* 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.
With aluminum (III) chloride In dichloromethane at 0 - 20℃; for 12 h;
Step 1: Synthesis of ethyl 2-(4-chlorophenyl)-2-oxoacetate To a stirred solution of chlorobenzene (10 mL, 100.0 mmol) and ethyl 2-chloro-2-oxoacetate (17 mL, 146.0 mmol) in DCM (250 mL) was slowly added aluminum trichloride (25.5 g, 192.0 mmol) at 0° C. After the addition was completed, the reaction was allowed to warm to room temperature and stir for another 12 h. The reaction was diluted with EtOAc (500 mL) and washed with water (300 mL) and brine (300 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EtOAc=10:1 to 5:1) to afford the title compound (14 g, 67percent) as a light oil. MS (ES+) C10H9ClO3 requires: 212, 214. found: 213, 215 [M+H]+.
Reference：
[1] Journal of Organic Chemistry, 1996, vol. 61, # 18, p. 6407 - 6415
[2] Patent: US2017/22206, 2017, A1, . Location in patent: Paragraph 0174; 0175; 0176
[3] Journal of Organic Chemistry, 2008, vol. 73, # 10, p. 3842 - 3847
[4] Organic Letters, 2011, vol. 13, # 24, p. 6520 - 6523
[5] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2013, vol. 52, # 6, p. 818 - 823
[6] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 8, p. 1958 - 1962
[7] Tetrahedron, 2017, vol. 73, # 39, p. 5813 - 5819
2
[ 64-17-5 ]
[ 4640-66-8 ]
[ 34966-48-8 ]
Yield
Reaction Conditions
Operation in experiment
90%
With oxygen In tetrahydrofuran at 20℃; for 24 h; Irradiation
General procedure: alcohols0.6 mmolbenzoylacetonitrile0.4 mmolTHF2 mLwere added to grass tube. The reaction mixture was irradiated byone halogen tungsten lamp (500W) for 24 h accompanied with a fan beingsufficient to allow reaction temperature down to room temperature. After thereaction was completed (monitored by TLC), the reaction liquid was purifiedby chromatography on silica gel (20:1 petroleum ether/EtOAc) to give theproduct 3a-3s.
75%
With [bis(acetoxy)iodo]benzene In dichloromethane for 0.5 h; Reflux
General procedure: β-Oxo-benzenepropanenitrile 1(1.0 mmol),PIDA (2.2 mmol) were dissolved in EtOH (8 mL) and stirred under refluxing for 0.5h. After the reaction was completed (monitored by TLC), thereaction mixture was concentrated under vacuum. The residue was purified by chromatographyon silica gel (20:1 petroleum ether/EtOAc) to give the product 3a-o .Thesolvent for the synthesis of 3o was MeOH.
Stage #1: With iodine; magnesium In tetrahydrofuran at 40℃; Inert atmosphere Stage #2: at -45 - 20℃; Inert atmosphere
Reference Example-1 A solution of 1-bromo-4-chlorobenzene (15.0 g, 38.4 mmol) in THF was added dropwise to a suspension of magnesium (2.1 g, 86.2 mmol) in THF at 40° C. (oil bath temperature) in the presence of a catalytic amount of iodine in an argon gas atmosphere, whereby a Grignard reagent was prepared. The Grignard reagent was added dropwise to a solution of diethyl oxalate (17.7 g, 94.2 mmol) in THF at -45° C., and the temperature was slowly raised to room temperature, followed by stirring for 18 hours. After the reaction was completed, the reaction solution was poured into ice, then, acidified with concentrated hydrochloric acid, and the resultant product was extracted with ether (100 mL*2). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, whereby a yellow oily crude product (14.8 g) was obtained. This was purified by silica gel column chromatography (hexane:ethyl acetate=5:1), whereby ethyl 2-(4-chlorophenyl)-2-oxoacetate (4.68 g, yield: 22percent) was obtained as a yellow oily material. 1H-NMR (400 MHz, CDCl3): δ1.43 (t, J=7.2 Hz, 3H), 4.45 (q, J=7.2 Hz, 2H), 7.49 (d, J=8.7 Hz, 2H), 7.99 (d, J=8.7 Hz, 2H).
