* 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 lithium hexamethyldisilazane In tetrahydrofuran at 0 - 20℃; Stage #2: With hydrogenchloride In water; ethyl acetate
Into a 500 mL flask was weighed 20.0 g (181.6 mmol) of 2-acetylfuran, 50 mL of THF, and 24 mL of ethyl trifluoroacetate. The resulting solution was cooled to 0-3 °C in an ice bath and 1.0 M LiHMDS was added (200 mL). The reaction was allowed to warm to room temperature where it remained overnight. The reaction was then concentrated in vacuo to remove THF and the residue was washed into a separatory funnel with ethyl acetate and 1.0 M HCl. The ethyl acetate was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The resulting 4,4,4-trifluoro-1-furan-2-yl-butane-1,3-dione was recovered as a brown semisolid, yield: 32.5 g (100+percent).
82.6%
With sodium In ethanol at 20℃;
General procedure: Ethyl trifluoroacetate 9 (0.047 mol) and 2-acetyl furan (0.047 mol) were added dropwise to a solution of ethanol (55 mL) containing thinly sliced sodium (0.047 mol), and stirred over night at room temperature. Then,the solution was poured in ice-water containing concentrated sulfuric acid. The solution was extracted with dichloromethane, dried, concentrated and purified on a column of silica using a 10percent gradient of ethyl acetate in hexanes to afford 10 (82.6percenty). 10(0.020 mmol) was added drop wise into a solution of hydrazinobenzene(0.020 mmol), ethanol(50ml)and acetic acid(0.5 ml), then refluxed.The cooled mixture was concentrated under vacumm and the pyrazole11(66.7percenty) was obtained after purification by silicagel(a5percentgradient of ethyl acetate in hexanes). Pyrazole 11(0.043mol) was dissolved in acetone (120 ml) and KMnO4(0. 071mmol) was added. This mixture was heated at 60°C for 3 h and cooled to room temperature.Then isopropyl alcohol was added and stirred at room temperature overnight. The reaction mixture was filtered and concentrated. The residue was dissolved in 1N NaOH, washed and acidified with 2N HCl solution to obtain 12(46.3 percent y).The amide derivatives 13-14 were prepared through acyl chlorides derived from 12. A solution of 12 (0.004mol) in thionyl chloride(10mL) was refluxed for 5 hand then concentrated under vacuum. The crude acylchloride was added dropwise to a cooled solution(0°C) of substituted aniline(0.004mol) and TEA (0.008mol) in dichloromethane (10mL). The mixture was stirred over night at room temperature, and then purified on a column of silica using a gradient of e thyl acetate in hexanes to afford the pure products.
Reference:
[1] Patent: WO2008/73825, 2008, A1, . Location in patent: Page/Page column 134
[2] Chinese Chemical Letters, 2016, vol. 27, # 4, p. 566 - 570
[3] Synthesis, 1997, # 11, p. 1321 - 1324
[4] Journal of the American Chemical Society, 1950, vol. 72, p. 2948,2949
[5] Journal of Fluorine Chemistry, 2002, vol. 118, # 1-2, p. 135 - 147
[6] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 2, p. 343 - 346
[7] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 15, p. 5370 - 5383
[8] Journal of Fluorine Chemistry, 2006, vol. 127, # 6, p. 780 - 786
[9] Russian Journal of General Chemistry, 2007, vol. 77, # 10, p. 1732 - 1741
[10] Chemistry of Heterocyclic Compounds, 2008, vol. 44, # 5, p. 606 - 614[11] Khim. Geterotsikl. Soedin., 2008, # 5, p. 765 - 775,11
[12] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 6, p. 1581 - 1588
[13] Advanced Synthesis and Catalysis, 2015, vol. 357, # 14-15, p. 3076 - 3080
[14] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 545 - 551
[15] Chinese Chemical Letters, 2018, vol. 29, # 6, p. 911 - 914
2
[ 1192-62-7 ]
[ 326-90-9 ]
Yield
Reaction Conditions
Operation in experiment
39%
Stage #1: With potassium <i>tert</i>-butylate In benzene Stage #2: at 5 - 20℃; for 16.3333 h; Stage #3: With sulfuric acid In waterCooling with ice
[00141] Scheme 6: Synthesis of the diketone intermediate 4,4,4-trifluoro- 1 -(furan-2- vDbutane- 1 ,3-dione 19 6 1; [00142] The diketone 19 was synthesized from acetylfuran and trifluoracetate to obtain the 4,4,4-trifluoro-1-(furan-2-yl)butane-1,3-dione 19 product as follows. 2- Acetylfuran 18 (11.0 g, 210 mmol) was dissolved in benzene (210 mL). At room temperature was added KOtBu (23.6 g, 210 mol). The resulting red solution was cooled to 5° C. Ethyl trifluoracetate 6 (25 mL, 29.8 g, 210 mmol) was added dropwise in approximately 20 minutes keeping the temperature below 15 °C. Then the mixture was stirred for 16 hours at room temperature. The mixture was poured in ice- water (300 mL) containing concentrated sulfuric acid (5 g). The aqueous mixture was extracted with tBME (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4) and concentrated to give a dark brown oil (20.8 g). The crude product was purified by kugelrohr distillation to give compound 19 (17.0 g, 39percent) as a yellowish oil.
