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Structure of 1550-35-2 * 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] Journal of Organic Chemistry, 2009, vol. 74, # 16, p. 6331 - 6334
[2] Patent: WO2014/152144, 2014, A1, . Location in patent: Paragraph 0217
2
[ 1550-35-2 ]
[ 367-27-1 ]
[ 1583-58-0 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2005, vol. 347, # 7-8, p. 1027 - 1034
3
[ 452-76-6 ]
[ 1550-35-2 ]
Yield
Reaction Conditions
Operation in experiment
31.1%
With sodium molybdate; dihydrogen peroxide; sodium bromide In acetic acid at 105℃; for 0.111111 h;
(1) Device: Refer to Figure 2 to determine the connection of the tubular reactor. The pipe types are: (3a + 3b) DC type channel +Round cakes pulse diameter adjustable rectangular flat pipe, pipe diameter and volume based on the flow rate and reaction residence time to determine the heat transfer mediumHeat conducting oil.(2) 6.06 g of cobalt acetate and 6.06 g of sodium molybdate were respectively dissolved in 200 ml of 2,4-difluorotoluene and 200 ml of acetic acidInto a mixed solution, at this time n (cobalt acetate): n (2,4-difluorotoluene) = 0.015: 1 6.06g sodium bromide was dissolved in 30percent H2O2 to form H2O2-acetic acid solution, then n Sodium): n (2,4-difluorotoluene) = 0.015: 1,2,4- difluorotoluene-acetic acid solutionWith and H2O2-acetic acid solution at a flow rate of 5.33 ml / min and 10.67 ml / min, respectively, through a constant flow pump into the tubeType reactor, n (H2O2): n (2,4-difluorotoluene) = 2: 1, using the microchannel reactor in Figure 2, the reaction temperature is controlled105 , residence time 400s. The outlet was cooled at 0 ° C and the reaction quenched with difluoromethane. After GC analysis, 2,4-difluoromethaneThe conversion of benzene was 49.5percent and the yield of 2,4-difluorobenzaldehyde was 31.1percent.
Reference：
[1] Patent: CN106588600, 2017, A, . Location in patent: Paragraph 0040-0066
[2] Kogyo Kagaku Zasshi, 1956, vol. 59, p. 1160[3] Chem.Abstr., 1958, p. 13265
[4] Monatshefte fuer Chemie, 1959, vol. 90, p. 683,687
[5] Patent: US5998477, 1999, A,
[6] Patent: US5401774, 1995, A,
[7] Patent: US4424229, 1984, A,
[8] Patent: EP485172, 1992, A2,
[9] Patent: US6232312, 2001, B1,
4
[ 56456-47-4 ]
[ 1550-35-2 ]
Yield
Reaction Conditions
Operation in experiment
89%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; copper diacetate In water; acetonitrile at 20℃; for 6 h; Green chemistry
General procedure: A mixture of alcohol (5.0 mmol), Cu(OAc)2 (9.1 mg, 0.05 mmol), and TEMPO (7.8 mg, 0.05 mmol) in CH3CN/H2O (5/10 mL) was stirred at room temperature for specified time. After completion of the reaction (monitored by TLC, eluents: petroleum ether/ethyl acetate = 4/1), dichloromethane (10 mL) was added to the resulting mixture. The dichloromethane phase was separated, and the aqueous phase was further extracted with dichloromethane (10 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give a residue, which was purified by column chromatography (eluents: petroleum ether/ethyl acetate = 10/1) to provide the desired product.
Reference：
[1] Journal of Fluorine Chemistry, 1996, vol. 78, # 2, p. 113 - 119
14
[ 1550-35-2 ]
[ 56456-47-4 ]
Yield
Reaction Conditions
Operation in experiment
100%
With sodium tetrahydroborate In methanol at 0℃; Inert atmosphere
General procedure: Aldehyde (1 mmol) was dissolved in 10 ml ofmethanol(ethanol for ketones) and cooled to 0oC. NaBH4 (3 mmol) was then added inone portion and the reaction was allowed to stir until completion as indicatedby TLC (9:1 heptanes/ethyl acetate). The reaction was quenched with 0.1 N NaOH(10 ml) and extracted three times with ethyl actetate. The organic layer waswashed with brine and dried over Na2SO4. The solvent wasremoved under reduced pressure and the resulting yellow oil was subjected toflash chromatography.
88%
at 0℃; for 1 h;
Example 13; Preparation of Intermediates (1-(Bromomethyl)-2,4-difluorobenzene) (I-1)To a stirred solution of 2,4-difluorobenzaldehyde (500 mg, 3.52 mmol) in CH3OH (8 mL) was added NaBH4 (266 mg, 7.04 mmol) portion wise at 0° C., and the reaction mixture was stirred at 0° C. for 1 h. After completion of the reaction (by TLC), CH3OH was removed under reduced pressure, diluted with ice-cold H2O (40 mL) and extracted with EtOAc (2.x.20 mL). The combined organic layers were washed with H2O (40 mL) and brine (40 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography eluting with 10percent EtOAc/hexanes afforded the alcohol G (450 mg, 3.12 mmol, 88percent) as colorless liquid. 1H NMR (200 MHz, CDCl3): δ 7.45-7.33 (m, 1H), 6.83-6.75 (m, 2H), 4.72 (s, 2H), 1.79 (br s, OH).
