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Structure of 6334-18-5 * 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.
(1) Device: Refer to Figure 2 to determine the connection of the tubular reactor, the type of pipe: (3a + 3e) DC channel + Corningde Heart Cel 1 structure, pipe diameter and volume according to the flow rate and reaction time to determine the heat transfer Medium for the heat transfer oil. [0040] (2) 6.06 g of cobalt acetate and 6.06 g of sodium molybdate were dissolved in 200 ml of 2,3-dichlorotoluene and 200 ml of acetic acid to form a mixed solution at which time η (cobalt acetate): η (2,3-dichlorotoluene ) = 0.015: 1, 6.06 g of sodium bromide was dissolved in 25percent H22 to form H22-acetic acid solution, where η (sodium bromide): η (2,3-dichlorotoluene) = 0.015: 1 , 2,3-dichlorotoluene-acetic acid solution and H22-acetic acid solution were injected into the continuous heat transfer tubular reactor at a flow rate of 5.56 ml / min and ll.llml / min, respectively, when η (H2? 2):? (2,3-dichlorotoluene) = 2: 1, using Figure 2 microchannel reactor, Control reaction temperature 90 ° C, residence time 1200s. The outlet material was cooled at 0 ° C and the reaction was quenched with dichloromethane. The yield of 2,3-dichlorotoluene was 42.8percent and the yield of 2,3-dichlorobenzaldehyde was 29.0percent by GC analysis
Reference：
[1] Patent: CN106699525, 2017, A, . Location in patent: Paragraph 0039; 0040
[2] Journal of the American Chemical Society, 1946, vol. 68, p. 861,863[3] Industrial and Engineering Chemistry, 1947, vol. 39, p. 1486,1487
[4] Journal of the Chemical Society. Perkin transactions 1, 1965, p. 5976 - 5983
[5] Patent: CN107032968, 2017, A,
2
[ 38594-42-2 ]
[ 6334-18-5 ]
Yield
Reaction Conditions
Operation in experiment
48.19 g
With hydrogen bromide; dihydrogen peroxide In 1,4-dioxane at 25℃; for 7 h;
In a 1L reactor,add 61.5 g of 2,3-dichlorotoluene, 3.075 g of azobisisobutyronitrile (5percent), 215.25 g of 2-dichloroethane, heat the mixture at 75 ° C and add 44 g of bromine drop wise,reflux reaction till red bromine fades , Intermittent drip and 136.2g27.5percent hydrogen peroxide continues to react till red bromine no longer generates. Add a 49.2g30percent aqueous solution of sodium carbonate to the reaction solution, reflux reaction for 8 h ,at the same time recover1,2-dichloroethane.The hydrolyzate is heated and filtered at 80° C, into organic phase add 246g 1,4-Dioxane , add 40percent of the catalyst HBr6.15g, add 27.5percent hydrogen peroxide 38.3g,react at 25 ° C for 7 h. The reaction system is extracted three times with 1,2-dichloroethane,the organic phase is concentrated and obtained crude 2,3-dichlorobenzaldehyde, re-crystallization from ethanol and obtained 48.19 g of 2,3-dichlorobenzaldehyde, GC purity is 99.26percent and yield is 72.1percent.
Reference：
[1] RSC Advances, 2014, vol. 4, # 91, p. 49974 - 49978
[2] European Journal of Organic Chemistry, 2013, # 21, p. 4503 - 4508
[3] Patent: CN107032968, 2017, A, . Location in patent: Paragraph 0015; 0017; 0018; 0019; 0022
Reference：
[1] Patent: US4572908, 1986, A,
[2] Patent: US4572909, 1986, A,
[3] Patent: US4559351, 1985, A,
6
[ 29027-17-6 ]
[ 6334-18-5 ]
Reference：
[1] Journal of the American Chemical Society, 1946, vol. 68, p. 861,863[2] Industrial and Engineering Chemistry, 1947, vol. 39, p. 1486,1487
7
[ 111011-80-4 ]
[ 6334-18-5 ]
[ 115578-90-0 ]
Reference：
[1] Synthesis, 1993, # 7, p. 705 - 713
[2] Synthesis, 1993, # 7, p. 705 - 713
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1984, # 3, p. 385 - 390
13
[ 6334-18-5 ]
[ 38594-42-2 ]
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.
92%
With sodium borohydrid In methanol; sodium hydroxide
1. Preparation of 2,3-Dichlorobenzyl alcohol To 2,3-dichlorobenzaldehyde (500 g, 2.85 mole) in methanol (3.5 liters) was added an alkaline solution of sodium borohydride (113.5 g, 2.975 mole) in 0.2N sodium hydroxide solution (241 ml) over a period of 1 hour. After 2 hours the reaction mixture was quenched into water (3.7 liters) and the pH was adjusted to pH 6 using glacial acetic acid (125 ml). Filtration afforded 2,3-dichlorobenzyl alcohol as a white solid (467 g, 92percent yield).
Reference：
[1] European Journal of Medicinal Chemistry, 2016, vol. 108, p. 564 - 576
[2] Patent: US6124308, 2000, A,
[3] Journal of Medicinal Chemistry, 1981, vol. 24, # 4, p. 382 - 389
[4] Organic and Biomolecular Chemistry, 2014, vol. 12, # 30, p. 5781 - 5788
Reference：
[1] ChemSusChem, 2015, vol. 8, # 10, p. 1664 - 1675
[2] Journal of Organic Chemistry, 2015, vol. 80, # 12, p. 6375 - 6380
[3] Journal of Organic Chemistry, 2016, vol. 81, # 22, p. 11065 - 11071
16
[ 6334-18-5 ]
[ 38594-42-2 ]
[ 50-45-3 ]
Reference：
[1] Monatshefte fuer Chemie, 1959, vol. 90, p. 683,687
17
[ 38594-42-2 ]
[ 124-63-0 ]
[ 6334-18-5 ]
[ 3218-45-9 ]
Yield
Reaction Conditions
Operation in experiment
72%
With sodium borohydrid; triethylamine In methanol; water; acetone; toluene; Petroleum ether
1. Preparation of 2,3-Dichlorophenylacetonitrile To a suspension of 2,3-dichlorobenzaldehyde (40 kg, 228.6 mole) in toluene (254 liters) and methanol (40 liters), was added sodium borohydride (2.59 kg, 68.6 mole) portionwise over a period of 1 hour. The mixture was stirred for a period of 30 minutes prior to treatment with acetone (20 liters). On decomposition of the excess borohydride, water (80 liters) was added. Toluene (54 liters) was added to the toluene phase and the suspension was warmed to 42° C.+-2° C. to attain a solution prior to separation. The organic phase was distilled to remove 54 liters of azeotrope and so effect the removal of water, acetone, and isopropyl alcohol. The resulting toluene solution of 2,3-dichlorobenzyl alcohol was cooled. To the resulting suspension was added triethylamine (27.8 kg, 274.3 mole) followed by methanesulphonyl chloride (31.4 kg, 274.3 mole) over a period of 11/2 hours so as to maintain the temperature at 0° C.+-2° C. The mixture was stirred for 1 hour then water (,100 liters) was charged to the suspension and the mixture was stirred vigorously prior to separation. To the methanesulphonate in the toluene phase was added tetrabutylammonium hydrogen sulphate (15.6 kg, 45.8 mole) and aqueous potassium cyanide solution (22.4 kg, 342.8 mole) in water (70 liters) over a period of 40 minutes. The two phase mixture was stirred overnight, separated and the organic phase was washed with water (70 liters). The toluene phase was distilled to remove 130 kg of toluene in the presence of charcoal (2.8 kg) and dicalite (2.8 kg). Petroleum ether 60/80 (300 liters) was charged to the residue, the mixture was filtered hot and crystallized under vacuum to afford 2,3-dichlorophenylacetonitrile (30 kg, 72percent yield).
Reference：
[1] Patent: US6124308, 2000, A,
18
[ 6334-18-5 ]
[ 3218-45-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 1981, vol. 24, # 4, p. 382 - 389
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1993, vol. 41, # 1, p. 108 - 116
[2] Applied Catalysis A: General, 2017, vol. 530, p. 203 - 210
22
[ 626-34-6 ]
[ 105-45-3 ]
[ 6334-18-5 ]
[ 72509-76-3 ]
Yield
Reaction Conditions
Operation in experiment
94.3%
Stage #1: With piperidine; pyridine In neat (no solvent) at 75 - 80℃; for 9 h; Stage #2: for 1 h; Reflux
20.0-dichlorobenzaldehyde 70.0 g (0.40 mol), β-aminocrotonate ethyl ester in a 500 mL round bottom flask55.8g (0.48mol),62.0 g (0.48 mol) of methyl acetoacetate, followed by 4.5 g (0.053 mol) of piperidine and 4.2 g (0.053 mol) of pyridine.The heating was started slowly and the temperature was raised. The reaction was maintained at 75-80 ° C for 9 h, and 200 g of absolute ethanol was added while heating, and the mixture was heated to reflux for 1 h, and filtered while hot.The mixture was cooled to 15 ° C and stirred for 1 h, and suction filtered. The filter cake was washed with a small amount of dry ethanol and dried to give 145 g of pale yellow solid.Yield: 94.3percent, purity 99.1percent
Reference：
[1] Patent: CN108840819, 2018, A, . Location in patent: Paragraph 0014; 0040-0042; 0045-0048; 0051-0053
23
[ 105-45-3 ]
[ 6334-18-5 ]
[ 72509-76-3 ]
[ 91189-59-2 ]
[ 79925-38-5 ]
Yield
Reaction Conditions
Operation in experiment
66%
Stage #1: at 40 - 45℃; for 6 h; Stage #2: for 4 h; Heating / reflux
To a solution of 2,3-dichlorobenzaldehyde (8.76 g, 0.05 mol) in isopropanol (80 mL) is added picolinic acid (0.65 g, 5.4 mmol), piperidine (0.45 g, 5.4 mmol) and methyl acetoacetate (86.3 g, 0.06 mol). The solution is stirred at 40-45 C. for 6 h, and then isopropanol is distilled under vacuum. The residue is dissolved in ethyl acetate (80 mL) and washed with water (60 mL). Ethyl acetate is then removed under vacuum. To the residue is added ethyl aminocrotonate (7.74 g, 0.06 mol) and isopropanol (60 mL). The mixture is heated under reflux for 4 hours. Isopropanol is distilled and heptanes (60 mL) is added. The resulting solid is filtered and washed with heptanes. After drying 12.7 g (66percent) felodipine is obtained as pale yellow solid with a purity of 94.4percent (diethyl and dimethyl have a concentration of 2.02percent and 3.38percent (a/a), respectively).