Stage #1: 1-(2-furyl)-1-ethanone; ethyl trifluoroacetate, With lithium hexamethyldisilazane In tetrahydrofuran at 0 - 20℃;
Stage #2: With hydrogenchloride In water; ethyl acetate
1.a
Into a 500 mL flask was weighed 20.0 g (181.6 mmol) of 2-acetylfuran, 50 mL of THF, and 24 mL of ethyl trifluoroacetate. The resulting solution was cooled to 0-3 °C in an ice bath and 1.0 M LiHMDS was added (200 mL). The reaction was allowed to warm to room temperature where it remained overnight. The reaction was then concentrated in vacuo to remove THF and the residue was washed into a separatory funnel with ethyl acetate and 1.0 M HCl. The ethyl acetate was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The resulting 4,4,4-trifluoro-1-furan-2-yl-butane-1,3-dione was recovered as a brown semisolid, yield: 32.5 g (100+%).
100%
With sodium ethanolate In ethanol for 2h; Reflux;
4.4.1 General procedure for the synthesis of β-diketones
General procedure: To a solution of freshly prepared NaOEt from Na (1.67 equiv.) and absolute EtOH (15mL), aryl/alkyl methylketone (1.0 equiv.) was added. After 5min, ethyl trifluoroacetate (1.07 equiv.) was added, and the reaction mixture was then stirred for 2h under reflux. When possible, the product was isolated by precipitation of the reaction mixture, which was poured onto a solution of 1M HCl (25mL) in ice (25g), with the crude product collected by filtration and further used without purification. If a precipitate was not formed, extraction with EtOAc (3×15mL) from the water phase was performed. The combined organic phases were washed with brine (30mL) and dried over anhydrous Na2SO4 before the final evaporation of solvents under reduced pressure. 4,4,4-trifluoro-1-(furan-2-yl)-3-hydroxybut-2-en-1-one (13a): Yield quantitative; brown transparent oil; 1H NMR (400MHz, CDCl3): δ (ppm)=6.50 (s, 1H,=CH), 6.64 (dd, J1=1.7Hz, J2=3.6Hz, 1H, furanyl-H4), 7.35 (dd, J1=0.8Hz, J2=3.6Hz, 1H, furanyl-H3), 7.69 (dd, J1=0.8Hz, J2=1.7Hz, 1H, furanyl-H5), 1H from OH is exchanged; MS (ESI-) m/z calc. for C8H4F3O3 [M-H]- 205.0, found 204.9; Rf=0.51 (EtOAc/n-Hex, 2:1, v/v).
82.6%
With sodium In ethanol at 20℃;
General procedure for synthesis of compounds 13-14
General procedure: Ethyl trifluoroacetate 9 (0.047 mol) and 2-acetyl furan (0.047 mol) were added dropwise to a solution of ethanol (55 mL) containing thinly sliced sodium (0.047 mol), and stirred over night at room temperature. Then,the solution was poured in ice-water containing concentrated sulfuric acid. The solution was extracted with dichloromethane, dried, concentrated and purified on a column of silica using a 10% gradient of ethyl acetate in hexanes to afford 10 (82.6%y). 10(0.020 mmol) was added drop wise into a solution of hydrazinobenzene(0.020 mmol), ethanol(50ml)and acetic acid(0.5 ml), then refluxed.The cooled mixture was concentrated under vacumm and the pyrazole11(66.7%y) was obtained after purification by silicagel(a5%gradient of ethyl acetate in hexanes). Pyrazole 11(0.043mol) was dissolved in acetone (120 ml) and KMnO4(0. 071mmol) was added. This mixture was heated at 60°C for 3 h and cooled to room temperature.Then isopropyl alcohol was added and stirred at room temperature overnight. The reaction mixture was filtered and concentrated. The residue was dissolved in 1N NaOH, washed and acidified with 2N HCl solution to obtain 12(46.3 % y).The amide derivatives 13-14 were prepared through acyl chlorides derived from 12. A solution of 12 (0.004mol) in thionyl chloride(10mL) was refluxed for 5 hand then concentrated under vacuum. The crude acylchloride was added dropwise to a cooled solution(0°C) of substituted aniline(0.004mol) and TEA (0.008mol) in dichloromethane (10mL). The mixture was stirred over night at room temperature, and then purified on a column of silica using a gradient of e thyl acetate in hexanes to afford the pure products.