Reference：
[1] European Journal of Medicinal Chemistry, 2016, vol. 108, p. 564 - 576
[2] Organometallics, 2015, vol. 34, # 20, p. 5175 - 5182
[3] Patent: US2012/329788, 2012, A1, . Location in patent: Page/Page column 26
[4] European Journal of Inorganic Chemistry, 2015, vol. 2015, # 16, p. 2732 - 2743
[5] Dalton Transactions, 2016, vol. 45, # 45, p. 18133 - 18141
[6] European Journal of Medicinal Chemistry, 2018, vol. 143, p. 1345 - 1360
15
[ 1550-35-2 ]
[ 108-24-7 ]
[ 94977-52-3 ]
Reference：
[1] Monatshefte fuer Chemie, 1959, vol. 90, p. 683,687
16
[ 874-42-0 ]
[ 1550-35-2 ]
[ 84194-36-5 ]
[ 61072-56-8 ]
Reference：
[1] Journal of Fluorine Chemistry, 1990, vol. 46, # 3, p. 529 - 537
[2] Journal of Fluorine Chemistry, 1990, vol. 46, # 3, p. 529 - 537
[3] Journal of Fluorine Chemistry, 1990, vol. 46, # 3, p. 529 - 537
17
[ 874-42-0 ]
[ 1550-35-2 ]
[ 84194-36-5 ]
[ 61072-56-8 ]
Reference：
[1] Journal of Fluorine Chemistry, 1990, vol. 46, # 3, p. 529 - 537
[2] Journal of Fluorine Chemistry, 1990, vol. 46, # 3, p. 529 - 537
[3] Journal of Fluorine Chemistry, 1990, vol. 46, # 3, p. 529 - 537
18
[ 1550-35-2 ]
[ 23915-07-3 ]
Reference：
[1] Patent: US2012/329788, 2012, A1,
19
[ 1550-35-2 ]
[ 84163-13-3 ]
Reference：
[1] Patent: WO2008/108957, 2008, A2,
20
[ 1550-35-2 ]
[ 205055-10-3 ]
Reference：
[1] Bioorganic and medicinal chemistry, 2004, vol. 12, # 9, p. 2251 - 2273
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 1, p. 264 - 281
21
[ 1550-35-2 ]
[ 247564-66-5 ]
Reference：
[1] Canadian Journal of Chemistry, 2007, vol. 85, # 4, p. 283 - 292
22
[ 1550-35-2 ]
[ 593-51-1 ]
[ 696589-32-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 972 - 986
With sodium molybdate; dihydrogen peroxide; sodium bromide; In acetic acid; at 105℃; for 0.111111h;
(1) Device: Refer to Figure 2 to determine the connection of the tubular reactor. The pipe types are: (3a + 3b) DC type channel +Round cakes pulse diameter adjustable rectangular flat pipe, pipe diameter and volume based on the flow rate and reaction residence time to determine the heat transfer mediumHeat conducting oil.(2) 6.06 g of cobalt acetate and 6.06 g of sodium molybdate were respectively dissolved in 200 ml of <strong>[452-76-6]2,4-difluorotoluene</strong> and 200 ml of acetic acidInto a mixed solution, at this time n (cobalt acetate): n (<strong>[452-76-6]2,4-difluorotoluene</strong>) = 0.015: 1 6.06g sodium bromide was dissolved in 30% H2O2 to form H2O2-acetic acid solution, then n Sodium): n (<strong>[452-76-6]2,4-difluorotoluene</strong>) = 0.015: 1,2,4- difluorotoluene-acetic acid solutionWith and H2O2-acetic acid solution at a flow rate of 5.33 ml / min and 10.67 ml / min, respectively, through a constant flow pump into the tubeType reactor, n (H2O2): n (<strong>[452-76-6]2,4-difluorotoluene</strong>) = 2: 1, using the microchannel reactor in Figure 2, the reaction temperature is controlled105 , residence time 400s. The outlet was cooled at 0 C and the reaction quenched with difluoromethane. After GC analysis, 2,4-difluoromethaneThe conversion of benzene was 49.5% and the yield of 2,4-difluorobenzaldehyde was 31.1%.
With bromine; calcium carbonate; In water;
(A) 2,4-difluorobenzaldehyde. A 250 ml, three-necked flask is fitted with a stirrer, a thermometer, a dropping funnel with a long stem to the bottom of the flask and a reflux condenser with a tube leading to the back of a hood. 50 g (0.38 mol) of <strong>[452-76-6]2,4-difluorotoluene</strong> is heated to reflux with stirring and irradiated with a Hanovia ultraviolet lamp. 41.5 ml of bromine is gradually added. The reaction is completed in 2.5 hours during which time the reflux temperature rises from 112 C. to 155 C. A 21 three-necked flask is fitted with a stirrer and reflux condenser. In the flask is placed 200 ml of water and 140 g calcium carbonate. The cooled above-described reaction mixture is transferred using some ether for rinsing. The hydrolysis is completed by refluxing with stirring for 18 hours. The aldehyde is isolated by steam distillation from the reaction flask. The oil is separated and the aqueous phase is extracted once with ether. The combined oil and ether extract is dried over anhydrous MgSO4 and concentrated under reduced pressure to leave 2,4-difluorobenzaldehyde, still containing some ether which is distilled through a short Vigreux column under reduced pressure and separated into several fractions. These are combined to give 2,4-difluorobenzaldehyde, B.P. 56-58 C. 12 mm.
With bromine; calcium carbonate; In water;
(A) 2,4-difluorobenzaldehyde. A 250 ml., three-necked flask is fitted with a stirrer, a thermometer, a dropping funnel with a long stem to the bottom of the flask and a reflux condenser with a tube leading to the back of a hood. 50 g. (0.38 mole) of <strong>[452-76-6]2,4-difluorotoluene</strong> is heated to reflux with stirring and irradiated with a Hanovia ultraviolet lamp. 41.5 ml. of bromine is gradually added. The reaction is completed in 2.5 hours during which time the reflux temperature rises from 112 to 155. A 2 l. three-necked flask is fitted with a stirrer and reflux condenser. In the flask is placed 200 ml. of water and 140 g. calcium carbonate. The cooled above-described reaction mixture is transferred using some ether for rinsing. The hydrolysis is completed by refluxing with stirring for 18 hours. The aldehyde is isolated by steam distillation from the reaction flask. The oil is separated and the aqueous phase is extracted once with ether. The combined oil and ether extract is dried over anhydrous MgSO4 and concentrated under reduced pressure to leave 2,4-difluorobenzaldehyde, still containing some ether which is distilled through a short Vigreux column under reduced pressure and separated into several fractions. These are combined to give 2,4-difluorobenzaldehyde, B.P. 56-58 12 mm.
The NMR-spectrum shows the following characteristics: 2,4-Difluorobenzaldehyde can be prepared from <strong>[452-76-6]2,4-difluorotoluene</strong> according to Gunther Lock: Montash. 90, 680 (1959).
With bromine; calcium carbonate; In water;
(A) 2,4-difluorobenzaldehyde. A 250 ml., three-necked flask is fitted with a stirrer, a thermometer, a dropping funnel with a long stem to the bottom of the flask and a reflux condenser with a tube leading to the back of a hood. 50 g. (0.38 mole) of <strong>[452-76-6]2,4-difluorotoluene</strong> is heated to reflux with stirring and irradiated with a Hanovia ultraviolet lamp. 41.5 ml. of bromine is gradually added. The reaction is completed in 2.5 hours during which time the reflux temperature rises from 112 to 155. A 2 l. three-necked flask is fitted with a stirrer and reflux condenser. In the flask is placed 200 ml. of water and 140 g. calcium carbonate. The cooled above-described reaction mixture is transferred using some ether for rinsing. The hydrolysis is completed by refluxing with stirring for 18 hours. The aldehyde is isolated by steam distillation from the reaction flask. The oil is separated and the aqueous phase is extracted once with ether. The combined oil and ether extract is dried over anhydrous MgSO4 and concentrated under reduced pressure to leave 2,4-difluorobenzaldehyde, still containing some ether which is distilled through a short Vigreux column under reduced pressure and separated into several fractions. These are combined to give 2,4-difluorobenzaldehyde, B.P. 56-58 12 mm.
