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Structure of 2632-13-5 * 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.
Stage #1: With thiamine hydrochloride In ethanol at 20℃; for 0.25 h; Green chemistry Stage #2: at 20℃; for 2 h; Green chemistry
General procedure: To prepare catalyst, 0.21 g of thiamine hydrochloride (0.6 mmol) was dissolved in 0.64 mL of water and added 2.4 mLof 95percent ethanol (water : 95percent ethanol = ~1:4). The solution was cooled in an ice bath, then added 0.40 mL of 3 M NaOH(1.2 mmol) dropwise with stirring in a manner such that thetemperature remained below 20 °C. Intense yellow coloured solution changed to pale yellow solution of thiamine (thiazolium ion)/N-heterocyclic carbene (Scheme 1).47 In a 25-mL round bottom flask, a mixture of phenacylbromide 1 (2.5 mmol, 0.5 g in case of 1a) and thiamine (0.6 mmol, 25 mol percent) in ethanol (4 mL) was stirred at room temperature for 15 min. Then, salicylaldehyde 2 (2.5 mmol, 0.26 mL in case of 2a) was added slowly and the mixture was stirred at room temperature until the reaction was completed (as monitored by TLC) (Table 3) . The reaction mixture was then poured into 20 mL of distilled water and extracted with ethyl acetate (3 × 10 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The resulting product isoflavone 3 was further purified either by recrystallizationor by column chromatography (Ethyl acetate:Hexane, 1:4v/v). All compounds were characterized by their mp and 1HNMR, 13CNMR and mass spectral data.
Reference:
[1] Bulletin of the Korean Chemical Society, 2013, vol. 34, # 4, p. 1070 - 1076
3
[ 90-05-1 ]
[ 2632-13-5 ]
[ 19513-80-5 ]
Reference:
[1] Green Chemistry, 2017, vol. 19, # 3, p. 702 - 706
[2] Green Chemistry, 2016, vol. 18, # 24, p. 6545 - 6555
[3] Journal of the American Chemical Society, 2014, vol. 136, # 4, p. 1218 - 1221
[4] Journal of Organic Chemistry, 2014, vol. 79, # 22, p. 11091 - 11100
[5] Organic Letters, 2016, vol. 18, # 19, p. 5166 - 5169
[6] Green Chemistry, 2016, vol. 18, # 7, p. 2029 - 2036
[7] Green Chemistry, 2016, vol. 18, # 23, p. 6229 - 6235
[8] Journal of Catalysis, 2017, vol. 346, p. 170 - 179
[9] Green Chemistry, 2017, vol. 19, # 19, p. 4538 - 4543
4
[ 2632-13-5 ]
[ 108-59-8 ]
[ 22027-50-5 ]
Yield
Reaction Conditions
Operation in experiment
7%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at 0℃; for 1 h; Inert atmosphere; Sealed tube Stage #2: at 0 - 20℃; for 18 h; Inert atmosphere; Sealed tube
General procedure: Reaction of dimethyl malonate/LHMDS system with benzyl bromide. A 1M LHMDS solution in anhydrous THF (1.0mL, 1.0mmol) was treated at 0°C with a solution of dimethyl malonate (0.132g, 1.0mmol) in anhydrous THF (3.0mL) and the reaction mixture was stirred at the same temperature for 1h. A solution of benzyl bromide (0.171g, 0.12mL, 1.0mmol) in anhydrous THF (0.5mL) was added dropwise at 0°C and the reaction mixture was stirred for 18h at room temperature. Dilution with Et2O and evaporation of the washed (saturated aqueous NaCl) organic solution afforded a crude reaction mixture (0.19g) consisting of a 35:33:32 mixture (68percent conversion) of dimethyl benzylmalonate (10a), methyl phenylacetate (11a) and unreacted dimethyl malonate (1H NMR) which was subjected to preparative TLC by using a 9:1 hexane/AcOEt mixture as the eluant. Extraction of the two most intense bands (the faster moving band contained 10a) afforded pure dimethyl benzylmalonate (10a) (0.027g, 12percent yield) and methyl phenylacetate (11a) (0.017g, 11percent yield).
