* 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] Advanced Synthesis and Catalysis, 2005, vol. 347, # 7-8, p. 1027 - 1034
3
[ 85118-05-4 ]
[ 455-86-7 ]
[ 34036-07-2 ]
Reference:
[1] Advanced Synthesis and Catalysis, 2011, vol. 353, # 6, p. 855 - 859
4
[ 34036-07-2 ]
[ 455-86-7 ]
Reference:
[1] Chemical Research in Toxicology, 1996, vol. 9, # 1, p. 268 - 276
[2] Biochemical Journal, 2010, vol. 425, # 3, p. 585 - 593
5
[ 34036-07-2 ]
[ 23384-72-7 ]
Reference:
[1] Patent: US6159990, 2000, A,
6
[ 75-29-6 ]
[ 348-61-8 ]
[ 68-12-2 ]
[ 34036-07-2 ]
Yield
Reaction Conditions
Operation in experiment
86%
Stage #1: With iodine; magnesium In tetrahydrofuran at 20 - 40℃; for 5.66667 h; Inert atmosphere Stage #2: at 0 - 10℃; Stage #3: at 0 - 10℃; for 0.666667 h;
5L four-necked flask, mechanical stirring, nitrogen protection, followed by adding magnesium strips, 400g iodine granules in tetrahydrofuran, further, 41.7 g of 2-chloropropane was added at room temperature, 10min after the addition, temperature up to 40 deg. C, cooling, 30-40 ° C drop with a solution of 2-chloropropane, 4.5h dropwise additon is completed, insulation 1h, basically no magnesium. Cooling, a solution of 3,4-difluorobromobenzene (654 g of 3,4-difluorobromobenzene in 700 g of tetrahydrofuran) was dropwise added at 0 to 10 ° C, and the addition was completed in 50 minutes. Insulation reaction, can be done at room temperature. Reaction is completed, cooling, a solution of DMF (291.3 g of DMF in 300 g of tetrahydrofuran) was added dropwise at 0-10 ° C over 40 min. The temperature below 10 deg. C, dropping 700g of water, and then dropping concentrated hydrochloric acid to adjust pH to about 4, about 840g hydrochloric acid, phase separation, the lower aqueous phase with 500g toluene extraction twice, combine the organic layer, washed once with 500 g of saturated saline solution, and washed once with 500 g of water. 65 deg. C pump vacuum concentration to no solvent, was crude, vacuum distillation, the purity of more than 99.5percent, 86percent yield.
Reference:
[1] Patent: CN105859536, 2016, A, . Location in patent: Paragraph 0016; 0017
7
[ 2927-34-6 ]
[ 34036-07-2 ]
Yield
Reaction Conditions
Operation in experiment
30.7%
at 65℃;
6.06 g of cobalt acetate and 6.06 g of sodium molybdate were dissolved in 200 ml3,4-difluorotoluene and 200 mlAcetic acid to form a mixed solution,At this time η (cobalt acetate):Η (3,4-difluorotoluene) = 0.015:1, 6.06 g of sodium bromide was dissolved in 15percentH202formH202- acetic acid solution,At this time η (sodium bromide):Η (3,4-difluorotoluene) = 0.015: 1,3,4-difluorotoluene-acetic acid solutionWith H22-acetic acid solution at 8.33 ml / min and 16.67 ml / min, respectivelyOf the flow rate through the constant flow into the continuous heat exchanger tube reactor,At this time η (H2 2): η (3,4-difluoromethyl = 2: 1,The reaction temperature was controlled Using Figure 2 microchannel reactor,Control the reaction temperature65 ° C, residence time 200s. Export material 0 ° C cooling,The reaction was quenched with difluoromethane.After GC analysis,The conversion of 3,4-difluorotoluene was 42.0percent and the yield of 3,4-difluorobenzaldehyde was 30.7percent.
Reference:
[1] Molecular Crystals and Liquid Crystals, 2010, vol. 528, p. 138 - 146
14
[ 85118-05-4 ]
[ 455-86-7 ]
[ 34036-07-2 ]
Reference:
[1] Advanced Synthesis and Catalysis, 2011, vol. 353, # 6, p. 855 - 859
15
[ 348-61-8 ]
[ 109-94-4 ]
[ 34036-07-2 ]
[ 182192-98-9 ]
Reference:
[1] Journal of Fluorine Chemistry, 1996, vol. 78, # 2, p. 113 - 119
16
[ 34036-07-2 ]
[ 452-11-9 ]
Reference:
[1] Patent: EP2940031, 2015, A1,
17
[ 34036-07-2 ]
[ 220362-31-2 ]
Reference:
[1] Patent: WO2008/39882, 2008, A1,
18
[ 141-82-2 ]
[ 34036-07-2 ]
[ 112897-97-9 ]
Yield
Reaction Conditions
Operation in experiment
92%
for 4 h; Reflux
General procedure: The suitable aldehyde (10 mmol), malonic acid (30 mmol, 3.12 g) and piperidine (0.5 mL) were dissolved in pyridine (20 mL) and the mixture was heated under reflux for 4 h. The solution was cooled to room temperature and poured in ice-cold aqueous HCl (100 mL,3 M). The white solid precipitate was filtered, washed with water (350 mL), aqueous NaHCO3 (20 mL, 5percent w/v), then again with water (250 mL) and dried in an oven (60 C). If required, the crude solid was recrystallysed from EtOH/H2O. 4.3.1. (E)-3-(3,4-Difluorophenyl)acrylic acid (2j). Yield: 1.70 g (92percent). 1H NMR (DMSO-d6, 400 MHz), d: 7.85e7.91 (m, 1H), 7.55e7.57 (m,1H), 7.56 (d, J16.0 Hz, 1H), 7.43e7.50 (m, 1H), 6.57 (d, J16.0 Hz,1H). 13C NMR (DMSO-d6, 101 MHz), d: 167.30, 150.35 (dd, 1JCF248 Hz, 2JCF13 Hz), 149.64 (dd, 1JCF244 Hz, 2JCF13 Hz),141.64, 132.03 (dd, 3JCF6 Hz, 4JCF4 Hz), 125.82 (dd, 3JCF7 Hz, 4JCF3 Hz), 120.68, 117.88 (d, 2JCF17 Hz), 116.65 (d, 2JCF18 Hz).
Reference:
[1] Tetrahedron, 2016, vol. 72, # 46, p. 7256 - 7262
[2] Molecular Crystals and Liquid Crystals, 2010, vol. 528, p. 138 - 146
[3] Chemical Biology and Drug Design, 2013, vol. 81, # 2, p. 275 - 283
[4] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 20, p. 5726 - 5732
Stage #1: 5-fluoro-2-methyl-1H-indene-3-acetic acid With 2-chlorotrityl chloride resin; N-ethyl-N,N-diisopropylamine In dichloromethane at 21℃; for 2h;
Stage #2: 3,4 difluorobenzaldehyde With 1,8-diazabicyclo[5.4.0]undec-7-ene at 60℃;
Stage #3: With trifluoroacetic acid In dichloromethane
Methane sulfinic acid sodium salt (20.1 g, 200 mmol) was added to a stirred solution of 3,4- difluorobenzaldehyde (22.5 g, 158 mmol) in dry DMSO (200 ml) at 75 C. After 2 hours the reaction was poured onto ice-water (200 ml). The precipitate was filtered, washed with water and dissolved in chloroform (400 ml). The organic extract was washed with water (2 x 200 ml), dried over MgSO 4, filtered, and the solvent removed to give the title compound as a white solid.
1.00 g 2,3-diamino-5-nitro-pyridine and 0.95 g 3,4-difluorobenzaldehyde were stirred in 60 ml nitrobenzene at 160 C for 26 hrs. The solvent was removed under vacuum and the residue dissolved in 40 ml pyridine at 60 C. The solution was cooled in an ice bath. Precipitated product was isolated by filtration and dried to yield 0.5 g of the title product.
In nitrobenzene; at 160℃; for 26h;
Example 10-1 [2-(3,4-Difluoro-phenyl)-3H-imidazo[4,5-b]pyridin-6-yl]-carbamic acid isopropyl ester a) 2-(3,4-Difluoro-phenyl)-6-nitro-3H-imidazo[4,5-b]pyridine; 1.00 g 2,3-diamino-5-nitro-pyridine and 0.95 g 3,4-difluorobenzaldehyde were stirred in 60 ml nitrobenzene at 160 C. for 26 hrs. The solvent was removed under vacuum and the residue dissolved in 40 ml pyridine at 60 C. The solution was cooled in an ice bath. Precipitated product was isolated by filtration and dried to yield 0.5 g of the title product.
