tetrahydrofuran; toluene for 0.166667h;
Stage #3: 4-fluorophenylhydrazine In tetrahydrofuran; ethanol; toluene Reflux;
Stage #1: phenoxyacetic acid ethyl ester With lithium hexamethyldisilazane In tetrahydrofuran; toluene at -30℃; for 0.0333333h;
Stage #2: isopentanoyl chloride In tetrahydrofuran; toluene for 0.166667h;
Stage #3: 4-fluorophenylhydrazine In tetrahydrofuran; ethanol; toluene Reflux;
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In ethyl acetate at 110℃; for 0.166667h; Microwave irradiation; Sealed vessel;
1. Typical procedure for a T3P mediated Fischer indole synthesis
General procedure: T3P (50% in EtOAc) (0.55-0.68 mmol) was added to a mixture of hydrazine (59 mg, 0.55 mmol) and ketone/aldehyde (0.55 mmol) in a microwave vial. The reaction volume was then made up to 0.5 mL with EtOAc and the vessel was sealed under air. The mixture was heated under microwave irradiation (Biotage Initiator) at 100-150 °C for 5-15 min. The solvent was evaporated under reduced pressure and the oily residue was purified by filtration through a plug of silica gel (eluent: isohexane/EtOAc, 8:2) to yield the desired indole or tetrahydrocarbazole. When the reaction was conducted on a 5 mmol scale the product (3a) was purified by precipitation from acetone/water.
70%
With sulfonic acid functionalized mesoporous silica SBA-15-Pr-SO3H In ethanol for 6h; Reflux; Green chemistry;
65.38%
With acetic acid for 0.25h; Reflux;
General Procedure for Synthesis of Substituted2,3,4,9-tetrahydro-1H-carbazoles (3-6)
General procedure: The amalgamation of tetrahydrocarbazoles were based on Fischer-indole synthesis method. In general it was carried out by dissolving 8.8 g (0.08 mol) of cyclohexanone in 50 ml of glacial acetic acid, to this 8.8 g (0.08 mol) of substituted phenyl hydrazine was added and boiled under reflux for 15 min. the solution was cooled, crystals formed were isolated by filtration. Crude product was further purified by recrystallization from aqueous ethanol. A total of four derivatives were synthesized by this route and were subjected to characterization.
With hydrogenchloride In water at 50 - 60℃; for 5h;
General procedure: Substituted phenyl hydrazine (14 mmol) was solved in the mixture of concentrated hydrochloric acid and water (50 mL, 1:20) and then ketone (16.8 mmol) was added dropwise at rt. After that, the mixture was stirred for more than 5 h at 50-60 . When the reaction cooled to rt, some rice shape solids appeared in the system. The mixture was filtered and the solid was washed with enough water until neutral.T he crude product was recrystallized in hexane to afford 1k-1q in 72-95% yield.
In 1-methyl-pyrrolidin-2-one; at 20 - 185℃; for 18.33h;Inert atmosphere; capped;
To a dry 16x100mm Chem-Glass reaction tube under 2 was added 2-fluoro- 4-iodonicotinaldehyde (600 mg, 2.390 mmol), (4-fluorophenyl)hydrazine (332 mg, 2.63 mmol) and anhydrous NMP (3.2 mL). The reaction mixture was flushed with argon, securely capped, stirred for 20 min at room temperature, and then placed in a 185C oil bath for 2h. The reaction mixture was then allowed to stir at room temperature for 16h. The reaction mixture was diluted with EtOAc (200 mL) and the organic layer was extracted with water (5 x 50 mL), brine (1 x 50 mL), dried over Na2S04, filtered and evaporated to dryness. The residue was purified by Biotage Silica gel chromatography on a 90g Thompson Single Step silica cartridge using a linear gradient from 100% hexanes to 100% dichloromethane over 12 column volumes to give 480 mg (59.2%) of the title compound, Intermediate 2A, as an off white solid. 1H NMR (500 MHz, methanol-d4) delta ppm 8.22-8.28 (3 H, m), 8.15 (1 H, s), 7.78 (1 H, d, J=4.88 Hz), 7.25-7.37 (2 H, m).LC/MS (Condition A): 100% purity; ret. T = 2.9 min, (M+H)+ 339.97.
59.2%
In 1-methyl-pyrrolidin-2-one; at 20 - 185℃; for 18.33h;Inert atmosphere; Sealed vial;
Intermediate 1A: l-(4-Fluorophenyl)-4-iodo-lH-pyrazolo[3,4-b]pyridine[00114] To a dry 16x100mm CHEMGLASS reaction tube under N2 was added 2- fluoro-4-iodonicotinaldehyde (600 mg, 2.390 mmol), (4-fluorophenyl)hydrazine (332 mg, 2.63 mmol), and anhydrous NMP (3.2 mL). The reaction mixture was flushed with argon, securely capped, stirred for 20 min at room temperature, and then placed in a 185 C oil bath for 2h. The reaction mixture was then allowed to stir at room temperature for 16h. The reaction mixture was diluted with EtOAc (200 mL) and the organic layer was extracted with water (5 x 50 mL), brine (1 x 50 mL), dried over Na2S04, filtered and evaporated to dryness. The residue was purified by BIOTAGE Silica gelchromatography on a 90g Thompson Single Step silica cartridge using a linear gradient from 100% hexanes to 100% dichloromethane over 12 column volumes to give 480 mg (59.2%) of the title compound, Intermediate 1A, as an off white solid. XH NMR (500 MHz, CD3OD) delta ppm 8.22-8.28 (3 H, m), 8.15 (1 H, s), 7.78 (1 H, d, J=4.88 Hz), 7.25- 7.37 (2 H, m). LC/MS (Condition A): 100% purity; ret. T = 2.9 min, (M+H)+ 339.97
General procedure: The appropriate substituted phenylhydrazine (1a-g, 1.0 mmol) and substituted acetophenone (2a-f, 1.0 mmol) were mixed in ethanol (20 mL) and a few drops of glacial AcOH were added. The solution was heated under reflux at 80 C for 1-2 h. The solvents were evaporated in vacuo to give a solid that was added to polyphosphoric acid (PPA) (30 mL), and the mixture slowly heated to 120 C and kept at this temperature for a few hours until the reaction was complete (TLC monitoring). The mixture was allowed to cool and then poured into cold water (50 mL). The acidic solution was neutralised by the slow addition of 1 M NaOH (aq) and the solid precipitate of crude product was collected. Purification by column chromatography (hexane/ethyl acetate) gave the required product(s) (3a-q).
e. <strong>[6940-57-4]2-acetyl-6-methylpyridine</strong> 6(10.0 g, 99%, 73.2 mmol) was dissolved in absolute ethanol (100 mL), 4-Fluoro-phenylhydrazine (25.1 g, 95%, 147 mmol) was added and the solution was refluxed for 30 mm. After cooling to room temperature the precipitate obtained was collected by filtration, washed with cold ethanol. The residue was redissolved in saturated sodium carbonate solution and extraced with dichloromethane twice. The combined organic layers were dried over sodium sulphate, filtered and evaporated to dryness under reduced pressure. The off-white solid was identified as compound 7 in a yield of 92.5% (16.5 g, 67.8 mmol) and was used without further purification.
