* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6842 - 6846
[2] European Journal of Medicinal Chemistry, 2017, vol. 127, p. 100 - 114
3
[ 455-19-6 ]
[ 711-33-1 ]
Reference：
[1] Journal of Organic Chemistry, 2003, vol. 68, # 4, p. 1594 - 1596
[2] Journal of Medicinal Chemistry, 1995, vol. 38, # 20, p. 3918 - 3932
[3] Synthetic Communications, 1989, vol. 19, # 9-10, p. 1735 - 1744
[4] Organic Letters, 2015, vol. 17, # 24, p. 6102 - 6105
[5] Patent: WO2006/112565, 2006, A1,
4
[ 455-19-6 ]
[ 68755-37-3 ]
Reference：
[1] Tetrahedron, 2007, vol. 63, # 2, p. 389 - 395
[2] Chemistry - A European Journal, 2015, vol. 21, # 37, p. 13052 - 13057
5
[ 455-19-6 ]
[ 35852-58-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 14, p. 3347 - 3351
6
[ 455-19-6 ]
[ 1891-90-3 ]
Yield
Reaction Conditions
Operation in experiment
54%
Stage #1: at -33℃; for 1 h; Inert atmosphere Stage #2: at -33℃; for 1 h; Inert atmosphere; Reflux
General procedure: Under an argon atmosphere, liquid NH3 (25 mL) was condensedin a two-neck round-bottom flask immersed in a dry ice coolingbath and equipped with a dry ice reflux condenser. Aldehyde(7.34 mmol) was added, and the resulting solution (or suspension)was stirred for 1 h. KMnO4 (7.34 mmol, 1.16 g) was added,the cooling bath was removed, and the reaction mixture wasstirred for another hour with gentle reflux of NH3. Na2SO3 (22.0mmol, 2.78 g) was added, the reflux condenser was removed,and the NH3 was allowed to evaporate spontaneously. The darkbrownresidue was treated with 6 M HCl (30 mL), and theresulting precipitate was filtered, washed with H2O (100 mL)and sat. aq NaHCO3 (20 mL). All products were recrystallizedfrom EtOH.
54%
Stage #1: at -33℃; for 1 h; Inert atmosphere Stage #2: for 1 h; Inert atmosphere; Reflux
General procedure: Under an argon atmosphere, liquid NH3 (25 mL) was condensedin a two-neck round-bottom flask immersed in a dry ice coolingbath and equipped with a dry ice reflux condenser. Aldehyde (7.34 mmol) was added, and the resulting solution (or suspension)was stirred for 1 h. KMnO4 (7.34 mmol, 1.16 g) was added,the cooling bath was removed, and the reaction mixture wasstirred for another hour with gentle reflux of NH3. Na2SO3 (22.0mmol, 2.78 g) was added, the reflux condenser was removed,and the NH3 was allowed to evaporate spontaneously. The darkbrownresidue was treated with 6 M HCl (30 mL), and theresulting precipitate was filtered, washed with H2O (100 mL)and sat. aq NaHCO3 (20 mL). All products were recrystallizedfrom EtOH.
Reference：
[1] Journal of Chemical Research, 2012, vol. 36, # 8, p. 460 - 462
[2] RSC Advances, 2015, vol. 5, # 55, p. 44524 - 44529
[3] RSC Advances, 2016, vol. 6, # 43, p. 37093 - 37098
[4] Synlett, 2014, vol. 25, # 9,
[5] Synlett, 2015, vol. 26, # 1, p. 84 - 86
[6] Organic and Biomolecular Chemistry, 2014, vol. 12, # 3, p. 414 - 417
[7] Journal of Organic Chemistry, 2012, vol. 77, # 18, p. 8007 - 8015,9
[8] Journal of Organic Chemistry, 2012, vol. 77, # 18, p. 8007 - 8015
[9] Organic Letters, 2007, vol. 9, # 1, p. 73 - 75
7
[ 455-19-6 ]
[ 455-18-5 ]
[ 1891-90-3 ]
Yield
Reaction Conditions
Operation in experiment
79 %Chromat.