Reference：
[1] Organic Letters, 2014, vol. 16, # 13, p. 3528 - 3531
[2] Angewandte Chemie - International Edition, 2011, vol. 50, # 10, p. 2249 - 2252
[3] Journal of Organic Chemistry, 2003, vol. 68, # 10, p. 3990 - 3998
[4] Journal of Agricultural and Food Chemistry, 2012, vol. 60, # 6, p. 1470 - 1479
[5] Patent: US2016/24110, 2016, A1, . Location in patent: Paragraph 0420; 0421
[6] Patent: EP1486483, 2004, A1, . Location in patent: Page 32
[7] Chemical Communications, 2013, vol. 49, # 32, p. 3300 - 3302
4
[ 873-77-8 ]
[ 95-92-1 ]
[ 34966-48-8 ]
Reference：
[1] Organic Letters, 2015, vol. 17, # 22, p. 5614 - 5617
[2] Chemistry - A European Journal, 2012, vol. 18, # 14, p. 4375 - 4379
[3] Angewandte Chemie - International Edition, 2013, vol. 52, # 47, p. 122414 - 122417[4] Angew. Chem., 2013, p. 12640 - 12643,4
[5] Organic Letters, 2014, vol. 16, # 22, p. 5956 - 5959
[6] Chemical Communications, 2015, vol. 51, # 2, p. 342 - 345
[7] Organic Letters, 2017, vol. 19, # 11, p. 2869 - 2872
5
[ 13014-48-7 ]
[ 34966-48-8 ]
Yield
Reaction Conditions
Operation in experiment
54%
With sodium bromide; sulfuric acid In ethanol
Example 1b Preparation of ethyl 4-chlorophenylglyoxylate 4-Chlorobenzoyl cyanide (13.0 g, 0.079 mol) prepared in Example 1a was added to a stirred mixture of sodium bromide (1.0 g, 0.01 mol) and 80percent sulphuric acid (10 ml). An exothermic reaction took place with the formation of a solid yellow mass. Ethanol (50 ml) was added and the mixture was heated under reflux to give a yellow solution. On cooling, a colourless precipitate formed. The mixture was diluted with cold water and extracted with isopropyl ether. The organic extract was washed with water, sodium bicarbonate solution and then again with water and dried over sodium sulphate. Evaporation and distillation of the solution gave the product as a yellow oil (8.2 g, 54percent)--b.p. 82°-84° C./0.05 mm Hg.
Reference：
[1] Patent: US5508251, 1996, A,
[2] Bulletin de la Societe Chimique de France, 1959, p. 850,852
Reference：
[1] Journal of Organic Chemistry, 2009, vol. 74, # 9, p. 3520 - 3523
9
[ 1147869-46-2 ]
[ 1575-95-7 ]
[ 34966-48-8 ]
Reference：
[1] Journal of Organic Chemistry, 2009, vol. 74, # 9, p. 3520 - 3523
10
[ 637-87-6 ]
[ 34966-48-8 ]
Reference：
[1] Journal of Organic Chemistry, 1990, vol. 55, # 10, p. 3114 - 3118
11
[ 108-90-7 ]
[ 34966-48-8 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1959, p. 850,852
[2] Collection of Czechoslovak Chemical Communications, 1964, vol. 29, p. 97 - 120
12
[ 64-17-5 ]
[ 13651-12-2 ]
[ 34966-48-8 ]
Reference：
[1] Synlett, 2011, # 10, p. 1381 - 1384
13
[ 64-17-5 ]
[ 7099-88-9 ]
[ 34966-48-8 ]
Reference：
[1] Collection of Czechoslovak Chemical Communications, 1964, vol. 29, p. 97 - 120
14
[ 106-39-8 ]
[ 75716-82-4 ]
[ 34966-48-8 ]
Reference：
[1] Journal of Organic Chemistry, 1981, vol. 46, # 1, p. 211 - 213