With bromine; calcium carbonate; In water;
(A) 2,4-difluorobenzaldehyde A 250 ml., three-necked flask is fitted with a stirrer, a thermometer, a dropping funnel with a long stem to the bottom of the flask and a reflux condenser with a tube leading to the back of a hood. 50 g. (0.38 mole) of <strong>[452-76-6]2,4-difluorotoluene</strong> is heated to reflux with stirring and irradiated with a Hanovia ultraviolet lamp. 41.5 ml. of bromine is gradually added. The reaction is completed in 2.5 hours during which time the reflux temperature rises from 112 to 155. A 2 l. three-necked flask is fitted with a stirrer and reflux condenser. In the flask is placed 200 ml. of water and 140 g. calcium carbonate. The cooled above-described reaction mixture is transferred using some ether for rinsing. The hydrolysis is completed by refluxing with stirring for 18 hours. The aldehyde is isolated by steam distillation from the reaction flask. The oil is separated and the aqueous phase is extracted once with ether. The combined oil and ether extract is dried over anhydrous MgSO4 and concentrated under reduced pressure to leave 2,4-difluorobenzaldehyde, still containing some ether which is distilled through a short Vigreux column under reduced pressure and separated into several fractions. These are combined to give 2,4-difluorobenzaldehyde, B.P. 56-58 12 mm.
With N-ethyl-N,N-diisopropylamine; In ISOPROPYLAMIDE; at 160℃;
Example 36 1-(2-Amino-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one; 2,4-difluorobenzaldehyde (4.26 g, 30 mmol), guanidine carbonate (5.40 g, 30 mmol), N,N-diisopropylethylamine (3.87 g, 30 mmol), and N,N-dimethylacetamide (25 mL) are heated at 160 degrees Celsius overnight. The crude product is taken up in ethyl acetate/water. The organic layer is dried over magnesium sulfate, then concentrated and subjected to chromatography, affording the desired 7-fluoroquinazolin-2-amine (0.95 g, 19%). LC/MS m/z=164 [M+H]+.
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; copper diacetate In water; acetonitrile at 20℃; for 6h; Green chemistry;
General procedure: A mixture of alcohol (5.0 mmol), Cu(OAc)2 (9.1 mg, 0.05 mmol), and TEMPO (7.8 mg, 0.05 mmol) in CH3CN/H2O (5/10 mL) was stirred at room temperature for specified time. After completion of the reaction (monitored by TLC, eluents: petroleum ether/ethyl acetate = 4/1), dichloromethane (10 mL) was added to the resulting mixture. The dichloromethane phase was separated, and the aqueous phase was further extracted with dichloromethane (10 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give a residue, which was purified by column chromatography (eluents: petroleum ether/ethyl acetate = 10/1) to provide the desired product.
80%
With nitric acid; ytterbium(III) triflate In 1,2-dichloro-ethane for 2h; Heating;
A solution of <strong>[1016234-89-1]2-amino-4-bromo-5-fluorophenol</strong> (10.1 g, 49 mmol), 2,4-difluorobenzaldehyde (5.36 mL, 49 mmol) and p-toluenesulfonic acid (100 mg, 0.52 mmol) in toluene (250 mL) was heated to reflux in a Dean-Stark apparatus for 0.5 h and then allowed to cool to ambient temperature. After adding triethylamine (1 mL) the reaction mixture was concentrated under reduced pressure to give the crude compound which was used without further purification. (16.1 g, 99%). 1H-NMR (400 MHz, CDCl3) 6.83 (d, J=10.2, 1H), 6.93 (m, 1H), 7.01 (m, 1H), 7.49 (d, J=7.6, 1H), 8.13 (m, 1H), 8.85 (s, 1H).
99%
toluene-4-sulfonic acid; In toluene; for 0.5h;Heating / reflux; Dean-Stark apparatus;
A solution of <strong>[1016234-89-1]2-amino-4-bromo-5-fluorophenol</strong> (10.1 g, 49 mmol), 2,4-difluorobenzaldehyde (5.36 mL, 49 mmol) and /?-toluenesulfonic acid (100 mg, 0.52 mmol) in toluene (250 mL) was heated to reflux in a Dean-Stark apparatus for 0.5 h and then allowed to cool to ambient temperature. After adding triethylamine (1 mL) the reaction mixture was concentrated under reduced pressure to give the crude compound which was used without further purification. (16.1 g, 99%). 1H-NMR (400 <n="17"/>MHz, CDCl3) 6.83 (d, J = 10.2, IH), 6.93 (m, IH), 7.01 (m, IH), 7.49 (d, J = 7.6, IH), 8.13 (m,IH), 8.85 (s, IH).
With tert.-butyl lithium In diethyl ether; pentane at -78 - 20℃; for 72.5h;
74.A (2,4-difluoro-phenyl)-[1-(2,2,2-trifluoro-ethyl)-1H-indazol-5-yl]-methanone
Step A: 5-bromoindazole (compound 2f; 9.852 g, 50.0 mmol) was dissolved in 150 mL of ether and the solution was cooled to -78 C. t-BuLi (1.70 M in pentane, 88.2 mL, 150 mmol) was added slowly at -78 C. After 0.5 hours at -78 C., the reaction was quenched with 2,4-difluorobenzaldehyde (10.9 mL, 100.0 mmol) and slowly warmed to room temperature. The mixture was stirred for 72 hr. at room temperature under nitrogen atmosphere and quenched with 100 mL of water. The layers were separated and the aqueous layer was extracted with CH2Cl2 (6x50 mL). The combined organic extracts were washed with saturated NaCl solution (100 mL), dried over anhydrous MgSO4, filtered through Celite, and concentrated under reduced pressure to provide a yellow solid. The reaction was purified by chromatography, eluting with 5% MeOH in CH2Cl2. During the sample handling for chromatography, it was found that the desired fractions had poor solubility in CH2Cl2. Mixed fractions were combined and concentrated under reduced pressure. The resulting oil was treated with CH2Cl2 (approximately 50 mL) and the solid was formed. The solid was collected by filtration. 1H NMR for flashed and filtered were identical. Since the samples had poor solubility in CHCl3, a couple of drops of DMSO-d6 were added to the 1H-NMR samples, 6.034 g of 8f-1 as a pale yellow solid (46.4% yield) was obtained. MS (ESI+) m/z 261 (M+H) detected.
With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran; toluene at -78 - 20℃; for 32h;
34 Methyl (2Z)-3-(2,4-difluorophenyl)acrylate
Preparation 34 Methyl (2Z)-3-(2,4-difluorophenyl)acrylate To a solution of 18-crown-6 (30 g, 110 mmol), bis(2,2,2-trifluororethyl) (methoxycarbonylmethyl)phosphonate (6 mL, 28 mmol) in tetrahydrofuran at -78° C. was added potassium hexamethyldisilazide (0.5 M in toluene) (50 mL, 25 mmol) followed by 2,4-difluorobenzaldehyde (4 g, 28 mmol). The reaction mixture was stirred at this temperature for 8 hours and slowly warmed to room temperature over 24 hours. The reaction mixture was then poured into a saturated solution of ammonium chloride (200 mL). The phases were separated, the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude residue. Purification of the residue by column chromatography using pentane:ethyl acetate (99:1-98:2) as eluent afforded the desired product as a colourless oil, 5.1 g (91%). 1H NMR (400 MHz, CDCl3) [13.70 (s, 3H), 6.05 (d, 1H), 6.80 (m, 1H), 6.86 (m, 1H), 6.97 (d, 1H), 7.69 (q, 1H). LRMS (APCI) 199 [MH+]
With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at -78℃;
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 70 - 80℃; for 3 - 4h;
A mixture of 2,4-difluorobenzaldehyde (0.278 g) and N,N-diisopropylethylamine (1.41 mL) was added to a solution of the compound obtained from the step a of Example 1 above (0.550 g) in dimethylsulphoxide (10 mL). The reaction mixture was stirred at 70-80 0C for about 3-4 h. The reaction mixture was poured into a large excess of ice-cold water and the compound was extracted with dichloromethane followed by evaporation of the solvent under vacuum to obtain the title compound (0.6 g).