With hydroxylamine hydrochloride; zinc trifluoromethanesulfonate In toluene at 100℃; for 24 h;
General procedure for the synthesis of nitriles: A pressure tube was charged with an appropriate amount of Zn(OTf)2 (0.036 mmol, 5.0 mol percent), the corresponding aldehyde (0.72 mmol) and hydroxylamine hydrochloride (1.2 equiv, 0.86 mmol). After the addition of toluene (2.0 mL) the reaction mixture was stirred in a preheated oil bath at 100 °C for 24 h. The mixture was cooled in an ice bath and biphenyl (internal standard) was added. The solution was diluted with dichloromethane and an aliquot was taken for GC-analysis (30 m Rxi-5 ms column, 40-300 °C). The solvent was carefully removed and the residue was purified by column chromatography (n-hexane/ethyl acetate). The analytical properties of the corresponding nitriles are in agreement with the literature.
With Amberlite IRC-84; In xylene, o-; at 140℃; for 6h;
A suspension of 4-trifluoromethylbenzaldehyde (819 1L, 6.00 mmol), 3-methyl-4- NITROANILINE (609 mg, 4.00 mmol), and Amberlite IRC-84 (200 mg, H+ form) in o- xylene (4 ML) was heated under nitrogen at 140C for 6 hours. It was then cooled to room temperature, diluted with ethyl acetate (5 mL), dried over sodium sulfate, filtered, and volatiles were evaporated. The residue was dissolved in acetonitrile (20 ML) and sodium cyanoborohydride (503 mg, 8.00 mmol) was added in one portion, followed by acetic acid (1 ML) in several portions over 15 minutes. After a further 30 minutes solvents were evaporated and the residue was partitioned between ethyl acetate (50 ML), brine (25 mL), and 10% aqueous potassium carbonate (25 mL). The organic layer was dried over sodium sulfate, solvents were evaporated, and the residue was purified on a FlashMaster system (silica, eluted with heptane/ethyl acetate mixtures) to yield the title compound as a yellow powder (1.02 g, 82%). TH NMR (CDC13) : 2.59 (s, 3H), 4.50 (d, 2H), 4.76 (br. T, 1H), 6.40 (d, 1H), 6.43 (dd, 1H), 7.45 (d, 2H), 7.63 (d, 2H), 8.05 (d, 1H).
With sodium hydroxide; hydrogen;platinum; In acetic acid;
4-Trifluoromethylbenzaldehyde (20.0 g) was dissolved in acetic acid (100 ml) and treated with hydrogen in the presence of platinum (0.5 g) at ambient temperature and pressure for 10 hours. The solution was filtered, poured into water (400 ml), basified by addition of aqueous sodium hydroxide solution (2 M), extracted with ether (3*100 ml). The combined extracts were washed with water (2*100 ml), dried over anhydrous magnesium sulphate, evaporated to dryness. The residue was distilled to give 4-trifluoromethyltoluene (14.3 g) b.p. 131°-132° C. as a colourless mobil liquid.
EXAMPLE 2 2,2'-[1,2-Ethanediylbis(thio)]bis[4,5-bis(4-trifluoromethylphenyl)-1H-imidazole] A solution of p-trifluoromethylbenzaldehyde (50 g, 0.24 mol), <strong>[54016-70-5]3-ethyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium bromide</strong> (3.6 g, 0.014 mol) and triethylamine (8.8 g. 0.087 mol) in ethanol (200 ml) was refluxed 1.5 hours under an argon atmosphere. After cooling, the mixture was poured into water and extracted immediately into chloroform, taking precautions to exclude air as much as possible. The chloroform extracts were washed with 5percent aqueous sodium bicarbonate solution and water and then dried (MgSO4). Removal of the solvent at reduced pressure gave a nearly quantitative yield of crude 4,4'-di(trifluoromethyl)benzoin which was used without further purification.
With hydrogen bromide; sodium hydrogencarbonate; In ethanol; water;
(Third step) Ethanol (200 ml) was added to the above 4-trifluoromethylbenzylaldehyde (17.5 g, 93 mmol), followed by cooling the mixture down to 0C in a nitrogen atmosphere, adding thereto sodiumboronhydride (1.78 g, 47.1 mmol) so that the liquid temperature might not exceed 10C, stirring the mixture at 0C for 2 hours, extracting the resulting product with ethyl acetate, washing the organic layer successively with a saturated, aqueous solution of sodium bicarbonate and water, drying over magnesium sulfate, distilling off the solvent, adding an aqueous solution of HBr (47%) (100 ml) to the residue (about 18 g), refluxing the mixture for 7 hours and distilling under reduced pressure by means of Vigoureux tube, to obtain 2-(4-trifluoromethylphenyl)bromoethane (19.5 g, 77.1 mmol) (b.p.: 94C under 9 Torr). Yield: 82.9%.