1-(3-Chloro-2,6-difluoro-phenyl)-ethanol and other phenylethanol derivatives (examples 11, 14, 15, 17, 18) were prepared by treatment of the corresponding phenyl-carboxaldehyde with methylmagnesiumbromide (1 equivalent) in THF at room temperature
Step 1: Preparation of (E)-3-(3,4-difluorophenyl)-2-propenoic acid. A stirred mixture of pyridine (15.5 kg) and piperidine (0.72 kg) were heated to 90 C. Malonic acid (17.6 kg) was added, followed by slow addition, over 50 minutes, of 3,4-difluorobenzaldehyde (12.0 kg). The reaction mixture was stirred at 90 C. for a further 4 hours and 36 minutes. Water (58.5 kg) was added and 32 litres of the pyridine/water mixture then was distilled out of the reactor under reduced pressure. The reaction mixture was acidified to pH 1 with 37% hydrochloric acid (6.4 kg) over a 40 minute period, then cooled to 25 C. with strong stirring. The solids were collected by filtration, washed twice with 1% hydrochloric acid (34.8 L per wash), once with water (61 L) and then deliquored thoroughly in the filter. The product was then dried under vacuum at 40 C. for 24 hours and 40 minutes, affording 13.7 kg of the crystalline product.
With pyridine; malonic acid; In water;
Example 1 This example illustrates the preparation of (E)-3-(3,4-difluorophenyl)-2-propenoic acid A stirred mixture of pyridine (15.5 kg) and piperidine (0.72 kg) were heated to 90 C. Malonic acid (17.6 kg) was added, followed by slow addition, over 50 minutes, of 3,4-difluorobenzaldehyde (12.0 kg). The reaction mixture was stirred at 90 C. for a further 4 hours and 36 minutes. Water (58.5 kg) was added and 32 litres of the pyridine/water mixture then was distilled out of the reactor under reduced pressure. The reaction mixture was acidified to pH 1 with 37% hydrochloric acid (6.4 kg) over a 40-minute period, then cooled to 25 C. with strong stirring. The solids were collected by filtration, washed twice with 1% hydrochloric acid (34.8 L per wash), once with water (61 L) and then deliquored thoroughly in the filter. The product was then dried under vacuum at 40 C. for 24 hours and 40 minutes, affording 13.7 kg of the crystalline product.
With bromine; calcium carbonate; In dichloromethane;
(A) 3,4-difluorobenzaldehyde. In a 250 ml three-necked flask equipped with a magnetic stirrer, thermometer, condenser, and dropping funnel is placed 25.6 g (0.2 mol) of <strong>[2927-34-6]3,4 difluorotoluene</strong>. The liquid is heated to 105 C. and illuminated as 67 g (0.42 mol) of bromine is added slowly. The temperature is kept between 105-110 C. while the first half of the bromine is added over a period of one hour. The rest of the bromine is added over approximately a 2-hour period and the temperature is raised to 150 C. and kept there for 5 minutes. The reaction mixture is cooled and transferred to a 1 liter 3-necked flask with a motor driven stirrer and condenser. 120 ml H2 O and 90 g of calcium carbonate are added, and the mixture is refluxed for 20 hours with good stirring. The reaction mixture is steam distilled until no further oil is collected. The oil is taken up in methylene chloride and dried over MgSO4. Evaporation of the solvent yields 3,4-difluorobenzaldehyde which is used without further purification.
With bromine; calcium carbonate; In dichloromethane;
(A) 3,4-Difluorobenzaldehyde <strong>[2927-34-6]3,4-difluorotoluene</strong> (25.6 g, 0.2 mol) is heated to 105 C. in a 250 ml 3-necked flask equipped with a magnetic stirrer, thermometer, condenser, and dropping funnel, and is illuminated as bromine (67 g, 0.42 mol) is added slowly. The temperature is kept between 105-110 C. while the first half of the bromine is added over a period of one hour. The rest of the bromine is added over approximately a two-hour period, and the temperature is raised to 150 C., and is kept there for 5 minutes. The reaction mixture is cooled and is transferred to a 1 liter 3-necked flask with a motor-driven stirrer and condenser. H2 O (120 ml) and calcium carbonate (90 g) are added, and the mixture is refluxed for 20 hours with good stirring. The reaction mixture is steam distilled until no further oil is collected. The oil is taken up in methylene chloride and dried over MgSO4. Evaporation of the solvent yields 3,4-difluorobenzaldehyde that is used without further purification.
With bromine; calcium carbonate; In dichloromethane;
(A) 3,4-difluorobenzaldehyde. In a 250 ml. three-necked flask equipped with a magnetic stirrer, thermometer, condenser, and dropping funnel is placed 25.6 g (0.2 mole) of <strong>[2927-34-6]3,4 difluorotoluene</strong>. The liquid is heated to 105 and illuminated as 67 g. (0.42 mole) of bromine is added slowly. The temperature is kept between 105-110 while the first half of the bromine is added over a period of one hour. The rest of the bromine is added over approximately a 2 hour period and the temperature is raised to 150 and kept there for 5 minutes. The reaction mixture is cooled and transferred to a 1 liter 3-necked flask with a motor driven stirrer and condenser. 120 ml. H2 O and 90 g. of calcium carbonate are added, and the mixture is refluxed for 20 hours with good stirring. The reaction mixture is steam distilled until no further oil is collected. The oil is taken up in methylene chloride and dried over MgSO4. Evaporation of the solvent yields 3,4-difluorobenzaldehyde which is used without further purification.
With bromine; calcium carbonate; In dichloromethane;
(A) 3,4-difluorobenzaldehyde In a 250 ml three-necked flask equipped with a magnetic stirrer, thermometer, condenser, and dropping funnel is placed 25.6 g (0.2 mol) of <strong>[2927-34-6]3,4-difluorotoluene</strong>. The liquid is heated to 105 and illuminated as 67 g (0.42 mol) of bromine is added slowly. The temperature is kept between 105-110 C. while the first half of the bromine is added over a period of one hour. The rest of the bromine is added over approx. a 2 hour period, and the temperature is raised to 150 and kept there for 5 minutes. The reaction mixture is cooled and transferred to a 1 liter 3-necked flask with a motor driven stirrer and condenser. 120 ml H2 O and 90 g of calcium carbonate are added, and the mixture is refluxed for 20 h with good stirring. The reaction mixture is steam distilled until no further oil is collected. The oil is taken up in methylene chloride and dried over MgSO4. Evaporation of the solvent yields 3,4-difluorobenzaldehyde which is used without further purification.
With acetic acid; urea In tetrahydrofuran; toluene
3 5-Methoxycarbonyl-6-methoxymethyl-4-(3 4-difluorophenyl)-3,4-dihydropyrimidin-2(1H)-one STR27
EXAMPLE 3 5-Methoxycarbonyl-6-methoxymethyl-4-(3 4-difluorophenyl)-3,4-dihydropyrimidin-2(1H)-one STR27 To a dry round bottom flask containing methoxy acetoacetate (2.0 g, 13.7 mmol), 3,4-difluorobenzaldehyde (1.95 g, 13.7 mmol) and urea (1.23 g, 20.6 mmol) in 28 ml of dry THF (0.5M) was added AcOH (10 mol %), CuCl (10 mol %) or Cu(OAC)2 and 1.3 e.g. of BF3 *Et2 O (2.6 mmol). The reaction was heated at 65° C. for up to 18 h. The reaction was quenched with one volume equivalent of 10% Na2 CO3 solution and diluted with EtOAc (one volume equivalent). The organic layer containing the product was turned over to toluene and the title compound was crystallized in 90% yield; mp: 116°-120° C. 1 H NMR (250 MHz, CDCl3)δ 7.70 (br s, 1H), 7.06 (m, 3H), 6.91 (br s, 1H), 5.32 (s, 1H), 4.62 (s, 2H), 3.63 (s, 3H), 3.44 (s, 3H).
5-pentyl-2-(3',4'-difluorophenyl)-l,3dioxane[ No CAS ]
5-pentyl-2-(3',4'-difluorophenyl)-1,3-dioxane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With toluene-4-sulfonic acid; In benzene;
Step 3 83 g (0.57 mol) of the <strong>[25462-23-1]2-<strong>[25462-23-1]pentylpropane-1,3-diol</strong></strong>, 81 g (0.57 mol) of 3,4-difluorobenzaldehyde (manufactured by Aldrich Corp.), and 4.9 (0.02 mol) of p-toluenesulfonic acid was dissolved in 285 cm3 of benzene. The solution was refluxed for 5 hours, and the water formed was removed with a water separator. The solution was sequentially washed with water, an aqueous 5% NaHCO3 solution, and water and the solution was boiled to distill off the benzene. The residual oily substance formed was subjected to vacuum distillation (b.p. 140 C./3.5 Torrs) to yield 121 g (0.45 mol) of a mixture of the trans and a cis isomers of 5-pentyl-2-(3',4'-difluorophenyl)-1,3-dioxane. The mixture was 80% of the trans isomer and 20% of the cis isomer. The mixture was an isotropic liquid at room temperature. The following are other examples of the compounds in accordance with this embodiment of the invention which may be prepared following the procedures of Example 1.
