* 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.
Stage #1: With potassium phosphate; N,N'-bis(2,5-dimethylpyrrol-1-yl)oxalamide; cetyltrimethylammonim bromide; copper(I) bromide In water at 110℃; for 0.166667 h; Sealed tube; Inert atmosphere Stage #2: With hydrazine hydrate In water at 110℃; for 1 h; Sealed tube; Inert atmosphere Stage #3: With hydrogenchloride In dichloromethane; water
General procedure: CuBr (36 mg, 0.25 mmol, 2.5 mol percent), L3 (110 mg, 0.4 mmol,4 mol percent), H2O (0.5 mL), and K3PO4 (254 mg, 1.2 mmol) were mixedin a 15 mL screw cap test tube. After STAC (110 mg, 0.3 mmol,3 mol percent) and aryl bromide (10 mmol) were added, the resulting mixture was stirred at 80-110° C (bath temperature) for 10 min.Then K3PO4 (2.29 g, 10.8 mmol) and N2H4*H2O (1 g, 20 mmol) were added and argon (flow rate 5-7 mL/min) was bubbled through thereaction mixture for 5 min.28 The reaction mixture was stirred ina closed test tube at 80-110° C (bath temperature) for 1-2 h until complete consumption of starting material was observed as monitoredby TLC (eluentehexane), then cooled to room temperatureand diluted with SH2Cl2 (50 mL). The resulting solutionwas filteredand washed with brine (225 mL). Aq HCl (37percent) was added to the CH2Cl2 solution dropwise until pH 3-4. The formed precipitate was filtered, washed with SH2Cl2 (15 mL) and dried atroom temperature. NMR spectra of certain synthesized aryl hydrazine hydrochlorides showed that they contained 1-5 mol percent of the corresponding aniline hydrochlorides as impurities (see Supplementary data). Analytical samples of aryl hydrazine hydrochlorides were purified via precipitation from methanol solution by adding 2-3 volumes of diethyl ether.
Reference:
[1] Chinese Journal of Chemistry, 2018, vol. 36, # 11, p. 1003 - 1006
[2] Tetrahedron, 2014, vol. 70, # 26, p. 4043 - 4048
2
[ 98-16-8 ]
[ 3107-33-3 ]
Reference:
[1] Journal of Chemical Research, 2015, vol. 39, # 10, p. 594 - 600
1,3,3-Trimethyl-6-trifluoromethyl-2-{(1E,3E)-5-[1,3,3-trimethyl-6-trifluoromethyl-1,3-dihydro-indol-(2E)-ylidene]-penta-1,3-dienyl}-3H-indolium; perchlorate[ No CAS ]
1,3,3-Trimethyl-4-trifluoromethyl-2-{(1E,3E)-5-[1,3,3-trimethyl-4-trifluoromethyl-1,3-dihydro-indol-(2E)-ylidene]-penta-1,3-dienyl}-3H-indolium; perchlorate[ No CAS ]
EXAMPLE 12 2-Bromo-N-[1-(alpha,alpha,alpha-trifluoro-m-tolyl)-2-pyrazolin-3-yl]-propionamide Sodium metal (2.8 g.) is dissolved in 125 ml. of absolute ethanol, then 21.2 g. of m-trifluoromethylphenylhydrazine hydrochloride is added followed by 5.5 g. of acrylonitrile. The reaction mixture is refluxed for 18 hours. The solvent is removed in vacuo and water is added to the residue to give a tacky solid. The solid is dissolved in dichloromethane. The solution is dried over anhydrous magnesium sulfate and passed through a short column of a hydrous magnesium silicate. The effluent is collected and concentrated to separate tan crystals. This material is recrystallized from acetone-hexane to give 14.8 g. of 3-amino-1-(alpha,alpha,alpha-trifluoro-m-tolyl)-2-pyrazoline as pale yellow needles, m.p. 104-105 C.