16.5 g
In ethanol; for 0.5h;Reflux;
<strong>[6940-57-4]2-acetyl-6-methylpyridine</strong> 6 (10.0 g, 99%, 73.2 mmol) was dissolved in absolute ethanol (100 ml), 4-Fluoro-phenylhydrazine (25.1 g, 95%, 147 mmol) was added and the solution was refluxed for 30 min. After cooling to room temperature the precipitate obtained was collected by filtration, washed with cold ethanol. The residue was redissolved in saturated sodium carbonate solution and extracted with dichloromethane twice. The combined organic layers were dried over sodium sulphate, filtered and evaporated to dryness under reduced pressure. The off-white solid was identified as compound 7 in a yield of 92.5 % (16.5 g, 67.8 mmol) and was used without further purification.
With palladium diacetate; caesium carbonate; catacxium A; In 1,4-dioxane; at 140℃; for 1h;Microwave irradiation; Inert atmosphere;
General procedure: To a solution of 2-bromobenzaldehyde (1) (1.00 mmol) and phenylhydrazine (2) (1.00 mmol)in anhydrous 1,4-dioxane (2 mL) was added cesium carbonate (3.00 mmol) in a 2-5 mLcapacity microwave vial. The mixture was stirred and degassed with argon gas for 5 min. Tothis mixture were added Pd(OAc)2 (0.10 mmol) and di-1-adamantyl-n-butylphosphine (0.20mmol) under argon atmosphere, and purged with argon gas for 2 min and then molybdenumhexacarbonyl (2.50 mmol) was added and the vial was sealed and irradiated in microwave at140 C for 1 h. The vial was cooled to room temperature over a period of 10 min and filteredthrough Celite pad, washed with ethyl acetate (10 mL). The combined filtrate was concentrated in vacuo and the obtained residue was purified by flash column chromatography over 4 g SNAP cartridge by eluting with gradient of 20-40% ethyl acetate in hexane to afford2-phenylphthalazin-1(2H)-one (3) (60%).
With cobalt(II) phthalocyanine; copper(II) sulfate In methanol at 30℃;
20 Synthesis of 4-fluorodiphenylamine
Aniline reaction flask was added 0.093 g (1 mmol), 4- fluorophenyl hydrazine 0.164g (1.3 mmol), CoPc 0.057 Ke (0.1 mmol), Cu (SO 4) 20.026 g (0.1 mmol) and 10 ml ofmethanol, 30 °C reaction; TLC until complete reaction was followed over; After the reaction, the crude product obtained was purified by column chromatography (petroleumether: ethyl acetate = 100: 1) to give the desired product (75% yield).
68%
Stage #1: aniline With copper diacetate In acetonitrile at -5℃; for 0.25h;
Stage #2: With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In acetonitrile at -5℃; for 0.0833333h;
Stage #3: 4-fluorophenylhydrazine In acetonitrile at -5℃; for 3.33333h;
65%
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 palladium diacetate; triphenylphosphine; Trimethylacetic acid In 1-methyl-pyrrolidin-2-one at 90℃; for 4h;
69%
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 tetrakis(triphenylphosphine) palladium(0); sodium carbonate In toluene at 40℃; for 2h; Sealed tube;
80%
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 N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 16h;
To a solution of <strong>[120-36-5]2-(2,4-dichlorophenoxy)propanoic acid</strong> (100 mg, 0.43 mmol) in DMF (2 mL) wereadded 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumhexafluorophosphate (HATU; 200 mg, 0.53 mmol), 4-fluorophenylhydrazine(63 mg, 0.50 mmol), and diisopropylethylamine(100 lL, 0.57 mmol). The resulting mixture was stirred at roomtemperature for 16 h, then poured into water (20 mL). The aqueousmixture was then stirred at room temperature until solids precipitated.The solids were filtered, rinsed with water, and dried to provide124 mg (84%) of product as an off-white crystalline solid: mp112-117 C; Rf 0.54 (1:1 hexane/EtOAc); 1H NMR (CDCl3) d 8.39 (d, br, 1H), 7.45 (d, 1H), 7.23 (dd, 1H), 6.95-6.89 (m, 3H), 6.77-6.72(m, 2H), 6.04 (d, 1H), 4.85 (q, 1H), 1.67 (d, 3H); m/z expected342.0 found 343.1 (M+H)+.
With bis(benzonitrile)palladium(II) dichloride; camphor-10-sulfonic acid; tetrabutyl ammonium fluoride; In tetrahydrofuran; at 50℃; for 3h;
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.
With hydrogenchloride; In water; for 0.416667h;Heating;
General procedure: To a solution of the corresponding arylhydrazine (1a-e) (10 mmol) in concentrated hydrochloric acid (5 mL), 820 mg of 3-aminocrotonitrile (2) (10 mmol) was added with magnetic stirring. The mixture was left to react for 10 minutes and then more HCl was added (5 mL) while heating for 15 additional minutes. After completion of the reaction, a yellow solution was obtained which was then cooled by addition of crushed ice and neutralized with concentrated ammonium hydroxide. Finally, the formed precipitate corresponding to aminopyrazoles 3a-e, was vacuum filtered and washed with cold water.
General procedure: To a solution of aryl-aldehydes (5.0 mmol) and the corresponding phenylhydrazines (5.0 mmol)in ethanol (25 mL), was added one drop of acetic acid. The reaction mixture was stirred at roomtemperature for 8 h. After removing of the solvent, the residue was dissolved in CH2Cl2 (DCM) (20 mL),washed by water (10 mL), dried over Na2SO4, filtered and concentrated to give the hydrazones M2that were used without further purification.