Stage #1: With sodium diformamide In acetonitrile at 20 - 70℃; for 4 h; Stage #2: With hydrogenchloride In ethanol for 1 h; Heating / reflux
To a stirred solution of 2-Bromo-4'-methoxyacetophenone (20.0 g, 87.3 mmol) in CH3CN (90 mL), was added sodium diformylamide (9.95 g, 104.76 mmol, 1.2 [EQ).] The resulting mixture was stirred for 2h at RT, and heated for 2 h at [70 °C] (monitored by TLC). Solvent was removed under reduced pressure. Then [ETOH] (250 mL) and Conc. HCl (40 mL) were added. The reaction mixture was refluxed for 1h. Solvent was removed by rotavap. The crude product was suspended in iPr-OH (100 mL) and stirred at RT O/N. The off-white pure product was obtained by filtration (17.28 g, [98percent). 1H NMR] (300 MHz, [DMSO-D6)] 8 8.4 (br), 8.0 (d, 2H), 7.1 (d, 2H), 4.5 (s, 2H), 3.9 (s, 3H). MS (APCI+) [M/Z] 166 [(M-HCL).] Yield: 98percent
Reference:
[1] Patent: WO2004/18428, 2004, A1, . Location in patent: Page 356
[2] Journal of Medicinal Chemistry, 1982, vol. 25, # 9, p. 1045 - 1050
[3] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 5, p. 1119 - 1121
[4] Synthesis, 1990, # 7, p. 615 - 618
[5] Patent: US4898862, 1990, A,
[6] Patent: EP238357, 1991, B1,
[7] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 5, p. 2550 - 2557
[8] Journal of Pharmaceutical Sciences, 2014, vol. 103, # 9, p. 2797 - 2808
[9] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 3, p. 849 - 853
[10] Journal of Medicinal Chemistry, 2017, vol. 60, # 22, p. 9275 - 9289
[11] Patent: WO2007/149395, 2007, A2, . Location in patent: Page/Page column 57
6
[ 100-97-0 ]
[ 2632-13-5 ]
[ 3883-94-1 ]
Reference:
[1] Patent: US5217645, 1993, A,
7
[ 18197-26-7 ]
[ 2632-13-5 ]
[ 3883-94-1 ]
Reference:
[1] Synthesis, 1990, # 7, p. 615 - 618
8
[ 2632-13-5 ]
[ 84449-65-0 ]
Reference:
[1] Journal of Medicinal Chemistry, 1984, vol. 27, # 8, p. 1057 - 1066
9
[ 2632-13-5 ]
[ 82640-04-8 ]
Reference:
[1] Journal of Medicinal Chemistry, 1984, vol. 27, # 8, p. 1057 - 1066
10
[ 2632-13-5 ]
[ 92409-15-9 ]
Reference:
[1] Green Chemistry, 2016, vol. 18, # 24, p. 6545 - 6555
11
[ 2632-13-5 ]
[ 92409-23-9 ]
Reference:
[1] Organic Letters, 2016, vol. 18, # 19, p. 5166 - 5169
[2] Green Chemistry, 2016, vol. 18, # 24, p. 6545 - 6555
12
[ 90-05-1 ]
[ 2632-13-5 ]
[ 92409-23-9 ]
Reference:
[1] Journal of the American Chemical Society, 2014, vol. 136, # 4, p. 1218 - 1221
Example 3 - METHOD A1 - Condensation 1A mixture of 2-bromo-4'-methoxyacetophenone (1.4 g, 6.13 mmol), 2-amino-3,5- dichloropyridine (1.0 g, 6.13 mmol) in absolute ethanol (15 mis) was heated to reflux. After 2 h, NaHCU3 (309 mg, 3.68 mmol) was slowly added to the dark brown solution. The reaction mixture continued to reflux for another 15 h before another portion of NaHCU3 was slowly added (206 mg, 2.45 mmol). After 15 mins, the reaction was cooled and kept in the fridge for 20 h. The resulting precipitate was collected by filtration, washed with cold ethanol followed by water. The solid was then boiled in hot ethanol for 10 mins before it was cooled to RT and then collected by filtration to give 6,8-dichloro-2-(4-methoxyphenyl)imidazo[1,2-a]pyridine as beige coloured crystals (1.34 g, 75percent).