With magnesium sulfate; In acetonitrile; at 20℃;Reflux;
To a stirred mixture of 4-(trifluoromethyl)benzaldehyde (2.8 g, 16.1 mmol) and anhydrous Magnesium sulfate (16 g, 134 mmol) in anhydrous acetonitrile (200 mL) was added <strong>[59434-19-4]4-aminoisobenzofuran-1(3H)-one</strong> (2 g, 13.4 mmol) at room temperature. After the addition, the mixture was stirred at reflux for overnight. The mixture was filtered and the cake was washed with ethyl acetate (50 mL×3). The filtrate was concentrated to give crude product. The crude product was washed with petroleum ether and re-crystallized from ethyl acetate to give the title compound (2.8 g, yield: 68%). LC-MS (ESI) m/z: 306 (M+1)+
68%
With magnesium sulfate; In acetonitrile; at 20℃;Reflux;
Example 105A(E)- Example 106A(£,)-4-(4-(Trifluoromethyl)benzylideneamino)isobenzofuran-l(3H)-one[00707] To a stirred mixture of 4-(trifluoromethyl)benzaldehyde (2.8 g, 16.1 mmol) and anhydrous Magnesium sulfate (16 g, 134 mmol) in anhydrous acetonitrile (200 mL) was added 4- aminoisobenzofuran- l(3H)-one (2 g, 13.4 mmol) at room temperature. After the addition, the mixture was stirred at reflux for overnight. The mixture was filtered and the cake was washed with ethyl acetate (50 mL x 3). The filtrate was concentrated to give crude product. The crude product was washed with petroleum ether and re-crystallized from ethyl acetate to give the title compound (2.8 g, yield: 68%). LC- MS (ESI) m/z: 306 (M+l)+.
General procedure: A 10 mL glass tube containing the 4-carboxyphenylboronic acid ester (248 mg, 1.00 mmol), benzaldehyde (0.10 mL, 1.00 mmol), and D.I. H2O (1 mL) was first microwave irradiated for 6 min (45 C, 150 W) under medium speed magnetic stirring. Cyclohexyl isocyanide (3, 0.124 mL, 1.00 mmol) was then added to the reaction mixture. The additional microwave irradiation was applied for 120 min (45 C, 150 W) under medium speed magnetic stirring. After being diluted in dichloromethane, the resulted reaction mixture was washed twice with a saturated aqueous solution of NaHCO3 and with brine. The resulted organic layer was collected and dried over MgSO4 and concentrated in vacuo. The crude product was then dissolved in ethyl acetate (3 mL) prior the slow addition of n-hexane. The resulting precipitate was formed and collected by filtration affording the desired product in 88% yield.
General procedure: To 12 mL of KOH in absolute EtOH (5%, w/v), compound 7 [16] (4.46 mmol) and the appropriate substituted aromatic aldehyde (4.46 mmol) were added (4-cyanobenzaldehyde was used to obtain compound 8l). The reaction was refluxed under stirring for 3-5 h. After cooling, the mixture was concentrated in vacuo, diluted with ice-cold water (20-25 mL), and acidified with 2 N HCl. The suspension was extracted with CH2Cl2 (3×25 mL). Removal of the solvent resulted in compounds 8a-l, which were purified by crystallization in ethanol. For compounds 8e,k, an additional purification step was performed by flash column chromatography using cyclohexane/ethyl acetate 2:1 (for 8e) or NH4OH/EtOH/CH2Cl2/petroleum ether 4:25:150:50 (for 8k) as eluents.
N,N'-((4-(trifluoromethyl)phenyl)methylene)bis(3,5-bis(trifluoromethyl)benzamide)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
8%
With chloro-trimethyl-silane; In N,N-dimethyl-formamide; at 50℃; for 18h;Inert atmosphere;
General procedure: Benzamide (476 mg, 3.9 mmol) and benzaldehyde(203 mL, 2 mmol) were dissolved in dry DMF (8 mL).TMSCl (507 mL, 4mmol) was added as a catalyst and wasstirred at 50 °C for 18 h under nitrogen. Awhite precipitatewas formed with the addition of a few drops of water andwas purified by stirring with diethyl ether for 30 min. Theproduct was isolated using vacuum filtration. Yield 31percent
6-fluoro-2-[2-(4-(trifluoromethyl)benzylidene)hydrazino]benzothiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With acetic acid; In ethanol; at 80℃; for 0.166667h;Microwave irradiation;
General procedure: A mixture of compound 2 (0.0549 g, 0.0003 mol), the appropriate aromatic aldehyde (0.00033 mol) and glacial acetic acid (0.1 mL) in ethanol (5 mL) was heated under microwave (20 W) at 80 °C for 10 min. On cooling, the precipitated solid was collected by filtration, washed with water, dried and crystallized to give compounds 3-29.