1-(3,4-difluorobenzylidene)-2-(4-propylbenzylidene)hydrazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydrogencarbonate; triethylamine; In ethanol; dichloromethane;
(Example 4) Synthesis of 1-(3,4-difluorobenzylidene)-2-(4-propylbenzylidene)hydrazine (Compound No. 7 set forth in Table 1) To 40 g of a monohydrate of hydrazine was added a solution of 10 g of <strong>[28785-06-0]4-propylbenzaldehyde</strong> in 50 m of ethanol. The mixture was stirred at room temperature for 30 minutes. To the mixture was then added 150 m of saturated aqueous solution of sodium bicarbonate. To the mixture was then added 100 m of dichloromethane. The mixture was then washed with 150 m of saturated aqueous solution of sodium bicarbonate twice. To the resulting organic phase was then added 5 m of triethylamine. The mixture was then dehydrated and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. To the residue was then added 5 m of triethylamine. To the mixture were then added 50 m of ethanol and 8.5 g of 3,4-difluorobenzaldehyde. The mixture was then stirred at room temperature for 6.5 hours. To the mixture was then added 150 m of saturated aqueous solution of sodium bicarbonate. To the mixture was then added 100 m of dichloromethane. The mixture was then washed with 150 m of saturated aqueous solution of sodium bicarbonate twice. The solvent was then distilled off under reduced pressure. The residue was purified through alumina (basic) column chromatography (dichloromethane), and then recrystallized from methanol to obtain 5.7 g of 1-(3,4-difluorobenzylidene)-2-(4-propylbenzylidene)hydrazine. The compound thus obtained had a melting point of 50°C and exhibited nematic phase up to 59.5°C. The foregoing procedure was followed except that 4-methylbenzaldehyde, 4-ethylbenzaldehyde, 4-butylbenzaldehyde, 4-pentylbenzaldehyde, 4-heptylbenzaldehyde or 4-methoxybenzaldehyde was used instead of <strong>[28785-06-0]4-propylbenzaldehyde</strong>.
With sodium molybdate; dihydrogen peroxide; cobalt(II) acetate; acetic acid; sodium bromide; at 65℃;
6.06 g of cobalt acetate and 6.06 g of sodium molybdate were dissolved in 200 ml<strong>[2927-34-6]3,4-difluorotoluene</strong> and 200 mlAcetic acid to form a mixed solution,At this time eta (cobalt acetate):Eta (<strong>[2927-34-6]3,4-difluorotoluene</strong>) = 0.015:1, 6.06 g of sodium bromide was dissolved in 15%H202formH202- acetic acid solution,At this time eta (sodium bromide):Eta (<strong>[2927-34-6]3,4-difluorotoluene</strong>) = 0.015: 1,<strong>[2927-34-6]3,4-difluorotoluene</strong>-acetic acid solutionWith H22-acetic acid solution at 8.33 ml / min and 16.67 ml / min, respectivelyOf the flow rate through the constant flow into the continuous heat exchanger tube reactor,At this time eta (H2 2): eta (3,4-difluoromethyl = 2: 1,The reaction temperature was controlled Using Figure 2 microchannel reactor,Control the reaction temperature65 C, residence time 200s. Export material 0 C cooling,The reaction was quenched with difluoromethane.After GC analysis,The conversion of <strong>[2927-34-6]3,4-difluorotoluene</strong> was 42.0% and the yield of 3,4-difluorobenzaldehyde was 30.7%.
With bromine; calcium carbonate; In dichloromethane;
(A) 3,4-difluorobenzaldehyde. In a 250 ml. three-necked flask equipped with a magnetic stirrer, thermometer, condenser, and dropping funnel is placed 25.6 g (0.2 mole) of <strong>[2927-34-6]3,4 difluorotoluene</strong>. The liquid is heated to 105 and illuminated as 67 g. (0.42 mole) of bromine is added slowly. The temperature is kept between 105-110 while the first half of the bromine is added over a period of one hour. The rest of the bromine is added over approximately a 2 hour period and the temperature is raised to 150 and kept there for 5 minutes. The reaction mixture is cooled and transferred to a 1 liter 3-necked flask with a motor driven stirrer and condenser. 120 ml. H20 and 90 g. of calcium carbonate are added, and the mixture is refluxed for 20 hours with good stirring. The reaction mixture is steam distilled until no further oil is collected. The oil is taken up in methylene chloride and dried over MgSO4. Evaporation of the solvent yields 3,4-difluorobenzaldehyde which is used without further purification.
With bromine; calcium carbonate; In dichloromethane; water;
(A) 3,4-difluorobenzaldehyde In a 250 ml. three-necked flask equipped with a magnetic stirrer, thermometer, condenser, and dropping funnel is placed 25.6 g (0.2 mole) of <strong>[2927-34-6]3,4 difluorotoluene</strong>. The liquid is heated to 105 and illuminated as 67 g. (0.42 mole) of bromine is added slowly. The temperature is kept between 105-110 while the first half of the bromine is added over a period of one hour. The rest of the bromine is added over approximately a 2-hour period and the temperature is raised to 150 and kept there for 5 minutes. The reaction mixture is cooled and transferred to a 1 liter 3-necked flask with a motor driven stirrer and condenser. 120 ml. H2O and 90 g. of calcium carbonate are added, and the mixture is refluxed for 20 hours with good stirring. The reaction mixture is steam distilled until no further oil is collected. The oil is taken up in methylene chloride and dried over MgSO4. Evaporation of the solvent yields 3,4-difluorobenzaldehyde which is used without further purification.
methyl 2-[(3,4-difluorophenyl)-methylene]-3-oxo-4-methoxybutyrate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With piperdinium acetate;silica gel; In chloroform; ethyl acetate; benzene;
a Methyl 2-[(3,4-difluorophenyl)methylene]-3-oxo-4-methoxybutyrate (Scheme 2; C) To a solution of methyl 4-methoxyacetoacetate (84.32 g, 0.577 mol), 3,4-difluorobenzaldehyde (82 g, 0.577 mmol), and piperidinium acetate (5.86 g, 0.068 mol) in benzene (1.5 L) were added molecular sieves (400 g) and the mixture was stirred at room temperature for 48 h. The molecular sieves were removed by filtration and the solvent was evaporated from the filtrate under reduced pressure. The residue was purified by column chromatography on silica gel using chloroform/ethyl acetate (100:3) to get the product as an oil (67 g, 47percent). This product was a mixture of cis and trans isomers.
With piperdinium acetate;silica gel; In chloroform; ethyl acetate; benzene;
a) Methyl 2-[(3,4-difluorophenyl)methylene]-3-oxo-4-methoxybutyrate. A solution of methyl 4-methoxyacetoacetate (84.32 g, 0.577 mol), 3,4-difluorobenzaldehyde (82 g, 0.577 mmol), and piperidinium acetate (5.86 g, 0.068 mol) in benzene (1.5 L) were added molecular sieves (400 g) and the mixture was stirred at room temperature for 48 h. The molecular sieves were removed by filtration and the solvent was evaporated from the filtrate under reduced pressure. The residue was purified by column chromatography on silica gel using chloroform/ethyl acetate (100:3) to get the product as an oil (67 g, 47percent).
3-(3,4-Difluoro-benzylamino)-4-methoxy-N-phenyl-benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 274 3-(3,4-Difluoro-benzylamino)-4-methoxy-N-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 3,4-difluorobenzaldehyde as starting materials, which can be purchased from Aldrich; m.p. 150-152 C.