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1994, vol. 42, # 8, p. 1579 - 1589
[2] Chemical and Pharmaceutical Bulletin, 1993, vol. 41, # 1, p. 108 - 116
[3] Patent: CN102464608, 2016, B,
[4] Patent: CN103242220, 2016, B,
28
[ 68-11-1 ]
[ 6334-18-5 ]
[ 90407-16-2 ]
Yield
Reaction Conditions
Operation in experiment
82%
With potassium hydroxide In diethyl ether at 120℃; for 2 h;
First Step Synthesis of 7-Chloro-1-benzothiophene-2-carboxylic acid To an aqueous solution (10 mL) of potassium hydroxide (1.3 g, 22 mmol), 2-mercaptoacetic acid (0.70 mL, 10 mmol) and 2,3-dichlorobenzaldehyde (1.8 g, 10 mmol) were added, and the resulting mixture was stirred at 120° C. Two hours later, the reaction solution was cooled to room temperature, and after adding distilled water until precipitated solid was dissolved, diethyl ether was added thereto. The reaction solution was separated into an organic layer and water layer, and after adding 1.0 N hydrochloric acid to the water layer until the pH reached 5, the water layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to obtain the title compound (1.7 g; 82percent) as a colorless liquid. 1H-NMR (400 MHz, DMSO-d6): 7.48-7.54 (1H, m), 7.62-7.70 (1H, m), 7.98-8.04 (1H, m), 8.16-8.22 (1H, m).MS (ESI) [M+H]+213
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1984, # 3, p. 385 - 390
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1984, # 3, p. 385 - 390
With sodium molybdate; dihydrogen peroxide; cobalt(II) acetate; acetic acid; sodium bromide; at 90℃;
(1) Device: Refer to Figure 2 to determine the connection of the tubular reactor, the type of pipe: (3a + 3e) DC channel + Corningde Heart Cel 1 structure, pipe diameter and volume according to the flow rate and reaction time to determine the heat transfer Medium for the heat transfer oil. [0040] (2) 6.06 g of cobalt acetate and 6.06 g of sodium molybdate were dissolved in 200 ml of <strong>[32768-54-0]2,3-dichlorotoluene</strong> and 200 ml of acetic acid to form a mixed solution at which time eta (cobalt acetate): eta (<strong>[32768-54-0]2,3-dichlorotoluene</strong> ) = 0.015: 1, 6.06 g of sodium bromide was dissolved in 25% H22 to form H22-acetic acid solution, where eta (sodium bromide): eta (<strong>[32768-54-0]2,3-dichlorotoluene</strong>) = 0.015: 1 , <strong>[32768-54-0]2,3-dichlorotoluene</strong>-acetic acid solution and H22-acetic acid solution were injected into the continuous heat transfer tubular reactor at a flow rate of 5.56 ml / min and ll.llml / min, respectively, when eta (H2? 2):? (<strong>[32768-54-0]2,3-dichlorotoluene</strong>) = 2: 1, using Figure 2 microchannel reactor, Control reaction temperature 90 C, residence time 1200s. The outlet material was cooled at 0 C and the reaction was quenched with dichloromethane. The yield of <strong>[32768-54-0]2,3-dichlorotoluene</strong> was 42.8% and the yield of 2,3-dichlorobenzaldehyde was 29.0% by GC analysis
General procedure: Under an argon atmosphere, liquid NH3 (25 mL) was condensedin a two-neck round-bottom flask immersed in a dry ice coolingbath and equipped with a dry ice reflux condenser. Aldehyde (7.34 mmol) was added, and the resulting solution (or suspension)was stirred for 1 h. KMnO4 (7.34 mmol, 1.16 g) was added,the cooling bath was removed, and the reaction mixture wasstirred for another hour with gentle reflux of NH3. Na2SO3 (22.0mmol, 2.78 g) was added, the reflux condenser was removed,and the NH3 was allowed to evaporate spontaneously. The darkbrownresidue was treated with 6 M HCl (30 mL), and theresulting precipitate was filtered, washed with H2O (100 mL)and sat. aq NaHCO3 (20 mL). All products were recrystallizedfrom EtOH.
With alumina; In neat (no solvent); at 120℃;Microwave irradiation; Green chemistry;
General procedure: A mixture of the aldehyde 1 (2 mmol), the 1,3-dicarbonyl compound 2 (2 mmol) and the 3D printed Al2O3 structure (0.350 g) was submitted to microwave irradiation (120 C) for in coated vial. Once the aldehyde component was consumed (TLC control) the corresponding 3-aminocrotonate 6 (2 mmol) was added and the mixture heated at 90 C (microwave irradiation). After completion of the reaction, as indicated by TLC, the mixture was cooled and the desired compound solidified. For those 1,4-dihydropyridines that not solidified, the reaction mixture was poured onto crushed ice and stirred for 5-10 min. The solid obtained was filtered under suction, washed with ice-cold water (20 mL) and then purified by column chromatography or recrystallization from the appropriate solvent.
With ammonium hydroxide; In methanol;Inert atmosphere; Reflux;
Weigh take 6.6g methyl acetoacetate That's 57mmol, 5.0g 28.7mmol namely 2,3-di Chlorobenzaldehyde, 2.0 g of aqueous ammonia 57mmol i.e. in single-neck flask, methanol was added 40mL, Bao nitrogen Protection under heating to reflux the reaction overnight, after completion of the reaction, the solvent was removed by rotary evaporation, the residual reaction It was purified by column chromatography to give compound S138.9g, yield 84%,
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.
92%
With sodium borohydrid; In methanol; sodium hydroxide;
1. Preparation of 2,3-Dichlorobenzyl alcohol To 2,3-dichlorobenzaldehyde (500 g, 2.85 mole) in methanol (3.5 liters) was added an alkaline solution of sodium borohydride (113.5 g, 2.975 mole) in 0.2N sodium hydroxide solution (241 ml) over a period of 1 hour. After 2 hours the reaction mixture was quenched into water (3.7 liters) and the pH was adjusted to pH 6 using glacial acetic acid (125 ml). Filtration afforded 2,3-dichlorobenzyl alcohol as a white solid (467 g, 92% yield).
piperidine; 2-Picolinic acid; In isopropyl alcohol; at 40 - 45℃; for 6h;
To a solution of 2,3-dichlorobenzaldehyde (101.0 g, 0.58 mol) in isopropanol (450 mL) is added picolinic acid (3.5 g, 29 mmol), piperidine (2.4 g, 29 mmol) and methyl acetoacetate (86.3 g, 0.74 mol). The solution is stirred at 4045 C. for 6 h, cooled to room temperature and the solid is filtered and washed with isopropanol. The damp cake is dried to yield 125.9 g (80%) benzylidene 4a as white solid.
80%
With piperidine; acetic acid; at 30 - 60℃;
2, 3-dichlorobenzaldehyde (50.0g, 0.28 mol) reacts with methyl acetoacetate (33.17g, 0.28 mol) in the presence of acetic acid (17.14 gm, 0.28 mol) and piperidine (5.95g, 0.07 mol) in an alcoholic solvent at temperature of 30-60C. The reaction was maintained for 4-10 hrs and monitor on TLC till completion. After distillation of alcoholic solvent, MDC was added and it was washed with NaHC03 solution. MDC layer was distilled out under reduced pressure; the resultant product was isolated by addition of mixture of IPA and heptane. The solids were filtered and washed with mixture of IP A/heptane. The solid was dried under vacuum to provide methyl benzylidene in a yield of about 75-80% with HPLC purity NLT 99.0%.
25%
With piperidine; 2-Picolinic acid; In isopropyl alcohol; at 45℃;
Example 17 - Formula 154 - compound 17aIntermediate B: (Z)-Methyl 2-(2,3-dichlorobenzylidene)-3-oxobutanoate To a solution of compound A (10.1 g, 57 mmol, 1.0 eq) and methyl 3-oxobutanoate (8.60 g, 74 mmol, 1 .3 eq) in isopropanol (100 mL) was added piperidine (0.24 g, 2.8 mmol, 0.05 eq) and picolinic acid (0.35 g, 2.8 mmol, 0.05 eq) at room temperature. The resulting mixture was heated at 45 C overnight then cooled to 0 C and the crystalline solid was collected by suction filtration, washed with isopropanol (20 mL) and dried under vacuum to give (Z)-methyl 2-(2,3- dichlorobenzylidene)-3-oxobutanoate (4.00 g, 25%) as a white solid.LC-MS (Agilent): Rt 3.62 min; m/z calculated for Ci2H10CI2O3 [M+H]+ 273.1 , [M+Na]+ 295.0, found [M+H]+ 273.0, [M+Na]+ 294.9.
25%
With piperidine; 2-Picolinic acid; In isopropyl alcohol; at 45℃;
To a solution of compound A (10.1 g, 57 mmol, 1.0 eq) and methyl 3-oxobutanoate (8.60 g, 74 mmol, 1.3 eq) in isopropanol (100 mL) was added piperidine (0.24 g, 2.8 mmol, 0.05 eq) and picolinic acid (0.35 g, 2.8 mmol, 0.05 eq) at room temperature. The resulting mixture was heated at 45 C. overnight then cooled to 0 C. and the crystalline solid was collected by suction filtration, washed with isopropanol (20 mL) and dried under vacuum to give (Z)-methyl 2-(2,3-dichlorobenzylidene)-3-oxobutanoate (4.00 g, 25%) as a white solid. LC-MS (Agilent): Rt 3.62 min; m/z calculated for C12H10Cl2O3 [M+H]+ 273.1, [M+Na]+ 295.0. found [M+H]+ 273.0, [M+Na]+ 294.9.
General procedure: A mixture of sodium hydroxide (12 mmol), the aldehyde (3 mmol) and the ketone (3 mmol) in methanol (10 mL) was stirred at room temperature. After the reaction completion byTLC, the mixture was filtered at reduced pressure and the solid collected and washed with cold methanol.
2-amino-7,7-dimethyl-5-oxo-4-(2,3-dichlorophenyl)-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With water; boric acid; at 70℃; for 0.116667h;
General procedure: A mixture of aromatic aldehydes (1 mmol), dimedone(1 mmol) and malononitrile (1mmol) was heated in thepresence of boric acid (10mol%) and a few drops of waterat 70C. After completion of the reaction, as monitored byTLC, the reaction mixture was washed with water to separatethe catalyst. Then, the solid residue (crude product)was purified by recrystallization in a mixture of ethanoland water (9:1) to give the desired tetrahydrobenzo[b]pyrans 1-15 (see the Supplementary Information for theircharacterization).
88%
With aminopropylated silica gel; In water; at 70℃; for 1.5h;Green chemistry;
General procedure: The mixture of aromatic aldehyde (1 mmol), 5,5-dimethylcyclohexane-1,3-dione 2 (1 mmol), and malononitrile 3 (1 mmol) was taken in water. To this mixture 10 mol% of solid aminopropylated SiO2 catalyst was added. The reaction mixture was stirred at 70 C for the appropriate time (as shown in Table 1) and the progress of reaction was monitored by thin layer chromatography. After completion of reaction as indicated by TLC, the reaction mixture was cooled at room temperature. The solvent was removed under vacuum to obtain the crude product. To the crude product, ethyl acetate was added and the solid catalyst was filtered off. The organic layer was evaporated to obtain the solid product. The obtained product was purified by recrystallization using ethyl acetate to get the desired compound 4a-n. All compounds were characterized by comparing their spectral data with those reported in literature [15,26-27]. Spectral data for representative and newly synthesized compounds is listed below. 2-Amino-7,7-dimethyl-5-oxo-4-(2,3-dichlorophenyl)-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4i): White solid, mp 225-227 C, 1H NMR (300 MHz, CDCl3): delta 7.17-7.21 (m, 1H), 7.40-7.47 (m, 1H), 7.82-7.90 (m, 1H), 6.72 (brs, 2H, NH), 4.24 (s, 1H), 2.61 (s, 2H), 2.28 (m, 1H), 2.06 (m, 1H), 0.94 (s, 3H), 0.74 (s, 3H); 13C NMR (75 MHz, CDCl3): delta 200.7, 159.8, 154.0, 140.1, 131.3, 130.2, 130.0, 119.2, 113.2, 67.6, 60.0, 44.3, 41.2, 32.1, 28.6; GC-MS: m/z 363 (M+); Elem. Anal. Calcd. for C18H16Cl2N2O2: C, 59.52; H, 4.44; Cl, 19.52; N, 7.71; O, 8.81; found: C, 59.53; H, 4.43; Cl, 19.55; N, 7.69; O, 8.83.