General procedure: To a solution of aryl-aldehydes (5.0 mmol) and the corresponding phenylhydrazines (5.0 mmol)in ethanol (25 mL), was added one drop of acetic acid. The reaction mixture was stirred at roomtemperature for 8 h. After removing of the solvent, the residue was dissolved in CH2Cl2 (DCM) (20 mL),washed by water (10 mL), dried over Na2SO4, filtered and concentrated to give the hydrazones M2that were used without further purification.
3.1.3. General Procedure for the Preparation of M2
General procedure: To a solution of aryl-aldehydes (5.0 mmol) and the corresponding phenylhydrazines (5.0 mmol)in ethanol (25 mL), was added one drop of acetic acid. The reaction mixture was stirred at roomtemperature for 8 h. After removing of the solvent, the residue was dissolved in CH2Cl2 (DCM) (20 mL),washed by water (10 mL), dried over Na2SO4, filtered and concentrated to give the hydrazones M2that were used without further purification.
General procedure: To a solution of aryl-aldehydes (5.0 mmol) and the corresponding phenylhydrazines (5.0 mmol)in ethanol (25 mL), was added one drop of acetic acid. The reaction mixture was stirred at roomtemperature for 8 h. After removing of the solvent, the residue was dissolved in CH2Cl2 (DCM) (20 mL),washed by water (10 mL), dried over Na2SO4, filtered and concentrated to give the hydrazones M2that were used without further purification.
General procedure: To a solution of aryl-aldehydes (5.0 mmol) and the corresponding phenylhydrazines (5.0 mmol)in ethanol (25 mL), was added one drop of acetic acid. The reaction mixture was stirred at roomtemperature for 8 h. After removing of the solvent, the residue was dissolved in CH2Cl2 (DCM) (20 mL),washed by water (10 mL), dried over Na2SO4, filtered and concentrated to give the hydrazones M2that were used without further purification.
General procedure: To a solution of aryl-aldehydes (5.0 mmol) and the corresponding phenylhydrazines (5.0 mmol)in ethanol (25 mL), was added one drop of acetic acid. The reaction mixture was stirred at roomtemperature for 8 h. After removing of the solvent, the residue was dissolved in CH2Cl2 (DCM) (20 mL),washed by water (10 mL), dried over Na2SO4, filtered and concentrated to give the hydrazones M2that were used without further purification.
A flask equipped with a Dean-Stark trap was charged with biphenyl ether(1000 mL)and pyridine- 2,4-diol (67 g,0.6 mol), followed with (4-fluoro-phenyl)-hydrazine (242 g, 1.92 mol). The mixture was heated to 230 C for 5h. Upon cooling, toluene was added and the precipitate was collected, washed with petroleum ether and methanol to afford 8-fluoro-5H- pyrido[4,3-bjindol-1-ol. ?HNMR(400 MHz, DMSO-d6) oe 11.79 (s, 1H), 11.14 (s, 1H), 7.73(dd,J1= 2.8 Hz, J2= 9.6 Hz,1H), 7.47 (dd,Ji= 4.4 Hz, J2 8.8 Hz,1H), 7.31 (t,J 6.0 Hz,1H), 7.097.15 (m, 1H), 6.49 (d,J= 7.2 Hz,1H) ppm.
(E)-2-((2-(4-fluorophenyl)hydrazono)methyl)-1H-benzo[d]imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76.8%
In methanol; at 20℃; for 2h;
General procedure: The equimolar aldehyde 3a?3d (1 mmol) and substituted phenylhydrazine 5a?5s (1 mmol) weremixed in CH3OH (10 mL) and stirred at room temperature [18]. After about 2 h, the reaction wascompleted (monitored by TLC). The residual crude was purified via silica gel column chromatogramusing a gradient mixture of petroleum ether and ethyl acetate to obtain the pure target compounds6a?6ai (in 45?80percent yield).
General procedure: A solution of (4-fluorophenyl)hydrazine (HCl salt, 802 mg, 5.8 mmol) and 3-oxo-butyronitrile (500 mg, 5.8 mmol) in EtOHIAcOH (10 mL/0.2 mL) was stirred at refluxing overnight. The reaction solution was concentrated in vacuum to give crode 2-(4-fluorophenyl)-5-methyl-2H-pyrazol-3-ylamine (1.1 g, yield:quantitative) as a yellow solid which was used for the next step without any purification. ?H NMR (400 MHz,DMSO-d6): = 7.6-7.64 (m, 2H), 7.45 (t, J= 8.8 Hz, 1H), 5.66 (s, 1H), 2.24 (s, 3H).
4-(3-(4-hydroxyphenyl)-1-(4-fluorophenyl)-4,5-dihydropyrazol-5-yl)-5-methoxy-2-(2-methylbut-3-en-2-yl)phenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43.27%
With triethylamine; In ethanol; at 80.0℃; for 8.0h;
To the reactor was added 200 mg (1 mmol)Licorice chalcone A and 96.91 mg (1.3 mmol) of (4-fluorophenyl) hydrazine, Add 50ml of anhydrous ethanol as the reaction solvent, add 0.5mL of triethylamine as a catalyst, placed on a magnetic stirrer, with electric The mixture was heated to 80 C and refluxed for 8 hours. The solid solution was mixed with the above reaction system after the reaction was completed The residue was purified by column chromatography under reduced pressure and dried to give brown crystalline powder (114.2 mg) in a total yield of 43.27%.
1-(2-fluoro-5-nitrobenzylidene)-2-(4-fluorophenyl)hydrazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With toluene-4-sulfonic acid; In ethanol; for 1h;Reflux;
<strong>[27996-87-8]2-Fluoro-5-nitrobenzaldehyde</strong> (50 mg, 0.27 mmol)Was dissolved in EtOH (1 ml)4-Fluorophenylhydrazine (37 mg, 0.29 mmol)And TSA.H2O (3 mg, 0.02 mmol) were added and refluxed for 1 hour.Concentrated and solidified to obtain the desired compound (65 mg, 87%).
87%
With toluene-4-sulfonic acid; In ethanol; for 1h;Reflux;
To asolution of <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (50 mg,0.27 mmol) in ethanol was added 4-fluorophenylhydrazine(37 mg, 0.29 mmol) and toluenesulfonic acid monohydrate(3.0 mg, 0.02 mmol), and the mixture was stirred at refluxfor 1 h. After cooling to room temperature, the precipitatedsolid was collected by filtration to give 1-(2-fluoro-5-nitrobenzylidene)-2-(4-fluorophenyl)hydrazine (16a, 65 mg,87%). 1H NMR (300 MHz, CDCl3): delta 8.84 (dd, J = 6.2,2.9 Hz, 1H), 8.12 (m, 1H), 7.86 (s, 1H), 7.23 (t,J = 9.3 Hz, 1H), 7.08 (m, 4H); MS (ESI): m/z forC13H9F2N3O2, found 278 [M + H+].