With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane at 20℃; for 18h;
3
Description 3; 8-(3,4-Difluorobenzyl)-l,4-dioxa-8-azaspiro[4.5]decane (D3); A solution of 3,4-difluorobenzaldehyde (4.40 g, 30.9 mmol), 4,4-ethylenedioxy- piperidine (4.40 g, 30.9 mmol), sodium triacetoxyborohydride (6.40 g, 30.2 mmol) and acetic acid (1.8 g, 30.0 mmol) in dichloroethane (200 ml) was stirred at room temperature for 18 h. After this period, the reaction mixture was washed with IN sodium hydroxide. The organic layer separated, dried (MgSO4) and the solvents evaporated in vacuo to give D3 (7.9 g, 98 %). Ci4Hi7F2NO2 requires 269; Found 270 (MH+)
With potassium carbonate In N,N-dimethyl-formamide at 110℃; for 18h; Inert atmosphere;
8.1
A- Methyl- 1 /-/-imidazole (1.67 g, 20.3 mmol) and potassium carbonate (3.52 g, 25.5 mmol) were added to a solution of 3,4-difluorobenzaldehyde (2.24 ml_, 20.4 mmol) in dimethylformamide (25 ml_). The mixture was heated at 110 0C for 18 hours, whereupon it was allowed to cool to room temperature. The reaction was poured into aqueous sodium bicarbonate solution (150 ml_) and extracted with ethyl acetate (3 x 100 ml_). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (60 ml_) and brine (60 ml_), dried over magnesium sulfate and concentrated under reduced pressure provided a residue. Chromatography on silica (Gradient: 70% to 100% ethyl acetate in heptane) provided the title compound as a white solid. Yield: 88 mg, 0.43 mmol, 2%. 1H NMR (400 MHz, CDCI3) δ 2.30 (d, J=1 Hz, 3H), 7.07 (m, 1 H), 7.56 (dd, J=7.6, 7.6 Hz, 1 H), 7.76-7.79 (m, 2H), 7.85 (m, 1 H), 9.99 (d, J=1.9 Hz, 1 H).
With potassium carbonate In N,N-dimethyl-formamide at 20 - 90℃; for 6h;
74; 82; 83 Synthesis of 3-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde
Synthesis of 3-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde To a solution of 3,4-difluorobenzaldehyde (40.0 g) in DMF (533 mL), 4-methylimidazole (46.4 g) and potassium carbonate (78.0 g) were added at room temperature, and the reaction solution was stirred at 90° C. for six hours. The reaction solution was left to cool to room temperature. Ethyl acetate was added to the reaction solution, which was then sequentially washed with water and brine. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) and solidified with tert-butyl methyl ether to obtain 10.1 g of the title compound. The property values of the compound are as follows. 1H-NMR (CDCl3) δ (ppm): 2.33(d,J=0.8 Hz,3H), 7.07(brs,1H), 7.57(dd,J=7.2,7.2 Hz,1H), 7.76-7.82(m,2H), 7.87(brs,1H), 10.01(d,J=1.6 Hz,1H). Synthesis of 3-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde 3,4-Difluorobenzaldehyde (30.0 g) was dissolved in DMF (400 mL), and 4-methyl-1H-imidazole (34.8 g) and potassium carbonate (58.5 g) were added to the solution at room temperature. The reaction solution was stirred at 90° C. for six hours. The reaction solution was left to cool to room temperature. Then, ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system), solidified with tert-butyl methyl ether, and separated by filtration to obtain 6.28 g of the title compound. The property values of the compound are as follows. 1H-NMR (CDCl3) δ (ppm): 2.32(d,J=0.8 Hz,3H), 7.07(brs,1H), 7.57(dd,J=7.2,7.2 Hz, 1H), 7.76-7.82(m,2H), 7.87(brs,1H), 10.01(d,J=1.6 Hz,1H).
With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 6h;
5 Synthesis of 3-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde
Synthesis of 3-fluoro-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde 4-Methylimidazole (46.4 g) and potassium carbonate (78.0 g) were added to a DMF solution (533 mL) of 3,4-difluorobenzaldehyde (40.0 g) at room temperature. This reaction solution was stirred at 90° C. for 6 hr and then was allowed to cool to room temperature. To the reaction solution, ethyl acetate and water were added. The organic layer was separated, washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluding solvent: heptane-ethyl acetate system) and further solidified with tert-butylmethylether to give 10.1 g of the title compound. The physical property values of this compound were as follows: 1H-NMR (CDCl3) δ (ppm): 2.33 (d, J=0.8 Hz, 3H), 7.07 (brs, 1H), 7.57 (dd, J=7.2, 7.2 Hz, 1H), 7.76-7.82 (m, 2H), 7.87 (brs, 1H), 10.01 (d, J=1.6 Hz, 1H).
With potassium carbonate In N,N-dimethyl-formamide Heating;
Methyltriphenylphosphonium bromide (251.31 g, 0.7037 mol), l,8-diazabicyclo[5.4.0]undec- 7-ene (117.84 g, 0.7741 mol) and toluene (250 ml) were taken into a clean and dry reaction assembly. The resulting mixture was heated at 40-45C, followed by stirring for 30 minutes. 3,4-Difluorobenzaldehyde (50 g, 0.3518 mol) was slowly added to the hot solution and the reaction mixture was heated at reflux temperature, followed by maintaining for 5 hours at reflux. After completion of the reaction, the mass was cooled to 25-30C, followed by washing with water (2 x 250 ml). The resulting mass was distilled under reduced pressure while maintaining the temperature at below 50C to give 3,4-difiuorostyrene.
Example 1 Preparation of 3,4-Difluorostyrene Methyltriphenylphosphonium bromide (71 g, 0.2111 mol), 1,8-diazabicyclo[5.4.0]undec-7-ene (35.37 g, 0.2311 mol) and toluene (75 ml) were taken into a clean and dry reaction assembly. The resulting mixture was heated at 40-45 C., followed by stirring for 30 minutes. 3,4-Difluorobenzaldehyde (15 g, 0.1055 mol) was slowly added to the above hot solution and the reaction mixture was heated at reflux temperature, followed by maintaining for 6 hours at reflux. After completion of the reaction, the mass was cooled to 25-30 C., followed by washing with water (2*250 ml). The resulting mass was distilled under reduced pressure while maintaining the temperature at below 50 C. to give 3,4-difluorostyrene.
General procedure: To a stirred suspension of methyltriphenylphosphonium bromide (1.61 g, 4.51 mmol, 1.5 equiv.)in 10 mL dry THF at -78 C under argon atmosphere, n-butyllithium (2.8 mL, 4.51 mmol, 1.6 Msolution in THF, 1.5 equiv.) was added dropwise. The yellow solution was allowed to stir for 15min. before addition of the 3,4 dimethoxybenzadehyde 5a (0.5 g, 3 mmol, 1 equiv.) in 5 mL dryTHF, upon which, the mixture turned white or pale yellow. After 2 h (or observed completion ofthe reaction by TLC), saturated ammonium chloride was added and the mixture extracted withCH2Cl2. The combined organic extracts were then dried (Na2SO4), and concentrated in vacuo. Evaporation of the solvent under reduced pressure gave the crude product. Purification by flashcolumn chromatography (Silica gel 230-400 mesh, 1-10% ethyl acetate/ petroleum ether)afforded the desired styrene 6a as a colorless liquid.
With piperidine; pyridine; at 90℃; for 2h;Inert atmosphere;
Under the protection of nitrogen,Add 3,4-difluorobenzaldehyde (0.1mol) and malonic acid (0.1mol) to the dry reaction bottle,Add piperidine (0.01mol) and pyridine (0.3mol),Heat to 90 C with stirring for 2h,Then add 200mL of 2mol / L hydrochloric acid solution,There is solid precipitation, filtration,The filter cake was recrystallized with ethanol to obtain (E) -3- (3,4-difluorophenyl) acrylic acid (17.48 g, 95%).
92%
With piperidine; pyridine; for 4h;Reflux;
General procedure: The suitable aldehyde (10 mmol), malonic acid (30 mmol, 3.12 g) and piperidine (0.5 mL) were dissolved in pyridine (20 mL) and the mixture was heated under reflux for 4 h. The solution was cooled to room temperature and poured in ice-cold aqueous HCl (100 mL,3 M). The white solid precipitate was filtered, washed with water (350 mL), aqueous NaHCO3 (20 mL, 5% w/v), then again with water (250 mL) and dried in an oven (60 C). If required, the crude solid was recrystallysed from EtOH/H2O. 4.3.1. (E)-3-(3,4-Difluorophenyl)acrylic acid (2j). Yield: 1.70 g (92%). 1H NMR (DMSO-d6, 400 MHz), d: 7.85e7.91 (m, 1H), 7.55e7.57 (m,1H), 7.56 (d, J16.0 Hz, 1H), 7.43e7.50 (m, 1H), 6.57 (d, J16.0 Hz,1H). 13C NMR (DMSO-d6, 101 MHz), d: 167.30, 150.35 (dd, 1JCF248 Hz, 2JCF13 Hz), 149.64 (dd, 1JCF244 Hz, 2JCF13 Hz),141.64, 132.03 (dd, 3JCF6 Hz, 4JCF4 Hz), 125.82 (dd, 3JCF7 Hz, 4JCF3 Hz), 120.68, 117.88 (d, 2JCF17 Hz), 116.65 (d, 2JCF18 Hz).