In tetrahydrofuran; methanol; sodium hydroxide; acetic acid;
Preparation of [5-(2,4-difluoro-benzyl)-hexahydro-pyrrolo[3.4-c]pyrrole-2-carboxylic Acid Tert-Butyl Ester (I-1f): 6.0 mmols of 2,4-difluorobenzaldehyde was added to a 1.0 M tetrahydrofuran solution containing 3.0 mmols of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (I-1e). To this solution was added 24 mL of anhydrous methanol containing 1% glacial acetic acid. This mixture was allowed to proceed at room temperature under gentle agitation on a shaker plate for 1 hour. Then, 9.0 mmols of sodium tri-acetoxy-borohydride was added in one batch at room temperature. The reaction mixture was allowed to stir overnight at room temperature. The solvent was then removed in vacuo and 25 mL of 1.0 M sodium hydroxide was added. The crude product was extracted into ethyl acetate, dried over sodium sulfate and the solvent removed in vacuo. The material was purified by liquid chromatography to afford intermediate I-1f in 75% yield (2.27 mmol).
1-Acetyl-3-(2,4-difluorobenzylidene)-2,5-piperazinedione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In N,N-dimethyl-formamide
12 Preparation of Compound 1977
EXAMPLE 12 Preparation of Compound 1977 1-Acetyl-3-(2,4-difluorobenzylidene)-2,5-piperazinedione was prepared by a process analogous to that described in Reference Example 3, but replacing benzaldehyde by 2,4-difluorobenzaldehyde. That compound was treated with 4-(3-dimethylaminopropoxy)benzaldehyde in the presence of Cs2 CO3 (1 to 1.1 equivalents) in DMF at 80 to 100° C. for 1 to 8 hours to yield Compound 1977. Compound 1977 was converted to its salt by the method described in Example 11.
nBuLi (2.5M in hexanes, 56 mL, 140 mmol) was added dropwise to a solution of the title compound of Preparation 1a (10 g, 56.2 mmol) in dry THF (140 mL) at -78 0C under argon and the resulting mixture was stirred at that temperature for 15 minutes and then at 0 0C for 3 hours. Then, the reaction mixture was cooled down to -780C and 2,4-difluoro- benzaldehyde (11.9 g, 84 mmol) in 14 mL of tetrahydrofuran was carefully added. After 15 minutes, the cooling bath was removed and the mixture was stirred overnight at room temperature. Subsequently, the mixture was poured into water (600 mL) and extracted with ethyl acetate (3 x 300 mL). The organic solution was washed with brine, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure. The <n="51"/>residue was purified by column chromatography on silica gel, using n-hexane/ethyl acetate (1 :4 to 100% ethyl acetate) as eluent, to yield the title compound (9.5 g, 53%) as a white solid.
In a flask with a dry inert atmosphere are introduced 260 ml of anhydrous THF, it is cooled to -78C and 225 ml are added of LDA 2M solution in THF/n-heptane at a rate allowing to maintain the temperature under -65C. After this diethylmethylphosphonate (34.25 g, 0.225 mol) is quickly added dropwise dissolved in 30 ml of THF and it is shaken for 30 minutes at -78C. N-phenyltrifluoroacetymidoyl chloride is then added dropwise (46.7 g, 0.225 mol) dissolved in 40 ml of THF and it is left with shaking in the same conditions for 1 hour. A solution is added of 2,4-difluorobenzaldehyde (33.6 g, 0.236 mol) in 40 ml of THF, the cold bath is removed and the temperature is allowed to rise to ambient temperature. It is left shaking overnight in these conditions. The following morning 450 ml of HCl 2N are added and the shaking continued for 24 hours. The THF is removed in the rotovapor and the resulting aqueous solution is extracted with AcOEt ( 2x200 ml), washed with a solution of 5% NaHCO3 and with a saturated NaCl solution, it is dried with sodium sulphate, filtered and the solvent evaporated with the rotovapor. In this way are obtained 54.6 g of a reddish liquid crude that solidifies. The crude is distilled at a pressure of 35 mbar and a fraction is collected of (E)-1,1,1-trifluoro-4-(2,4-difluorophenyl)-3-buten-2-one at 107-14C (43 g, 81%). Melting point : 50-1C IR (KBr, cm-1) : 1717, 1602, 1583, 1277, 1146, 1059, 7061H-RMN (CDCl3) : 6,9 (m, 2H), 7.05 (d, J=16 Hz, 1H), 7,6 (m, 1H), 8.0 (d, J=16Hz, 1H)13C-RMN (CDCl3): 105.1 (t,J=26Hz), 112,6(dd, J=4, 22Hz) , 116.4 (q, J=291Hz), 118.2, 118.5, 131.5 (dd, J=4, 11Hz), 141.5, 162.5 (dd, J=13, 193Hz), 165,7 (dd, J=13, 190Hz), 180 (q, J=36Hz)
EXAMPLE 3; Preparation of [5-(3-nitro-1,2,4-triazolyl)-2-difluoromethylphenyl]2,2,2-trifluoroethyl sulfide (Compound No. 11 of the present invention); (1) Synthesis of 4-(3-nitro-1,2,4-triazolyl)-2-fluorobenzaldehyde; 10 ml of a N,N-dimethylformamide solution of 3.4 g of <strong>[24807-55-4]3-nitro-1,2,4-triazole</strong> was added dropwise to a suspension of 1.2 g (60%) of sodium hydride and 50 ml of N,N-dimethylformamide under cooling with ice. After generation of hydrogen stopped, 4.3 g of 2,4-difluorobenzaldehyde was added, followed by stirring at 70C for 3 hours. The mixture was concentrated under reduced pressure, 200 ml of water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were washed with diisopropyl ether to obtain 1.6 g of 4-(3-nitro-1,2,4-triazolyl)-2-fluorobenzaldehyde.