88%
With PEG-600; In water; at 20℃; for 4h;
General procedure: A mixture of aldehyde (2 mmol), cyclic 1-3dione / 4-hydroxy coumarin (2 mmol), and malononitrile (2 mmol) in PEG-600-water (8:2, 5 ml) was stirred at room temperature and refluxed for 4-7 h. The progress of reaction was monitored by thin-layer chromatography (TLC) using petroleum ether-ethyl acetate (6:4) as solvent system. After completion of the reaction, H2O (20 ml) was added, the product was extracted with ethyl acetate (2x40 ml), and combined organic layers were washed with H2O and dried over anhydrous Na2SO4. The solid product separated out with high purity without the need of column chromatography. PEG-600 can be recovered from the aqueous phase by passing the aqueous solution through activated charcoal and evaporation of water.
2-amino-4-(2,3-dichlorophenyl)-4,5-dihydro-5-oxopyrano[3,2-c]chromene-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With copper chromite nanoparticles; In water; at 20℃; for 0.0666667h;Green chemistry;
General procedure: A solution of aromatic aldehyde (1 mmol), malononitrile (1.2 mmol), 4-hydroxycoumarin (1 mmol), and nano-CuCr2O4 (10 mol%) in 5.0 mL water was stirred at room temperature for the appropriate times (Table 1). Completion of the reaction was monitored by TLC. The solid was filtered off and washed with water (2 * 20 mL) and purified by recrystallization from ethanol. The product was dissolved in acetone and the catalyst was separated by filtration (Tables 2, 3). The physical data (mp, IR, NMR) of known compounds were found to be identical with those reported in the literature.
90%
With sodium bromide; In ethanol; at 25℃;Electrolysis; Green chemistry;
General procedure: A mixture of aryl aldehyde (10 mmol), malononitrile(12 mmol), 4-hydroxycoumarin (10 mmol), and NaBr(0.1 g, 1 mmol) in EtOH (20 mL) was electrolyzed in anundivided cell equipped with a magnetic stirrer, a graphiteanode, and an iron cathode at 25 8C under a constantcurrent density of 10 mA/cm2 [electrodes square 5 cm2],until the catalytic quantity of 0.1 F/mol of electricity waspassed. After electrolysis was finished, the mixture wasfiltered, then rinsed twice with an ice-cold ethanol/watersolution (9:1, 5 mL), and dried under reduced pressure.
85%
With cholin hydroxide; In ethanol; for 0.333333h;Reflux;
1 mmol of 2,3-dichlorobenzaldehyde, 1 mmol of malononitrile, 1 mmol of 4-hydroxycoumarin and 0.07 mmol of basic ionic liquid were added to a 25 ml single neck flask with stirrer and condenser containing 5 ml of ethanol. The reaction was refluxed with vigorous stirring 20min, TLC (thin layer chromatography) detection, the raw material point disappears, cooled to room temperature, crushed precipitated solid, standing, suction filtration, residue by After drying in vacuo, 2-amino-5-oxo-4- (2,3-dichlorophenyl) -4,5-dihydropyrano [c] chromene- The rate is 85%. The filtrate was directly added 2,3-dichlorobenzaldehyde, malononitrile and 4-hydroxycoumarin for repeated use.
80%
With piperidine; In ethanol; for 0.0333333h;Microwave irradiation;
General procedure: A mixture of 4-hydroxy-2H-chromen-2-one 1 (0.01mol), various aromatic aldehyde 2a-m (0.01mol), malononitrile 3(0.01mol), and 0.5ml of piperidine in ethanol (30 mL) in a100mL round bottom flask was heated under microwave irradiation conditions for 2 min. After successful completion of the reaction, monitored by TLC, the reaction mixture was cooled to room temperature, the obtained solid product was separated by filtration and washed with methanol and purified by recrystallization from ethanol to afford the pure products 4a-m.
1,2-dichloro-3-(2-methanesulfinyl-2-methylsulfanyl-vinyl)-benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67.5%
With N-benzyl-trimethylammonium hydroxide In tetrahydrofuran; methanol for 4h; Heating / reflux;
46.A A. 1. 2 [DICHLORO-3- (2-METHANESULFINYL-2-METHILSUFANYL-VINVL-BENZENE.]
To a stirred solution of methyl methylthiomethyl sulfoxide (4.97 g, 40.0 [MMOL)] and 2, [3-DICHLOROBENZALDEHYDE] (5.00 g, 28.6 [MMOL)] in 10 mL of THF was added 4 mL of triton-B (40% in [MEOH).] The resultant mixture was [REFLUXED] for 4 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (5: 95 EtOAc/hexane) to afford 5.4 g (67. [5%)] of 1,2- [DICHLORO-3-(2-METHANESULFINYL-2-METHYLSUFANYL-VINYL)-BENZENE.] HPLC: Rt = 8.99. (Method A). 1H NMR (400 MHz, [CDCI3)] : 7.86 (s, [1H),] 7.73 (dd, J= 8.4, 0.9 Hz, 1 H), 7.47 (dd, [J =] 9.0, 0.6 Hz, 1 H), 7.38-7. 23 (m, 1 H), 2.83 (s, 3H), 2.24 (s, 3H).
67.5%
With N-benzyl-trimethylammonium hydroxide In tetrahydrofuran; methanol for 4h; Heating / reflux;
46.A
To astirred solution of methyl methylthiomethyl sulfoxide (4.97 g, 40.0 mmol) and2,3-dichlorobenzaldehyde (5.00 g, 28.6 mmol) in 10 ml of THF was added 4ml of triton-B (40% in MeOH). The resultant mixture was refluxed for 4 h. Thesolvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (5:95 EtOAc/hexane) to afford 5.4 g (67.5%) of 1,2-dichloro-3-(2-methanesulfinyl-2-methylsufanyl-vinyl)-benzene. HPLC: Rt =8.99. (Method A). 1H NMR (400 MHz, CDCI3): 7.86 (s, 1H), 7.73 (dd, J = 8.4,0.9 Hz, 1H), 7.47 (dd, J= 9.0, 0.6 Hz, 1H), 7.38-7.23 (m, 1H), 2.83 (s, 3H),5 2.24 (s, 3H).
67.5%
With N-benzyl-trimethylammonium hydroxide In tetrahydrofuran; methanol for 4h; Heating / reflux;
46.A
A. 1,2 Dichloro-3-(2-methanesulfinyl-2-methylsufanyl-vinyl)-benzene. To a stirred solution of methyl methylthiomethyl sulfoxide (4.97 g, 40.0 mmol) and 2,3-dichlorobenzaldehyde (5.00 g, 28.6 mmol) in 10 mL of THF was added 4 mL of triton-B (40% in MeOH). The resultant mixture was refluxed for 4 h. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (5:95 EtOAc/hexane) to afford 5.4 g (67.5%) of 1,2-dichloro-3-(2-methanesulfinyl-2-methylsufanyl-vinyl)-benzene. HPLC: Rt=8.99. (Method A). 1H NMR (400 MHz, CDCl3): 7.86 (s, 1H), 7.73 (dd, J=8.4, 0.9 Hz, 1H), 7.47 (dd, J=9.0, 0.6 Hz, 1H), 7.38-7.23 (m, 1H), 2.83 (s, 3H), 2.24 (s, 3H).
Compound 16; A mixture of 2,3-dichlorobenzaldehyde (90.0 g, 514 mmol) and cyclopropylamine (72 mL, 1.02 mol) in dry MeOH (1300 mL) was stirred at rt overnight. The EPO <DP n="19"/>reaction mixture was cooled to 0 C, and NaBH4 (25.3 g, 668 mmol) was added. The reaction mixture was stirred again at rt overnight. Ice was added to the reaction mixture, and the solvents were evaporated under reduced pressure. The residue was dissolved in EtOAc, and was washed with aq. IM NaOH. The aq. layer was extracted with EtOAc (3x). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc / heptane 9:1 - > 1:1) yielded the title compound (97.4 g, 87%). LC-MS: tR = 0.64 min; ES+: 216.15.
A mixture of <strong>[6334-18-5]2,3-dichloro benzaldehyde</strong> (1 eq), cyclopropyl amine (1.2 eq) and sodium bicarbonate (1.5 eq) were heated at refluxed in methanol (10 v) for 1 h. The reaction mixture was then cooled in ice and sodium borohydride (1.2 eq) was introduced portion wise. After complete addition mixture was allowed to warm to RT and stirred for 3 h. The volatiles were then removed in vacuo and the resulting residue was partitioned between water and DCM. The organic layer was separated, washed with water, dried over sodium sulfate and filtered. Concentration of the organic layer in vacuo afforded the title compound as light yellow oil. Purification of crude product thus obtained by the way of chromatography using (Silica, Hexane to 40 % EtOAc inHexane) afforded title compound as light yellow oil.
N-(2,3-dichlorobenzyl)cyclopropanamine (1A) To a mixture of the aldehyde (8.75 g, 50.0 mmol) and cyclopropylamine (3.43 g, 60.0 mmol) in 100 mL of dichloromethane was added 1 mL of AcOH at 0 C. Then NaBH(OAC)3 (11.65 g, 55.0 mmol) was added in portions over 20 mins at 0 C. The mixture was stirred at 0 C. for 4 hrs. A solution of NaOH (4 g in 4 mL of water) was added, and the mixture was stirred for 30 min, filtered through a pad of SiO2. The filtrate was concentrated to give the clean product 1A (10.7 g) as colorless liquid. ESI-MS:m/z 216.3 (M+H)+ and 218.2 (M+2H)+, HPLC retention time: T=1.377 min (FAST-2).
Amine 2: N-(2,3-Dichlorobenzyl)cyclopropanamine A mixture of <strong>[6334-18-5]2,3-dichloro benzaldehyde</strong> (1 eq), cyclopropyl amine (1.2 eq) and sodium bicarbonate (1.5 eq) were heated at refluxed in methanol (10 v) for 1 h. The reaction mixture was then cooled in ice and sodium borohydride (1.2 eq) was introduced portion wise. After complete addition mixture was allowed to warm to RT and stirred for 3 h. The volatiles were then removed in vacuo and the resulting residue was partitioned between water and DCM. The organic layer was separated, washed with water, dried over sodium sulfate and filtered. Concentration of the organic layer in vacuo afforded the title compound as light yellow oil. Purification of crude product thus obtained by the way of chromatography using (Silica, Hexane to 40% EtOAc in Hexane) afforded title compound as light yellow oil.
Step B. Synthesis of Felodipine In a four necked, 3 liter flask, a solution of MBI (about 268.4 g, 0.98 mole) in isopropanol was brought to reflux and a solution of ethyl 3-aminocrotonate (about 114.2 g, 0.8 mole) in isopropanol was added at such a rate to maintain the internal temperature at about 81-83 C. and refluxed for about 1 hour. The temperature of the reaction was then lowered to about 40-50 C. and excess isopropanol removed under reduced pressure maintaining the internal temperature at about 40-45 C. to furnish a viscous yellow orange residue. LC analysis of this residue indicated about 75% felodipine product, 13% MBI, 4% dichlorobenzaldehyde and about 0.5% symmetrical dimethyl dihydropyridine analog and about 0.4% diethyl dihydropyridine analog. Hexane was added to the residue and the suspension stirred under reflux for about 1 hr. The temperature was allowed to fall to about 40 C. during which solids formed. The solids were filtered and washed with fresh hexane and dried to yield felodipine in about 62% yield. LC analysis indicated about 92.8% purity of felodipine.