With piperidine; pyridine; at 90℃;Inert atmosphere;
General procedure: To a stirred solution of malonic acid (10 mmol) in pyridine(5 mL) and piperidine (3-5 drops) the corresponding aldehydes1a-p (8 mmol) were added. The resulting mixture was stirred at 90C for 8-12 h. The progress of the reaction was monitored byTLC analyses which indicated the disappearance of the starting material. After the completion of the reactions the reaction mixture were cooled to ambient temperature and the reaction mixture was neutralized with 1N HCl in ice bath resulting a white solid.This soled was filtered and washed three times with cold water.The recrystallization were done from aqueous ethanol (1:1)afforded the product 2a-p.
In a 300 ml 4-neck flask purged with nitrogen,30 ml of THF dried with Molecular Sieves 4A,Then, 3.83 g of metal magnesium was added and stirred.To this was added 690 mg of (3,4-difluorophenyl) magnesium bromide and stirred for 5 minutes.The temperature rose 0.7 C.To this, a solution of 29.54 g of <strong>[348-61-8]1-bromo-3,4-difluorobenzene</strong> dissolved in 60 ml of toluene,Add in dropping funnel over 1 hour, 30 C. ± 0.Let react at 5 C for 1 hour,A liquid containing organomagnesium bromide was obtained.Cool this solution to 10 C,To this solution, 11.51 g of DMF dried with Molecular Sieves 4A was added with a dropping funnel at 10 C. to 12 C. over 30 minutes, and reacted at 10 C. to 15 C. for 1 hour.A reaction product solution was obtained.120 g of 12.5 wt% hydrochloric acid was prepared in a 500 ml 4-neck flask. This is cooled to 10 C.The reaction product solution there, under a nitrogen atmosphere,Using a cannula, the solution was added dropwise at 10 C. ± 0.5 C. over 25 minutes, and reacted at 10 C. to 15 C. for 1 hour.The obtained liquid was separated to obtain 98.49 g (concentration 20.95 wt%, yield 96.2 mol%) of a toluene solution of 3,4-difluorobenzaldehyde.
With sodium hydroxide In ethanol; water at 20℃; for 3h;
8.1. General procedure for benzylidene derivatives 2-17
General Procedure: The ethanol (25 mL) and NaOH (4 M, 3 mL) were mixed, cooled in an ice bath, and then compound 1 (0.3 mmol, 100 mg) was added. The aromatic aldehyde (0.6 mmol) was added dropwise. The mixture was stirred for three hrs, and then neutralized by adding 2 M HCl. The precipitates were filtered, washed with acidic water (10 mL x 2), and neutral water (20 mL), and dried in vacuum.
Stage #1: Tetraisopropyl methylenediphosphonate With sodium hydride In tetrahydrofuran at 18 - 25℃; for 1.5h;
Stage #2: 3,4 difluorobenzaldehyde In tetrahydrofuran at 45 - 55℃; for 1.05h;
25.A
Example 25 A. (E)-[2-(3,4-Difluoro-phenyl)-vinyl]-phosphonic acid diisopropyl ester. To a suspension of 60% NaH (0.35 g, 8.7 mmol) in THF (8.7 mL), at ambient temperature, was added drop-wise diisopropyl methylenediphosphonate (Compound 25a) (3.0 g, 8.7 mmol) with a small amount of THF to complete the transfer. The addition was completed in 5 min, and a small rise in temperature was noted (up from 18° C. to 25° C.). The reaction was stirred for a minimum of 25 min, and as long as 1 hr. A solution of 3,4-difluorobenzaldehyde (Compound 25b) (0.96 mL, 8.7 mmol) in THF (1 mL) was added over 3 min. The internal reaction temperature rose to 45° C., and 1 hr at 55° C. The reaction was cooled to room temperature, quenched with H2O (10 mL), extracted with ether (2×10 mL), ethyl acetate (1×10 mL) and the combined organics were dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure to afford a crude oil. The resulting residue was purified by flash column chromatography (SiO2) eluting with ethyl acetate-CH2Cl2 to afford Compound 25c. 1H-NMR (300 MHz, CDCl3): δ 7.41-7.11 (m, 4H), 6.18 (t, J=16 Hz, 1H), 4.72 (m, 2H), 1.37 (d, 6H), 1.32 (d, 6H).
Stage #1: Tetraisopropyl methylenediphosphonate With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 1h;
Stage #2: 3,4 difluorobenzaldehyde In tetrahydrofuran; mineral oil at 45 - 55℃; for 1.05h;
25.A
A. (E)-[2-(3,4-Difluoro-phenyl)-vinyl]-phosphonic acid diisopropyl ester. To a suspension of 60% NaH (0.35 g, 8.7 mmol) in THF (8.7 mL), at ambient temperature, was added drop-wise diisopropyl methylenediphosphonate (Compound 25a) (3.0 g, 8.7 mmol) with a small amount of THF to complete the transfer. The addition was completed in 5 min, and a small rise in temperature was noted (up from 18° C. to 25° C.). The reaction was stirred for a minimum of 25 min, and as long as 1 hr. A solution of 3,4-difluorobenzaldehyde (Compound 25b) (0.96 mL, 8.7 mmol) in THF (1 mL) was added over 3 min. The internal reaction temperature rose to 45° C., and 1 hr at 55° C. The reaction was cooled to room temperature, quenched with H2O (10 mL), extracted with ether (2*10 mL), ethyl acetate (1*10 mL) and the combined organics were dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure to afford a crude oil. The resulting residue was purified by flash column chromatography (SiO2) eluting with ethyl acetate-CH2Cl2 to afford Compound 25c. 1H-NMR (300 MHz, CDCl3): δ 7.41-7.11 (m, 4H), 6.18 (t, J=16 Hz, 1H), 4.72 (m, 2H), 1.37 (d, 6H), 1.32 (d, 6H).
With caesium carbonate; at 80℃; for 1h;Microwave irradiation;
D53: 4-[4-Chloro-3-(trifluoromethyl)phenyl]oxy}-3-fluorobenzaldehydeThe mixture of <strong>[6294-93-5]4-chloro-3-(trifluoromethyl)phenol</strong> (7.61 g, 38.7 mmol), 3,4- difluorobenzaldehyde (5.0 g, 35.2 mmol) and CS2C03 (11.46 g, 35.2 mmol) was heated with a microwave reactor at 80°C for lh. Purification via a flash column chromatography then afforded the title compound (9.0g, 80 percent yield). LCMS: rt = 3.80 min, [M+H+] =319
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 hydride; In tetrahydrofuran; at 0 - 20℃; for 1h;Inert atmosphere;
To a stirred solution of tert-butyl 2-(diethoxyphosphoryl)acetate (8.8 g, 34.89 mmol, 1.00 equiv) in THF (30 mL) under argon at 0 C. was added 60% sodium hydride (1.4 g, 58.33 mmol, 1.10 equiv) batch wise. The mixture was stirred for 30 min at 0 C. and 3,4-difluorobenzaldehyde (5.0 g, 35 mmol, 1.0 equiv) was added. The resulting solution was warmed to room temperature, stirred for 1 hour, quenched with ice water (60 mL) and extracted with EtOAc (3×50 mL). The organic layers were combined and concentrated in vacuo to yield 8 g (crude) of the title compound as oil. 1H-NMR (400 MHz, CDCl3): delta 7.49 (m, 1H), 7.36-7.14 (m, 3H), 6.30 (m, 1H), 1.53 (s, 9H) ppm.
With potassium carbonate In N,N-dimethyl-formamide at 100℃;
l-^-Ethynyl-l-fluorophenyl^-methyl-l/Z-imidazole.3,4-Difluorobenzaldehyde (4.82 g, 33.9 mmol), 4-methylimidazole (5.57 g, 67.8 mmol), and K2CO3 (7.03 g, 50.9 mmol) were dissolved in 35 ml of DMF and stirred at 100 0C overnight. Cooled to room temperature and DMF removed in vacuo. The concentrated mass was taken up in EtOAc and water. Layers were separated and the aqueous layer was extracted twice with EtOAc. The organic extracts were combined, dried (Na2SO4), and concentrated. Chromatography on SiO2 (0-75% EtOAc/CH2Cl2) gave a cream-colored solid (mixture of isomers). This mass was taken up in a minimum amount of EtOH and treated with water until the formation of a precipitate. The precipitate was collected as a white solid and yielded 522.5 mg (2.6 mmol, 8%) after drying under high vacuum overnight. A solution of aldehyde intermediate (516 mg, 2.53 mmol) in 20 ml of MeOH was treated with K2CO3 (698 mg, 5.05 mmol) and a solution of dimethyl (l-diazo-2-oxopropyl)phosphonate (583 mg, 3.03 mmol) in 10 ml of MeOH and stirred at room temperature for 2.5 hours. MeOH was removed in vacuo and the concentrated mass was dissolved in aqueous NaHCO3 and EtOAc. Layers were separated and the aqueous layer was extracted twice with EtOAc. The organic extracts were combined, dried (Na2SO4), and concentrated to a yellow powder (506 mg, 2.5 mmol, 100%). 1H NMR (600 MHz, CDCl3) δ 7.74 (s, 1 H), 7.33 (m, 3 H), 6.96 (s, 1 H), 3.16 (s, 1 H), 2.29 (s, 3 H); MS (EI) [M+l]+ calc'd 201.1, found 201.2.