15
[ 64-17-5 ]
[ 52119-96-7 ]
[ 34966-48-8 ]
Reference：
[1] Synlett, 2011, # 10, p. 1381 - 1384
16
[ 7099-88-9 ]
[ 34966-48-8 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1959, p. 850,852
17
[ 122-01-0 ]
[ 34966-48-8 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1959, p. 850,852
18
[ 622-98-0 ]
[ 34966-48-8 ]
Reference：
[1] Synlett, 2011, # 10, p. 1381 - 1384
19
[ 622-98-0 ]
[ 141-78-6 ]
[ 34966-48-8 ]
[ 7099-88-9 ]
[ 536-38-9 ]
Reference：
[1] Synlett, 2011, # 10, p. 1381 - 1384
20
[ 64-17-5 ]
[ 13651-12-2 ]
[ 34966-48-8 ]
[ 536-38-9 ]
Reference：
[1] Synlett, 2011, # 10, p. 1381 - 1384
21
[ 34966-48-8 ]
[ 7099-88-9 ]
Yield
Reaction Conditions
Operation in experiment
86%
With water; lithium hydroxide In tetrahydrofuran; methanol at 25℃; for 3 h;
Step 2: Synthesis of 2-(4-chlorophenyl)-2-oxoacetic acid A mixture of ethyl 2-(4-chlorophenyl)-2-oxoacetate (4.0 g, 18.9 mmol) and lithium hydroxide (1.98 g, 47.1 mmol) in THF:MeOH:H2O (76 mL, v/v/v=10:6:3) was stirred at 25° C. for 3 h. The mixture was neutralized with conc. HCl to pH=2-3. The formed white precipitate was collected via filtration, washed with water three times and dried under vacuum to afford the title compound (3.0 g, 86percent) as a white solid. MS (ES+) C8H5ClO3 requires: 184, 186. found: 185, 187 [M+H]+.
Reference：
[1] Organic Letters, 2014, vol. 16, # 13, p. 3528 - 3531
[2] Patent: US2017/22206, 2017, A1, . Location in patent: Paragraph 0176; 0177; 0178
[3] Journal of the American Chemical Society, 1995, vol. 117, # 14, p. 3999 - 4013
[4] Patent: EP1486483, 2004, A1, . Location in patent: Page 32
[5] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2013, vol. 52, # 6, p. 818 - 823
[6] Organic Letters, 2014, vol. 16, # 3, p. 776 - 779
[7] Chemical Communications, 2014, vol. 50, # 34, p. 4489 - 4491
[8] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 8, p. 1958 - 1962
[9] Advanced Synthesis and Catalysis, 2018, vol. 360, # 21, p. 4184 - 4190
22
[ 622-98-0 ]
[ 141-78-6 ]
[ 34966-48-8 ]
[ 7099-88-9 ]
[ 536-38-9 ]
Reference：
[1] Synlett, 2011, # 10, p. 1381 - 1384
Example 1b Preparation of ethyl 4-chlorophenylglyoxylate 4-Chlorobenzoyl cyanide (13.0 g, 0.079 mol) prepared in Example 1a was added to a stirred mixture of sodium bromide (1.0 g, 0.01 mol) and 80% sulphuric acid (10 ml). An exothermic reaction took place with the formation of a solid yellow mass. Ethanol (50 ml) was added and the mixture was heated under reflux to give a yellow solution. On cooling, a colourless precipitate formed. The mixture was diluted with cold water and extracted with isopropyl ether. The organic extract was washed with water, sodium bicarbonate solution and then again with water and dried over sodium sulphate. Evaporation and distillation of the solution gave the product as a yellow oil (8.2 g, 54%)--b.p. 82-84 C./0.05 mm Hg.