(2E)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-[4-(trifluoromethyl)phenyl]prop-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
With potassium hydroxide; In ethanol; for 10h;
General procedure: Equimolar quantities of substituted benzaldehyde and 1-(2H-1,3-benzodioxol-5-yl)ethan-1-one or <strong>[2879-20-1]1-(2,3-dihydro-1,4-benzodioxin-6-yl)ethan-1-one</strong> were dissolved in 40% KOH and ethanol. The reactionmixture was then stirred for 10 h and poured into ice-cold water. Theprecipitated product was washed with water, dried, and recrystallizedfrom ethanol.
With sodium hydroxide; In ethanol; at 20℃;
General procedure: To <strong>[2879-20-1]1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-one</strong>(A) (1 mmol) alcohol solution (5 mL) was added substituted benzaldehyde(1 mmol). After dissolution, 50% NaOH (0.5 mL) was added. After confirming the completion of the reaction by thin layer chromatography, the sediment was filtered, washed with ethanol and dried to obtain chalcone
1,4,6,7,8,9-hexahydro-3-methyl-1-phenyl-7-thioxo-4-[4-(trifluoromethyl)phenyl]-5H-pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidin-5-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With piperidine; In ethanol; at 80℃; for 3h;
General procedure: A mixture of 0.174 g of 3-methyl-1-phenyl-2-pyrazoline-5-one (1, 1.0 mmol), 0.150 g of 4-chlorobenzaldehyde (2,1 mmol), 0.160 g of 6-amino-2-thiouracil (3, 1 mmol) and 9.8 mm3 of piperidine as a catalyst (10%) in 8 cm3 of ethanol in a 100-cm3 round-bottomed flask fitted with areflux condenser was heated with stirring in an oil bath maintained at 80 C. After the complete appearance of the white solid and monitored by TLC, the reaction mixture was cooled to room temperature and resulting solid product was filtered, washed with ethanol to give products 4a-4r.
1-(3-chlorophenyl)-1,4,6,7,8,9-hexahydro-3-methyl-7-thioxo-4-[4-(trifluoromethyl)phenyl]-5H-pyrazolo[4′,3′:5,6]-pyrido[2,3-d]pyrimidin-5-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With piperidine; In ethanol; at 80℃; for 3h;
General procedure: A mixture of 0.174 g of 3-methyl-1-phenyl-2-pyrazoline-5-one (1, 1.0 mmol), 0.150 g of 4-chlorobenzaldehyde (2,1 mmol), 0.160 g of 6-amino-2-thiouracil (3, 1 mmol) and 9.8 mm3 of piperidine as a catalyst (10%) in 8 cm3 of ethanol in a 100-cm3 round-bottomed flask fitted with areflux condenser was heated with stirring in an oil bath maintained at 80 C. After the complete appearance of the white solid and monitored by TLC, the reaction mixture was cooled to room temperature and resulting solid product was filtered, washed with ethanol to give products 4a-4r.
2-amino-6-hydroxy-5,8-dioxo-4-(4-(trifluoromethyl)phenyl)-7-undecyl-5,8-dihydro-4H-chromene-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With triethylamine; In ethanol; for 1.5h;Reflux;
General procedure: To a mixture of 0.1mmol of malononitrile, 0.1mmol of the corresponding aldehyde, and 10mol % of Et3N in 5mL of EtOH were added 30mg of <strong>[550-24-3]embelin</strong> (0.1mmol). The reaction mixture was stirred and refluxed until disappearance of the starting benzoquinone. The solvent was removed under vacuum, and the crude product was purified by preparative-TLC to yield the corresponding dihydropyran derivative.
(1R,4R)-N-benzyl-N-[2-(tert-butylamino)-2-oxo-1-[4-(trifluoromethyl)phenyl]ethyl]-4-isopropylcyclohexane-1-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
General procedure: A solution of amine 6 (1 mmol), aldehyde 7 (1 mmol), andacid 8 (1 mmol) in 0.2 cm3 EtOH was allowed to stir, after6-h isocyanide 9 (1 mmol) was added. The mixture wasstirred for 48 h at ambient temperature. The progress of thereaction was monitored using TLC (n-hexane/ethyl acetate5:1). After completion of the reaction and evaporation, theprecipitate was filtered.