54%
With potassium <i>tert</i>-butylate In benzene for 15h; Ambient temperature;
With diethyl ether; sodium ethanolate
Stage #1: ethyl trifluoroacetate, With sodium methylate In diethyl ether for 0.0833333h;
Stage #2: 1-(2-furyl)-1-ethanone In diethyl ether at 20℃;
Stage #1: 1-(2-furyl)-1-ethanone With sodium methylate In methanol at 20℃; for 1h;
Stage #2: ethyl trifluoroacetate, In methanol for 24h; Heating;
Stage #1: ethyl trifluoroacetate, With sodium methylate In diethyl ether for 0.0833333h;
Stage #2: 1-(2-furyl)-1-ethanone In diethyl ether at 20℃; Further stages.;
With sodium hydride
With sodium hydride
With sodium methylate In tetrahydrofuran; methanol at 0 - 20℃;
Step a
General procedure: To a freshly prepared sodium methylate solution in methanol and THF ethyl trifluoroacetate (1.2 equiv) was added under stirring at 0° followed by addition of ketone 2 (1.0 equiv). The reaction mixture was allowed to stir for additional 3-24 h until the starting materials were consumed, as determined by thin-layer chromatography (TLC). Then the solvent was removed under reduced pressure and the residue was acidified with hydrochloric acid (1 N), followed by extracted with acetic ether. The combined organic layers were dried (MgSO4), Fitered and the filtrate was concentrated under reduced pressure. The crude product was puried by column chromatography. Yield: 40-90%. For some cases, the crude products can be straight used for step c without the column chromatography procedure.
With sodium hydride In tetrahydrofuran Reflux;
With sodium ethanolate In benzene
With sodium In ethanol at 20℃; Inert atmosphere;
General procedure for synthesis of compounds A10-A11
General procedure: Ethyl trifluoro acetate 18 (0.048 mol) and 2-acetyl furan(0.048 mol) were added dropwise to a solution of ethanol (55 mL) containing thinly sliced sodium (0.048 mol), and stirredovernight at room temperature. Then, the solution was poured in ice-water containing concentrated sulfuric acid. The solutionwas extracted with dichloromethane, dried, concentrated and purified on a column of silica using a 10% gradient of ethyl acetatein hexanes to afford 19. 19 (0.020 mmol) was added dropwise into a solution of substituted-hydrazine (0.020 mmol), ethanol (50mL) and acetic acid (0.5 mL), then refluxed. The cooled mixture was concentrated under vacumm and the pyrazole 20 wasobtained after purification by silica gel (a 5% gradient of ethyl acetate in hexanes). Pyrazole 20 (0.043 mol) was dissolved inacetone (120 mL) and KMnO4 (0. 071 mmol) was added. This mixture was heated at 60 oC for 3 h and cooled to roomtemperature. Then isopropyl alcohol was added and stirred at room temperature overnight. The reaction mixture was filtered andconcentrated. The residue was dissolved in 1 mol/L NaOH, washed and acidified with 2 mol/L HCl solution to obtain 21. Theamide derivatives 22 were prepared through the acyl chlorides derived from 21. A solution of 21 (0.004 mol) in thionyl chloride(10 mL) was refluxed for 5 h and then concentrated under vacuum. The crude acylchloride was added dropwise to a cooledsolution (0 oC) of 2-aminoethanol (0.004 mol) and TEA (0.008 mol) in dichloromethane (10 mL). The mixture was stirred atroom temperature for 0.5h to afford 22, The compound 6 was added dropwise to a cooled solution (0 oC) of compound 22 (0.004mol) and TEA (0.008 mol) in dichloromethane (10 mL). The mixture was stirred overnight at room temperature, and thenpurified on a column of silica using a gradient of ethyl acetate in hexanes to afford the pure products.