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 2h;
To a solution of 3,4-difluorobenzaldehyde (3.49 g, 24.53 mmol) and 6-(trifluoromethyl)pyridin-3- ol (4 g, 24.53 mmol) in DMF (50 mL) was added potassium carbonate (3.73 g, 27.0 mmol). The reaction mixture was stirred at 110 °C for 2h. The resultant mixture was extracted with EtOAc, washed with water, and concentrated to afford the title compound (6.9 g). LC-MS (ESI): m/z 286[M + 1] + , 1.10 min (ret time).
With sodium hydroxide In ethanol; water at 5 - 8℃;
24
General procedure: The piperid-4-one (2 mmol) and corresponding aryl (4 mmol) aldehydes are dissolved in the mixture solvent of ethanol and water (10:1), and other ketones (2 mmol) and corresponding aryl aldehydes (4 mmol) are dissolved in ethanol absolute. The compounds containing -OH group in the benzene ring were catalyzed by HCl. Other compounds were catalyzed by NaOH at 5-8 °C. All reactions were monitored by the silica gel TLC. At the end of the reaction, water is added into the reaction mixture to precipitate the product. Compound F3-F6, F9, F11-F16, F19-F21, F25, F27-F36 were purified by column chromatography using PE/EA or CHCl3/CH3OH. The crude of other compounds were recrystallized in the ethanol or the mixture of trichloromethane and ethanol. Their structures were determined by spectral data from ESI-MS and 1H NMR. The spectral data of new or unreported compounds are shown below. 4.1.24 (3E,5E)-3,5-Bis(3,4-difluorobenzylidene)-1-ethylpiperid-4-one (F25) 68.69% Yield, mp 122.2-124.3 °C. 1H NMR (CDCl3), δ: 7.688 (s, 2H, Ar-CH=C * 2), 7.191-7.232 (m, 4H, Ar-H2 * 2, Ar-H6 * 2), 7.133-7.151 (m, 1H, Ar-H5 * 2), 3.766 (s, 4H, N-CH2 * 2), 2.635 (q, J = 7.2 Hz, 2H, N-CH2), 1.082 (t, J = 7.2 Hz, 3H, CH3). ESI-MS m/z: 376.0, calcd for C21H17F4NO: 375.36.
General procedure: The method by Liang etal. was followed[49](Scheme 2). To a solution of substituted benzaldehyde (30mmol) in methanol (20mL) was added appropriately substituted ketone (15mmol) such as acetone (Series 2), cyclohexanone (Series 3) and cyclopentanone (Series 4). For the synthesis of Series 5 analogs, 15mmol of substituted benzaldehyde and 15mmol of substituted ketone were used instead. The resultant mixture was stirred at room temperature for 20min before 20% (w/v) NaOH (3.0mL, 15mmol) was added dropwise. After the reaction has completed, the residue was poured into saturated NH4Cl solution and filtered. The precipitate was washed with brine and cold ethanol, dried with anhydrous NaSO4, evaporatedin vacuoto give either a solid or liquid residue and purified by column chromatography on silica gel using hexane:ethyl acetate as eluting solvents. Further purification by re-crystallization from ethyl acetate or ethanol yielded yellow crystals.
In dimethyl sulfoxide; at 75℃; for 4h;Inert atmosphere;
3,4-Difluorobenzaldehyde 100 (23.50 g, 165.38 mmol) was treated with <strong>[20035-08-9]sodium ethanesulfinate</strong> (23.00 g, 198.09 mmol) in DMSO (230 mL) at the room temperature. The reaction mixture was heated at 75 C under N2for 4 h then cooled to the room temperature, and poured into a beaker of ice-water. The white precipitates were collected by filtration, washed with water, and dried in a vacuum oven at 45 C. The solid was then recrystallized from CH2CI2/iPr20 to give 4- (ethylsulfonyl)-3-fluorobenzaldehyde 113 (28.48 g, 80%) as a white powder: m.p. 107-110 C; 1HNMR (CDCI3) delta 10.09 (d, J = 1.9 Hz, 1H), 8.16 (dd, J = 6.5 Hz, 1.4, 1H), 7.87 (dd, J = 7.9 Hz, 1.4, 1H), 7.75 (dd, J = 9.4 Hz, 1.4, 1H), 3.38 (2q, J = 7.4 Hz, 2H), 1.33 (2t, J = 7.5 Hz, 3H). Anal.calcd for C9H9F03S: C, 49.99; H, 4.20; F, 8.79%; found: C, 50.19; H, 4.23; F, 8.91%.
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 potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 3h;Sealed tube; Microwave irradiation;
An alternative synthetic process is provided: A mixture of <strong>[170886-13-2]2-(trifluoromethyl)pyridin-4-ol</strong> (5 g, 30.7 mmol), 3,4-difluorobenzaldehyde (4.36 g, 30.7 mmol) and potassium carbonate (8.47 g, 61.3 mmol) in Nu,Nu-dimethylformamide (DMF) (30 mL) was sealed and heated under microwave at 110 C for 3 h. Then the reaction mixture was cooled, and concentrated in vacuo. The concentrate was purified via Biotage column (Hexane/EtOAc 100% to 3/1) to afford the title compound (6.4 g, 37.6%) as a white solid. LCMS (ESI): m/z 286 [M + H]+; 1.35 min (ret time)
Multi-step reaction with 3 steps
1: dichloromethane / 0.5 h / 20 °C
2: palladium on activated charcoal; hydrogen / tetrahydrofuran; ethanol / 48 h / 20 °C
3: sodium hydroxide / water; methanol / 1 h / 20 °C
Multi-step reaction with 2 steps
1: pyridine; piperidine / 6 h / 0 °C / Reflux
2: hydrogen; 10% palladium hydroxide on charcoal / methanol; ethyl acetate / 4 h / 20 °C
ethyl 2-(2-fluoro-4-formylphenoxy)-6-methylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6.98 g
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 0.5h;Inert atmosphere;
To a solution of <strong>[6555-40-4]ethyl 2-hydroxy-6-methylbenzoate</strong> (5.00 g) and potassium carbonate (11.50 g) in DMF (100 mL) was added 3,4-difluorobenzaldehyde (3.37 mL), and the mixture was stirred under an argon atmosphere at 90C for 30 min. The reaction mixture was diluted with water and ethyl acetate, and the organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (hexane-ethyl acetate) to give the title compound (6.98 g). MS: [M+H]+ 303.1 1H NMR (300 MHz, CDCl3) delta 1.20 (3H, t, J = 7.1 Hz), 2.43 (3H, s), 4.28 (2H, q, J = 7.2 Hz), 6.88 (1H, d, J = 8.3 Hz), 6.98 (1H, t, J = 8.0 Hz), 7.12 (1H, d, J = 7.7 Hz), 7.30-7.37 (1H, m), 7.54-7.60 (1H, m), 7.70 (1H, dd, J = 10.4, 1.9 Hz), 9.90 (1H, d, J = 1.9 Hz).
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.
5,7-dibromo-2-(3,4-difluorophenyl)-1H-benzimidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
Stage #1: 3,4 difluorobenzaldehyde With sodium metabisulfite In ethanol; water
Stage #2: 3,5-dibromo-1,2-phenylendiamine In N,N-dimethyl-formamide at 110℃; for 4h;
With silica gel; In chloroform; at 20℃; for 70.0h;Molecular sieve; Sealed tube; Inert atmosphere;
General procedure: Briefly, to synthesize 4-Fluorophenyl t-butyl nitrone (4-F-PBN), 4-fluorobenzaldehyde (8 mmol) and N-tertbutylhydroxylamine (120 mmol) were mixed in chloroform with molecular sieves (50 g, 4 A) and silica gel (10 g). The mixture was sealed under argon gas and stirred for 70 h at room temperature. The mixture was then filtered and the solid washed with ethyl acetate and the combined solution was rotary evaporated to give the crude product.