With sodium carbonate; In ethanol; water; at 70℃; for 5h;Green chemistry;
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 70C 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 4h;Green chemistry;
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 70C 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].
10 Example 10
2.52 g (20 mmol) of p-fluorobenzoquinone,2.70 g (18 mmol) of o-carboxybenzaldehyde was added to a 10 mL single-neck round bottom flask.Heated to 126 ° C,The reaction was kept under mechanical stirring for 15 minutes.TLC or gas phase monitoring reaction,After the reaction is over,2 mL of ethanol and 2 mL of ethylene glycol were added to the reaction system.After stirring for 0.5 hours, it was allowed to stand and filtered to give 4.43 g of a white solid.TargetingCompound 10, the yield was 92.27%.
91%
With NiCl2·6H2O In lithium hydroxide monohydrate at 20℃; for 3h; 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.
With hydrogenchloride; acetic acid; In methanol; at 60℃;Inert atmosphere;
General procedure: To a solution of 1,2-cyclohexanedione (2243?mg, 20?mmol) and concentrated hydrochloric acid (13?mL) in acetic acid (40?mL), p-tolylhydrazine hydrochloride (1586?mg, 10?mmol) in methanol (25?mL) was added dropwise slowly over 10?min. After the addition, the resulting mixture was heated to 60?C, and stirred overnight. The solvent was evaporated, and the residue was pH adjusted to weak alkaline with saturated NaHCO3. The mixture was extracted with AcOEt (3?*?20?mL). The combined organic extract was washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel chromatography (petroleum ether/AcOEt, 12/1 v/v) to give intermediate 7 (1235?mg, 62%) as a brown powder. The mixture of intermediate 7 (102?mg, 0.5?mmol), 4-phenylbutylamine (0.12?mL, 0.8?mmol) and catalytic p-TsOH in toluene (10?mL) was refluxed at 140?C for 16?h with a Dean-Stark trap in place. The solvent was evaporated and the residue was dissolved in methanol. NaBH4 (177?mg) was then added at 0?C. The solution was heated to 80?C until TLC indicated the reaction was complete. The reaction was quenched with water and concentrated. Subsequently, the mixture was extracted with AcOEt twice and the combined organic layers were dried over anhydrous Na2SO4. After evaporation of the solvent, the resulting residue was purified by column chromatography on silica gel (petroleum ether/AcOEt, 4/1 v/v) to give compound 5 (123?mg, Yield: 72%).
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.
General procedure: (E)-3-aminobut-2-enenitrile (2.3 g, 28 mmol) and (4-(trifluoromethyl)phenyl)hydrazine (5.0 g, 28 mmol) were taken EtOH (30 mL) heated to reflux for 16 hr. The mixture was cooled and poured into water (100 mL) and extracted with EtOAc (2x 100 mL). The organic phase was washed with brine, dried over MgSO4, filtered and then concentrated to yield 6.7 g (99% crude yield) of SI-1 as a dark red oil, which was used in the next step without further purification.
tert-butyl (2-(2-(4-uorophenyl)hydrazineyl)-2-oxoethyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
Stage #1: BOC-glycine With benzotriazol-1-ol; dicyclohexyl-carbodiimide In tetrahydrofuran at 0℃; for 0.25h;
Stage #2: 4-fluorophenylhydrazine In tetrahydrofuran at 0 - 20℃; for 1.5h;
4.1.1. Synthesis of Hydrazides-General Procedure
General procedure: A solution of N-Boc amino acid (0.25 g, 1.43 mmol, 1 equiv.), HOBt (2 equiv.) and DCC (1.2 equiv.)was dissolved in THF (7.5 mL), cooled to 0 C and stirred for 15 min. The solution was treatedwith N-Aryl/Alkyl hydrazine * (1.2 equiv.) before warming to room temperature and stirring fora further 1.5 h. The mixture was then poured into sat. aq. NH4Cl (20 mL) before separating andextracting the aqueous layer with EtOAc (40 mL). The organic layer was further washed with sat.aq. NaHCO3 (20 mL) and then brine (20 mL). The combined organic layers were dried over MgSO4,filtered, concentrated and dried in vacuo. Flash chromatography (DCM/EtOH/NH3 [600:8:1], [400:8:1],[200:8:1]) afforded the desired N-Boc amino acid hydrazides. * When the hydrazine hydrochlorides were used, Et3N (1.2 equiv.) is added to neutralise the salt
3-(2,4-dimethylthiazol-5-yl)-1-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
Themixture of <strong>[38205-60-6]1-(2,4-dimethylthiazol-5-yl)ethanone</strong> (0.05 mol) and 4-fluorophenylhydrazine (0.05 mol) in absolute ethanol was refluxed for 3 hours. Aftercompletion of the reaction (TLC) the reaction mixture was cooled and thesolvent was removed under reduced pressure. The residue was dissolved in dryDMF (10 mL) and added in a mixture of DMF-POCl3 (2:3, 20 mL) at 0C. The reaction mixture was stirred for 10 hours at room temperature. Aftercompletion of reaction, the reaction mixture was poured on crushed ice andneutralized with sodium bicarbonate solution and extracted with ethyl acetate(30 mL x 3). Organic layer was washed with water and removed under reducedpressure. The crude product was purified by column chromatography using ethylacetate:hexane (2:8) afforded 3-(2,4-dimethylthiazol-5-yl)-1-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde (yield 62%).
With sulfuric acid; In 1,4-dioxane; at 110℃; for 3.0h;Cooling with ice;
To a solution of 4-fluorophenyl hydrazine (1 g, 7.9 mmol) and terf-butyl 4-oxopiperidine-1- carboxylate (1.2 g, 8.3 mmol) in 1 ,4-dioxane (10 mL) was added cone. H2S04 (1 mL) at ice bath temperature. Then the reaction mixture was heated at 110 C for 3h. The reaction mixture was cooled to room temperature, the precipitate was filtered off. The solid was dissolved in water basified with NaOH solution and extracted with DCM (dichloromethane). The organic phase was separated and dried over Na2S04 and the solvent was removed to give the title compound as a pale yellow solid (950 mg, 59 %).MS: 191 (M+H)+.1H-NMR (400 MHz, DMSO-d6) d = 10.91 (s, 1 H), 7.23-7.24 (m, 1 H), 7.09-7.09 (m, 1 H), 6.80- 6.81 (m, 1 H), 3.91 (s, 2H), 3.11 (t, J = 5.56 Hz, 2H), 2.75 (d, J = 4.96 Hz, 2H).