EXAMPLE 4 1,4-Bis-(alpha,alpha,alpha-trifluoro-3-tolyl)-2-methyl-3-pyrazolin-5-one A 3.5 gram portion of the atropic ester of Example 1 was reacted with 2.7 grams alpha,alpha,alpha-trifluoro-3-tolylhydrazine hydrochloride in the presence of triethylamine to produce 2.4 grams 1,4-bis-(alpha,alpha,alpha-trifluoro-3-tolyl)-3-pyrazolin-5-one, m.p. 207-208 C. A 1.8 gram portion of the above pyrazolinone was alkylated with 2 grams methyl iodide to produce 1.25 grams of the desired product, m.p. 110-111 C. Calculated: C, 56.26; H, 2.62; N, 7.29; Found: C, 56.04; H, 2.86; N, 7.19.
3-amino-4-methyl-1-(α,α,α-trifluoro-m-tolyl)-2-pyrazoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol; dichloromethane; water;
EXAMPLE 39 2,2,2-Trifluoro-N-[4-methyl-1-(alpha,alpha,alpha-trifluoro-m-tolyl)-2-pyrazolin-3-yl]acetamide A 0.7 g. amount of sodium metal is dissolved in 35.0 ml. of absolute ethanol, then 5.3 g. of m-trifluoromethylphenylhydrazine hydrochloride is added followed slowly by the addition of 1.7 g. of methacrylonitrile. The reaction mixture is refluxed for 18 hours. The solvent is removed in vacuo and water is added to separate a solid. The solid is collected and dissolved in dichloromethane. The solution is dried over anhydrous magnesium sulfate then is passed through a short column of a hydrous magnesium silicate. The effluent is evaporated to give a solid. The solid is recrystallized from ether-hexane to give 3.6 g. of (+-)-3-amino-4-methyl-1-(alpha,alpha,alpha-trifluoro-m-tolyl)-2-pyrazoline as white crystals.
EXAMPLE 10 4-(3-Chlorophenyl)-2-ethyl-1-(alpha,alpha,alpha-trifluoro-3-tolyl)-3-pyrazolin-5-one A mixture of 12 grams of the 3-chloroatropic acid, methyl ester (prepared in Example 9 above), 13 grams <strong>[3107-33-3]3-(trifluoromethyl)phenylhydrazine hydrochloride</strong> and 100 ml. methanol was refluxed overnight to yield 4.6 grams of 4-(3-chlorophenyl)-1-(alpha,alpha,alpha-trifluoro-3-tolyl)-3-pyrazolin-5-one, m.p. 190-192 C.
EXAMPLE 9 2-methyl-1,4-bis(alpha,alpha,alpha-trifluoro-m-tolyl)-3-pyrazolin-5-one A 3.5 g. portion of the atropic ester of Example 1 was reacted with 2.7 g. of alpha,alpha,alpha-trifluoro-m-tolylhydrazine hydrochloride in the presence of triethylamine to produce 2.4 g. of 1,4-bis(alpha,alpha,alpha-trifluoro-m-tolyl)-3-pyrazolin-5-one, m.p. 207-208 C. A 1.8 g. portion of the above pyrazolinone was reacted with 2 g. of methyl iodide to produce 1.25 g. of 2-methyl-1,4-bis(alpha,alpha, alpha-trifluoro-m-tolyl)-3-pyrazolin-5-one, m.p. 110-111 C.
General procedure: A mixture of compound 5 (0.360 g, 1 mmol) and various phenylhydrazines 6a-6ad (0.145-0.225 g,1 mmol) in dry EtOH (10 mL) were stirred at 78C in the presence of CH3COONa (0.099 g,1.2 mmol). After completion of the reaction monitored by TLC, the solution was then poured into water (10 mL), the white precipitate was filtered and washed with water and dried. The crude product was recrystallized from ethyl acetate/light petroleum ether to give compounds 7a-7ad. Then to a solution of compounds 7a-7ad(0.450-0.529 g, 1 mmol) in toluene (5 mL), 48% BF3*OEt2 (48% solution in Et2O, 0.05 mL, 0.17 mmol) was added dropwise and the mixture was heated under a nitrogen atmosphere at 118C. After completion of the reaction monitored by TLC, water (10 mL) was added to the mixture, which was next neutralized with NaHCO3, and the organic phase was separated and dried over Na2SO4. After evaporation in vacuo, the crude product was purified by column chromatography to give product 9a-9ad.