With hydrazine; In tetrahydrofuran; at 105℃; for 60h;
0217] To a stirring solution of 2,4-difluorobenzaldehyde 112 (4.0 g, 28.15 mmol) in THF (18.0 mL) was added hydrazine (24.0 mL, 763 mmol). The mixture was stirred at 105 C for 2.5 days. The mixture was concentrated to 1/3 its volume. Water was added and the product precipitated out. The solid was filtered off, washed with ample amounts of water and dried in a vacuum oven to afford compound 113 (1.20 g) as a bright yellow solid. No further purification was performed
With sodium hydroxide In ethanol; water at 0 - 20℃;
1.1
I. Synthesis examples; 1. Preparation of 5-(2,4-difluorobenzyl)-1 -(5-mercapto-[1 ,2,4]-triazol-1 -ylmethyl)-2,2- dimethylcyclopentanol; 1.1 5-[1-(2,4-Difluorophenyl)-meth-(E)-ylidene]-2,2-dimethylcyclopentanone; To a solution of 2,2-dimethylcyclopentanone (5.00 g, 44.57 mmol) and 2,4- difluorobenzaldehyde (6.97 g, 49.03 mmol) in ethanol (50 ml.) cooled at 0 °C was slow- Iy added 10% aq. sodium hydroxide (50 ml_). The reaction mixture was alllowed to warm up to room temperature and stirring continued overnight. The mixture was concentrated in vacuo and dichloromethane (100 ml.) was added. The aqueous phase was acidified with hydrochloric acid and the phases were separated. The aqueous phase was extracted with dichloromethane (2 x 100 ml.) and the combined organic extracts were dried over magnesium sulfate. Removal of the solvent under reduced pressure afforded the title product (9.30 g, 39.22 mmol, 88%).
With potassium tert-butylate; In dichloromethane; tert-butyl alcohol; at 20℃; for 3h;Inert atmosphere;
General procedure: 1,4-Diacetyl-piperazine-2,5-dione 2 (11.7 g, 50 mmol) was dissolved in dry CH2Cl2 (50 mL) under N2 atmosphere. Benzaldehyde (5 mL, 50 mmol) and potassium tert-butoxide (5.61 g, 50 mmol), dissolved in a minimum amount of tert-butanol (?25 mL), were added to this solution. The reaction mixture was stirred for 3 h, then a saturated aqueous solution of NH4Cl (100 mL) was added to quench the reaction and the mixture was extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated in vacuo. The product 3a (11.2 g, 92%) was obtained as a white solid.
tert-butyl (E)-3-(2',4'-difluorophenyl)prop-2-enoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
General procedure: MeMgBr (1.20 equiv) was added dropwise to a stirred solution of <strong>[27784-76-5]ter<strong>[27784-76-5]t-butyl diethylphosphonoacetate</strong></strong> 27 (1.20 equiv) in anhydrous THF at rt under nitrogen and the resultant mixture was stirred at rt for 15 min. The requisite aldehyde (1.00 equiv) was added dropwise via syringe and the reaction mixture was then heated at reflux for 15 h. Satd aq NH4Cl was added and the reaction mixture was extracted with EtOAc. The combined organic extracts were washed with brine, then dried and concentrated in vacuo.
With sodium tetrahydroborate In methanol at 0℃; Inert atmosphere;
2,4-Difluoro-benzenemethanol.(39a)
General procedure: Aldehyde (1 mmol) was dissolved in 10 ml ofmethanol(ethanol for ketones) and cooled to 0oC. NaBH4 (3 mmol) was then added inone portion and the reaction was allowed to stir until completion as indicatedby TLC (9:1 heptanes/ethyl acetate). The reaction was quenched with 0.1 N NaOH(10 ml) and extracted three times with ethyl actetate. The organic layer waswashed with brine and dried over Na2SO4. The solvent wasremoved under reduced pressure and the resulting yellow oil was subjected toflash chromatography.
92%
Stage #1: 2,4-difluorobenzaldehyde With C36H44F4N2Ni2P2; diphenylsilane In tetrahydrofuran at 45℃; for 3h; Schlenk technique; Inert atmosphere;
Stage #2: With sodium hydroxide In tetrahydrofuran; methanol at 60℃; for 24h; Schlenk technique; Inert atmosphere;
88%
With methanol; sodium tetrahydroborate at 0℃; for 1h;
13
Example 13; Preparation of Intermediates (1-(Bromomethyl)-2,4-difluorobenzene) (I-1)To a stirred solution of 2,4-difluorobenzaldehyde (500 mg, 3.52 mmol) in CH3OH (8 mL) was added NaBH4 (266 mg, 7.04 mmol) portion wise at 0° C., and the reaction mixture was stirred at 0° C. for 1 h. After completion of the reaction (by TLC), CH3OH was removed under reduced pressure, diluted with ice-cold H2O (40 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with H2O (40 mL) and brine (40 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography eluting with 10% EtOAc/hexanes afforded the alcohol G (450 mg, 3.12 mmol, 88%) as colorless liquid. 1H NMR (200 MHz, CDCl3): δ 7.45-7.33 (m, 1H), 6.83-6.75 (m, 2H), 4.72 (s, 2H), 1.79 (br s, OH).
Multi-step reaction with 2 steps
1: C22H32F6FeNP3 / tetrahydrofuran / 2 h / 45 °C / Inert atmosphere; Schlenk technique
2: sodium hydroxide / methanol / 24 h / 60 °C / Inert atmosphere; Schlenk technique
Multi-step reaction with 2 steps
1: C22H37ClFeNP3 / tetrahydrofuran / 3 h / 55 °C / Schlenk technique; Inert atmosphere
2: sodium hydroxide / tetrahydrofuran; methanol / 12 h / 60 °C / Schlenk technique; Inert atmosphere
With sodium tetrahydroborate In methanol at 0 - 20℃; for 4h;
With potassium <i>tert</i>-butylate In 1,4-dioxane at 20℃; for 0.25h;
Step 1 : (S)-3-(5-fluoro-2-formyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester
tBuOK (434 mg; 3.87 mmol; 1.1 eq.) was added to a solution of 2,4-difluoro- benzaldehyde (500 mg; 3.52 mmol; 1 eq.) and (S)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (779 mg; 3.87 mmol; 1.1 eq.) in 1 ,4-dioxane (3 mL) and reaction mixture was stirred at room temperature for 15 minutes. The solution was diluted with water and extracted with DCM. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (heptanes/EA) afforded the title compound (208 mg, 18%) as white solid. HPLC (max plot) 92.8%; Rt 4.46 min.
With diethylamine In ethanol for 0.25h; Microwave irradiation;
3.1.3.2. Microwave Assisted Synthesis of 1-Benzofuran-2-yl-3-phenyl-prop-2-en-1-one (5a-g)
General procedure: A mixture of 2-acetyl benzofuran (3.1 mmol), fluorinatedbenzaldehyde (3.2 mmol) and diethylamine (0.6 mL) inethanol (2 mL) was taken in microwave tube (10 mL). Theresulting reaction mixture was exposed to microwaveirradiation for 10-15 minutes. Reaction was monitored byTLC. After completion of reaction, the reaction mixture waspoured into ice cold water and extracted with ethyl acetate(310 mL), organic layer was dried over sodium sulphateand concentrated under reduced pressure. The obtainedresidues were purified by column chromatography usingethylacetate: hexane (5%) mixture as eluent which afforded1-benzofuran-2-yl-3-phenyl-prop-2-en-1-one (5a-g) in goodyields. Eluted product was matched with authentic spotsynthesized by conventional method.