2-methyl-3-((4-(trifluoromethyl)benzylidene)amino)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In methanol; at 60℃; for 3h;
General procedure: The general condensation reaction to form Schiff base underwentaddition-elimination procedure. To a vial, 1 equiv. (1 mmol)of aromatic aldehyde (A moiety) and 1 equiv. of aromatic primaryamine (B moiety) were added and dissolved in 6 mL of absolutemethanol. After heating and stirring at 60 C for 3 h (or longerbased on TLC), the mixture was set for 48-72 h to generate thesolid Schiff base. Collecting the crystal from the solvent andchecked with TLC, if aromatic aldehyde or aromatic primary amine presented, removing them by column chromatography with 1:4ethyl acetate: petroleum ether to obtain pure product (80-90%).
2-amino-8,8-dimethyl-5-(4-(trifluoromethyl)phenyl)-5,8,9,10-tetrahydropyrimido[4,5-b]quinoline-4,6(3H,7H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With MIL-100(Cr)/NHEtN(CH2PO3H2)2; In N,N-dimethyl-formamide; at 100℃; for 0.333333h;
General procedure: In a 10 mL round-bottomed flask, a mixture of aldehyde (1 mmol),uracil derivatives (1 mmol), dimedone (1 mmol, 0.14 g) and MIL-100(Cr)/NHEtN(CH2PO3H2)2 (0.01 g) were stirred at 100 C in DMF(5 ml) as solvent. After completion of the reaction as monitored by TLC,the reaction mixture was cooled to room temperature. Then, the catalystwas separated from the solution of reaction mixture by centrifugation(1000 rpm). Then, H2O (5 ml) was added to reaction mixtureto give the solid sediment. The prepared solid was collected by simplefiltration. The crude product was purified by recrystallization fromEtOAc (Scheme 3). The pure products were identified by FT-IR, 1H, 13CNMR and mass spectra.
The mixture of l-(tert-butyl) 2-methyl (S)-piperazine-l,2-dicarboxylate (2.4 g, 10 mmol), 4-(trifluoromethyl)benzaldehyde, 28A, (1.7 g,l0 mmol), and 1H-benzo[d][l,2,3]triazole, 39A, (1.2 g, 10 mmol) in toluene (100 mL) was heated at 110 C for 16 hours, with azeotropic removal of water. The mixture was concentrated to give a crude Compound 39B: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.
methyl 4-bromo-2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-6-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With sodium metabisulfite; In N,N-dimethyl-formamide; at 130℃; for 12h;
To a solution of compound 89 (200 mg, 0.816 mmol) in A/TV-dimethylformamide (10 mL) was added 4-(trifluoromethyl)benzaldehyde (0.222 mL, 1.632 mmol) and sodium metabisulfite (310 mg, 1.632 mmol) at room temperature, and this reaction mixture was stirred at 130 C for 12 h. After cooling, the reaction mixture was partitioned ethyl acetate (20 mL) and water (20 mL), and extracted with ethyl acetate (20 mL x 2). The combined organic layer was washed brine (5 mL), dried over MgSGi, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=6: l) to afford compound 90 (212 mg, 65%) as a white solid; NMR (400 MHz, CDCfi) d 8.38 (broad s, 1H), 8.25-8.18 (m, 3H), 7.82 (d, J =8.16 Hz, 2H), 3.97 (s, 3H); MS (ESI, m/z) 399.0, 401.0 [M+l]+; ESI-HRMS calcd. m/z for Ci6HnN202F379Br 398.9956, found 398.9950 [M+lf.
2-(4-(trifluoromethyl)phenyl)-3-((2,4,4-trimethylpentan-2-yl)amino)-1H-imidazo[1,2-b]pyrazole-7-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With trifluoroacetic acid; In ethanol; water; at 20℃; for 6.0h;
General procedure: To a suspension of pyrazole of general formulas (I) or (G) (0.50 mmol) in EtOH/water mixture (1 :1, lmL) aldehyde of general formula (II) (0.55 mmol), TFA (20 mol%), and isocyanide of general formula (III) (0.55 mmol) were added and stirred at room temperature for 15 minutes. (0136) Then the desired compound of general formulas (IV) or (IV?) was isolated by simple filtration followed by washing with water, then with EtOH.
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