59%
With sulfuric acid; In 1,4-dioxane; at 110℃; for 3.0h;Cooling with ice;
To a solution of 4-fluorophenyl hydrazine (1 g, 7.9 mmol) and te/7-butyl 4-oxopiperidine- 1 -carboxylate (1.2 g, 8.3 mmol) in 1 ,4-dioxane (10 ml_) was added cone. H2SO4 (1 ml_) at ice bath temperature. Then the reaction mixture was heated at 110 C for 3h. The reaction mixture was cooled to room temperature, the precipitate was filtered off. The solid was dissolved in water basified with NaOH solution and extracted with DCM (dichloromethane). The organic phase was separated and dried over Na2S04 and the solvent was removed to give the title compound as a pale yellow solid (950 mg, 59 %). MS: 191 (M+H)+.1H-NMR (400 MHz, DMSO-cfe) d = 10.91 (s, 1 H), 7.23-7.24 (m, 1 H), 7.09-7.09 (m, 1 H), 6.80-6.81 (m, 1 H), 3.91 (s, 2H), 3.11 (t, 2H), 2.75 (d, 2H).
3-(4-chlorophenyl)-1-(4-fluorophenyl)-5-(5-methylfuran-2-yl)-4,5-dihydro-1H-pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With acetic acid In ethanol at 40 - 50℃;
4.2.2. Synthesis of target compounds 2a-I
General procedure: As shown in Scheme 1, a mixture of intermediate 1 (10 mmol), anhydrous ethanol (20 mL) and glacial acetic acid (3 mL) was stirred at room temperature. The solution of 4-fluorophenylhydrazine (10 mmol) and anhydrous ethanol (10 mL) was slowly added to the above mixture. The reaction was kept at 40-50 °C for 4-6 h. The process of the reaction was monitored by TLC. After completion, the reaction mixture was poured into distilled water and neutralized by 10% NaOH till the solution became neutral and extracted with ethyl acetate (15 mL × 3). The organic phase was dried with anhydrous Mg2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel (200-300 mesh) chromatography using petroleum ether (60-90 °C)/ ethyl acetate (v/v = 10:1) as eluting systems to give compounds 2a-l .
88%
With toluene-4-sulfonic acid In methanol at 50 - 60℃;
2
0.02 mol of the self-made intermediate was dissolved in 20 mL of anhydrous methanol, and 0.005 mol of p-toluenesulfonic acid was added thereto. Under stirring conditions, a mixed solution of 0.02 mol 4-fluorophenylhydrazine and 20 mL of methanol was slowly dropped into the mixed solution with a constant pressure dropping funnel, reacted at 50-60 ° C, and checked by TLC to see if the reaction was completed. After the reaction is completed, the pH value of the solution is adjusted to neutral with 10% NaOH, a precipitate is precipitated, filtered, washed and then recrystallized with absolute ethanol to obtain the target product, its physical and chemical properties are as follows: Yellow crystal; yield: 88%;
3-(4-chlorophenyl)-1-(4-fluorophenyl)-5-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With toluene-4-sulfonic acid In methanol at 50 - 60℃;
3 Example 3
0.02 mol of the self-made intermediate was dissolved in 20 mL of anhydrous methanol, and 0.005 mol of p-toluenesulfonic acid was added thereto. Under stirring conditions, a mixed solution of 0.02 mol 4-fluorophenylhydrazine and 20 mL of methanol was slowly dropped into the mixed solution with a constant pressure dropping funnel, reacted at 50-60 ° C, and checked by TLC to see if the reaction was completed. After the reaction is completed, the pH value of the solution is adjusted to neutral with 10% NaOH, a precipitate is precipitated, filtered, washed and then recrystallized with absolute ethanol to obtain the target product, its physical and chemical properties are as follows: Yellow crystal; yield: 81%;
81%
With acetic acid In ethanol at 40 - 50℃;
4.2.2. Synthesis of target compounds 2a-I
General procedure: As shown in Scheme 1, a mixture of intermediate 1 (10 mmol), anhydrous ethanol (20 mL) and glacial acetic acid (3 mL) was stirred at room temperature. The solution of 4-fluorophenylhydrazine (10 mmol) and anhydrous ethanol (10 mL) was slowly added to the above mixture. The reaction was kept at 40-50 °C for 4-6 h. The process of the reaction was monitored by TLC. After completion, the reaction mixture was poured into distilled water and neutralized by 10% NaOH till the solution became neutral and extracted with ethyl acetate (15 mL × 3). The organic phase was dried with anhydrous Mg2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel (200-300 mesh) chromatography using petroleum ether (60-90 °C)/ ethyl acetate (v/v = 10:1) as eluting systems to give compounds 2a-l .
1-(4-chlorophenyl)-3-(5-bromo-2-thienyl)-2-propen-1-one[ No CAS ]
[ 371-14-2 ]
5-(5-bromothiophen-2-yl)-3-(4-chlorophenyl)-1-(4-fluorophenyl)-4,5-dihydro-1H-pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With acetic acid In ethanol at 40 - 50℃;
4.2.2. Synthesis of target compounds 2a-I
General procedure: As shown in Scheme 1, a mixture of intermediate 1 (10 mmol), anhydrous ethanol (20 mL) and glacial acetic acid (3 mL) was stirred at room temperature. The solution of 4-fluorophenylhydrazine (10 mmol) and anhydrous ethanol (10 mL) was slowly added to the above mixture. The reaction was kept at 40-50 °C for 4-6 h. The process of the reaction was monitored by TLC. After completion, the reaction mixture was poured into distilled water and neutralized by 10% NaOH till the solution became neutral and extracted with ethyl acetate (15 mL × 3). The organic phase was dried with anhydrous Mg2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel (200-300 mesh) chromatography using petroleum ether (60-90 °C)/ ethyl acetate (v/v = 10:1) as eluting systems to give compounds 2a-l .