(E)-1-(3-trifluoromethylphenyl)-2-(1-p-tolylethylidene)hydrazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With acetic acid; In methanol; water; at 20℃; for 18h;Inert atmosphere;
To a solution of 4'-methylacetophenone (0.5 g, 3.73 mmol) in 8 mL of acetic acid and 5 mL of water/MeOH, 3-trifluoromethylphenylhydrazine hydrochloride (0.66 g, 3.73 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with an additional 30 mL of water and subsequently filtered. The solid was dried in vacuo to afford 1.01 g of beige solid 1d (93% yield): mp 103.7 C. 1H NMR (CDCl3) delta 7.72 (d, 2H), 7.44 (m, 4H), 7.28 (d, 2H), 7.14 (s, 1H), 2.41 (s, 3H), 2.27 (s, 3H).
93%
With acetic acid; In methanol; water; at 20℃; for 18h;
To a solution of 4 '-methylacetophenone (0.5 g, 3.73 mmol) in 8 mL of acetic acid and 5 mL of water/MeOH, 3- trifluoromethylphenylhydrazine hydrochloride (0.66 g, 3.73 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with an additional 30 mL of water and subsequently filtered and the solid was dried in vacuo to afford 1.01 g of beige solid Id (93% yield): mp 103.7 C. XH NMR (CDC13) delta 7.72 (d, 2H), 7.44 (m, 4H), 7.28 (d, 2H), 7.14 (s, 1H), 2.41 (s, 3H), 2.27 (s, 3H).
General procedure: CuBr (36 mg, 0.25 mmol, 2.5 mol %), L3 (110 mg, 0.4 mmol,4 mol %), H2O (0.5 mL), and K3PO4 (254 mg, 1.2 mmol) were mixedin a 15 mL screw cap test tube. After STAC (110 mg, 0.3 mmol,3 mol %) and aryl bromide (10 mmol) were added, the resulting mixture was stirred at 80-110 C (bath temperature) for 10 min.Then K3PO4 (2.29 g, 10.8 mmol) and N2H4*H2O (1 g, 20 mmol) were added and argon (flow rate 5-7 mL/min) was bubbled through thereaction mixture for 5 min.28 The reaction mixture was stirred ina closed test tube at 80-110 C (bath temperature) for 1-2 h until complete consumption of starting material was observed as monitoredby TLC (eluentehexane), then cooled to room temperatureand diluted with SH2Cl2 (50 mL). The resulting solutionwas filteredand washed with brine (225 mL). Aq HCl (37%) was added to the CH2Cl2 solution dropwise until pH 3-4. The formed precipitate was filtered, washed with SH2Cl2 (15 mL) and dried atroom temperature. NMR spectra of certain synthesized aryl hydrazine hydrochlorides showed that they contained 1-5 mol % of the corresponding aniline hydrochlorides as impurities (see Supplementary data). Analytical samples of aryl hydrazine hydrochlorides were purified via precipitation from methanol solution by adding 2-3 volumes of diethyl ether.