To the solution of EtONa (4.08 g, 60 mmol) in EtOH (60 mL) was added compound 104 (10 g, 60 mmol) at 0 0C under nitrogen. The mixture was stirred for 20 minutes and 2-bromo-4'-methyloxy-acetophenone was added. After stirring at room temperature overnight, the mixture was concentrated and the residue was taken up in ethyl acetate, washed with water, brine, dried and concentrated to give a residue which was purified by column chromatography to afford the product 402 as a solid (5.2 g, 67 %yield). 1H NMR (DMSOd6) delta 10.62 (s, IH), 7.41 (d, J = 6.6 Hz, 2H), 6.88 (d, J = 6.6 Hz, 2H), 6.30 (d, J = 3.0 Hz, IH), 5.59 (s, 2H), 4.13 (q, J = 6.9 Hz, 2H), 3.74 (s, 3H), 1.24 (t, J = 7.2 Hz, 3 H). LC-MS: 260 (M+l).
67%
To the solution of EtONa (4.08 g, 60 mmol) in EtOH (60 mL) was added compound 104 (10 g, 60 mmol) at 0 0C under nitrogen. The mixture was stirred for20 minutes and 2-bromo-4'-methyloxy-acetophenone was added. After stirring at room temperature overnight, the mixture was concentrated and the residue was taken up in ethyl acetate, washed with water, brine, dried and concentrated to give a residue which was purified by column chromatography to afford the product 402 as a solid (5.2 g, 67 %yield). 1H NMR (DMSO-d6) delta 10.62 (s, 1eta), 7.41 (d, J = 6.6 Hz,2H), 6.88 (d, J = 6.6 Hz, 2H), 6.30 (d, J = 3.0 Hz, IH), 5.59 (s, 2H), 4.13 (q, J = 6.9 Hz, 2H), 3.74 (s, 3H), 1.24 (t, J = 7.2 Hz, 3 H). LC-MS: 260 (M+l).
General procedure: The following is representative: <strong>[57508-48-2]ethyl 3-amino-3-iminopropanoate hydrochloride</strong> (3) (8.3 g, 50.0 mmol) and NaOEt (5.1 g, 75.0 mmol) were dissolved in abs. EtOH at 0 C and stirred for 20 min under argon. The mixture was heated to 60 C, and 2-bromo-1-phenylethanone (4b) (5.0 g, 25.0 mmol) was added portion wise over 5 min. After 1.5 h the mixture was cooled to 20 C and the solvent was evaporated under reduced pressure. The residue was diluted with distilled water (20 mL) and extracted with EtOAc (3 × 80 mL). The organic layer was washed with water (3 × 20 mL) and brine (3 × 20 mL). The combined water fractions were back extracted with EtOAc (2 × 20 mL). The organic phases were dried over MgSO4, and the solvent was evaporated under reduced pressure. Purification was by silica-gel column chromatography (EtOAc/n-pentane, 7/3).
Step 12.1: 2-Amino-3-ethoxycarbonyl-5-(4-methoxy-phenyl)-1H-pyrrole Analogously to Step 8.1, 1.67 g (10 mmol) of 2-amidino-acetic acid ethyl ester hydro-chloride in 20 ml of abs. ethanol are reacted with 716 mg (10 mmol) of sodium ethanolate and 1.145 g (5.0 mmol) of 4-methoxy-phenacyl bromide (Fluka; Buchs/Switzerland) to form the title compound; m.p. 141-142 C.; TLC-Rf =0.4 (hexane/ethyl acetate [1:1]); FAB-MS: (M+H)+ =261.