Stage #1: ethyl trifluoroacetate, With sodium methylate In tetrahydrofuran; methanol at 0℃; for 0.5h;
Stage #2: 1-(2-furyl)-1-ethanone In tetrahydrofuran; methanol at 20℃;
Synthesis of 1,3-diones 6a-6c
General procedure: To a freshly prepared sodium methylate solution (1.5 equiv) in methanol and THF, ethyl trifluoroacetate (1.2 equiv) was added under stirring at 0 °C. The mixture was stirred for 30 min followed by addition of ketone 5a-5c (1.0 equiv). The reaction mixture was stirred for another 12-24 h until the starting materials were consumed. Then the mixture was concentrated under reduced pressure and the resulted residue was acidified with hydrochloric acid (1 N) and extracted with acetic ether. The combined organic layers were dried (MgSO4), filtered and concentrated to dryness. The product was purified by column chromatography. Yield: 72-84 %
To a suspension of <strong>[53312-81-5]5-amino-2-fluorobenzonitrile</strong> (222g) (25 g, 184 rnmol) in 1 2N KCI(55.1 mL, 661 mmol) was added a solution of sodium nitrite(l5.21 g, 220 mmol) in water(75 mL) at 0C. After stirring for I h, to the mixture was added tin(ll) chloride dihydrate(83g. 367 mrnol) pre-dissolved in l2N HC?I (55.1 rnL, 661 rnmol) at such a rate that thetemperature was not allowed to go above 5 C. After stirring for 2 h, a solution of 4,4,4- trifluoro-1-(furan-2-yl)butane-1,3-dione (lOb) (37.9g. 184 rnrnol) in ethanol (305 mL) was added and heated at 60 C for 21 h. The reaction mixture was cooled to room temperature and concentrated in vacuum to remove ethanol. The aqueous was basified with saturatedNaHCO6 and extracted with ethyl acetate (3 x 500 mL). The organic layers were combined dried over MgSO4, filtered, and concentrated to dryness. The residue obtained was purified by flash column chromatography [silica gel 750 g, eluting with ethyl acetate in hexanes, from 0-100%] to furnish 5-(5-(furan-2-yl)-3-(trifluoromethyl)- 1 H-pyrazol- l-yl )benzonitrile (222h) (11.5 g, 35.8 mrnol, 19.49% yield) as a white solid; ?H NMR (300 MHz, DMSO25 d6) 6 8.30 (dd, J = 5.7, 2.7 Hz, 1K), 8.06- 7.98 (m, IH), 7.82 - 7.70 (n1, 2H), 7.34 (s, I H),6.59 (dd, J = 3.5, 1.8 Hz, 11-1), 6.49 (d, J = 3.5 Hz, IH); MS (ES): JVIS (ES+) 665.3(2M+Na).
To a solution of 4,4,4-trifluoro-l-(2-furyl)-l,3-butanedione (5Og, 0.240mol) in IM solution of hydrogen chloride in ethanol (EtOH) (24ml, 0.024mol) and further EtOH (520ml) was added <strong>[20570-96-1]benzylhydrazine dihydrochloride</strong> (5Og, 0.248mol) in small portion at room temperature. The reaction mixture was then heated under reflux for 7h. After cooling to room temperature the reaction mixture was neutralized with saturated NaHCO3, the EtOH was distilled off and the residual oil/water mixture was extracted with dichloromethane (300ml). The organic phase was washed twice with water (100ml) and dried over Na2SO4 and concentrated in vacuo to give 73.7g l-benzyl-5-furan-2-yl-3-trifluoromethyl-lH-pyrazole as a brown oil which was used crude for the next reaction. MS: M = 293.0 (API+)
With hydrogenchloride; In ethanol; at 20℃; for 7h;Heating / reflux;
To a solution of 50 g (0.240 mol) 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione in 24 ml (0.024 mol) 1M solution of hydrogen chloride in ethanol and further 520 ml EtOH was added. 50 g (0.248 mol) <strong>[20570-96-1]benzylhydrazine dihydrochloride</strong> in small portion at room temperature. The reaction mixture was then heated under reflux for 7 h. After cooling to room temperature the reaction mixture was neutralized with saturated NaHCO3, the EtOH was distilled off and the residual oil/water mixture was extracted with 300 ml dichloromethane. The organic phase was washed twice with 100 ml water and dried over Na2SO4 and concentrated in vacuo to give 73.7 g 1-benzyl-5-furan-2-yl-3-trifluoromethyl-1H-pyrazole as a brown oil which was used crude for the next reaction. MS: M=293.0 (API+)
Into a 500 mL flask was weighed 25.0 g (139.6 mmol) of 2-chlorophenylhydrazine hydrochloride, 27.4 g (153 mmol) of 4,4,4-trifluoro-1-furan-2-yl-butane-1,3-dione, and 200 mL of acetic acid. The resulting solution was heated at 80 °C for 18 h then was cooled and was washed into a separatory funnel with 1.0 M NaOH and ethyl acetate. The ethyl acetate was separated, washed with 1.0 M NaOH, brine, dried (Na2SO4), and was concentrated in vacuo. The residue was filtered through a short column of silica gel affording 1-(2- chlorophenyl)-5-furan-2-yl-3-trifluoromethyl-1H-pyrazole as a brown oil, yield: 37.31 g (85percent); MS (ES): 313 [M+H]+.