With aluminum oxide; In methanol; for 48h;Reflux; Inert atmosphere;
General procedure: To a solution of benzofuran-3(2H)-one (134mg, 1mmol) in dry methanol (20mL) at room temperature was added the appropriate aldehyde (1.2mmol) and Al2O3 (1mmol). The mixture was refluxed, under N2, for 48h. After, the solvent was removed and the solid residue was dissolved in CH2Cl2. The organic layer was washed with water, dried with anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product.
With sodium hydroxide In ethanol at 10 - 20℃; for 0.5h;
88%
With sodium hydroxide In ethanol at 0 - 20℃; for 0.5h;
General procedure for the synthesis of 1,1-bis(methylthio)-5-arylpenta-1,4-dien-3-one (2a-y)
General procedure: To a solution of 4,4-bis(methylthio)but-3-en-2-one (1mol) in ethanol (10 ml) were added NaOH (1.5mol) and aryl aldehyde (1.1 mol) under constant stirring. After the starting material was consumed as indicated by TLC, the reaction mixture was poured into ice water and the resulting solid was filtered, washed well with water (20 ml). The solid material obtained was crystallized from ethanol to furnish 81-99% of 1,1-bis(methylthio)-5-arylpenta-1,4-dien-3-one as a yellow solid.
3-(2,4-difluorophenyl)-3-hydroxy-2-(naphthalen-2-yl)propanenitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32.4%
Stage #1: 2-naphthaleneacetonitrile With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere;
Stage #2: 2,4-difluorobenzaldehyde In tetrahydrofuran; hexane Inert atmosphere;
107 Example 107 - Synthesis of Compound ID No. 107 (Yli 5V3-amino-l-f2,4- difluorophenyl)-2-fnaphthalen-2-yl)propan- 1 -ol) syn-3-(2,4-difiuorophenyl)-3-hydroxy-2-(naphthalen-2-yl)propanenitrile:
2- Naphthylacetonitrile (2.5 g, 14.95 mmol) was taken in an oven-dried round bottom flask containing a stir bar and 170 mL of dry THF was added under nitrogen.Diisopropylamine (2.5 mL, 17.94 mmol) was added and the mixture was stirred and cooled to -78°C for 20 minutes. Butyllithium (2.5 M in hexane, 7.18 mL, 17.94 mmol) was then added slowly via syringe. After 30 minutes, 2,4-difluorobenzaldehyde (1.964 mL, 17.94 mmol) was added dropwise via syringe slowly. After 10 min, the reaction was quenched with quick addition of a mixture of 10 mL 2:1 THF /acetic acid (add all at once). Cold bath was removed, and the reaction was warmed to room temperature. Water was added, and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 100 mL), and the combined organic layers were washed with water and brine, and dried over MgS04. The combined organic layers were concentrated using a rotary evaporator. The residue was dissolved in 25 mL of DCM and 80 mL of hexane. A turbid solution resulted that was kept at 4 °C for 2 hours. After filtration, the product from first crystallization was redissolved in 30 mL of DCM, and 150 ml of hexane was slowly added. The resulting white crystals were filtered and dried under vacuum (yield 0.5 g, 4.85 mmol, 32.4%). 1H NMR (CDC13) δ 7.88-7.76 (m, 3 H), 7.70 (s, 1 H), 7.57-7.48 (m, 2 H), 7.40-7.26 (m, 2 H), 6.89-6.72 (m, 2 H), 5.47 (t, 1 H, J = 4.9 Hz), 4.35 (d, 1 H, J = 6.0 Hz), 2.42 (d, 1 H, J = 6.0 Hz). MS m z (ESI) 309.45 (MH+).
(E)-Methyl 3-(2,4-difluorophenyl)acrylateTo a solution of <strong>[5927-18-4]trimethyl phosphonoacetate</strong> (1.425 mL, 8.80 mmol) in THF (30 mL) was added KOtBu (0.987 g, 8.80 mmol) and stirred at RT for 10 min before was added 2,4-difluorobenzaldehyde (0.875 mL, 8 mmol) in THF (5 mL). The resulting reaction mixture was stirred at RT for 160 min. To the reaction mixture was added more <strong>[5927-18-4]trimethyl phosphonoacetate</strong> (0.648 mL, 4.00 mmol) then KOtBu (0.449 g, 4.00 mmol). The resulting reaction mixture was stirred at RT for 30 min. To the reaction mixture was added H20 (20 mL), extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine (20 mL), dried over MgS04, filtered, evaporated down under vacuum to afford desired intermediate (E)-methyl 3-(2,4-difluorophenyl)acrylate (1.5710 g, 7.93 mmol, 99 % yield). LC-MS m/z 199.1 (M+H)+, 0.94 min (ret. time).
86%
With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 5.5h;
Step1 To a stirred solution of methyl (dimethoxyphosphoryl) acetate (12.8 mL, 77.46 mmol, 1.1 eq) in THF (70.0 mL)) was added KOtBu (8.69 g, 77.46 mmol, 1.1 eq) at RT and the reaction mixture was stirred for 10 min. Then 2,4-difluorobenzaldehyde (10.0 g, 70.42 mmol, 1.0 eq) in THF (20 mL) was added drop wise stirred at RT for 2 h. Methyl (dimethoxyphosphoryl) acetate (5.8 mL, 35.21 mmol, 0.5) and KOtBu (3.95 g, 35.21 mmol, and 0.5 eq) was added as lot-2 and stirred for 30 minutes. After 3 h, reaction mixture was diluted with water (200 mL) extracted with EtOAc (2*100 mL), organic layer was dried over anhydrous Na2SO4, and evaporated under reduced pressure gave crude compound, which was purified by column chromatography on silica gel (100-200 mesh) using EtOAc/pet ether (1:9) as eluent to get (E)-methyl 3-(2,4-difluorophenyl)acrylate (12.0 g, 86%) as a white solid. TLC system: EtOAc: Pet ether (1:9), Rf: 0.5.
In a round-bottom flask containing a magnetic stirrer, a mixture of aldehyde (1 mmol) and heteroaryl amine (1 mmol) was placed andstirred at about 80-85 8C for 20 min. Then <strong>[23612-48-8]2-methyl-7-azaindole</strong>(1 mmol) was added in portions, and the mixture was heated to 80-85 8C. Completion of the reaction was monitored by thin-layerchromatography (TLC) analysis. After completion, the reactionmixture was cooled to room temperature and a small quantity ofethanol was added. The solution was poured into ice-water, and theprecipitate formed was filtered, washed with an ice cold ethanol-water (1:1) mixture. The crude products were stirred in boiling nhexaneand filtered to afford the pure products.
In a round-bottom flask containing a magnetic stirrer, a mixture of aldehyde (1 mmol) and heteroaryl amine (1 mmol) was placed andstirred at about 80-85 8C for 20 min. Then <strong>[23612-48-8]2-methyl-7-azaindole</strong>(1 mmol) was added in portions, and the mixture was heated to 80-85 8C. Completion of the reaction was monitored by thin-layerchromatography (TLC) analysis. After completion, the reactionmixture was cooled to room temperature and a small quantity ofethanol was added. The solution was poured into ice-water, and theprecipitate formed was filtered, washed with an ice cold ethanol-water (1:1) mixture. The crude products were stirred in boiling nhexaneand filtered to afford the pure products.