5L four-necked flask, mechanical stirring, nitrogen protection, followed by adding magnesium strips, 400g iodine granules in tetrahydrofuran, further, 41.7 g of 2-chloropropane was added at room temperature, 10min after the addition, temperature up to 40 deg. C, cooling, 30-40 C drop with a solution of 2-chloropropane, 4.5h dropwise additon is completed, insulation 1h, basically no magnesium. Cooling, a solution of <strong>[348-61-8]3,4-difluorobromobenzene</strong> (654 g of <strong>[348-61-8]3,4-difluorobromobenzene</strong> in 700 g of tetrahydrofuran) was dropwise added at 0 to 10 C, and the addition was completed in 50 minutes. Insulation reaction, can be done at room temperature. Reaction is completed, cooling, a solution of DMF (291.3 g of DMF in 300 g of tetrahydrofuran) was added dropwise at 0-10 C over 40 min. The temperature below 10 deg. C, dropping 700g of water, and then dropping concentrated hydrochloric acid to adjust pH to about 4, about 840g hydrochloric acid, phase separation, the lower aqueous phase with 500g toluene extraction twice, combine the organic layer, washed once with 500 g of saturated saline solution, and washed once with 500 g of water. 65 deg. C pump vacuum concentration to no solvent, was crude, vacuum distillation, the purity of more than 99.5%, 86% yield.
3-[(tetradecylamino)(3,4-difluorophenyl)methyl]-2-hydroxy-1,4-naphthoquinone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47%
Stage #1: 2-hydroxynaphtho-1,4-quinone; tetradecylamine In ethanol at 20℃; for 0.0833333h;
Stage #2: 3,4 difluorobenzaldehyde In ethanol at 20℃; for 5h;
4.1.1. 3-[(Dodecylamino)(2-pyridyl)methyl]-2-hydroxy-1,4-naphthoquinone (2a)
General procedure: 2-Hydroxy-1,4-naphthoquinone (435 mg, 2.5 mmol) was suspended in EtOH (15 mL), dodecylamine (510 mg, 2.75 mmol) was added and the resulting solution was stirred at room temperature for 5 min. Pyridine-2-carboxaldehyde (287 mL, 3.0 mmol) was added and the reaction mixture was stirred at room temperature for 5 h. The formed precipitate was collected, washed with EtOH and dried in vacuum.
(E)-1,2-difluoro-4-(4-methoxystyryl)benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
Stage #1: diethyl 4-methoxybenzylphosphonate With sodium hydride In tetrahydrofuran at 0 - 5℃; for 0.5h;
Stage #2: 3,4 difluorobenzaldehyde In tetrahydrofuran at 0 - 20℃; for 20h;
5.2.2. General procedure for synthesis of stilbenes
General procedure: The appropriately substituted phosphonate ester (10 mmol) was dissolved in dry tetrahydrofuran (20 ml) and stirred at 0-5 °C. Sodium hydride (25 mmol) was added to the solution slowly and after thirty minutes the appropriate freshly distilled aldehyde(10 mmol) in tetrahydrofuran (30 ml) was added dropwise. The mixture was allowed to stir at room temperature overnight. In order to increase the yield, compounds 35, 37 and 40 were heated under reflux for 3-4 h. The mixture was cooled and quenched with ice water (10 ml) and poured onto ice. Dilute hydrochloric acid(1 M) was added until acidic and the solution was extracted with ethyl acetate (4 50 ml). The combined organic layers were washed with saturated salt and dried over magnesium sulfate. Filtration and evaporation of the ethyl acetate afforded crude stilbene products as oils or solids. The solids were crystallized from 95% ethanol to afford crystalline stilbenes. The oils were chromatographed on silica gel using methylene chloride to give pure products.
ethyl 4-[(3,4-difluorophenyl)methylidene]amino}-3-methylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
In ethanol; for 18h;Reflux;
Step 1. Synthesis of ethyl 4-[(3,4-difluorophenyl)methylidene]amino}-3-methylbenzoate A solution of <strong>[40800-65-5]ethyl 4-amino-3-methylbenzoate</strong> (0.706 g, 3.94 mmol) and 3,4-difluorobenzaldehye (1.00 mL, 9.08 mmol) in ethanol (10 mL) was stirred at reflux for 18 h and cooled to room temperature. The crude was washed with diethyl ether/n-hexane (1:20) to give ethyl 4-[(3,4-difluorophenyl)methylidene]amino}-3-methylbenzoate (0.986 g, 83%) as an orange solid. 1H NMR (CDCl3, 400 MHz) delta 8.28 (s, 1H), 7.91-7.81 (m, 3H), 7.62-7.59 (m, 1H), 7.31-7.27 (m, 1H), 6.91 (d, 1H), 4.38 (q, 2H), 2.36 (s, 3H), 1.40 (t, 3H).
(1S*,2R*)-N-(3,4-difluorobenzyl)-2-phenylcyclopropan-1-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
General procedure: Trans-2-phenylcyclopropylamine hydrochloride (1.0 eq.), acetic acid (1.0eq.) and the appropriate aldehyde (0.9 eq.) were dissolved in around bottom flask in 10 mL dry DCE. The reaction mixture was stirred gently at room temperature for 2 h before sodium triacetoxyborohydride (3.0 eq.) was added in small portions to the reaction vessel. The reaction was monitored by TLC and quenched using 10 mL of an aqueous (5%) NaHCO3 solution. The organic layer was separated and the aqueous layer extracted three times with10 mL of DCE. All organic layers were combined, dried over anhydrous Na2SO4, concentrated in vacuo and purified using flash chromatography (silica gel; cyclohexane/ethyl acetate) to give the desired compound.
1,3-dimethyl-2-trifluoromethylbenzimidazolium tetrafluoroborate[ No CAS ]
[ 3097-21-0 ]
[ 945978-37-0 ]
Yield
Reaction Conditions
Operation in experiment
59%Chromat.; 5%Chromat.
With potassium carbonate; In N,N-dimethyl-formamide; at 10 - 35℃; for 15h;
To a 10 mL eggplant-shaped flask equipped with a magnetic stirrer, 18 mg (0.125 mmol) of 3,4-difluorobenzaldehyde, 35 mg (0.25 mmol) of potassium carbonate and 1 mL of DMF were added. While the mixture was stirred at room temperature, 45 mg (0.15 mmol) of 1,3-dimethyl-2-trifluoromethylbenzimidazolium tetrafluoroborate was added thereto. The mixture was stirred at room temperature for 15 hours. The formation of 1-(3,4-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: 5% of 1-(3,4-difluorophenyl)-2,2,2-trifluoroethanol (target compound), 35% of 3,4-difluorobenzaldehyde (starting compound) and 59% of 1,3-dimethylbenzimidazole-2-one (compound derived from the fluoroalkylating agent). The yield of 1-(3,4-difluorophenyl)-2,2,2-trifluoroethanol (target compound) was 12% in terms of GC area percentage.
4-(2-fluoro-4-formylphenoxy)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With potassium carbonate In N,N-dimethyl-formamide at 100℃;
1.2; 2.2; 3.2 Step 2. Synthesis of 4-(2-fluoro-4-formylphenoxy)benzonitrile (C44)
3,4-Difluorobenzaldehyde (3.00 g, 21.1 mmol) was added to a mixture of 4-hydroxybenzonitrile (3.02 g, 25.4 mmol) and potassium carbonate (5.84 g, 42.2 mmol) in N,N-dimethylformamide (42 mL), and the reaction mixture was allowed to stir at 100° C. overnight. It was then cooled to room temperature and poured into water (300 mL) with stirring; after 15 minutes, the solid was collected via filtration to provide the product as an off-white solid. Yield: 4.52 g, 18.7 mmol, 89%. 1H NMR (500 MHz, CDCl3) δ 9.98 (d, J=2.0 Hz, 1H), 7.77 (dd, half of ABX pattern, J=10.2, 1.8 Hz, 1H), 7.73 (ddd, half of ABXY pattern, J=8.3, 1.7, 1.0 Hz, 1H), 7.68 (br d, J=9.0 Hz, 2H), 7.29-7.25 (m, 1H, assumed; partially obscured by solvent peak), 7.09 (br d, J=8.8 Hz, 2H).