With sodium acetate; In acetic acid;
Step A Preparation of 1-(2-Chlorophenyl)-5-(2-furanyl)-3-(trifluoromethyl)-1H-pyrazole To a solution containing 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione (30.0 g, 146 mmol) in glacial acetic acid (65 mL) was added sodium acetate (12.1 g, 148 mmol). The mixture was cooled to about 25° C., 2-chlorophenylhydrazine hydrochloride (25.6 g, 145 mmol) was added portionwise and, following a mild exotherm, the mixture was heated to 60° C. for 4 h, then cooled to 25° C. The mixture was diluted with dichloromethane (400 mL) and the organic phase was washed with water (3*250 mL), saturated aqueous sodium carbonate (2*250 mL) and brine, then dried over magnesium sulfate and evaporated under reduced pressure to yield 43.2 g of the title compound as a brown oil. 1H NMR (CDCl3): delta 7.6 (m, 5H), 6.9 (1H), 5.7 (d, 1H).
With sodium acetate; acetic acid; at 20 - 60℃; for 1h;
To a mixture of 12.96 g of 4 , 4 , 4-trifluoro-1- (2-furyl) - 1, 3-butanedione, 8.56 g of sodium acetate and 40 ml of acetic acid was added 11.26 g of 2-chlorophenylhydrazme hydrochloride at room temperature. The mixture was stirred at 6O0C for 1 hour, and concentrated under reduced pressure . After the reaction mixture was concentrated under reduced pressure and water was poured into the residue, the mixture was extracted with chloroform three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 18.43 g of 1- (2-chlorophenyl) -5- (2-furyl) -3-trifluoromethyl-lH-pyrazole of the formula: EPO <DP n="493"/>1- (2-Chlorophenyl) -5- (i2-furyl) -3-trifIuoromethyl-1H- pyrazole1H-NMR (CDCl3, TMS) delta (ppm) : 5.76 (IH, d, J=3Hz) , 6.31 (IH, dd, J=3Hz, 2Hz), 6.95 (IH, s), 7.40 (IH, d, J=2Hz), 7.43-7.59 (4H, m) .
With hydrogenchloride; In water; isopropyl alcohol;Heating / reflux;
Example 5; (S)-1-(6-((2-aminopropanamido)methyl)pyridin-2-yl)-N-(2-methoxybenzyl)-3-(trifluoromethyl)-1 H-pyrazole-5-carboxamide (51); Step 1 2-chloro-6-(5-(furan-2-yl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl)pyridine (45); [0225] To a stirred solution of 2-chloro-6-hydrazinopyridine (300 mg, 2 09 mmol) in 2- propanol (10 4 ml_), was added 4,4,4-trifluoro-1-(2-furyl)-1 ,3-butanedione (0 310 mL, 2 090 mmol) followed by 2 drops of cone HCI The resulting mixture was heated to reflux overnight and then evaporated to dryness A 2 1 mixture of regioisomeric products 45 (588 mg, 90 % yield) were isolated as a pale yellow oil LRMS (ESI) calc 313 6, found 313 6 (M)+
Stage #1: 4-amino-2-cyanothiophene With hydrogenchloride; sodium nitrite In water at 0℃; for 0.666667h;
Stage #2: With hydrogenchloride; tin(ll) chloride In water at 0℃; for 72h;
Stage #3: 4,4,4-trifluoro-1-(2-furanyl)-1,3-butanedione With acetic acid for 12h; Heating / reflux;
1a.4
Step 4 4-(5-(furan-2-yl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl)thiophene-2-carboxamide (4); [0173] Ice cold solution of NaNO2 (99 3 mg, 1 44 mmol) in H2O (0 43 mL) was added drop- wise to ice cold solution of amine 3 (0 177 g, 1 43 mmol) in cone HCI (1 43 mL) the mixture was stirred at O0C for 40 minutes according to the procedure of M L Quan et al (JMC, 2005, 48, 1729-1744) Ice cold solution of SnCI2 (1 007 g, 4 464 mmol) in cone HCI (0 58 mL) was added dropwise, and the mixture was left at O0C for 16h The precipitate that formed was filtered and washed with ice-cold brine (4 5 mL) then with 2 1 Hex ether (4 5 mL) and was air dried leaving 0 398 g of a beige solid The material was refluxed with 4,4,4-trifluoro-1-(furan-2- yl)butane-1 ,3-dione (0 24 g, 1 16 mmol) in acetic acid (4 6 mL) for 16h The solvent was evaporated, EtOAc and 1 N HCI solution were added and organic layer was separated and washed with brine, dried over MgSO4, filtered and concentrated The crude material was purified by column chromatography eluting with 20-100% EtOAc hexanes to give compound 4 as a light yellow solid in 30 6% yield LRMS (ESI) calc 327 3, found 328 0 (MH)+