ethyl (S)-2-hydroxy-2-(4-chlorophenyl)acetate[ No CAS ]
ethyl (R)-2-hydroxy-2-(4-chlorophenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With Sucrose; In aq. phosphate buffer; ethanol; at 37℃; for 24h;pH 7.0;Enzymatic reaction;
General procedure: A suspension of baker's yeast (3.75 g) in 20 mL potassium phosphate buffer (pH 7.0) and 0.9 g (2.6 ×10-3) sucrose was put into a 250 mL Erlenmeyer flask. The resulting mixture was stirred at 37 C. After this stage of fermenting yeast (30 min), the solution of ketones/ketoesters (1.25 × 10-4 mol in 0.5 mL EtOH) was added. The reaction progress was monitored by TLC. After 24 h the yeast cells were removed by filtration of celit filter. The yeast cells were washed with 2× 25 mL water. The filtrate was saturated with NaCl and then extracted with 5 ×20 mL portions of ethyl acetate. The combined organic layers were dried over MgSO4 and the solvent was evaporated under reduced pressure to leave a residue of the crude product, which was purified by PLC using hexane:ethyl acetate (3:1) as eluent. The enantiomeric ratios were determined on an HPLC system using a chiral column.
ethyl (R)-2-hydroxy-2-(4-chlorophenyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%Chromat.
With D-glucose; In aq. phosphate buffer; ethanol; at 37℃;pH 7.0;Enzymatic reaction;
General procedure: For a typical experiment, 0.14 g glucose (7.6 × 10-4 mol) was added to a suspension of Boni Protect (2 g) in 30 mL of potassium phosphate buffer (pH 7.0) and the resulting suspension was stirred at 37 C for 30 min. Then an additive compound (1.25 ×10-5 mol; see Table 2) and substrate (1.25 × 10-4 mol in 0.5 mL EtOH) were added and stirring was continued at the same temperature. The reaction progress was monitored by TLC (the solvent system used was hexane:ethyl acetate 3:1). After the reaction, hyflo-super celit and ethyl acetate were added and the mixture was filtered. The celit was washed with ethyl acetate and combined filtrates were extracted with ethyl acetate (5 × 20 mL). The organic portion was dried with MgSO4. The solvent was evaporated under reduced pressure. The crude product was purified by PLC (Preparative Layer Plate) using hexane:ethyl acetate (3:1) as eluent. The enantiomeric ratios were determined on an HPLC system using a chiral column.
To a solution of ethyl 2-(4-chlorohenyl)-2-oxoacetate (510 mg) in THF (4 ml), cyclopentylmagnesium chloride (2M-ether solution, 1.8 ml) was added at -70 C and stirred for an hour. To the reaction liquid saturated aqueous ammonium chloride solution was added and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The residue as obtained by condensing the organic layer under reduced pressure was purified on silica gel column chromatography (hexane/ethyl acetate = 50/1) to provide ethyl 2-(4-chlorophenyl)-2-cyclopentyl-2-hydroxyacetate (149 mg).
Ethyl 2-(4-Chlorophenyl)spiro[1,3-dioxane-5,9'-xanthene]-2-carboxylate (Example 77) 0.3 ml of BF3.OEt2 is added dropwise to a mixture of 1 g (4.7 mmol) of ethyl para-chlorophenyloxoacetate and 0.7 g of the diol prepared above in 20 ml of CH2Cl2, stirred at room temperature. After stirring for 2 hours at room temperature, the reaction medium is washed twice with 20 ml of saturated NaHCO3. The organic phase is dried over Na2SO4 and then evaporated. The residual oil is chromatographed on a column of silica and eluted with an EtoAc/cyclohexane mixture (1:9). 0.4 g of whitish crystals is obtained and this product is recrystallized from acetone. 0.32 g of white crystals is collected (yield: 25%). m.p.=131-132 C.