84%
With toluene-4-sulfonic acid In methanol at 50 - 60℃;
4 Example 4
0.02 mol of the self-made intermediate was dissolved in 20 mL of anhydrous methanol, and 0.005 mol of p-toluenesulfonic acid was added thereto. Under stirring conditions, a mixed solution of 0.02 mol 4-fluorophenylhydrazine and 20 mL of methanol was slowly dropped into the mixed solution with a constant pressure dropping funnel, reacted at 50-60 °C, and checked by TLC to see if the reaction was completed. After the reaction is completed, the pH value of the solution is adjusted to neutral with 10% NaOH, a precipitate is precipitated, filtered, washed and then recrystallized with absolute ethanol to obtain the target product, its physical and chemical properties are as follows: Yellow crystal; yield: 85%;
3-(4-chlorophenyl)-1-(4-fluorophenyl)-5-(furan-2-yl)-4,5-dihydro-1H-pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With toluene-4-sulfonic acid In methanol at 50 - 60℃;
1 Example 1
0.02 mol of the self-made intermediate was dissolved in 20 mL of anhydrous methanol, and 0.005 mol of p-toluenesulfonic acid was added thereto. Under stirring conditions, a mixed solution of 0.02 mol 4-fluorophenylhydrazine and 20 mL of methanol was slowly dropped into the mixed solution with a constant pressure dropping funnel, reacted at 50-60 ° C, and checked by TLC to see if the reaction was completed. After the reaction is completed, the pH value of the solution is adjusted to neutral with 10% NaOH, a precipitate is precipitated, filtered, washed and then recrystallized with absolute ethanol to obtain the target product, its physical and chemical properties are as follows:
83%
With acetic acid In ethanol at 40 - 50℃;
4.2.2. Synthesis of target compounds 2a-I
General procedure: As shown in Scheme 1, a mixture of intermediate 1 (10 mmol), anhydrous ethanol (20 mL) and glacial acetic acid (3 mL) was stirred at room temperature. The solution of 4-fluorophenylhydrazine (10 mmol) and anhydrous ethanol (10 mL) was slowly added to the above mixture. The reaction was kept at 40-50 °C for 4-6 h. The process of the reaction was monitored by TLC. After completion, the reaction mixture was poured into distilled water and neutralized by 10% NaOH till the solution became neutral and extracted with ethyl acetate (15 mL × 3). The organic phase was dried with anhydrous Mg2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel (200-300 mesh) chromatography using petroleum ether (60-90 °C)/ ethyl acetate (v/v = 10:1) as eluting systems to give compounds 2a-l .
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 80C and refluxed for 4h. After the reaction was completed, the mixture was vacuum filtered and concentrated to obtain intermediate 7.
3-(2-furyl)-1-(4-methoxyphenyl)propen-1-one[ No CAS ]
[ 371-14-2 ]
1-(4-fluorophenyl)-5-(furan-2-yl)-3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With toluene-4-sulfonic acid In methanol at 50 - 60℃;
1
0.02 mol of the self-made intermediate was dissolved in 20 mL of anhydrous methanol, and 0.005 mol of p-toluenesulfonic acid was added thereto. Under stirring conditions, a mixed solution of 0.02 mol 4-fluorophenylhydrazine and 20 mL of methanol was slowly dropped into the mixed solution with a constant pressure dropping funnel, reacted at 50 to 60 ° C, and checked by TLC to see if the reaction was completed. After the reaction is completed, the pH value of the solution is adjusted to neutral with 10% NaOH, a precipitate is precipitated, filtered, washed and then recrystallized with absolute ethanol to obtain the target product, its physical and chemical properties are as follows:
86%
With acetic acid In ethanol at 40 - 50℃;
4.2.2. Synthesis of target compounds 2a-I
General procedure: As shown in Scheme 1, a mixture of intermediate 1 (10 mmol), anhydrous ethanol (20 mL) and glacial acetic acid (3 mL) was stirred at room temperature. The solution of 4-fluorophenylhydrazine (10 mmol) and anhydrous ethanol (10 mL) was slowly added to the above mixture. The reaction was kept at 40-50 °C for 4-6 h. The process of the reaction was monitored by TLC. After completion, the reaction mixture was poured into distilled water and neutralized by 10% NaOH till the solution became neutral and extracted with ethyl acetate (15 mL × 3). The organic phase was dried with anhydrous Mg2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel (200-300 mesh) chromatography using petroleum ether (60-90 °C)/ ethyl acetate (v/v = 10:1) as eluting systems to give compounds 2a-l .
1-(4-fluorophenyl)-3-(4-methoxyphenyl)-5-(5-methylfuran-2-yl)-4,5-dihydro-1H-pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With toluene-4-sulfonic acid In methanol at 50 - 60℃;
2
0.02 mol of the self-made intermediate was dissolved in 20 mL of anhydrous methanol, and 0.005 mol of p-toluenesulfonic acid was added thereto. Under stirring conditions, a mixed solution of 0.02 mol 4-fluorophenylhydrazine and 20 mL of methanol was slowly dropped into the mixed solution with a constant pressure dropping funnel, reacted at 50 to 60 ° C, and checked by TLC to see if the reaction was completed. After the reaction is completed, the pH value of the solution is adjusted to neutral with 10% NaOH, a precipitate is precipitated, filtered, washed and then recrystallized with absolute ethanol to obtain the target product, its physical and chemical properties are as follows:
87%
With acetic acid In ethanol at 40 - 50℃;
4.2.2. Synthesis of target compounds 2a-I
General procedure: As shown in Scheme 1, a mixture of intermediate 1 (10 mmol), anhydrous ethanol (20 mL) and glacial acetic acid (3 mL) was stirred at room temperature. The solution of 4-fluorophenylhydrazine (10 mmol) and anhydrous ethanol (10 mL) was slowly added to the above mixture. The reaction was kept at 40-50 °C for 4-6 h. The process of the reaction was monitored by TLC. After completion, the reaction mixture was poured into distilled water and neutralized by 10% NaOH till the solution became neutral and extracted with ethyl acetate (15 mL × 3). The organic phase was dried with anhydrous Mg2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel (200-300 mesh) chromatography using petroleum ether (60-90 °C)/ ethyl acetate (v/v = 10:1) as eluting systems to give compounds 2a-l .
1-(4-methoxyphenyl)-3-(thiophen-2-yl)prop-2-en-1-one[ No CAS ]
1-(4-fluorophenyl)-3-(4-methoxyphenyl)-5-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With acetic acid In ethanol at 40 - 50℃;
4.2.2. Synthesis of target compounds 2a-I
General procedure: As shown in Scheme 1, a mixture of intermediate 1 (10 mmol), anhydrous ethanol (20 mL) and glacial acetic acid (3 mL) was stirred at room temperature. The solution of 4-fluorophenylhydrazine (10 mmol) and anhydrous ethanol (10 mL) was slowly added to the above mixture. The reaction was kept at 40-50 °C for 4-6 h. The process of the reaction was monitored by TLC. After completion, the reaction mixture was poured into distilled water and neutralized by 10% NaOH till the solution became neutral and extracted with ethyl acetate (15 mL × 3). The organic phase was dried with anhydrous Mg2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel (200-300 mesh) chromatography using petroleum ether (60-90 °C)/ ethyl acetate (v/v = 10:1) as eluting systems to give compounds 2a-l .