With sodium borohydrid; triethylamine;pyrographite; In methanol; water; acetone; toluene; Petroleum ether;
1. Preparation of 2,3-Dichlorophenylacetonitrile To a suspension of 2,3-dichlorobenzaldehyde (40 kg, 228.6 mole) in toluene (254 liters) and methanol (40 liters), was added sodium borohydride (2.59 kg, 68.6 mole) portionwise over a period of 1 hour. The mixture was stirred for a period of 30 minutes prior to treatment with acetone (20 liters). On decomposition of the excess borohydride, water (80 liters) was added. Toluene (54 liters) was added to the toluene phase and the suspension was warmed to 42 C.+-2 C. to attain a solution prior to separation. The organic phase was distilled to remove 54 liters of azeotrope and so effect the removal of water, acetone, and isopropyl alcohol. The resulting toluene solution of 2,3-dichlorobenzyl alcohol was cooled. To the resulting suspension was added triethylamine (27.8 kg, 274.3 mole) followed by methanesulphonyl chloride (31.4 kg, 274.3 mole) over a period of 11/2 hours so as to maintain the temperature at 0 C.+-2 C. The mixture was stirred for 1 hour then water (,100 liters) was charged to the suspension and the mixture was stirred vigorously prior to separation. To the methanesulphonate in the toluene phase was added tetrabutylammonium hydrogen sulphate (15.6 kg, 45.8 mole) and aqueous potassium cyanide solution (22.4 kg, 342.8 mole) in water (70 liters) over a period of 40 minutes. The two phase mixture was stirred overnight, separated and the organic phase was washed with water (70 liters). The toluene phase was distilled to remove 130 kg of toluene in the presence of charcoal (2.8 kg) and dicalite (2.8 kg). Petroleum ether 60/80 (300 liters) was charged to the residue, the mixture was filtered hot and crystallized under vacuum to afford 2,3-dichlorophenylacetonitrile (30 kg, 72% yield).
3-(RS)-(N-tert-butoxycarbonylaminomethyl)-1-(2,3-dichlorobenzyl)-pyrrolidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium tris(acetoxy)borohydride; In 1,1-dichloroethane;
Step 5 Sodium triacetoxyborohydride (3.2 g, 15 mmol, 1.5 equiv.) was added in one portion to a stirred solution of <strong>[149366-79-0]3-(RS)-(N-tert-butoxycarbonylaminomethyl)pyrrolidine</strong> (2.0 g, 10 mmol) and 2,3-dichlorobenzaldehyde (1.9 g, 11 mmol, 1.1 equiv.) in dichloroethane (60 mL) at room temperature. The suspension was stirred overnight, then concentrated in vacuo. The residue was diluted with ether and quenched with 1 M hydrochloric acid. The aqueous phase was basified with 4 M sodium hydroxide to pH 12, then extracted with ethyl acetate. The organic extracts were combined and washed with brine, then dried over sodium sulfate and concentrated. Flash chromatography of the residue afforded 3-(RS)-(N-tert-butoxycarbonylaminomethyl)-1-(2,3-dichlorobenzyl)-pyrrolidine as a colorless oil (2.9 g).
Stage A: 2-(2,3-Dichlorobenzylidene)-3-oxo-4-methoxybutanoic acid methyl ester A solution containing 160 ml of anhydrous benzene, 5 g of 2,3-dichlorobenzaldehyde, 4.2 g of 4-methoxy-3-oxobutanoic acid methyl ester, 16 drops of pyridine and 22 drops of hexanoic acid is heated under reflux for one hour, removing the water formed. The mixture is then washed with a saturated sodium bicarbonate solution and then with a 0.1N hydrochloric acid solution. The organic phase is taken and evaporated to dryness so as to obtain 8.3 g of an oil. Yield: 96.5percent Proton nuclear magnetic resonance spectrum (CDCl3): 3.3-3.4 ppm, d, 3H; 3.7-3.9 ppm, d, 3H; 4.0-4.3 ppm, d, 2H; 7.0-7.7 ppm, m, 3H; 8 ppm, d, 1H.
EXAMPLE 2 (method b1, b2) Preparation of 2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-ethylester-5-(2-methoxyethyl)ester 4.4 g of 2,3-dichlorobenzaldehyde, 3,2 g of 3-aminocrotonic acid ethylester, 4.0 g <strong>[22502-03-0]acetylacetic acid-2-methoxyethylester</strong> and 25 mls of ethanol were refluxed over night. The reaction mixture was poured out onto icewater, whereby the compound crystallized. After filtration recrystallization was carried out from ethanol, whereby pure 2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5l -dicarboxylic acid-3-ethylester-5-(2-methoxyethyl)ester was obtained. M.p. 139 C. Yield 36%.
2-(2,3-Dichlorobenzylidene)-3-oxo-4-methoxybutanoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96.5%
With pyridine; In benzene;
STAGE A 2-(2,3-Dichlorobenzylidene)-3-oxo-4-methoxybutanoic acid methyl ester. A solution containing 160 ml of anhydrous benzene, 5 g of 2,3-dichlorobenzaldehyde, 4.2 g of 4-methoxy-3-oxo-butanoic acid methyl ester, 16 drops of pyridine and 22 drops of hexanoic acid is heated under reflux for one hour, removing the water formed. The mixture is then washed with a saturated sodium bicarbonate solution and then with a 0.1N hydrochloric acid solution. The organic phase is taken and evaporated to dryness so as to obtain 8.3 g of an oil. Yield: 96.5percent. Proton nuclear magnetic resonance spectrum (CDCl3): 3.3-3.4 ppm, d, 3H; 3.7-3.9 ppm, d, 3H; 4.0-4.3 ppm, d, 2H; 7.0-7.7 ppm, m, 3H; 8 ppm, d, 1H.
2,6-diamino-3-(2,3-dichlorophenyl)pyrazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Potassium cyanide (500 mg, 7.7 mmol) and 2-aminoacetamidine dihydrobromide (1.77 g, 7.5 mmol) were stirred in methanol (15 ml) at room temperature for 1 hour. 2,3-Dichlorobenzaldehyde (1.34 g, 7.68 mmol) was added and the suspension was stirred at room temperature overnight. Lithium hydroxide monohydrate (1.0 g, 23.8 mmol) was added and the mixture was stirred whilst open to the atmosphere at room temperature for 24 hours. The reaction mixture was partitioned between ethyl acetate (80 ml) and water (50 ml). The ethyl acetate solution was washed with water (30 ml), then dried over anhydrous sodium sulphate and evaporated in vacuo to give a light brown gum. This was purified using silica gel column chromatography, eluting with ethyl acetate, to furnish 370 mg of the title product as a brown gum. 1HNMR (CDCl3): 4.26 (br s, 2H), 4.43 (br s, 2H), 7.26 (d, 1H), 7.31 (m, 1H), 7.46 (s, 1H), (7.50 (d, 1H) MS m/z 257 [MH]+
General procedure: The SBA-Pr-SO3H (0.02 g) was firstly activated undervacuum and then after cooling to room temperature, isatoic anhydride 1 (1 mmol, 0.163 g), aromatic aldehyde 2a-l(1 mmol) and ammonium acetate 3 (1.2 mmol) were addedto it. The mixture was heated under solvent-free conditionat 115 C for an appropriate time. Completion of the reactionwas monitored through thin layer chromatographytechnique (TLC). The resulting solid product was dissolvedin hot EtOH and filtered to remove the unsolvable catalyst,and then the filtrate was cooled to give the pure product.The spectroscopic and analytical data for the new productsare presented in the following part.
89%
With ammonium acetate; In neat (no solvent); for 0.25h;Microwave irradiation;
General procedure: Cu-CNTs nanocomposite (0.04 g) as an efficient catalyst was added to the mixture of isatoic anhydride (1 mmol), primary aromatic amine (1.1 mmol) or ammonium acetate (1.2 mmol) and aldehyde (1 mmol). The resulting mixture was heated at microwave oven under solvent free conditions with stirring for appropriate time until reaction complete. After the complete disappearance of the starting material, as monitored by TLC (eluent: petroleum ether:ethyl acetate: 4:1), hot ethanol (15 mL) was added and the catalyst was removed by filtration. The filtrate containing the catalyst was evaporated under reduced pressure to give a solid, and the recovered catalyst could be reused without a loss of catalytic activity. The corresponding pure product was obtained by recrystallization from ethanol.
85%
With ammonium acetate; In ethanol; at 40℃; for 0.25h;Sonication; Green chemistry;
General procedure: A stirred mixture of isatoic anhydride (1mmol), ammonium acetate (1.1mmol) or aniline (1.2mmol), benzaldehyde (1mmol) and Co-MWCNTs (0.04g) was sonicated at 35kHz at 40C. After completion of the reaction, as indicated by TLC (ethyl acetate: petroleum ether, 3:7), the solid catalyst was separated by filtration with hot ethanol. After that, the filtrate was poured into crushed ice with stirring for several min. The precipitated solids were filtered off and finally were purified by recrystallization from ethanol.
80%
With ammonium acetate; In toluene; at 110℃; for 3h;Reflux; Green chemistry;
General procedure: A mixture of isatoic anhydride (1 mmol), an aromatic aldehyde (1 mmol) and ammonium acetate (1.2 mmol) dissolved in 3 mL toluene, and PFPAT (10 mol%) was stirred for 3 h at 110 C. The reaction was monitored by TLC. The reaction mixture, after being cooled to room temperature was poured onto crushed ice and stirred for 5-10 min. The crystalline product was collected by filtration under suction (water aspirator), washed with ice-cold water (40 mL) and then recrystallized from hot ethanol to afford pure products.
With piperidine In acetic acid; isopropyl alcohol at 10 - 50℃; for 18h;
1
Example 1 Preparation of benzylidine tert-butyl ester (compound III) 50 g (0.285 mol) of 2,3-dichlorobenzaldehyde, 54.17 g (0.342 mol) tert-butyl 3-oxobutanoate, 1.45 g (0.017 mol) of piperidine, 200 ml isopropanol and 1.02 g (0.017 mol) acetic acid were charged in a one litre flask fitted with a reflux condenser. The reaction mass was heated up to 50 ºC and stirred for 1 hour. Afterwards, the mixture was cooled down to 25-30 ºC and stirred for 15 hours. The mixture was further cooled to 10 -15 ºC and stirred for 2 hours. The reaction mass was filtered and washed with 25 ml of chilled isopropanol and 50 ml of hexane. The white coloured solid was dried under reduced pressure at 50-55 °C for 7-8 hours. Yield: 70 g, Molar yield: 77.78 %, HPLC purity: 98-99% and m.p.: 94 to 96 ºC.
With sodium hydroxide; In ethanol; at 20℃; for 18h;
To a mixture of 1-(4-hydroxy-3-methylphenyl)ethanone (0.7 g, 4.66 mmol) (ICC, Indofine Chemical Company Inc.) and NaOH (0.36 g, 9.1 mmol) in 10 mL of 200 proof EtOH was added 2,3-dichlorobenzaldehyde (0.8 g, 4.66 mmol) (ACROS). The reaction mixture was stirred at rt for 18 h. Upon completion by LC/MS, 5 mL of H2O was added and the reaction mixture was acidified with conc. HCl to pH 5-6. The resulting precipitate was filtered, washed with water and dried to yield (E)-3-(2,3-dichlorophenyl)-1-(4-hydroxy-3-methylphenyl)prop-2-en-1-one, (0.45 g, 31%). MS (EI) for C16H12C2O2, 308.3 (MH+).