45
[ 108-20-3 ]
[ 34966-48-8 ]
[ 5464-86-8 ]
[ 255717-50-1 ]
Yield
Reaction Conditions
Operation in experiment
71%
With BF3.Et2O; In dichloromethane; sodium hydrogencarbonate;
EXAMPLE 3 Ethyl 2-(4-Chlorophenyl)-5,5-diphenyl[1,3]-dioxane-2-carboxylate 42.5 g (0.2 M) of <strong>[34966-48-8]ethyl 2-oxo-2-(4-chlorophenyl)acetate</strong> are placed in 400 ml of CH2Cl2 in a 500 ml reactor. 22.8 g (0.1 M) of 2,2-diphenylpropane-1,3-diol and then 14.2 g (0.1 M) of BF3.Et2O are added. The mixture is left to react with stirring for 72 h at room temperature. The reaction mixture is taken up in NaHCO3 solution. The organic phase is washed with saturated NaCl solution. After drying over Na2SO4 and concentration, a very thick oil is obtained. 150 ml of isopropyl ether are added and a white precipitate forms. After filtration, 30 g of product melting at 156-158 C. are obtained (yield: 71%).
5-(4-chlorophenyl)-4-hydroxy-5-methyl-3-phenylmethoxy-2(5H)-furanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
In tetrahydrofuran;
A. A total of 3.4 mL (10.2 mmol) of 3.0 M methylmagnesium iodide was added to a solution of 2.34 g (10 mmol) of ethyl 4-chlorobenzoylformate in THF in an analogous manner as described for the synthesis of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to give prior to hydrogenolysis 1.3 g (40% yield) of 5-(4-chlorophenyl)-4-hydroxy-5-methyl-3-phenylmethoxy-2(5H)-furanone as a yellow oil: 1 H NMR (CDCl3) delta 7.37-7.21 (m, 9H), 5.10 (s, 2H), 1.73 (s, 3H).
Example 1c Preparation of ethyl 2- (4-chlorophenyl) -3-methylbut-2-enoate) A solution of n-butyl lithium in hexane (20 ml, 0.03 mol) was added dropwise to a stirred solution of ethyl 4-chlorophenylglyoxylate (6.4 g, 0.03 mol) prepared in Example 1b, at -10 C. under nitrogen, during which time an exothermic reaction occurred and a red-brown suspension was formed. A solution of iso-propyltriphenylphosphonium iodide (13.0 g, 0.03 mol) in tetrahydrofuran (10 ml) was then added dropwise to the stirred mixture at -10 C. over 10 minutes. An exothermic reaction occurred and the solution became colourless. Stirring was continued for a further 15 minutes at -10 C. after the addition was complete, and the mixture was then allowed to warm to room temperature and stirred for a further 4 hours at this temperature. The reaction mixture was poured onto ice and extracted with isopropyl ether. The organic solution was evaporated in vacuo. The residue was stirred with isopropyl ether and the precipitate was filtered off. The solution was evaporated in vacuo and the product purified by flash silica column chromatography, eluding with petroleum ether/acetone (9:1) to give the title compound as a yellow oil (4.0 g, 56%).
(2R*,4R*)-2-(4-Chlorophenyl)-2-ethoxycarbonyl-3,4-dimethyloxetane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
In benzene;
PREPARATION 8 (2R*,4R*)-2-(4-Chlorophenyl)-2-ethoxycarbonyl-3,4-dimethyloxetane 2-Butene was bubbled into 200 ml of benzene at 0 C. until the benzene solution increased to about 1.25 times its original volume. 24.3 g (114.09 mmole) of ethyl 4-chlorophenylglyoxylate were then added to the mixture, and the resulting mixture was irradiated with a 450 watt medium pressure mercury-arc lamp (Hannovea Co., Inc.) at 15 C. for 3 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was subjected to column chromatography through silica gel, eluted with a 10:1 by volume mixture of hexane and ethyl acetate, to afford 23.4 g (yield 76%) of the title compound, boiling at 141-142 C./2.7 Torr.