88%
With toluene-4-sulfonic acid In methanol at 50 - 60℃;
3
0.02 mol of the self-made intermediate was dissolved in 20 mL of anhydrous methanol, and 0.005 mol of p-toluenesulfonic acid was added thereto. Under stirring conditions, a mixed solution of 0.02 mol 4-fluorophenylhydrazine and 20 mL of methanol was slowly dropped into the mixed solution with a constant pressure dropping funnel, reacted at 50 to 60 ° C, and checked by TLC to see if the reaction was completed. After the reaction is completed, the pH value of the solution is adjusted to neutral with 10% NaOH, a precipitate is precipitated, filtered, washed and then recrystallized with absolute ethanol to obtain the target product, its physical and chemical properties are as follows:
5-(5-bromothiophen-2-yl)-1-(4-fluorophenyl)-3-(4- methoxyphenyl)-4,5-dihydro-1H-pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With acetic acid In ethanol at 40 - 50℃;
4.2.2. Synthesis of target compounds 2a-I
General procedure: As shown in Scheme 1, a mixture of intermediate 1 (10 mmol), anhydrous ethanol (20 mL) and glacial acetic acid (3 mL) was stirred at room temperature. The solution of 4-fluorophenylhydrazine (10 mmol) and anhydrous ethanol (10 mL) was slowly added to the above mixture. The reaction was kept at 40-50 °C for 4-6 h. The process of the reaction was monitored by TLC. After completion, the reaction mixture was poured into distilled water and neutralized by 10% NaOH till the solution became neutral and extracted with ethyl acetate (15 mL × 3). The organic phase was dried with anhydrous Mg2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel (200-300 mesh) chromatography using petroleum ether (60-90 °C)/ ethyl acetate (v/v = 10:1) as eluting systems to give compounds 2a-l .
74%
With toluene-4-sulfonic acid In methanol at 50 - 60℃;
4
0.02 mol of the self-made intermediate was dissolved in 20 mL of anhydrous methanol, and 0.005 mol of p-toluenesulfonic acid was added thereto. Under stirring conditions, a mixed solution of 0.02 mol 4-fluorophenylhydrazine and 20 mL of methanol was slowly dropped into the mixed solution with a constant pressure dropping funnel, reacted at 50 to 60 ° C, and checked by TLC to see if the reaction was completed. After the reaction is completed, the pH value of the solution is adjusted to neutral with 10% NaOH, a precipitate is precipitated, filtered, washed and then recrystallized with absolute ethanol to obtain the target product, its physical and chemical properties are as follows:
1-(4-bromophenyl)-3-(furan-2-yl)prop-2-en-1-one[ No CAS ]
[ 371-14-2 ]
3-(4-bromophenyl)-1-(4-fluorophenyl)-5-(furan-2-yl)-4,5-dihydro-1H-pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With acetic acid In ethanol at 40 - 50℃;
4.2.2. Synthesis of target compounds 2a-I
General procedure: As shown in Scheme 1, a mixture of intermediate 1 (10 mmol), anhydrous ethanol (20 mL) and glacial acetic acid (3 mL) was stirred at room temperature. The solution of 4-fluorophenylhydrazine (10 mmol) and anhydrous ethanol (10 mL) was slowly added to the above mixture. The reaction was kept at 40-50 °C for 4-6 h. The process of the reaction was monitored by TLC. After completion, the reaction mixture was poured into distilled water and neutralized by 10% NaOH till the solution became neutral and extracted with ethyl acetate (15 mL × 3). The organic phase was dried with anhydrous Mg2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel (200-300 mesh) chromatography using petroleum ether (60-90 °C)/ ethyl acetate (v/v = 10:1) as eluting systems to give compounds 2a-l .
With toluene-4-sulfonic acid In methanol at 50 - 60℃;
1
0.02 mol of self-made intermediate was dissolved in 20 mL of anhydrous methanol, and 0.005 mol of p-toluenesulfonic acid was added thereto.Under stirring conditions, a mixed solution of 0.02 mol 4-fluorophenylhydrazine and 20 mL of methanol was slowly dropped into the above mixed solution with a constant pressure dropping funnel, reacted at 50 to 60°C, and checked by TLC for completion of the reaction. After the reaction is completed, the pH value of the solution is adjusted to neutral with 10% NaOH, a precipitate is precipitated, filtered, washed and then recrystallized with absolute ethanol to obtain the target product, its physical and chemical properties are as follows:Yellow crystal; yield: 83%;
3-(4-bromophenyl)-1-(4-fluorophenyl)-5-(5-methylfuran-2-yl)-4,5-dihydro-1H-pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With acetic acid In ethanol at 40 - 50℃;
4.2.2. Synthesis of target compounds 2a-I
General procedure: As shown in Scheme 1, a mixture of intermediate 1 (10 mmol), anhydrous ethanol (20 mL) and glacial acetic acid (3 mL) was stirred at room temperature. The solution of 4-fluorophenylhydrazine (10 mmol) and anhydrous ethanol (10 mL) was slowly added to the above mixture. The reaction was kept at 40-50 °C for 4-6 h. The process of the reaction was monitored by TLC. After completion, the reaction mixture was poured into distilled water and neutralized by 10% NaOH till the solution became neutral and extracted with ethyl acetate (15 mL × 3). The organic phase was dried with anhydrous Mg2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel (200-300 mesh) chromatography using petroleum ether (60-90 °C)/ ethyl acetate (v/v = 10:1) as eluting systems to give compounds 2a-l .