2-(p-methoxybenzyl)-3-methyl-5-benzyloxybenzofuran[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In hexane; ethyl acetate; acetone;
Step A A mixture of 2-hydroxy-5-benzyloxyacetophenone (93 g, 380 mmoles), p-methoxyphenacyl bromide (88 g, 384 mmoles) and potassium carbonate (106 g, 768 mmoles) in acetone (1.5 L) was refluxed for 46 hours. The reaction mixture was cooled and filtered. The filtrate was evaporated in vacuo. The residue was chromatographed on silica gel using 10% ethylacetate in hexane as eluent to yield (127 g, 89%) of 2-(p-methoxybenzyl)-3-methyl-5-benzyloxybenzofuran, E48. 1 H NMR delta: 2.55 (s, 3H, CH3), 3.85 (s, 3H, CH3 O), 5.1 (s, 2H, benzylic proton), 7.00 (d, J=9 Hz, 2H, proton ortho to methoxy), 7.15 (m, 2H, aromatic proton), 7.45 (m, 6H, benzylic proton +1 proton), 8.15 (d, J=9 Hz, 2H, proton ortho to benzoyl).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 5h;
Example 17 Production of N-hydroxy-4-(4-methoxyphenyl)-2-oxazolehexanamide (compound 17) (1) 4-(4-methoxyphenyl)-2-oxazolehexanoic acid ethyl ester; Potassium carbonate (9.1 g) and 4-methoxyphenacyl bromide (5.0 g) were added to monoethyl pimerate (4.6 g) in DMF (50 mL), and the resultant mixture was reacted at room temperature for 5 hours. The reaction liquid was added to water (500 mL), the resultant mixture was stirred, and an object material was extracted with ethyl acetate (200 mL). The organic layer was washed with water, dehydrated by magnesium sulfate, and then condensed under a reduced pressure to obtain an ester form (7.4 g). Ammonium acetate (8.5 g) was added to the ester form (7.4 g) in acetic acid (50 mL), and the resultant mixture was reacted under reflux for 3 hours. The reaction liquid was condensed under a reduced pressure, water (100 mL) was added to the residue, and an object material was extracted with ethyl acetate (100 mL). The organic layer was washed with water, dehydrated by magnesium sulfate, and then condensed under a reduced pressure to obtain a crude product. The crude product was purified with a silica gel column (chloroform) to obtain the subject compound (6.2 g, Y=89%).
2-Bromo-4'-methoxyacetophenone (1.64 g, 7.14 mmol) was added to a solution of 2- amino-3-benzyloxypyrazine (Compound m in scheme 1,1. 5 g, 6.80 mmol) in ethanol (10 mL). The reaction mixture was refluxed for 5 h. The reaction mixture was allowed to cool to r. t. and an off- white coloured solid precipitated out. The solid was collected and washed with ice-cold ethanol to give a white solid (1. 08 g, 66%). lH-NMR (CDC13) 6 11.4 (d, J4. 2 Hz, 1H), 8.23 (s, 1H), 7. 86 (t, J 2.9 Hz, 1H), 7. 83 (t, J2. 1 Hz, 1H), 7.52 (dd, J0. 7 & 5.5 Hz, 1H), 7.04 (t, J2. 9 Hz, 1H), 7.02 (t, J2. 0 Hz, 1H), 6.94 (t, J3.0 Hz, 1H), 3.79 (s, 3H) ; MS (ESI) 242.0 ([M+H]
With toluene-4-sulfonic acid; In toluene; at 130℃;Product distribution / selectivity;