(4R,12aS)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-9-carboxamide[ No CAS ]
[ 1335210-35-9 ]
Yield
Reaction Conditions
Operation in experiment
600 mg
With triethylsilane; trifluoroacetic acid; In toluene;Reflux;
Triethylsilane (3.4 g) was added to a mixture of (4R,12aS)-7-methoxy-4-methyl-6,8-dioxo- 3,4,6,8,12, 12a-hexahydro-2H-[l,3]oxazino [3,2-d]pyrido[l,2-a] pyrazine-9-carboxamide (formula 9, 3 g) and 2,4-diflurobenzaldehyde (4.2 g) in toluene (33 mL). Trifluoroacetic acid (3.25 g) was then added. The reaction mixture was heated to reflux and maintained until complete conversion of the starting material, after which the mass was cooled to 30 C. Water (9 mL) was added and the pH was adjusted to 7-7.5 using 5% aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (2 x 15 mL), washed with saturated aqueous sodium chloride solution, and distilled under reduced pressure to obtain a residue which was heated with isopropyl alcohol (6 mL) and n-heptane (25 mL) to 60 C and cooled to give (4R,12aS)-N- (2,4-difluorobenzyl)-7-methyloxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro- 2H-pyrido [l ',2':4,5]pyrazino[2,l-b][l,3]oxazine-9-carboximide (formula la, 600 mg).
(5-amino-4-(3-chlorobenzoyl)-3-(2,4-difluorophenyl)-1H-pyrrol-2-yl)(phenyl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34%
With potassium carbonate; In ethanol;Reflux;
General procedure: The synthesis of 2-aminopyrrole analogues was based on a multicomponent reaction by refluxing a solution of three reactants including a methylsulfonamidoacetophenone, an aldehydes and acyanoacetic acid with 0.6 equiv of K2CO3 in ethanol. This reaction results in three substituted 2-aminopyrroles [35]. Compounds1-30 in Tables 1 and 2, and Fig. 3 were synthesized as shown in Scheme 1.
1,3-dimethyl-2-trifluoromethylbenzimidazolium triflate[ No CAS ]
[ 3097-21-0 ]
[ 910866-32-9 ]
Yield
Reaction Conditions
Operation in experiment
71%Chromat.; 15%Chromat.
With potassium carbonate; In N,N-dimethyl-formamide; at 10 - 35℃; for 2h;
To a 10 mL eggplant-shaped flask equipped with a magnetic stirrer, 0.03 g (0.21 mmol) of 2,4-difluorobenzaldehyde, 0.06 g (0.42 mmol) of potassium carbonate and 1 mL of DMF were added. While the mixture was stirred at room temperature, 0.12 g (0.32 mmol) of 1,3-dimethyl-2-trifluoromethylbenzimidazolium triflate was added thereto. The mixture was stirred at room temperature for 2 hours. The formation of 1-(2,4-difluorophenyl)-2,2,2-trifluoroethanol (parent ion; 212) was confirmed by GC-MS analysis on the reaction mixture. As a result of GC analysis (area percentage) on the reaction mixture, the components in the reaction mixture excluding the solvents and the like were as follows: 15% of 1-(2,4-difluorophenyl)-2,2,2-trifluoroethanol (target compound), 13% of 2,4-difluorobenzaldehyde (starting compound) and 71% of 1,3-dimethylbenzimidazole-2-one (compound derived from the fluoroalkylating agent). The yield of 1-(2,4-difluorophenyl)-2,2,2-trifluoroethanol (target compound) was 52% in terms of GC area percentage.
bis(2,4-difluorobenzylidene)isophthalohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With acetic acid; In ethanol;Reflux;
General procedure: General procedure for the synthesis of hydrazones (4-36): Compound 3 (1 mmol) was dissolved in ethanol (10 mL/g of compound) and treated with appropriate aldehydes (2 mmol) in the presence of catalytic amount of glacial acetic acid. The reaction mixtures were refluxed for 7-8 hr and the completion of reaction was monitored by TLC. After completion of the reaction, the solvent was removed under reduced pressure and cooled by adding ice cold water. The resulting precipitate was filtered, washed with water and recrystallized from ethanol to obtain the desired dihydrazones (4-36).
2-amino-6-methoxy-4-(2,4-difluorophenyl)-4H-benzo[h]chromene-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With piperidine In ethanol at 140℃; for 0.0333333h; Microwave irradiation;
2.2.1. General procedure for synthesis of 4H-benzo[h]chromenederivatives (4a-m)
General procedure: A reaction mixture of 4-methoxy-1-naphthol 1 (0.01 mol),different aromatic aldehydes 2a-m (0.01 mol), malononitrile 3(0.01 mol), and piperidine (0.5 mL) in ethanol (30 mL) was heatedunder microwave irradiation conditions for 2 min at 140 C. Afterthe completion of the reaction, the reaction mixture was cooled toroom temperature, and the precipitated solid was filtered off,washed with MeOH, and recrystallized from ethanol or ethanol/benzene. The physical and spectral data of compounds 4a-m are asfollows.
tert-butyl 4-[(2,4-difluorophenyl)methyl]amino}-4-methylpiperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
366 mg
2,4-difluorobenzaldehyde (199 mg, 1.40 mmol) in dichloromethane (0.5 ml) was (0797) (0798) added to tert-butyl 4-amino-4-methylpiperidine-l-carboxylate (330 mg, 1.54 mmol) in dichloromethane (0.5 ml). After 10 minutes of stirring at room temperature sodium (0799) triacetoxyborohydride (445 mg, 2.10 mmol) was added. After another 18 hours of stirring sodium hydroxide (2 ml, 1 M aqueous) was added, the mixture was extracted with (0800) dichloromethane (2x1 ml), the combined organic phases were separated, dried using a phase separator, and concentrated. The crude material was purified by column chromatography using silicon dioxide gel, eluting with 0-10% methanol in dichloromethane, containing 1% ammonia (28% aqueous) to afford the desired intermediate (366 mg).