3,5-dichloro-2-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
acetic acid;Reflux;
(2) Synthesis of 3,5-dichloro-2-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine To a 250 mL flask, 4,4,4-trifluoro-1-(furan-2-yl)butane-1,3-dione (5.50 g, 26.7 mmol), <strong>[104408-23-3]3,5-dichloro-2-hydrazinylpyridine</strong> (4.75 g, 26.7 mmol) and glacial acetic acid (100 mL) were added. The reaction mixture was heated to reflux. When the reaction completed, the reaction mixture was concentrated by rotary evaporator. Then ethyl acetate (300 mL) and water (150 mL) was added, the organic extracts were washed with saturated sodium bicarbonate solution (150 mL) and brine (150 mL) in sequence, dried over anhydrous magnesium sulfate and concentrated by rotary evaporator. The residue was purified by silica gel column chromatography (Fluent: ethyl acetate/petroleum ether=1/5) to give the product (5.66 g) as a yellow oil in 61% yield. 1H NMR (300 MHz, CDCl3): 8.514 (d, 1H), 7.974 (d, 1H), 7.362 (d, 1H), 6.917 (s, 1H), 6.388 (dd, 1H), 6.148 (d, 1H).
With manganese(III) triacetate dihydrate; acetic acid; at 60 - 80℃;Inert atmosphere;
A solution of manganese(III) acetate dihydrate (5 mmol, 1.35 g) in 20 mL in glacial acetic acid was heated under nitrogen atmosphere at 80 C until it dissolved. After Mn(OAc)3 dissolved completely, the solution was cooled down to 60 C. A solution of trifluoromethyl-1,3-dicarbonyl compound (2.5 mmol) and alkene (2 mmol) in 5 mL acetic acid was added to this mixture and the temperature was raised to 80 C. The reaction was complete when the dark brown colour of the solution disappeared. Acetic acid was evaporated under reduced pressure. Water was added to the residue and extraction was performed with CHCl3 (3 x 20 mL). The combined organic extracts were neutralized with satd. NaHCO3 solution, and dried over anhydrous Na2SO4 and evaporated. Crude products were puried by column chromatography or preparative TLC (20 cm x 20 cm plates, 2 mm thickness) using n-hexane/EtOAc (5:1) as eluent.
2,2,2-trifluoro-1-(2-(2-furyl)-5-(4-methoxyphenyl)-4-methyl-4,5-dihydrofuran-3-yl)ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
28%
With manganese(III) triacetate dihydrate; acetic acid at 60℃; Inert atmosphere;
2,2,2-Trifluoro-1-(2-(2-furyl)-5-(4-methoxyphenyl)-4-methyl-4,5-dihydrofuran-3-yl)ethanone (5c)
General procedure: Manganese(III) acetate dihydrate (0.83g, 3 mmol) in 20 mL of glacial HOAc was heated under nitrogen atmosphere to 80 C until itdissolved. Thereafter the solution was cooled to 60 C, a solution of 1,3-dicarbonyl compound (2mmol) and alkene (1 mmol) in 5 mL HOAc was added to this mixture. The reaction wascompleted when the initial dark brown color of the solution had changed to red. H2O (20 mL)was added and the mixture extracted with CHCl3 (3x20 mL). The combined organic phases wereneutralized with saturated NaHCO3 solution, dried over anhydrous Na2SO4 and then evaporated.Crude products were purified by column chromatography on silica gel or preparative TLC usingn-hexane/EtOAc as eluent.