General procedure: Curcumin pyrazole, and N-(substituted) phenyl pyrazolesderivatives of curcumin were prepared according to previouslyreported procedure by us and others with some modifications(Schemes 1 and 2) [1,20,21]. Curcumin (1 mmol) was dissolved inglacial acetic acid (5 mL), hydrazine hydrate and the various phenylsubstituted hydrazine hydrochlorides (1.2 mmol) were added tothe solution. The solution was refluxed for 8 -24 hr, and then the solvent was removed in vacuum. Residue was dissolved in ethylacetate and washed with water. Organic portion was collected,dried over sodium sulfate, and concentrated in vacuum. Crudeproduct was purified by column chromatography.Knoevenagel condensates of curcumin was prepared bytreatment of curcumin with aromatic aldehyde (4-hydroxy-3-methoxybenzaldehyde; vanillin) in presence of piperidine(as catalyst) and anhydrous DMF (as solvent) to yield 4-(4-Hydroxy-3-methoxybenzylidene) curcumin. Likewise, butylidienecurcumin and benzylidiene curcumin were prepared in good yieldsusing the above procedure wherein isobutyraldehyde and benzyldehydewere used instead of (4- hydroxyl -3-methoxybenzaldehyde) (Scheme 3) [1,22-25]. Reaction mixture was dilutedwith ethyl acetate and washed with water and saturated brine. Theorganic phase was dried over Na2SO4 concentrated under vacuum,and purified by chromatography with EtOAC/hexanes mixtures toprovide pure compound.
1-(3-trifluoromethylphenyl)-5-hydroxypyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64.8%
In methanol; for 6h;Reflux;
To a three-necked flask, 21.2 g (100 mmol) of 3-trifluoromethylphenylhydrazine hydrochloride, 11.6 g (100 mmol) of methylMethyl acrylate, lOOmL methanol. The reaction mixture was heated to reflux for about 6 hours. The reaction solution was quantified by liquid chromatography, and 1- (3-Trifluoromethylphenyl) -5-hydroxypyrazole in a yield of 64.8percent.
In a 100 mL flask(3- (trifluoromethyl) phenyl)Hydrazine hydrochloride (25 g, 141.93 mmol) and ethanol (250 mL) were added and dissolved.Then, ethyl-2-oxopropanoate (24.7 g, 212.89 mmol),Acetic acid (5 mL) was added, and the mixture was refluxed with stirring for 5 hours.After completion of the reaction, the reaction mixture was concentrated under reduced pressure,After the organic layer was separated using ethyl acetate and water,Water contained in the organic layer was removed with magnesium sulfate.Then, after filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 5)To obtain (E) -ethyl-2- (2- (3-fluorophenyl)Hydrazano) propanoate (26 g, 94.8 mmol, 66%).
1-(4-cyano-phenyl)-1H-imidazole-2-carboxylic acid methyl ester[ No CAS ]
[ 3107-33-3 ]
1-(4-cyano-phenyl)-1H-imidazole-2-carboxylic acid N'-(3-trifluoromethyl-phenyl)-hydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.03 g
A mixture of 3-trifluoromethyl-phenylhydrazine hydrochloride (1.98 g, 9.3 mmol) and bis(trimethylaluminium)-1,4-diazabicyclo[2.2.2]octane adduct (2.38 g, 9.3 mmol) in dry THF (30 mL) was stirred at 40 C. for 1 h. A suspension of Intermediate 72B (1.40 g, 6.7 mmol) in dry THF (35 mL) was added and the mixture then heated at reflux for 16 h. After allowing to cool to ambient temperature the mixture was quenched by cautious dropwise addition with 4M hydrochloric acid (3.0 mL) and stirred vigorously for 5 minutes then made basic by addition of 5% aqueous potassium carbonate solution (30 mL). The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phase was washed with brine (30 mL), dried (sodium sulfate) and concentrated in vacuo. The residue was purified by flash column chromatography (80 g Si column eluted with 0-25% ethyl acetate in DCM) to afford Intermediate 72C (2.03 g, 5.47 mmol) as a yellow foam. (0308) LCMS (Method U2) Rt=1.39 min, m/z 372.2 [M+H]+
2.03 g
Intermediate 7C. 1-(4-Cyano-phenyl)-1H-imidazole-2-carboxylic acid N'-(3-trifluoromethyl-phenyl)-hydrazide A mixture of 3-trifluoromethyl-phenylhydrazine hydrochloride (1.98 g, 9.3 mmol) and bis(trimethylaluminium)-1,4-diazabicyclo[2.2.2]octane adduct (2.38 g, 9.3 mmol) in dry THF (30 mL) was stirred at 40 C. for 1 h. A suspension of Intermediate 7B (1.40 g, 6.7 mmol) in dry THF (35 mL) was added and the mixture then heated at reflux for 16 h. After allowing to cool to ambient temperature the mixture was quenched by cautious dropwise addition with 4M hydrochloric acid (3.0 mL) and stirred vigorously for 5 minutes then made basic by addition of 5% aqueous potassium carbonate solution (30 mL). The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3*30 mL). The combined organic phase was washed with brine (30 mL), dried (sodium sulfate) and concentrated in vacuo. The residue was purified by flash column chromatography (80 g Si column eluted with 0-25% ethyl acetate in DCM) to afford Intermediate 7C (2.03 g, 5.47 mmol) as a yellow foam. LCMS (Method U2) Rt=1.39 min, m/z 372.2 [M+H]+.