3-amino-9-bromo-1-(2,4-difluorophenyl)-1H-benzo[f]chromene-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With piperidine; In ethanol; at 140℃; for 0.0333333h;Microwave irradiation;
General procedure: The reaction mixture of 7-bromo-2-naphthol (1) (2.23g, 0.01mol), different aromatic aldehydes (2a-m) (1.24, 1.4, 1.85, 1.42, 1.75, 2.93g, 0.01mol), malononitrile (3) (0.01mol), and piperidine (0.5ml) in absolute ethanol (30ml) was heated under microwave irradiation conditions for 2min at 140C. After the completion of the reaction, the mixture of the reaction was cooled to room temperature. The precipitated solid was filtered off, washed with methanol, and recrystallized from ethanol or ethanol/benzene. The physical and spectral data of compounds 4a-m are as follows:
tert-butyl (5-((2,4-difluorophenyl)(hydroxy)methyl)thiazol-2-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
19%
Dissolved ferf-butyl thiazol-2-ylcarbamate (0.5 g, 2.49 mmol) in tetrahydrofuran (12.4 ml_ ) and cooled to -78 C. Carefully added n-butyllithium (1 .6 M in hexanes, 1 .39 ml_, 3.48 mmol) and stirred for 10 minutes, followed by 2,4-difluorobenzaldehyde (325 mI_, 2.98 mmol). Quenched with saturated aqueous ammonium chloride (1 5 ml_) and extracted with ethyl acetate (20 ml_). Washed with brine (10 ml_), then dried over sodium sulfate. Filtered and concentrated in vacuo. Purified reaction by column chromatography (eluting with 0-50% ethyl acetate/hexanes through 24 g of silica gel) to give ferf-butyl (5-((2,4-difluorophenyl)(hydroxy)methyl)thiazol-2-yl)carbamate as an orange solid (165 mg, 0.482 mmol, 19%). 1 H NMR (300 MHz, Chloroform-d) d 7.62 (d, J = 6.4 Hz, 1 H), 7.15 (s, 1 H), 6.96 (d, J = 10.0 Hz, 2H), 6.88 - 6.75 (m, 1 H), 6.26 (s, 1 H), 1 .53 (s, 9H).
General procedure: A mixture of compound A (5 mmol) and corresponding benzaldehyde (5 mmol) in 10 mL ethanol was refluxed for 24 hours in a reaction flask wrapped up by silver paper. Upon the reactions completed (monitored by TLC), tawny solids were obtained through suction filtration. The precipitates were washed with ethanol (5 mLx3) and recrystallized from ethanol with 50-84% yields.
12-(2,4-difluorophenyl)-2-hydroxy-9,9-dimethyl-9,10-dihyro-8H-benzo[a]xanthen-11(12H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
In neat (no solvent); at 60℃; for 0.383333h;Green chemistry;
General procedure: The mixtureof naphthalenediol (1a-b, 1 mmol), fluoro substituted benzaldehyde(2a-e, 1 mmol) and 1,3-dicarbonyl compound (3a-b,1 mmol) was stirred in a round bottom flask at 60 C under catalyst and solvent-free conditions for 20 min. After completionof the reaction (TLC) resulted solid was dissolved in THF, filtered and evaporated the solvent using rotary evaporator. After recrystallization by ethanol we obtained the pure products as white solids (4a-j).
With rhodium(III) chloride trihydrate; hydrogen; triethylamine; triphenylphosphine; In N,N-dimethyl acetamide; at 90℃; under 7500.75 Torr; for 12h;Autoclave;
General procedure: All reactions were carried out in an 80 mL Teflon-lined stainless steel reactor equipped with a magnetic stirring bar. Typically, in a glovebox, the aryl iodides (1.0 mmol), RhI3(0.025 mmol), PPh3 (0.1 mmol), Et3N (1.2 mmol), and DMA (2 mL) were loaded into the reactor. Then, the autoclave was screwed up, charged with CO and H2 to a total pressure of 10 bar (1:1) and transferred to an oil bath preheated at 90 C, which was controlled by a Haake-D3 temperature controller. After completion of the reaction, the reactor was cooled in iced water and the gas carefully vented. The conversion and yield of the aryl iodides and arylaldehydes were determined by GC analysis using dodecane as an internal standard. For yield determination of the other products, the reaction mixture was first analyzed by GC-MS to determine the structures of the aromatic aldehyde products. Then, CH2Cl2 (5 mL) was added to the reaction mixture, after which deionized water (10 mL) was added to extract the solvent DMA for 5 times. The organic layer was dried over anhydrous Na2SO4, concentrated by rotary evaporation and finally purified by column chromatography on silica gel using n-hexane/ethyl acetate as eluent to obtain the pure products and isolated yields.
3,5-bis-(2,4-difluorophenylmethylene)-1-n-propylpiperidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
With hydrogenchloride; acetic acid at 20 - 40℃; for 48h; Sealed tube;
Synthesis of Curcumin Analogs
General procedure: Curcumin analogs were synthesized as described, with some modifications. In short, piperidin-4-one (10.0 mmol) was added into a flask with a mixture of 24.0 mmol of aldehyde compound in 40 - 60 mL of saturated HCl-CH3CO2H, which was then sealed and placed at 20 - 40 °C for 48 hours. Ultrasonic oscillation was employed to dissolve aldehyde compound when necessary. The mixture was subsequently poured into 300 mL of water with stirring, and the solid product was obtained by filtration. The filter cake was grounded and washed twice with ethanol using ultrasonic oscillation, and the pure product was obtained by further filtration and dehydration. The structure characterization of some target compounds is showed below.
3-(2,4-difluorophenyl)-1-(1H-pyrrol-2-yl)prop-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90.23%
With sodium hydroxide In ethanol at 20℃;
3.3.2. General Procedure for the Synthesis of New Difluorinated Compounds (11-15)
General procedure: Two mmol of 2-acetylpyrrole and substituted benzaldehyde were dissolved in 5 mLof 95% ethanol and the mixture was stirred for 5 min, followed by a dropwise additionof 1 mL of NaOH (6 M). The reaction mixture was then left to stir overnight at roomtemperature. Once the reaction was completed, crushed ice was added to quench thereaction. Following that, diluted HCl was added to neutralize the reaction mixture beforebeing further extracted with ethyl acetate (3 10 mL). The organic layer was collected,dried with anhydrous MgSO4, and evaporated under reduced pressure. The crude productswere purified by column chromatography and/or recrystallization techniques to yieldpure compounds [9]. The chemical characterization was only discussed for the newlysynthesized molecules.
(E)-6-(2,4-difluorostyryl)-4-methoxy-2H-pyran-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
Stage #1: 4-methoxy-6-methyl-2H-pyran-2-one With potassium hexamethylsilazane In tetrahydrofuran at -78℃; for 0.166667h; Inert atmosphere;
Stage #2: 2,4-difluorobenzaldehyde In tetrahydrofuran at -78 - 0℃; for 0.666667h; Inert atmosphere; stereoselective reaction;
General Procedure for the synthesis of (E)-4-methoxy-6-styryl-2H-pyran-2-one using KHMDS
General procedure: To a solution of Pyrone (1.0 mmol, 1.0 equiv.) in THF (10 mL) was added KHMDS (1M in THF, 1.6 mmol, 1.6 equiv.) at -78 °C under nitrogen and stirred for 10 min, and then aldehyde (1.6 mmol, 1.6 equiv.) in THF (5 mL) was added in dropwise and stirred at -78 °C for 10 min and then slowly warmed to 0 °C over 30 min under stirring. The reaction mixture was quenched with 10 % HCl solution, extracted with DCM, washed with brine, dried over Na2SO4, and concentrated to afford crude product was purified by silica gel (100-200 mesh) column chromatography, eluted with 30-40 % EtOAc in pet ether to afford the corresponding styryl pyrones.
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