To a solution of 2,3-dichlorobenzaldehyde (8.76 g, 0.05 mol) in isopropanol (80 mL) is added picolinic acid (0.65 g, 5.4 mmol), piperidine (0.45 g, 5.4 mmol) and methyl acetoacetate (86.3 g, 0.06 mol). The solution is stirred at 40-45 C. for 6 h, and then isopropanol is distilled under vacuum. The residue is dissolved in ethyl acetate (80 mL) and washed with water (60 mL). Ethyl acetate is then removed under vacuum. To the residue is added ethyl aminocrotonate (7.74 g, 0.06 mol) and isopropanol (60 mL). The mixture is heated under reflux for 4 hours. Isopropanol is distilled and heptanes (60 mL) is added. The resulting solid is filtered and washed with heptanes. After drying 12.7 g (66%) felodipine is obtained as pale yellow solid with a purity of 94.4% (diethyl and dimethyl have a concentration of 2.02% and 3.38% (a/a), respectively).
a) 5-(2,3-Dichloro-phenyl)-pent-4-enoic acid (4a) (3-Carboxypropyl) triphenylphosphonium bromide (18.1 g, 42 mmol) was dissolved in anhydrous tetrahydrofuran (250 ml), treated dropwise with potassium tert-butoxide (92.4 mL, 1.0 M in tetrahydrofuran, 92.4 mmol) and stirred for 1.5 hours at 0 C. A solution of commercially available 2,3-dichlorobenzaldehyde (Aldrich Chemical Company) (5.25 g, 30 mmol) in tetrahydrofuran (50 ml) was added dropwise at 0 C., and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with 1N HCl (150 ml) and extracted with ethyl acetate (3*200 ml). The organic layer was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography over silica gel (hexane-ethyl acetate, 2:1) to give the title compound (7.30 g,~100%). 1H NMR (300 MHz, CDCl3) delta: 7.4-5.85 (m, 5H), 2.96-2.65 (m, 4H).
With N,N,N?,N?-tetrabromobenzene-1,3-disulfonamide; at 100℃; for 0.166667h;
General procedure: A mixture of dimedone (0.28 g, 2 mmol), phthalhydrazide (0.32 g, 2 mmol), benzaldehyde (0.24 g, 2.2 mmol), and TBBDA (0.05 g) or PBBS (0.1 g) was heated at 100 C for 10 min. After completion of the reaction [TLC acetone/n-hexane (3:10)]. The reaction mixture was cooled, filtered and washed with acetone (15 mL). Removal of the solvent under reduced pressure gave the catalyst. The crude product was recrystallized from ethyl acetate/n-hexane (1:3) to afford the pure product.
80%
With SBA-Pr-NH2; In neat (no solvent); at 80℃; for 0.166667h;Green chemistry;
General procedure: The SBA-Pr-NH2 (0.02 g) was activated under vacuum at 100 C and, after cooling to room temperature, aromatic aldehyde 1 (1 mmol), dimedone 2 (1 mmol, 0.14 g), and phthalhydrazide 3 (1 mmol, 0.16 g) were added. The mixture was heated at 80 C under solvent-free conditions until reaction was complete (monitored byTLC; petroleum ether-EtOAc, 4:1). The resulting solid product was dissolved in hot ethanol and the heterogeneous solid-base catalyst was removed by simple filtration. The filtrate was cooled to give the pure products 4a-j. The recovered catalyst washed consecutively with dilute Et3N solution, water, and acetone, then dried under vacuum.
70%
With sulfonic acid functionalized nanoporous silica (SBA-Pr-SO3H); In neat (no solvent); at 80℃; for 0.0833333h;Green chemistry;
General procedure: The SBA-Pr-SO3H (0.02 g) was activated in vacuum at 100 C. After cooling to room temperature, phthalhydrazide 1 (1 mmol, 0.16 g), aromatic aldehyde 2 (1 mmol), and dimedone 3 (1 mmol, 0.14 g) were added to it. The mixture was heated at 80 C under solvent-free condition until the reaction was completed. After completion of the reaction (monitored by TLC), the solid product was dissolved in hot ethanol (2 × 10 mL) and the heterogeneous solid catalyst was removed by simple filtration. Then, the filtrate was cooled to give the pure products 4a-k.
Example 1 - Synthesis of crude 5-methoxycarbonyl-4-(2,3-dichlorophenyl)-2,6- dimethyl-1 ,4-dihydropyridine-3-carboxylic acid[0020] The starting materials 2,2,6-trimethyl-4/-/-1 ,3-dioxin-4-one (89.2g, 0.63 mol) and 3-hydroxypropionitrile (44.6g, 0.63 mol) were heated in an oil bath at 120C for 3h, during which acetone (the reaction byproduct) was distilled off. The reaction mixture was cooled to room temperature, and isopropanol (570ml_), methyl 3-aminocrotonate (65.7g, 0.57 mol) and 2,3-dichlorobenzaldehyde (100.0g, 0.57 mol) were added. The reaction mixture was heated to reflux, and some of the isopropanol (340m L) was distilled off. The reaction mixture was then cooled in an ice-water bath and dichloromethane (230m L) and a solution of NaOH (28.7g, 0.72 mol) in water (290ml_) were added. After stirring at room temperature for several hours, the reaction mixture was diluted with water and the layers were separated. The aqueous phase was extracted once more with dichloromethane, after which it was cooled in an ice-water bath and phosphoric acid (85%, 25ml_) was added. After precipitation and stirring, the solids were collected by filtration and washed with water. Drying under high vacuum at 40C gave carboxylic acid 2 as a yellow powder (126 g, 62% yield). Analysis by HPLC indicates a purity of 89.23%, with 3.17% of diacid 5 present.
With sodium hydroxide; In methanol; water; at 0 - 20℃;
General procedure: 1-(4-Methyl-2-(alkylamino)thiazol-5-yl)ethanone (1 mol) in methanol (4.0-4.1 l), was added dropwise to a cooled solution of corresponding aromatic aldehydes (1 mol) in 10% NaOH (600-650 ml). The reaction mixture was kept under stirring at 0 C for 30 min and afterwards at room temperature for several hours (5-12 h) until solid started separating out. The solid was filtered under vacuum and recrystallized from dioxane to give the title chalcones. The yield range after recrystallization of chalcones was 18-73%.
With phospho sulphonic acid; In water; at 100℃; for 2h;Green chemistry;
General procedure: In 100-mL round bottom flask, a mixture of aldehyde(1 mmol) and indole (2 mmol) was charged to a stirring solution of phospho sulfonic acid (0.06 g) inH2O (40 mL), and the resulting reaction contents was vigorously stirred at 100C for appropriate period oftime (2-3 h). After completion of the reaction, asobserved by thin-layer chromatography (EtOAc : PETether = 1 : 2), the reaction content was filtered and washed with distilled water to separate the catalyst.The residue contains crude bis(indolyl)alkane productsand filtrate contains phospho sulfonic acid(recovered catalyst). The resulting residue was decontaminated via silica gel-mediated chromatographic purification technique using EtOAc in PET ether solution (2 : 8) as eluent to furnish the required products.After washing filtrate with EtOAc and then drying,the obtained phospho sulfonic acid was reused for subsequent reactions. All the products were identified by comparing the analytical data (melting point, IR,1H NMR) with those reported data.
With N-sulfonic acid pyridinium chloride; In neat (no solvent); at 100℃; for 0.15h;Green chemistry;
General procedure: A mixture of 2-naphthol (0.144g, 1mmol), dimedone (0.140g, 1mmol), aldehyde (1mmol) and [Pyridine-SO3H]Cl (0.03mmol) in a 10mL round-bottomed flask connected to a reflux condenser, was stirred in an oil-bath (100C). After completion of the reaction, as monitored by TLC, the reaction mixture was cooled to room temperature, extracted with warm EtOAc (20mL) to separate the catalyst. EtOAc was removed and the crude product was recrystallized from aqueous ethanol (90%) to afford the pure product which required no further purification. All products were isolated as racemate. The recovered catalyst was washed with EtOAc (2×20mL), dried and reused for another run. The catalyst was reused for four times without any significant changes in the yield and the reaction time
95%
With silica-bonded imidazolium-sulfonic acid chloride; In neat (no solvent); at 100℃; for 0.166667h;
General procedure: A mixture of 2-naphthol (0.144 g, 1 mmol), dimedone (0.140 g, 1mmol), arylaldehyde (1 mmol) and SBISAC (0.005 g) in a 10 mL round-bottomed flask connected to a reflux condenser, was stirred in an oil-bath at 100 C. After completion of the reaction, as monitored by TLC, the reaction mixture was cooled to room temperature, and extracted by warm EtOAc (20 mL) to separate the catalyst (the productis soluble in warmEtOAc; however, SBISAC isn't soluble in this solvent).EtOAc was removed, and the crude product was recrystallized from aqueous ethanol (90%) to afford the pure racemic product which required no further purification. The recovered catalyst was washed with EtOAc (2 × 20 mL), dried and reused for the next run. The catalyst was reused for four times without any significant changes in the yieldand the reaction time.
Stage #1: (3-bromophenyl)pentafluoro-λ6-sulfane With TurboGrignard In tetrahydrofuran at 0℃; for 1h; Inert atmosphere;
Stage #2: 2,3-dichlorobenzylaldehyde In tetrahydrofuran at 0 - 23℃; for 0.0833333h; Inert atmosphere;
To a mixture of malononitrile (2.64 g, 40 mmol) in 95% Ethanol (50 ml) was added 2,3-dichlorobenzaldehyde (7.00 g, 40.0 mmol). The reaction was stirred at rt for 18 h. EtOH(20 ml) was added and the mixture was stirred at rt for 20 min and cooled to 0C in anice bath. Sodium borohydride (0.424 g, 11.20 mmol) was introduced to the vigorouslystirred mixture and the reduction was complete in about 10 min. To the reaction mixturewas added water (40 ml). 1 N HCI was added in to quench the excess hydride. Morewater was added in until precipitation was complete. Filtration gave [(2,3-dichlorophenyl)methyl]propanedinitrile (7.86 g, 87%). To a solution of [(2,3-dichlorophenyl) methyl]propanedinitrile (7.86 g, 34.9 mmol) in Ethanol (80 ml) was addedhydrazine hydrate (2.57 ml, 52.4 mmol). The mixture is heated at reflux temperature for 8h. The reaction mixture was concentrated. The crude material was purified on a silicacolumn (MeOH/DCM: 0-10%) to give the product (4.2 g, 47%). 1H NMR (400 MHz,METHANOL-d4) 8 ppm 3.77 (s, 2 H) 7.09 (m, 1 H) 7.19 (t, J=7.96 Hz, 1 H) 7.38 (m, 1 H);LC/MS: MS (ES+) m/e 257.0 [M+Hr.
87%
With hydrogenchloride; sodium borohydrid; In ethanol; water;
a) 4-[(2,3-dichlorophenyl)methyl]-1H-pyrazole-3,5-diamine To a mixture of malononitrile (2.64 g, 40 mmol) in 95% Ethanol (50 mL) was added 2,3-dichlorobenzaldehyde (7.00 g, 40.0 mmol). The reaction was stirred at rt for 18 h. EtOH (20 mL) was added and the mixture was stirred at rt for 20 min and cooled to 0 C. in an ice bath. Sodium borohydride (0.424 g, 11.20 mmol) was introduced to the vigorously stirred mixture and the reduction was complete in about 10 min. To the reaction mixture was added water (40 mL). 1N HCl was added in to quench the excess hydride. More water was added in until precipitation was complete. Filtration gave [(2,3-dichlorophenyl)methyl]propanedinitrile (7.86 g, 87%).