5-furan-2-yl-1-(4-methanesulfonylphenyl)-3-trifluoromethyl-1H-pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
In ethanol; for 10h;Reflux;
General procedure: A solution of the dione (10a or 10b, 1 mmol) and (4-amino/methanesulphonylphenyl) hydrazine hydrochloride (11a or 11b, 1 mmol) in ethanol (40 mL) was heated under reflux with stirring for 10 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo to yield a gummy product which was further purified by silica gel column chromatography using ethylacetate/hexane (1:3, v/v) as eluent to give analytically pure compounds 12a, 12b, and 12d. Physical and spectral dataare listed below.
5-chloro-2-(5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50.7%
With hydrogenchloride; In ethanol; water;Reflux;
To a solution of 5-Chloro-2-hydrazinylpyridine(13b) (717.87 mg, 5.00 mmol) inEtOH (12 mL) was added 4,4,4-trifluoro-1-(furan-2-yl)butane-1,3-dione (lOb) (1134 mg,5.50 mmol), Water (3 rnL), and hydrogen chloride (cone. HCI, 1 .667 mL, 20.00 mmol). The resulting mixture was stirred at reflu.x overnight and concentrated in vacuum to remove organic solvent. The aqueous was basified with I N NaOH, and then partitioned twice with ethyl acetate. The organic layers were combined, dried filtered and concentrated iii vacuum to dryness. The residue obtained was purified by flash column chromatography (silica gel12 g, eluting with 0-50% ethyl acetate in hexane) to furnish 5-chloro-2-(5-(furan-2-yI)-3-(trifluoromethyl )- I H-pyrazol- 1 -yt)pyridine (1 3c)(795 rng, 2.53 mmol, 50.7 % yield) as light yellow solid, ?H NMR showed a mixture of 2compound, with a ratio of 2:1. MS (ES+) 314.0 (M±l), 335.9 (M±Na).
1-(6-bromonaphthalen-2-yl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27.3%
To a suspension of 6-bromonaphthalen-2-amine (14a) (2.6g. 11.71 inmol) in hydrogen chloride (7.02 mL, 84 mmol) was added a solution of sodium nitrite (0.969 g,14.05 mmol) in water (12 mL) at 0 0 C slowly. After stirring for I h, to this mixture wasadded tin(II) chloride dihydrate (5.28 g, 23.41 mmol) pre-dissolved in hydrogen chloride(7.02 mL, 84 mmol) at such a rate that the temperature was not allowed to exceed 5 0CAfter stirring for 2 h, a solution of 4,4,4-trifluoro-I-(furan-2-yl)butane-l,3-dione (lOb)(2.65 g, 12.88 mmol) in ethanol (24 mL) was added to the mixture and heated at 60 °Covernight. After cooling to room temperature, the reaction mixture was basified to pH 8using 10 N aqueous NaOH (15 rnL) and saturated NaHCO3. The reaction mixture was diluted with ethyl acetate and filtered through a pad of celite. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were combined dried, filtered and concentrated in vacuum to furnish crude residuewhich was purified by flash column chromatography (silica gel 12 g, eluting 0-100percent ethyl acetate in hexane) to afford 1 -(6- Bromonaphthalen-2-yl)-5-(furan-2-yl )-3-(tri fluoromethyl)lH-pyrazole (14b) (1.3 g, 3.19 mmol, 27.3 percent yield) as a semisolid; ?H NMR (300 MHz, DMSO-c16) 8.39 (d, J 2.0 Hz, lH), 8.22 (d, J 2.1 Hz, I H), 8.10 (d, .1 8.8 Hz, I H), 8.02 (d, J= 8.8 Hz, I H), 7.78 (dd, J = 8.8, 2.0 Hz, 1 H), 7.75 (dd, .1 1.8, 0.8 Hz, I H), 7.64(dd,.J= 8.8, 2.2 Hz, 11-1), 7.35 (s, 11-1), 6.53 (dd,.J 3.5, 1.8 Hz, 11-1), 6.32 (dd,.J= 3.5, 0.7 Hz, lH); ?9F NMR (300 MHz, DMSO-d6)oe ?60.85: MS (ES+) 406.9, 408.8 (M±l).
1-(2,6-Dichlorophenyl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With acetic acid;Reflux;
General procedure: Different substituted phenylhydrazine (6mmol) and 71 5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (1.24g, 6.0mmol) were dissolved in 10mL of 12 acetic acid. The reaction mixture was refluxed for 3-4h and evaporated in vacuum. The residue was washed with saturated sodium bicarbonate solution and then extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate and evaporated to obtain crude 10 5-(furan-2-yl)-1-phenyl-3-(trifluoromethyl)-1H-pyrazole 5a-k, which were used directly in the next step with further purification.