2-(4-cyanophenyl)-2H-pyrazole-3-carboxylic acid[ No CAS ]
[ 3107-33-3 ]
2-(4-cyanophenyl)-2H-pyrazole-3-carboxylic acid N'-(3-trifluoromethylphenyl)hydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; dichloromethane; at 20℃; for 20h;
HOBt (11.60 g, 75.72 mmol) was added at RT to a vigorously stirred, slightly cloudy, solution of Intermediate A (12.60 g, 59.10 mmol) in a mixture of dry DCM (125 mL) and dry THF (190 mL). EDCI (14.70 g, 76.76 mmol) was then added, followed by Et3N (19.0 mL, 136.3 mmol) to give a thick slurry. A suspension of <strong>[3107-33-3]3-(trifluoromethyl)phenylhydrazine hydrochloride</strong> (13.20 g, 62.09 mmol) in dry THF (50 mL) was then added and the resulting slurry stirred at RT for 20 hr. The mixture was poured into water (1 L) with vigorous stirring, and the resulting suspension stirred at RT for 30 min. The suspended solid was collected by filtration through a porosity-3 glass sinter filter funnel, the filter cake washed with water (50 mL) and sucked dry. The solid was then vacuum dried at 45 C./10 mbar over phosphorus pentoxide in a vacuum oven, to give Intermediate B as an off-white solid; 14.76 g, 67% yield. (0192) LCMS (Method 7): Rt=3.18 min, m/z 372 [M+H]+
2-(4-cyano-phenyl)-2H-[1,2,4]triazole-3-carboxylic acid methyl ester[ No CAS ]
[ 3107-33-3 ]
2-(4-cyano-phenyl)-2H-[1,2,4]triazole-3-carboxylic acid N'-(3-trifluoro-methyl-phenyl)-hydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.48 g
Intermediate 8C. 2-(4-Cyano-phenyl)-2H-[1,2,4]triazole-3-carboxylic acid N'-(3-trifluoro-methyl-phenyl)-hydrazide A mixture of 3-trifluoromethyl-phenylhydrazine hydrochloride (1.71 g, 8.03 mmol) and bis(trimethylaluminium)-1,4-diazabicyclo[2.2.2]octane adduct (2.06 g, 8.03 mmol) in dry THF (30 mL) were stirred at 40 C. for 1 h. A suspension of Intermediate 8B (1.22 g, 5.3 mmol) in dry THF (25 mL) was added and the mixture was then heated at reflux for 16 h. The cold mixture was treated by cautious dropwise addition with 4M hydrochloric acid (3.0 mL) and stirred vigorously for 5 minutes then made basic by addition of 5% aqueous potassium carbonate solution (30 mL). The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3*30 mL). The combined organic phase was washed with brine (50 mL), dried (sodium sulfate) and concentrated in vacuo. The residue was purified by flash column chromatography (40 g Si column eluted with 0-25% ethyl acetate in DCM) to afford Intermediate 8C (1.48 g, 3.98 mmol) as a cream solid. LCMS (Method U2) Rt=1.39 min, m/z 373.1 [M+H]+.