With indium; In tetrahydrofuran; water; at 20℃; for 24h;
General procedure: At room temperature, 1 mmol aldehyde (R1CHO), 1.2 mmol alpha- (bromomethyl) acrylic acid and 1.2mmol indium powder were added to a stirred mixture of THF (5 ml) and deionized water (5 ml). 6 M HCl was added to the above mixture when the starting aldehyde disappeared (monitored by TLC) and stirring went on for 3~6 hours. Then, the mixture was extracted with ethylacetate (3 × 10ml) and the organic phase dried over anhydrous Na2SO4 and evaporated. The resulting residue was purified by using the Biotage IsoleraTM Spektra One preparative chromatography (silica gel, elution with 0-40% of ethyl acetate in petroleum ether). Structures and yields are showed as follows.
With hydrogen bromide; dihydrogen peroxide; In 1,4-dioxane; at 25℃; for 7h;
In a 1L reactor,add 61.5 g of 2,3-dichlorotoluene, 3.075 g of azobisisobutyronitrile (5%), 215.25 g of 2-dichloroethane, heat the mixture at 75 C and add 44 g of bromine drop wise,reflux reaction till red bromine fades , Intermittent drip and 136.2g27.5% hydrogen peroxide continues to react till red bromine no longer generates. Add a 49.2g30% aqueous solution of sodium carbonate to the reaction solution, reflux reaction for 8 h ,at the same time recover1,2-dichloroethane.The hydrolyzate is heated and filtered at 80 C, into organic phase add 246g 1,4-Dioxane , add 40% of the catalyst HBr6.15g, add 27.5% hydrogen peroxide 38.3g,react at 25 C for 7 h. The reaction system is extracted three times with 1,2-dichloroethane,the organic phase is concentrated and obtained crude 2,3-dichlorobenzaldehyde, re-crystallization from ethanol and obtained 48.19 g of 2,3-dichlorobenzaldehyde, GC purity is 99.26% and yield is 72.1%.
General procedure for the synthesis of 2-amino-4-(aryl)-5,6,7,8,9,10-hexahydrobenzo[a]cyclooctene-1,3-dicarbonitriles 4
General procedure: A mixture ofcyclooctanone (3, 1 mmol), aromatic aldehyde (1 mmol) and malononitrile(2 mmol) was taken in water (10 mL) to which lithium ethoxide (0.5 equiv)was added. The reaction was heated under reflux at 100 C for 2 h. Aftercompletion of the reaction, the free flowing solid that separated on water wasfiltered, washed with ethanol (3 mL) and dried over vacuum to afford 4 aswhite or pale yellow solid. 2-Amino-4-(4-chlorophenyl)-5,6,7,8,9,10-hexahydrobenzo[a]cyclooctene-1,3-dicarbonitrile (4c).
With guanidine supported magnetic Fe3O4 nanoparticle; In neat (no solvent); at 80℃; for 1.5h;
General procedure: The MNPs-Guanidine (0.03 g) was added to a mixture of dimethylphosphite (0.110 g, 1 mmol) and aldehyde (1 mmol) at 80C and stirred for 90-120 min. The progress was monitored by TLC. After completion of the reaction, the catalyst was separated by an external magnet and the mixture was washed with CH2Cl2 (2 × 5 mL) and decanted. The combined organics were dried over anhydrous Na2SO4 and Na2SO4 and then evaporation of dichloromethane under reduced pressure gave the pure products in 62-98% yields.
With poly(ethylene glycol) 1000 based dicationic acidic ionic liquid; In toluene; at 80℃; for 1.5h;Ionic liquid;
General procedure: Aromatic aldehydes (2 mmol) and alcohols (3 mmol) were added into a 10 mL tube reactor preloaded with PEG1000-DAIL(2 mL) and toluene (2 mL). The reacution mixtre was stirred at 80Cfor 1 h. After the reaction, the mixture was cooled to room temperature and the mixture separated into two phases. After decantation of the upper phase, the below phase was reused for the next time after removing water under vacuum at 80C for 1 h.
With poly(ethylene glycol) 1000 based dicationic acidic ionic liquid; In toluene; at 80℃; for 1h;Ionic liquid;
General procedure: Aromatic aldehydes (2 mmol) and alcohols (3 mmol) were added into a 10 mL tube reactor preloaded with PEG1000-DAIL(2 mL) and toluene (2 mL). The reacution mixtre was stirred at 80Cfor 1 h. After the reaction, the mixture was cooled to room temperature and the mixture separated into two phases. After decantation of the upper phase, the below phase was reused for the next time after removing water under vacuum at 80C for 1 h.
With pyridine; hydroxylamine hydrochloride; In methanol; at 20℃; for 2.5h;
General procedure: Hydroxylamine hydrochloride (1.2equiv) was added to a solution of the aldehyde 2 (1equiv) in MeOH (60ml) followed by pyridine (1equiv). The reaction was stirred at rt for 2.5h. After the MeOH was removed in vacuo, the residue was suspended in DCM (120ml) and washed with 1M HCl solution (3×30ml), H2O (3×30ml) and brine solution. The organic phase was dried (Na2SO4) and then concentrated at reduced pressure. The oximes 5 were purified by silica gel column chromatography eluting with hexane-EtOAc or recrystallization.
With hydroxylamine hydrochloride; potassium carbonate; In methanol; at 20℃; for 3h;
General procedure: Substituted benzaldehyde (50mmol), hydroxylamine hydrochloride (50 mmol) and K2CO3 (50 mmol) were dissolved in 50mL methanol into a 125 mL round-bottom flask. The mixture was stirred at room temperature for 3h and monitored by TLC. After the reaction was completed, the solvent was removed with a rotary evaporator, water was then added to the residue, and the mixture system was extracted with ethyl acetate. The organic phase was dried over Na2SO4, and concentrated by rotary evaporator to yield intermediate benzaldoxime (90-96% yields).
14-(2,3-dichlorophenyl)-14H-dibenzo[a,j]xanthene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With 1-methyl-2-oxopyrrolidinium hydrogen sulfate; In neat (no solvent); at 110℃; for 0.333333h;Green chemistry;
General procedure: A mixture of aldehyde (1mmol, 0.15g), 2-naphthol (2mmol, 0.288g), [H-NMP][HSO4] (10mol %, 0.19g) was left under solvent-free conditions at 110C for the appropriate time indicated in Table 2. The progress of the reactions was monitored by TLC (ethyl acetate/petroleum ether 3:7). After completion of the reaction, the reaction mixture was cooled, and the mixture was extracted with (2×10ml of CH2Cl2) and [H-NMP][HSO4] was removed as a by-product by washing with water. The extract was dried on CaCl2 and evaporated to give the crude product, which was then purified by recrystallization from ethanol. Products were characterized by comparison of their physical and spectral data with those of authentic samples [31,32]. 14-(2,3-Dichlorophenyl)-14H-dibenzo[a.j]xanthene (3i):white solid, mp 250-253 C, IR (KBr)/upsilon(cm-1): 3057, 1625, 1593, 1514, 1459, 1405, 1401, 1251, 1107, 1070, 962, 869, 813, 807, 746; 1H NMR (CDCl3, 400 MHz)/delta ppm: 6.85 (s, 1H, CH), 6.87-6.89 (d, 1H, J = 8.0, Ar); 7.09-7.11 (d, 2H, J = 8.8, Ar), 7.32-7.35 (d, 1H, J = 9.2, Ar), 7.44-7.51 (m, 4H, Ar), 7.62-7.85 (t, 4H, J = 9.2, Ar), 8.69-8.67 (d, 2H, J = 8.4, Ar); UV (CH2Cl2)/lambdamax (nm): 248, 230.
90%
With C2H8NO7S2(1+)*HO4S(1-); at 110℃; for 0.25h;Green chemistry;
The 10mmol 2,3-dichlorobenzaldehyde, 20mmol 2-naphthol and equipped with a condenser 0.3mmol catalyst was added to a 50ml single jar.110 , reaction 15min, 10ml of water was added after the reaction was cooled with large amount of solid precipitated solid was crushed and allowed to stand, suction filtered, dried, and then the resulting residue was recrystallized from ethanol 95% aqueous solution, and dried in vacuo to give pure 14- (2 , 2,3-dichloro-phenyl) -14H- dibenzo [a, j] xanthenes, 90% yield.The filtrate (mainly water and catalyst) at 110 reduced pressure rotary evaporation can be reused after removal of water.14-(2,3-dichlorophenyl)-14H-dibenzo [a,j]xanthene: mp-286 ~ 287 deg.] C;1the H NMR (300MHz, CDCl3):delta6.87(s1H)7.09(tJ1.1Hz1H)7.25(s 1H)7.33(dJ8.0Hz1H)7.447.51(m4H)7.67(tJ7.8Hz2H) 7.82(dJ8.6Hz4H)8.70(dJ8.5Hz2H)
With sulfonic acid functionalized diatomite; In neat (no solvent); at 90℃;Green chemistry;
General procedure: A mixture of aldehyde (1 mmol), beta-naphthol (2 mmol, 0.288 g)and diatomite-SO3H (0.05 g) was heated at 90?C under solvent free conditions at 110?C for the appropriate time according to Table 3. The progress of the reactions was monitored by TLC (ethylacetate/petroleum ether 3/7). After completion of the reaction,the mixture was cooled to room temperature and 10 ml CH2Cl2 was added. The catalyst was filtered off by simple filteration. The obtained liquid was heated by evaporation on a rotary evaporator.The obtained product was purified by recrystallization from ethanol to afford the pure products. All of the pure products were characterized by comparison of their physical and spectral data with those of authentic samples
With N,N,N?,N?-tetrabromobenzene-1,3-disulfonamide; at 20℃; for 0.666667h;Green chemistry;
General procedure: To a stirred mixture of 4-methylbenzaldehyde (1 mmol, 0.120 g) and N,N,N',N'-tetrabromobenzene-1,3-disulfonamide [TBBDA] (0.05 g, 0.09 mmol) or poly(N-bromo-N-ethyl-benzene-1,3-disulfonamide) [PBBS] (0.12 g) at room temperature, was added 2-amino-4,6-dimethylpyrimidin (1 mmol, 0.123 g). Then, indole (1 mmol, 0.12 g) was added to the mixture after 10 min. The progress of the reaction was monitored by TLC (n-hexane/acetone, 17:2). After completion of the reaction, EtOH (5 mL) was added to the reaction mixture and the colorless precipitate was filtered (after evaporation of the ethanol, cool methylene dichloride (2 mL) was added, and the catalyst was recovered), washed with EtOH and dried and purified by recrystallization from ethanol.