With toluene-4-sulfonic acid In methanol at 50 - 60℃;
2
0.02 mol of self-made intermediate was dissolved in 20 mL of anhydrous methanol, and 0.005 mol of p-toluenesulfonic acid was added thereto.Under stirring conditions, a mixed solution of 0.02 mol 4-fluorophenylhydrazine and 20 mL of methanol was slowly dropped into the above mixed solution with a constant pressure dropping funnel, reacted at 50 to 60°C, and checked by TLC for completion of the reaction. After the reaction is completed, the pH value of the solution is adjusted to neutral with 10% NaOH, a precipitate is precipitated, filtered, washed and then recrystallized with absolute ethanol to obtain the target product, its physical and chemical properties are as follows:Yellow crystal; yield: 82%;
1-(4-bromophenyl)-3-(thiophene-2-yl)prop-2-en-1-one[ No CAS ]
[ 371-14-2 ]
3-(4-bromophenyl)-1-(4-fluorophenyl)-5-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With acetic acid In ethanol at 40 - 50℃;
4.2.2. Synthesis of target compounds 2a-I
General procedure: As shown in Scheme 1, a mixture of intermediate 1 (10 mmol), anhydrous ethanol (20 mL) and glacial acetic acid (3 mL) was stirred at room temperature. The solution of 4-fluorophenylhydrazine (10 mmol) and anhydrous ethanol (10 mL) was slowly added to the above mixture. The reaction was kept at 40-50 °C for 4-6 h. The process of the reaction was monitored by TLC. After completion, the reaction mixture was poured into distilled water and neutralized by 10% NaOH till the solution became neutral and extracted with ethyl acetate (15 mL × 3). The organic phase was dried with anhydrous Mg2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel (200-300 mesh) chromatography using petroleum ether (60-90 °C)/ ethyl acetate (v/v = 10:1) as eluting systems to give compounds 2a-l .
With toluene-4-sulfonic acid In methanol at 50 - 60℃;
3
0.02 mol of self-made intermediate was dissolved in 20 mL of anhydrous methanol, and 0.005 mol of p-toluenesulfonic acid was added thereto. Under stirring conditions, a mixed solution of 0.02 mol 4-fluorophenylhydrazine and 20 mL of methanol was slowly dropped into the above mixed solution with a constant pressure dropping funnel, reacted at 50 to 60°C, and checked by TLC for completion of the reaction. After the reaction is completed, the pH value of the solution is adjusted to neutral with 10% NaOH, a precipitate is precipitated, filtered, washed and then recrystallized with absolute ethanol to obtain the target product, its physical and chemical properties are as follows:Yellow crystal; yield: 80%;
1-(4-bromophenyl)-3-(5-bromo-2-thienyl)-2-propen-1-one[ No CAS ]
[ 371-14-2 ]
3-(4-bromophenyl)-5-(5-bromothiophen-2-yl)-1-(4-fluorophenyl)-4,5-dihydro-1H-pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With acetic acid In ethanol at 40 - 50℃;
4.2.2. Synthesis of target compounds 2a-I
General procedure: As shown in Scheme 1, a mixture of intermediate 1 (10 mmol), anhydrous ethanol (20 mL) and glacial acetic acid (3 mL) was stirred at room temperature. The solution of 4-fluorophenylhydrazine (10 mmol) and anhydrous ethanol (10 mL) was slowly added to the above mixture. The reaction was kept at 40-50 °C for 4-6 h. The process of the reaction was monitored by TLC. After completion, the reaction mixture was poured into distilled water and neutralized by 10% NaOH till the solution became neutral and extracted with ethyl acetate (15 mL × 3). The organic phase was dried with anhydrous Mg2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel (200-300 mesh) chromatography using petroleum ether (60-90 °C)/ ethyl acetate (v/v = 10:1) as eluting systems to give compounds 2a-l .
With toluene-4-sulfonic acid In methanol at 50 - 60℃;
4
0.02 mol of self-made intermediate was dissolved in 20 mL of anhydrous methanol, and 0.005 mol of p-toluenesulfonic acid was added thereto. Under stirring conditions, a mixed solution of 0.02 mol 4-fluorophenylhydrazine and 20 mL of methanol was slowly dropped into the above mixed solution with a constant pressure dropping funnel, reacted at 50 to 60°C, and checked by TLC for completion of the reaction. After the reaction is completed, the pH value of the solution is adjusted to neutral with 10% NaOH, a precipitate is precipitated, filtered, washed and then recrystallized with absolute ethanol to obtain the target product, its physical and chemical properties are as follows:Yellow crystal; yield: 85%;
With sodium carbonate In ethanol; water at 70℃; for 24h; 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].
2-amino-6-fluoro-N'-(4-fluorophenyl) benzohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran at 20℃; for 15h;
General procedure for the synthesis of compounds 1, 2, 6-16and 18-39.
General procedure: 1-10- Carbonyl diimidazole 43 (0.97 mmol; 1.5 eq) wasadded to a solution of 2-amino- 6-fluoro benzoic acid (0.65 mmol;1.0 eq) in tetrahydrofuran (7 ml) in a round-bottom flask equippedwith a stirring bar in dry conditions. The obtained mixture wasstirred for 24 h at room temperature and then the appropriatehydroxylamine 45a,b, amine 46a-k or hydrazine 47a-t was added(1.30 mmol; 2.0 eq) and the reaction mixture was stirred at roomtemperature for 16 h. At the end the mixture was quenched withsaturated aqueous sodium bicarbonate and the organic solutionwas extracted with ethyl acetate, washed with brine and dried overNa2SO4.After filtration and concentration, the crude material was purifiedby column chromatography on silica gel with a mixture ofdichloromethane/ethyl acetate in the opportune volumes to givethe expected products 1, 2, 6e16 and 18e37.Hydrochloride salts 38 and 39 were prepared by reacting a solutionof the hydrazides 20 or 21 (0.08 mmol, 1 eq) in ethanol(0.5 ml) with aqueous HCl 37% added dropwise. The mixture wasstirred for 30 min at room temperature and then the white precipitatewasseparated by filtration andwashed with cold ethanol toobtain the desired products.
2-(2-hydroxy-4-(trifluoromethyl)phenyl)-4Hbenzo[e] [1,3]oxazin-4-one[ No CAS ]
[ 371-14-2 ]
2-(1-(4-fluorophenyl)-5-(2-hydroxyphenyl)-1H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)phenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86.7%
With triethylamine In ethanol at 75℃; for 5h; Reflux;
2.2.2. General procedure for synthesis of compound 1-26
General procedure: Triethylaminewas added (1.5 mmol,1.5 equivalent) to a mixtureof intermediate (1 mmol, 1 equivalent) and substituent phenylhydrazinehydrochloride (1 mmol, 1 equivalent) in 5 ml ethanol.The resulting mixture was stirred at 75 C for 5 h. After completionof the reaction (TLC detection), the solvent was evaporated off, andthe crude product was purified by flash chromatography
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
HazMat Fee +
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