66%
With potassium carbonate In N,N-dimethyl acetamide at 115℃; for 5h; Inert atmosphere;
5.6.4 4-(2-Fluoro-4-formylphenoxy)benzonitrile 1d
A mixture of 3,4-difluorobenzaldehyde (5.68g, 0.040mol), 4-hydroxybenzonitrile (5.00g, 0.042mol), and K2CO3 (5.805g, 0.042mol) in DMA (31mL) under nitrogen was heated with stirring at 115°C for 5h. The mixture was poured onto ice (25g) and NaOH (10%, 6mL). With stirring a solid appeared which was isolated and washed with water (7.245g). The crude material was recrystallized from ethanol/water (6.38g, 66%). mp 91-92°C. IR (neat, cm-1) 3069, 2842, 2738, 2228, 1696, 1614, 1595, 1497, 1274, 1226, 1168, 969, 949, 863, 836, 781, 747. 1H NMR (400MHz, CHCl3-d1): δ 7.03 (AA’, 2H), 7.26 (t, J=7.8Hz, 1H), 7.68 (BB’, 2H), 7.72 (ddd, J=8.2, 1.9, 1.0Hz, 1H), 7.76 (dd, J=10.2, 1.9Hz, 1H), 9.97 (d, J=1.9Hz, 1H). 13C NMR (100MHz, CHCl3-d1): δ 107.7, 117.4, 117.6, 118.0, 118.3, 122.2, 127.3, 127.4. 134.3, 134.4, 147.4, 147.5, 153.1, 155.6, 159.7, 189.4. Anal. Calcd for C14H8FNO2: C, 69.71; H, 3.34; N, 5.81. Found: C, 69.90; H, 3.65; N 5.65.
0.15 g (1.05 mmol) of 5-aminomethyl-2-chloropyridine and 0.18 g (1.26 mmol)The 3,4-difluorobenzaldehyde was added to a 25 mL three-necked flask, and then 25 mL of methanol was added thereto.Stir at room temperature overnight. Then, 0.10 g (2.28 mmol) of sodium borohydride was slowly added thereto, and stirred at room temperature for 25 minutes.The reaction was stopped, a colorless clear solution was obtained, and the solvent was evaporated. 45 mL of water was added to the residue.Then extracted with dichloromethane (15 mL × 3), and the organic solvent was collected.Concentration under reduced pressure gave 0.28 g of 1-(6-chloropyridin-3-yl)-N-(3,4-difluorobenzyl)methylamine as a yield of 99.1percent.
4-(4-bromo-3-fluorophenoxy)-3-fluorobenzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 12h;
4-bromo-3-fluoro-phenol (670 mg, 3.51 mmol),3,4-difluorobenzaldehyde (500 mg, 3.52 mmol),Potassium carbonate (1.46 g, 10.6 mmol) and dissolved in DMF (10 mL).The reaction was carried out at 120 C for 12 h. Concentrated under reduced pressure,The residue obtained was purified by silica gel column chromatography(PE/EA(V/V)=20/1),The title compound is a white solid(721 mg, 65%).
65%
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 12h;
[00430]. 4-Bromo-3 -fluoro-phenol (670 mg, 3.51 mmol), 3 ,4-difluorobenzaldehyde (500 mg, 3.52 mmol) and potassium carbonate (1.46 g 10.6 mmol) were dissolved in D1VIF (10 mL), the mixture was stirred at 120 C for 12 hours. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (V/V) = 20/1) to give the title compound as a white solid (721 mg, 65%).
General procedure: A mixture of 4-Hydroxycoumarin (1 mmol, 0.162 g) and 4-chlorobenzaldehyde (1 mmol, 0.140 g), with 5 ml LTTM was takenin a 50 ml round bottomed flask at room temperature to form theKnoevenagel product, monitored by TLC and then 2-mino 5-methylthiazole (1 mmol, 0.106 g) were added and continued at reflux conditionfor 20 min. The progress of the reaction was monitored by TLCusing petroleum ether- ethyl acetate (8:2 v/v). After completion, thereaction mixture was cooled to room temperature. Water was addedto the reaction mixture and the product was collected by simple filtration,washed with hot ethanol and diethyl ether. Finally, thecrude product was recrystallized from ethanol to obtain the pureproduct (Scheme 1).
3,5-bis((E)-3,4-difluorobenzylidene)-4-oxocyclohexane-1-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To the mixture of the 4-oxocyclohexane-l -carboxylic acid (142.15 mg, 1 mmol, 1.0 equiv.) and ethanol (1.0 mL) in a round bottom flask added drop-wise 20% aqueous sodium hydroxide (1.0 mL) and stirred for five minutes. To this mixture was added 3,4- difluorobenzaldehyde (355.3 mg, 2.5 mmol, 2.5 equiv.). The reaction mixture was then allowed to stir at room temperature for 3 h. After such time, remove MeOH under vaccum, added 1 N HC1 (1 mL), the yellow precipitate thus obtained was filtered, washed with water and cold methanol, dried to get pure product (273 mg, 70% yield).
tert-butyl 5-((3,4-difluorophenyl)(hydroxy)methyl)thiazol-2-ylcarbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36.3%
To a solution of ferf-butyl thiazol-2-ylcarbamate (1 .5 g, 7.5 mmol) in tetrahydrofuran (30 ml_) at -75 C was added n-butyllithium (6.6 ml_, 16.5 mmol) dropwise. Reaction mixture was stirred for 30 minutes before 3,4-difluorobenzaldehyde (1 .6 g, 1 1 .3 mmol) was added slowly. Reaction was warmed to room temperature over 2 h. The reaction solution was poured into ice water (50 ml_) and pH was adjusted to 6~7 with aqueous 1 N hydrogen chloride. The aqueous layer was extracted with ethyl acetate (50 ml_ x 2). The combined organic layers were washed with brine (50 ml_), dried over sodium sulfate, filtered and concentrated. Treatment of crude residue with ferf-butyl methyl ether (5 ml_) provides ferf-butyl 5-((3,4-difluorophenyl)(hydroxy)methyl)thiazol-2-ylcarbamate (0.930 g, 2.72 mmol, 36.3%) as a white solid. LCMS (ESI) m/z: 343.1 [M+H]+. Used in the next step directly without additional purification.
2-[(E)-2-(3,4-difluorophenyl)ethenyl]quinazolin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With sulfuric acid at 190℃; for 1.5h; Microwave irradiation;
2.3 Synthesis of 2-[(E)-2-phenylethenyl]quinazolin-4(3H)-one intermediates using various benzaldehydes
General procedure: The 2-methylquinazolin-4(3H)-ones (1 mmol) were mixed with benzaldehydes (1.5 mmol) and 1 drop concentrated sulphuric acid was added to the mixtures. The reaction was carried out in microwave set (Personal Chemistry, Emrys Creator, heating power: 150 W, measured pressure 1-7 bar, reaction time: 1.5 hours) at 190 °C. The crude product was washed with 5% sodium hydrogen carbonate and filtered out. The products were crystallized from dimethyl formamide and dried under vacuum.
6-chloro-2-[(E)-2-(3,4-difluorophenyl)ethenyl]quinazolin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With sulfuric acid; at 190℃; under 750.075 - 5250.53 Torr; for 1.5h;Microwave irradiation;
General procedure: The 2-methylquinazolin-4(3H)-ones (1 mmol) were mixed with benzaldehydes (1.5 mmol) and 1 drop concentrated sulphuric acid was added to the mixtures. The reaction was carried out in microwave set (Personal Chemistry, Emrys Creator, heating power: 150 W, measured pressure 1-7 bar, reaction time: 1.5 hours) at 190 C. The crude product was washed with 5% sodium hydrogen carbonate and filtered out. The products were crystallized from dimethyl formamide and dried under vacuum.
6-bromo-2-[(E)-2-(3,4-difluorophenyl)ethenyl]quinazolin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With sulfuric acid; at 190℃; under 750.075 - 5250.53 Torr; for 1.5h;Microwave irradiation;
General procedure: The 2-methylquinazolin-4(3H)-ones (1 mmol) were mixed with benzaldehydes (1.5 mmol) and 1 drop concentrated sulphuric acid was added to the mixtures. The reaction was carried out in microwave set (Personal Chemistry, Emrys Creator, heating power: 150 W, measured pressure 1-7 bar, reaction time: 1.5 hours) at 190 C. The crude product was washed with 5% sodium hydrogen carbonate and filtered out. The products were crystallized from dimethyl formamide and dried under vacuum.
3,5-bis(3,4-difluorobenzylidene)tetrahydro-4H-thiopyran-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With sodium hydroxide In ethanol; water at 20℃;
General Procedure for the Synthesis of 2a-2e
General procedure: Cyclohexanone or tetrahydro-4H-thiopyran-4-one (1 mmol) and appropriate aromatic aldehydes(2 mmol) were reacted overnight in 20 mL of absolute ethanol in the presence of a catalytic amount of10 M NaOH aqueous solution. Then, the reaction mixture was poured into a 250 mL beaker containing100 mL of 3 M HCl followed by extraction with ethyl acetate. The ethyl acetate layer was collected anddried over anhydrous magnesium sulfate followed by evaporation with a rotatory evaporator to givethe crude of the desired compounds. Purifications with chromatography using an ethyl acetate/hexane(10:90) solvent system were then performed to obtain pure diarylpentanoids (Figures 9-14).
3-(3,4-difluorophenyl)-1-(1H-pyrrol-2-yl)prop-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47.51%
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.