propionic acid N'-(3-trifluoromethyl-phenyl)-hydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With triethylamine; In dichloromethane; at 20℃; for 2h;
Intermediate 15A. Propionic acid N'-(3-trifluoromethyl-phenyl)-hydrazide A suspension of 3-(trifluoromethyl)-phenylhydrazine hydrochloride (9.6 g, 45.2 mmol) was formed in DCM (300 mL) at room temperature. Triethylamine (4.08 mL, 100 mmol) was added followed by the dropwise addition of propionyl chloride (13.9 mL, 46.7 mmol). The mixture was stirred for 2 h at room temperature. The mixture was washed with aqueous sodium carbonate (100 mL, 50% saturated) and brine (100 mL) then dried (Na2SO4), filtered and evaporated. The residue was recrystallized from a 1:1 mixture of cyclohexane:ethyl acetate giving a first crop of Intermediate 15A as a white solid (3.09 g). The filtrate was concentrated dissolved in a mixture of ethyl acetate, cyclohexane and DCM then purified by flash chromatography on a 340 g Biotage column eluting with a gradient of 20%-80% ethyl acetate in cyclohexane. Concentration of the appropriate fractions gave further Intermediate 15A (5.22 g, 88% yield in total). LCMS (Method U2) Rt=1.09 min, m/z 233 [M+H]+
In N,N-dimethyl-formamide; at 50℃; for 2h;Inert atmosphere;
General procedure: To a stirred solution of the carbonyl compound (1.0 mmol) in DMF (5 mL) at 50 C (oil bath)was added ArNHNH2.HCl (3.0 mmol for 5, 2.0 mmol for 6) and the solution was stirred until TLC(20% EtOAc in hexanes) indicated complete conversion (roughly 2 h). The crude reaction mixture wasadded to water and extracted with EtOAc (2 Chi 15 mL). The combined organic layers were washedwith water and saturated aq NaCl, dried (MgSO4), filtered, and concentrated under vacuum to givethe crude hydrazones. The crude products were stirred with 20% ether/pentane for 1 h, filtered anddried to give arylhydrazones 9 and 10. Characterization data for these materials are given in the ESI.
In N,N-dimethyl-formamide; at 50℃; for 2h;Inert atmosphere;
General procedure: To a stirred solution of the carbonyl compound (1.0 mmol) in DMF (5 mL) at 50 C (oil bath)was added ArNHNH2.HCl (3.0 mmol for 5, 2.0 mmol for 6) and the solution was stirred until TLC(20% EtOAc in hexanes) indicated complete conversion (roughly 2 h). The crude reaction mixture wasadded to water and extracted with EtOAc (2 Chi 15 mL). The combined organic layers were washedwith water and saturated aq NaCl, dried (MgSO4), filtered, and concentrated under vacuum to givethe crude hydrazones. The crude products were stirred with 20% ether/pentane for 1 h, filtered anddried to give arylhydrazones 9 and 10. Characterization data for these materials are given in the ESI.
General procedure: The pyrazolo[4,3-c]pyridin-4-one derivatives were synthesizedby using compound 15 as starting material in two steps. Infirst step, the compound 15 (1 mmol, 137 mg) was dissolved inethanol (20 mL) and substituted phenylhydrazine hydrochloride(1.1 equivalent) was added. The reaction mixture was stirred atroom temperature for 2 h. The completion of reaction was monitoredby TLC. The resulted reaction mixture was allowed to cool toroom temperature. The solvent was evaporated under vacuum; ethanol (5 mL) was added and sonicated for 30 s to produce suspension.The resulted suspensions were kept in refrigerator for 1 hto settle down the suspended particles. The suspended particleswas filtered out and used for second step without further purification.In second step, the resulted solid was poured in boilingnitrobenzene at 210 C and stirred at same temperature for 15 min[27]. The completion of reaction was monitored by TLC. After thecompletion, the reaction mixture was allowed to cool to roomtemperature followed by silica gel column chromatography toisolate pure pyrazolo[4,3ec]pyridine4eone derivatives (12a-12p).