With potassium hydroxide; In diethyl ether; at 120℃; for 2h;
First Step Synthesis of 7-Chloro-1-benzothiophene-2-carboxylic acid To an aqueous solution (10 mL) of potassium hydroxide (1.3 g, 22 mmol), 2-mercaptoacetic acid (0.70 mL, 10 mmol) and 2,3-dichlorobenzaldehyde (1.8 g, 10 mmol) were added, and the resulting mixture was stirred at 120 C. Two hours later, the reaction solution was cooled to room temperature, and after adding distilled water until precipitated solid was dissolved, diethyl ether was added thereto. The reaction solution was separated into an organic layer and water layer, and after adding 1.0 N hydrochloric acid to the water layer until the pH reached 5, the water layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to obtain the title compound (1.7 g; 82%) as a colorless liquid. 1H-NMR (400 MHz, DMSO-d6): 7.48-7.54 (1H, m), 7.62-7.70 (1H, m), 7.98-8.04 (1H, m), 8.16-8.22 (1H, m).MS (ESI) [M+H]+213
General procedure: 2-Aminothiophenol (0.5 mmol; 1.0 equiv) and aromatic aldehydes (0.6 mmol; 1.2 equiv)were dissolved in DMSO (3 mL). Then, the reaction mixture was stirred at 60 C for 6 h. Afterthe reactionH2O was added to the mixture. The mixture was extracted with AcOEt (20 mL x 3).The combined organic layers were then washed with saturated aq. NaCl (30 mL). The solutionwas dried with anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue waspurified with silica gel chromatography (AcOEt- PE130) to give pure product.
75%
With H3PO4/TiO2-ZrO2(1/1)-cetyl pyridinium bromide; at 20℃; for 0.333333h;
General procedure: A mixture of 2-aminothiophenol (1 mmol, 0.995 g), aldehyde (1 mmol), and H3PO4-TiO2- ZrO2 (1/1) (40 mg, 30 wt%H3PO4) were added in a beaker and the reaction mixture was mixed properly with the help of glass rod under solvent-free condition at room temperature. The progress of the reaction was monitored by TLC (ethylacetate-hexane, 4:6). After completion of the reaction, the reaction mixture was dispersed in ethyl acetate (5 mL) and filtered and the catalyst was washed several times with ethyl acetate and acetone. Then, the filtrate was evaporated under reduced pressure to isolate a solid residue and recrystallized from hot ethanol (10 mL) to afford the corresponding products. All of the 2-arylbenzothiazole products were characterized by IR, 1H NMR, 13C NMR, and mass spectroscopy and identified by comparison of their physical and spectral data with those of authentic samples.[34,35]
73%
With nano silica-supported boron trifluoride (nano BF3/SiO2); In ethanol; at 20℃; for 0.5h;
General procedure: To a mixture of 2-aminothiophenol (1 mmol, 0.995 g) and aldehyde (1 mmol) in ethanol (10 ml), nano BF3/SiO2 (0.05 g, 25 mol% BF3) was added in a beaker and the reaction mixture was mixed properly with the help of a glass rod and stirred in ambient temperature for the time indicated in Table 3. The progress of the reaction was monitored by TLC (ethyl acetate:hexane, 6:4), after completion of the reaction the solvent was removed under reduced pressure, then the mixture was cooled and dichloromethane (15 ml) was added to the mixture and filtered to remove the catalyst. Then the filtrate was evaporated under reduced pressure to isolate a solid residue, and recrystallized from ethanol (10 ml) to afford the corresponding products and the catalyst residue was washed with acetone and reused. All of the 2-arylbenzothiazole products were identified by physical and spectroscopic data as follows.
With formic acid; hydroxylamine hydrochloride; sodium acetate; In water; at 80℃;
General procedure: A mixture of aromatic aldehydes (50mmol) (1?17), hydroxylamine hydrochloride (62.5mmol), sodium acetate (125mmol) were dissolved in the mixture of formic acid and water (60:40) and stirred at 80°C until TLC analysis indicated the disappearance of aromatic aldehydes. Then, cooling the reaction system to room temperature and put it into water to obtain the target compounds. Some desired products which were dissolved in the mixture of water and formic acid can be obtained by salting out. Then, solid target compounds were obtained by filtration and recrystallized by alcohol, and then dried under vacuum. While, some target compounds are oily. These oily compounds were obtained by extraction with ethyl acetate and the solvent was removed at the vacuum to afford aryl nitriles (a1?a17).
ethyl 6-amino-5-cyano-4-(2,3-dichlorophenyl)-2-ethoxy-3-fluoro-2-methyl-2,3-dihydro-4H-pyran-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With sodium hydroxide; at 20℃; for 8h;
General procedure: A mixture of ethyl 2-fluoroacetoacetate 1 (148.0 mg, 1.0 mmol),malononitrile 2 (66.0 mg, 1.0 mmol), and benzaldehydes 3a (106.0 mg, 1.0 mmol), NaOH (20.0 mg, 0.5 mmol) was stirred in 10 mL EtOH for 8 h at room temperature. After the completion of the reaction (monitored by TLC), the solvent was evaporated unde rreduced pressure and the residue was purified by chromatography on a silica column using petroleum ether-ethyl acetate (4/1, v/v) as eluent to afford the final product 4a, 261.1 mg, 75% yield.
benzyl (2,3-dichlorophenyl)(2-hydroxynaphthalen-1-yl)methylcarbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With {Fe3O4(at)SiO2(at)(CH2)3-NHNHC(O)NH-SO3H*HCl} In neat (no solvent) at 70℃; for 0.166667h; Green chemistry;
93%
With N,2-dibromo-6-chloro-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine-7-sulfonamide 1,1-dioxide In neat (no solvent) at 80℃; for 0.0333333h;
4.3. General procedure for the synthesis of 1-carbamato-alkyl-2-naphtols using DCDBTSD (compound 1a-1s)
General procedure: A mixture of 2-naphthols (0.288g, 2 mmol), aldehydes (2 mmol), benzylcarbamate (0.320 g, 2.2 mmol) and DCDBTSD (0.091 g, 10 mol%) in a 10 mL round-bottomed flask connected to a reflux condenser, was stirred in oil bath (80°C) for the appropriate time (Table 2). After completion of the reaction, as monitored by TLC, the reaction mixture was cooled to room temperature and recrystallized from ethanol (95%).
5.10 General procedure for the preparation of compounds 8a-n
General procedure: To the mixture of substituted benzaldehydes 7a-n (2.5mmol), pyridine (20.0mL), piperidine (0.2mL), propanedioic acid (5.0mmol) was added at room temperature and the mixture was heated and refluxed for 20h and monitored by TLC. The reaction mixture was cooled to room temperature and the solution was acidified to pH=5 to yielding a precipitate. The mixture was filtered and washed with water to furnish the compounds 8a-n.
Stage #1: diethyl 4-methoxybenzylphosphonate With sodium methylate In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere;
Stage #2: 2,3-dichlorobenzylaldehyde In tetrahydrofuran at 20℃; for 12h;
6d Synthesis of Compound 6d
Specifically, a 500 mE two-necked flask containing12.9 g (0.05 mol) of the prepared compound 3c was purgedwith argon gas and was stirred for 30 minutes at 0° C. afteraddition of 100 mE of dried tetrahydroffiran (THF) and 9.3 g(0.05 mol) of 28% sodium methoxide to the flask.Next, the flask was stirred for a further 12 hours at room temperature afier addition of 8 g (0.05 mol) of 2,3- dichlorobenzaldehyde dissolved in 300 mE of dried THF to the stirred liquid in the flask.10133] After stirring, the stirred liquid was poured into ion exchanged water and extraction was performed into toluene. The resultant organic layer was washed five times using ion exchanged watet Next, the organic layer was dried using anhydrous sodium sulfate and solvent was evaporated to leave a residue.The resultant residue was purified by recrystallization using a mixed solvent of 20 mE of toluene and 100 mE of methanol to yield 9.8 g (percentage yield: approximately 70%) of the compound 6d (white crystals).
ethyl 3,5-diamino-1-(2,3-dichlorophenyl)-1H-pyrano[3,2-a]phenazine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With 1,4-diaza-bicyclo[2.2.2]octane; In ethanol;Reflux;
General procedure: Compounds 12 (1 mmol), 13 (1 mmol), 14 (1 mmol) were addedto a 25-mL round-bottomed flask containing DABCO (0.3 mmol) inethanol (10 mL). The flask was fitted with a condenser, and theresulting mixture was heated to reflux under stirring. Aftercompletion of the reaction (0.5-2.5 h), as monitored by TLC, thereaction mixture was allowed to cool to room temperature andthen washed with saturated sodium carbonate solution for threetimes. The solid product was filtered off, washed with deionizedwater for three times, dried in vacuo, and subsequently recrystallizedfrom hot ethanol to give the final products.
(E)-3-(2,3-dichlorophenyl)-1-(3-methoxyphenyl)prop-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With potassium hydroxide In methanol at 20℃;
General procedure for the preparation of chalcones, 3(a-h)
General procedure: To a solution of 2,3-dichlorobenzaldehyde, 1 (10 mmole) and acetophenones, 2(a-h) (10 mmole) in methyl alcohol (30 mL), a solution of potassium hydroxide (5 mL, 40%) was added. Then the solution mixture was stirred at room temperature for 3 h. The progress of the reaction was monitored by TLC. After the completion, the reaction mixture was poured in to ice cold water and kept in the refrigerator for overnight. The solid formed was filtered, and washed with cold hydrochloric acid (5%) followed by cold water. Crude products were crystallized from methyl alcohol in a slow solvent evaporation technique. Single crystals of compounds 3a, 3b, 3f, 3g and 3h were obtained without any further purification.
ethyl 4‐(2,3‐dichlorophenyl)‐2,7,7‐trimethyl‐5‐oxo‐1,4,5,6,7,8‐hexahydroquinoline‐3‐carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With ammonium acetate; In ethanol; at 80℃; for 2.5h;Green chemistry;
General procedure: A mixture of aldehyde (1 mmol), dimedone (1 mmol), ethylacetoacetate (1 mmol), ammonium acetate (1.2 mmol) and TEDETA(at)BNPs (0.024 g) was stirred in ethanol at 80 C and the progress of the reaction was monitored by TLC. After completionof the reaction, catalyst was separated and washed with ethyl acetate. Then, the solvent was evaporated and all products was recrystallized in ethanol, which the pure polyhydroquinoline derivatives were obtained in good to excellent yields.
20.0-dichlorobenzaldehyde 70.0 g (0.40 mol), beta-aminocrotonate ethyl ester in a 500 mL round bottom flask55.8g (0.48mol),62.0 g (0.48 mol) of methyl acetoacetate, followed by 4.5 g (0.053 mol) of piperidine and 4.2 g (0.053 mol) of pyridine.The heating was started slowly and the temperature was raised. The reaction was maintained at 75-80 C for 9 h, and 200 g of absolute ethanol was added while heating, and the mixture was heated to reflux for 1 h, and filtered while hot.The mixture was cooled to 15 C and stirred for 1 h, and suction filtered. The filter cake was washed with a small amount of dry ethanol and dried to give 145 g of pale yellow solid.Yield: 94.3%, purity 99.1%
2‐(2,3‐dichlorophenyl)‐5‐methyl‐1H‐benzo[d]imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With nano 1-methyl-3-(3-trimethoxysilylpropyl)-1H-imidazol-3-ium chloride-supported Ni(at)Y-zeolite In ethanol at 30℃; for 0.0833333h; Green chemistry;
General procedure for the catalytic synthesis of 2-aryl benzimidazoles
General procedure: A mixture of o-arylendiamine (1 mmol), aromatic aldehyde (1 mmol) and Nizeolite-Im-IL (5 mg) in EtOH (3 mL) was stirred at 30 °C for desired time. Afterthe satisfactory completion of the reaction (monitored by TLC), the used nanocatalystwas separated by filtration. Cold water (10-15 mL) was added, the resultingprecipitate filtered and washed with water/ethanol (70:30) and air-dried to producethe product. The crude product was recrystallized from ethanol/water (8:2) to purifyexcess. All 2-aryl benzimidazole derivatives are known and were identified by comparingtheir melting point, FT-IR and 1H NMR with authentic samples
90%
With Thiocarbohydrazide/nickel-based nanocomposite supported on SBA-15 In ethanol at 20℃; for 0.0833333h;
2-amino-6-methoxy-4-(2,3-dichlorophenyl)-4H-benzo[h]chromene-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
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.