Example 23; Synthesis of (4S)-trans-,cis-2-(4-chlorophenyl)-2-bromomethyl-4-chloromethyl-1,3-dioxolane suppressing halogen exchange between substrates A mixture of 2-bromo-4'-chloroacetophenone (4.94 g, 2-chloro-4'-chloroacetophenone content=0.09%), p-toluenesulfonic acid monohydrate (0.20 g, 0.05 equivalent) and toluene (100 mL) was refluxed at 130C using an azeotropic distillation device with a Dean-Stark tube, and (S)-monochlorohydrin (2.59 g, 1.1 equivalents, >99%ee) was added dropwise under reflux such that the amount of the (S)-monochlorohydrin present in the reaction solution would be not more than 0.1 equivalent (not more than 2.1 mmol) relative to the amount of 2-bromo-4'-chloroacetophenone to be used (21.2 mmol), while analyzing the progress of the reaction by GC. After confirmation of the completion of the azeotropic distillation, the reaction mixture was cooled and washed with 10% aqueous sodium hydrogen carbonate solution and 10% brine. The solvent was evaporated under reduced pressure to give (4S)-trans-,cis-2-(4-chlorophenyl)-2-bromomethyl-4-chloromethyl-1,3-dioxolane (6.56 g, >99%ee). Here, the content percentage of (4S)-trans-,cis-2-(4-chlorophenyl)-2-chloromethyl-4-chloromethyl-1,3-dioxolane halogen-exchanged with a chlorine atom was 0.09%. Examples 30 to 41 Synthesis of (4S)-trans-cis-2-aryl-2-bromomethyl-4-chloromethyl-1,3-dioxolane suppressing halogen exchange In Examples 30 to 41, reactions were performed according to Example 23 and using aryl(bromomethyl)ketones (halogen-exchanged compound content<0.1%) shown in Table 7 and Table 8. The results are shown in Table 9 and Table 10 together with Example 23.
Step 1: To a solution of <strong>[934-07-6]methyl 5-bromopyrrole-2-carboxylate</strong> (340 mg, 1.7 mmol) in dry DMF (8 mL) was added sodium hydride (60% dispersion in mineral oil, 75 mg, 1 .9 mmol) portionwise under nitrogen. After 1 hour at 0 C a solution of 2-bromo-1-(4- methoxyphenyl)ethanone (500 mg, 2.2 mmol) in DMF (4 mL) was added. The resulting yellow solution was then stirred at room temperature for 2.5 hours. Saturated aqueous solution of NH4CI (30 mL) was added and the mixture extracted with EtOAc (100 mL). The organic layer was washed with brine (35 mL), dried (MgS04), filtered and concentrated in vacuo to give a liquid that was purified by flash chromatography (Biotage SP4, 40 g silica cartridge, 0 to 50% EtOAc gradient in hexanes) to give methyl 5-bromo-1 -[2-(4- methoxyphenyl)-2-oxoethyl]-1 H-pyrrole-2-carboxylate as a white solid (525 mg, yield 88%). 1H-NMR (400 MHz, CDCI3): delta 3.73 (s, 3 H), 3.90 (s, 3H), 5.89 (s, 2H), 6.33 (d, 1 H, J 4.1 Hz), 6.99-7.02 (m, 2H), 7.05 (d, 1 H), 7.99-8.02 (m, 2H).
69%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
A mixture of ethyl 5-bromo-lH-pyrrole-2-carboxylate (0.13 g, 0.64 mmol), 2-bromo- l-(4-methoxyphenyl)ethanone (160 mg, 0.69 mmol) and potassium carbonate (132 mg, 0.95 mmol) in N,N-dimethylformamide (4 mL) was stirred at room temperature overnight. At this time, the light brown reaction mixture was quenched with water. The resulting precipitate was collected by filtration and dried in vacuo. The resulting solid was dissolved in methylene chloride, concentrated in vacuo and then triturated with diethyl ether. The resulting solid was collected by filtration and dried in vacuo to afford 5-bromo-l-[2-(4-methoxy-phenyl)-2-oxo- ethyl]- lH-pyrrole-2-carboxylic acid methyl ester (155 mg, 69%) as light brown solid. 1H NMR (chloroform-;/) delta ppm 8.00 (d, J= 8.8 Hz, 2H), 6.96 - 7.07 (m, 3H), 6.85 (d, J= 1.8 Hz, 1H), 5.71 (s, 2H), 3.91 (s, 3H), 3.75 (s, 3H).