76%
In benzene;
PREPARATION 8 (2R*,4R*)-2-(4-Chlorophenyl)-2-ethoxycarbonyl-3,4-dimethyloxetane 2-Butene was bubbled into 200 ml of benzene at 0C until the benzene solution increased to about 1.25 times its original volume. 24.3 g (114.09 mmole) of ethyl 4-chlorophenylglyoxylate were then added to the mixture, and the resulting mixture was irradiated with a 450 watt medium pressure mercury-arc lamp (Hannovea Co., Inc.) at 15C for 3 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the resulting residue was subjected to column chromatography through silica gel, eluted with a 10: 1 by volume mixture of hexane and ethyl acetate, to afford 23.4 g (yield 76%) of the title compound, boiling at 141 - 142 C/2.7 Torr.
6-(4-chlorophenyl)-3-(pyridin-2-yl)-1,2,4-triazin-5(4H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In ethanol;
EXAMPLE 3 A mixture of 0.68 g (0.005 mol) of 2-pyridylhydrazidine, 1.06 g (0.005 mol) of ethyl 4-chlorophenylglyoxylate and 50 ml of ethanol was heated under reflux for 5 hours. The reaction mixture was filtered while hot to remove 5-(4-chlorophenyl)-3-(2-pyridyl)-1,2,4-triazin-6(1H)-one, which is an isomer of the desired product. The filtrate was cooled, and precipitated crystals of 6-(4-chlorophenyl)-3-(2-pyridyl)-1,2,4-triazin-5(4H)-one were collected by filtration. The infrared spectrum and melting point of the crystals were consistent with those of the product in Example 1.
In ethanol;
EXAMPLE 4 A mixture of 0.68 g (0.005 mol) of 2-pyridylhydrazidine, 1.06 g (0.005 mol) of ethyl 4-chlorophenylglyoxylate and 50 ml of ethanol was stirred under ice-cooling for 5 hours and at room temperature for 10 hours. Crystals of 6-(4-chlorophenyl)-3-(2-pyridyl)-1,2,4-triazin-5(4H)-one were precipitated from the reaction mixture and collected by filtration. The infrared spectrum and melting point of the crystals were consistent with those of the product in Example 1.
allyl hydrazonothiocarbamate hydrobromide[ No CAS ]
[ 925459-57-0 ]
Yield
Reaction Conditions
Operation in experiment
27%
With ethanol; water; sodium acetate; at 120℃; for 1h;
Example 6: 3-Allylmercapto-6-(4-chlorophenyl)-4H-H ,2,41-triazin-5-one; A mixture of allyl hydrazonothiocarbamate hydrobromide (211 mg, 1.0 mmol), ethyl oxo- (4-chlorophenyl)acetate (213 mg, 1.0 mmol) and sodium acetate (82 mg, 1.0 mmol) in water (3 ml) and ethanol (1.5 ml) is heated at 1200C in a sealed tube for 1 hour. A precipitate forms which is collected by filtration, washed with diethyl ether and dried to give the title compound (77 mg), m.p. 216-2180C. Yield: 27%. LCMS (MH+) 280.
2-(4-Chlorophenyl)-2-hydroxy-2-(3-pyridinyl) acetic acid To a solution of 3-bromopyridine (640mg) in diethyl ether (10 ml), n-butyl lithium (2.5M-hexane solution, 1.80 ml) was added at -74C. After 15 minutes' stirring at the same temperature, a solution of <strong>[34966-48-8]ethyl 2-(4-chlorophenyl)-2-oxoacetate</strong> (960 mg) in diethyl ether (100 ml) was added. The temperature of the system was raised to room temperature over 30 minutes, and to the reaction solution saturated aqueous ammonium chloride solution was added and extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer was condensed under reduced pressure, and the resulting residue was purified on silica gel column chromatography (hexane/ethyl acetate = 3/2) to provide ethyl 2-(4-chlorophenyl)-2- hydroxy-2-(3-pyridinyl)acetate (571 mg) as a yellow oily substance.
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