2-amino-4-(2,3-dichlorophenyl)-4H-pyrano[3,2-h]quinoline-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With 4-aminopyridine functionalized silica on magnetic nanoparticles In neat (no solvent) at 20℃; for 0.166667h;
General procedure for the synthesis of pyranoquinolines using MNPsSiO2-Pr-AP
General procedure: A mixture of aryl aldehyde (1 mmol), malononitrile (1 mmol, 66 mg) and 8-quinoline (1.25 mmol, 174 mg) in the presence of MNPsSiO2-Pr-AP (70 mg) was stirred at roomtemperature for the appropriate time as mentioned in Table 2, monitored by thin layerchromatography (silica gel, n-hexane/ethylacetate, 11/3). After completion of the reaction,an external super magnet was used to separate the nano catalyst. Then, ethanol(95%, 5 mL) was added and the product was recrystallized. All of the products areknown and were identified on the basis of comparison of their melting points with literaturevalues. In addition, IR, H-NMR, 13C-NMR and LRMS spectra were submittedfor each compound for review. For the sake of completeness, spectroscopic data areshown for compound 4a below.
85%
With piperidine In ethanol at 140℃; for 0.0333333h; Microwave irradiation;
General procedure for synthesis of 2-amino-4-aryl-4H-pyrano[3,2-h]quinoline-3-carbonitrile derivatives(4a-h, 6a-h, 8a-i)
General procedure: A reaction mixture of 8-hydroxyquinoline (1), 8-hydroxy-2-methylquinoline (5) or 5-chloro-8-hydroxyquinoline (7)(0.01 mol), with different aryl or hetaryl aldehydes (2a-h,or 2a-i) (0.01 mol) and malononitrile (3) (0.01 mol) inethanol catalyzed by piperidine under microwave irradiationconditions was heated for 2 min at 140 °C. After completionof the reaction, the reaction mixture was cooled to roomtemperature and the precipitated solid was filtered off,washed with methanol, and was recrystallized from ethanolor ethanol/benzene. The physical and spectral data ofcompounds 4a-h, 6a-h and 8a-i are as follows.
2-amino-4-(3,4-dichlorophenyl)-9-methyl-4H-pyrano[3,2-h]quinoline-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With piperidine In ethanol at 140℃; for 0.0333333h; Microwave irradiation;
General procedure for synthesis of 2-amino-4-aryl-4H-pyrano[3,2-h]quinoline-3-carbonitrile derivatives(4a-h, 6a-h, 8a-i)
General procedure: A reaction mixture of 8-hydroxyquinoline (1), 8-hydroxy-2-methylquinoline (5) or 5-chloro-8-hydroxyquinoline (7)(0.01 mol), with different aryl or hetaryl aldehydes (2a-h,or 2a-i) (0.01 mol) and malononitrile (3) (0.01 mol) inethanol catalyzed by piperidine under microwave irradiationconditions was heated for 2 min at 140 °C. After completionof the reaction, the reaction mixture was cooled to roomtemperature and the precipitated solid was filtered off,washed with methanol, and was recrystallized from ethanolor ethanol/benzene. The physical and spectral data ofcompounds 4a-h, 6a-h and 8a-i are as follows.
4-(9-(2,3-dichlorophenyl)-3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl)-N-(pyrimidin-2-yl)benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With toluene-4-sulfonic acid; In ethanol; acetonitrile; at 80℃; for 6h;
General procedure: One pot three component mixture of 2 mmol 5,5-dimethyl-1,3-cyclohexanedione, 1 mmol 2,3-dichlorobenzaldehyde, 1 mmol sulfacompound (<strong>[68-35-9]sulfadiazine</strong> or sulfathiazole) and a catalytic amount of p-toluenesulfonic acid (p-TSA) were heated with stirring at 80 C in20 mL ethanol: acetonitrile (1:1) mixture for 6 h. After the reaction was completed, monitored by TLC, the solid product formed uponcooling was filtered and purified by recrystallization from ethanol.
4-(9-(2,3-dichlorophenyl)-3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl)-N-(thiazol-2-yl)benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
With toluene-4-sulfonic acid; In ethanol; acetonitrile; at 80℃; for 6h;
General procedure: One pot three component mixture of 2 mmol 5,5-dimethyl-1,3-cyclohexanedione, 1 mmol 2,3-dichlorobenzaldehyde, 1 mmol sulfacompound (sulfadiazine or sulfathiazole) and a catalytic amount of p-toluenesulfonic acid (p-TSA) were heated with stirring at 80 C in20 mL ethanol: acetonitrile (1:1) mixture for 6 h. After the reaction was completed, monitored by TLC, the solid product formed uponcooling was filtered and purified by recrystallization from ethanol.
3-amino-9-bromo-1-(2,3-dichlorophenyl)-1H-benzo[f]chromene-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
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:
(E)-N-(5-chloro-2-(2-(2,3-dichlorobenzylidene)hydrazine-1-carbonyl)phenyl)-3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With acetic acid; In ethanol; at 90℃;Sealed tube; Microwave irradiation;
General procedure: To a 50 mL round-bottom flask with the intermediate 6 (1.0 mmol) and anhydrous ethanol (5 mL),the solutions of dierent substituted aromatic aldehydes (1.2 mmol) in anhydrous ethanol (5 mL) witha few drops of glacial acetic acid were added dropwise, and then the round-bottom flask was sealedand placed in the synthetic reactor and irradiated in a microwave at 90 C and 150 W for 12 h. Uponcompletion of the reaction (monitored by TLC), the mixture was concentrated under vacuum, filtered,and recrystallized from a mixture of ethanol and DMF (1:1 in volume) to obtain the target compounds 7a-7v.
(E)-N-(2-(2-(2,3-dichlorobenzylidene)hydrazine-1-carbonyl)-4-fluorophenyl)-3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With acetic acid; In ethanol; at 90℃;Sealed tube; Microwave irradiation;
General procedure: To a 50 mL round-bottom flask with the intermediate 6 (1.0 mmol) and anhydrous ethanol (5 mL),the solutions of dierent substituted aromatic aldehydes (1.2 mmol) in anhydrous ethanol (5 mL) witha few drops of glacial acetic acid were added dropwise, and then the round-bottom flask was sealedand placed in the synthetic reactor and irradiated in a microwave at 90 C and 150 W for 12 h. Uponcompletion of the reaction (monitored by TLC), the mixture was concentrated under vacuum, filtered,and recrystallized from a mixture of ethanol and DMF (1:1 in volume) to obtain the target compounds 7a-7v.
3-(6-trifluoromethoxy-benzo[d]thiazol-2-yl)-2-(2,3-dichlorophenyl)thiazolidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
In ethanol; at 100℃; for 0.5h;Sealed tube; Microwave irradiation;
General procedure: All microwave irradiation experiments were carried out in CEM-Discover monomode microwavedevice, operating at a frequency of 2.45 GHz. Substituted aminobenzothiazole, equimolar amount ofsubstituted benzaldehyde (1.5 mmol) and mercaptoacetic acid in absolut ethanol (3 mL) were placed ina 10 mL reaction vial containing a stirring bar. The vial was sealed with a Teflon septum and placedinto the microwave cavity. It was irradiated at 100 C using 100 W as maximum power for 30 min.at the end of the reaction the mixture was rapidly cooled with gas jet cooling to room temperature.The clean product was obtained after filter under reduced pressure.
3-amino-8-bromo-1-(2,3-dichlorophenyl)-1H-benzo[f]chromene-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With piperidine In ethanol at 140℃; for 0.0333333h; Microwave irradiation;
4.2. General procedure for synthesis of 1H-benzo[f]chromene derivatives(4a-4m) and 2-(2-Fluoro-4-(piperidin-1-yl)benzylidene)malononitrile (5)
General procedure: A reaction mixture of 6-bromo-2-naphthol (1) (0.01 mol), different aromatic aldehydes (2a-m) (0.01 mol), malononitrile (3) (0.01 mol),and piperidine (0.5 mL) in an ethanol solution (30 mL) was heated under microwave irradiation conditions for 2 min. at 140 °C. After the reaction reached completion, the reaction mixture was cooled to room temperature, and the precipitated solid was filtered off, washed with methanol, and recrystallised from ethanol or ethanol/benzene. Thephysical and spectral data of compounds 4a-m and 5 are as follows:
4-(2,3-dichlorophenyl)-6-(methylamino)-5-nitro-2-(1H-pyrrol-2-yl)-4H-pyran-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With piperidine In ethanol at 90℃; for 0.333333h; Sealed tube; Microwave irradiation;
4-Aryl-6-(methylamino)-5-nitro-2-(1H-pyrrol-2-yl)-4H-pyran-3-carbonitriles 4a-4o (general procedure).a. Microwave-assisted synthesis.
General procedure: A 30-mL microwaveglass vial was charged with 0.2 g (1.0 mmol)of 3-oxo-3-(1H-pyrrol-2-yl)propanenitrile (1), 1.0 mmol of aromatic aldehyde 3a-3o, 0.12 g(1.0 mmol) of (E)-N-methyl-1-(methylsulfanyl)-2-nitroethenamine (2), and a catalytic amount of piperidinein 10 mL of ethanol. The vial was sealed, placedin a microwave chamber, and irradiated at 90°C withstirring for 15-20 min. After completion of the reaction(TLC), the mixture was cooled to room temperatureand poured into ice-cold water (20 mL), and theprecipitate was filtered off, washed with cold ethanol(5-7 mL), and dried.
(E)-1-(2-aminophenyl)-3-(2,3-dichlorophenyl)prop-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With sodium hydroxide In methanol at 20℃; for 20h;
General procedure for the preparation of 2′-aminochalcones 3-14
General procedure: In a 50 mL round bottom flask, a mixture of 3 mmol of the aldehyde,3 mmol of 2-aminoacetophenone in 10 mL of methanol was stirred at room temperature. After a complete dissolution of reagents, 12 mmol ofNaOH (powder) were added. The reaction progress was monitored by TLC and after 20 h, the solid was filtered off under vaccum and successivelly washed with a cold mixture of methanol and water (1:1,10 × 5 mL). The solid was dried at room temperature and recrystallizedwhen necessary, as specified for each compound. Chalcone 11 was purified by flash chromatography.
3,5-bis-((2,3-dichlorophenyl)methylene)-1-propylpiperidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
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.
2-((3-chlorophenylamino)(2,3-dichlorophenyl)methyl)-4-methylcyclohexanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With ammonium chloride In ethanol at 25℃; for 8h; diastereoselective reaction;
General procedure for the synthesis of b-aminoketones
General procedure: To a suspension of aromatic aldehyde (1 mmol), aniline (0.5 g, 1 mmol) and ketone(1 mmol), 6ml of ethanol was added followed by the addition of NH4Cl (0.25 g,0.5 mmol) and the reaction mixture was stirred at 25 C for 8-24 h and monitored byTLC (15:75 ethyl acetate:hexane). The product was filtered off and washed using 3mlwater and then 3ml ethanol. The obtained solid was dried and crystallized from hexaneto obtain the pure b-aminoketone. For crystal formation for X-ray analysis, a mixtureof CH2Cl2/ethanol/toluene (4:4:1) was used as the solvent.
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