1-(2-chloro-5-(trifluoromethyl)phenyl)-5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65.1%
With acetic acid Reflux;
4.1.1. General synthetic procedure for compounds 4a-f21
General procedure: Different substituted phenylhydrazine (2a-f, 10.0 mmol) and 1,1,1-trifluoro-4-(furan-2-yl)-4-hydroxybut-3-en-2-one (3, 2.06 g, 10.0mmol) were dissolved in 10 mL acetic acid, and then the reaction mixture was heated to reflux. The reaction was detected by TLC. Aftercompletion, saturated sodium bicarbonate solution was slowly added to the reaction mixture, and the mixture was extracted by ethyl acetate.The organic layer was washed with brine and evaporated, and the residue was purified on silica gel with ethyl acetate/petroleum to affordcompounds 4a f.
With acetic acid Reflux;
3.6 4.1.2 Synthetic procedure for 5-(Furan-2-yl)-1-phenyl-3-(trifluoromethyl)-1H-pyrazole 5a-k10,38
General procedure: Different substituted phenylhydrazine (6mmol) and 71 5-(furan-2-yl)-3-(trifluoromethyl)-1H-pyrazole (1.24g, 6.0mmol) were dissolved in 10mL of 12 acetic acid. The reaction mixture was refluxed for 3-4h and evaporated in vacuum. The residue was washed with saturated sodium bicarbonate solution and then extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate and evaporated to obtain crude 10 5-(furan-2-yl)-1-phenyl-3-(trifluoromethyl)-1H-pyrazole 5a-k, which were used directly in the next step with further purification.
0.25mmol of Cu(NO3)2·3H2O was added to 0.25mmol (37muL) of 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione (tfa) in acetonitrile (4mL). The solution was stirred for 4h at room temperature. Next, 0.25mmol (0.0540g) of 4,4-dimethoxy-2,2-bipyridine (dmb) previously dissolved in acetonitrile was added dropwise. This new mixture was stirred for another 24h. After some days at room temperature, a green precipitate was removed by filtration, washed with acetonitrile and dried under reduced pressure. (0007) MM: 573.92gmol-1. Yield: 85%. Anal. Calc. for (CuC20H16F3N3O8)1.5H2O: C, 41.85; H, 3.34; N, 7.32%. Found: C, 41.89; H, 2.91; N, 8.08%. ATR-FTIR, nu (cm-1): 3128, 3083, 1589, 1567, 1519, 1503, 1474, 1442, 1421, 1375, 1320, 1287, 1265, 1230, 1191, 1132, 1103, 1078, 1040, 955, 912, 879, 843, 835, 780, 687, 591, 578, 434. UV-Vis (methanol), lambdamax (epsilon)=228 (4.7×104M-1 cm-1), 287 (1.9×104M-1 cm-1), 298 (1.9×104M-1 cm-1), 341 (1.8×104M-1 cm-1), 354 (1.9×104M-1 cm-1), 626 (4.3×101M-1 cm-1), 639 (solid state) nm. LambdaM (methanol)=106.20 S cm2mol-1.
Stage #1: copper(II) nitrate trihydrate; 4,4,4-trifluoro-1-(2-furanyl)-1,3-butanedione In methanol at 20℃; for 4h;
Stage #2: 5-Nitro-1,10-phenanthroline In methanol at 20℃; for 24h;
2.2.3 Complex III - [Cu(tfa)(nphen)(NO3)]
0.25mmol of Cu(NO3)2·3H2O was added to 0.25mmol (37μL) of 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione (tfa) in methanol (4mL). The solution was stirred for 4h at room temperature when 0.25mmol (0.0540g) of 5-nitro-1,10-phenanthroline (nphen) dissolved in methanol was added dropwise. After 24h, a green precipitate was removed by filtration, washed with methanol and dried under reduced pressure. (0009) MM: 555.86gmol-1. Yield: 88%. Anal. Calc. for (CuC20H11F3N4O8): C, 43.21; H, 1.99; N, 10.08%. Found: C, 43.55; H, 1.82; N, 10.13%. ATR-FTIR, ν (cm-1): 3126, 3099, 1599, 1571, 1535, 1518, 1460, 1418, 1388, 1367, 1348, 1297, 1259, 1194, 1138, 1101, 1025, 947, 913, 883, 840, 824, 807, 772, 753, 735, 720, 686, 615, 591, 538, 436. UV-Vis (methanol), λmax (ε)=277 (1.3×105M-1 cm-1), 341 (19.1×104M-1 cm-1), 354 (9.3×104M-1 cm-1), 641 (3.7×101M-1 cm-1), 618 (solid state) nm. ΛM (methanol)=91.80 S cm2mol-1.