methyl 4-bromo-1-(2-(4-methoxyphenyl)-2-oxoethyl)-1H-pyrrole-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium tert-butylate; In N,N-dimethyl-formamide; at -15 - 20℃; for 1.25h;
Step 1: To a mixture of methyl 4-bromo-1 H-pyrrole-2-carboxylate (1 g, 4.9 mmol) and 2- bromo-1 -(4-methoxyphenyl)ethanone (1.23 g, 5.3 mmol) in DMF (30 mL) was added potassium ie f-butoxide (0.60 g, 5.4 mmol) portionwise at -15 C. The mixture was stirred at that temperate for 15 minutes and then at room temperature for 1 hour. The mixture was quenched with aqueous HCI (1 M) and then extracted with EtOAc (3 x 100 mL). The organic layers were washed with brine, water and then concentrated in vacuo to give a liquid. This was azeotroped with toluene to give a residue corresponding to methyl 1-[2-(4- methoxyphenyl)-2-oxoethyl]-1 H-pyrrole-2-carboxylate. ESI-MI m/z [M+H]+ 353.8. The crude was used in the next step without purification
Step 1: To a solution of ethyl 4-nitro-1 /-/-pyrrole-2-carboxylate (884 mg, 4.8 mmol) in DMF (1 1 ml) was added NaH (60percent dispersion in mineral oil, 190 mg, 4.8 mmol) at 0 °C. After 5 min the reaction mixture was added to a solution of 2-bromo-1-(4-methoxy-phenyl)-ethanone (1 g, 4.4 mmol) at 0 °C and the resultant mixture was allowed to warm to room temperature. After one hour the LCMS analysis showed the presence of the desired product and the complete consumption of the bromo-ketone stating material was confirmed by TLC(EtOAc/Hexanes 1 :1 ). An aqueous solution of HCI (1 M) was then added until a white precipitate appeared. Water was added and the white solid filtrated, rinsed with water and dried in vacuo to give ethyl 1-[2-(4-methoxyphenyl)-2-oxoethyl]-4-nitro-1 /-/-pyrrole-2- carboxylate as a white solid (1 .32 g, yield 83percent). 1H-NMR (400 MHz, CDCI3): delta 1.29 (t, 3H, J 7.1 Hz), 3.90 (s, 3H), 4.22 (q, 2H, J 7.2 Hz), 5.77 (s, 2H), 6.98-7.20 (m, 2H), 7.50 (d, 1 H, J 1.8 Hz), 7.63 (d, 1 H, J 1.8 Hz), 7.95-8.00 (m, 2H).
General procedure: To a solution of 5-(4-substituted phenyl)-1,3,4-thiadiazole-2-amine 3a-l (0.01 mol) in 10 mLabsolute ethanol, the corresponding phenacyl bromide was added (0.02 mol). The mixture wasrefluxed for 18 h or more, depending of the reaction progress, monitored by TLC. After the reactionwas complete, the mixture was filtered and the solid hydrobromide was collected. The precipitatewas neutralized by aqueous sodium carbonate solution, filtered and purified by recrystallization or bycolumn chromatography to remove unwanted products. The purification method is indicated belowfor each individual compound.
General procedure: To prepare catalyst, 0.21 g of thiamine hydrochloride (0.6 mmol) was dissolved in 0.64 mL of water and added 2.4 mLof 95% ethanol (water : 95% ethanol = ~1:4). The solution was cooled in an ice bath, then added 0.40 mL of 3 M NaOH(1.2 mmol) dropwise with stirring in a manner such that thetemperature remained below 20 C. Intense yellow coloured solution changed to pale yellow solution of thiamine (thiazolium ion)/N-heterocyclic carbene (Scheme 1).47 In a 25-mL round bottom flask, a mixture of phenacylbromide 1 (2.5 mmol, 0.5 g in case of 1a) and thiamine (0.6 mmol, 25 mol %) in ethanol (4 mL) was stirred at room temperature for 15 min. Then, salicylaldehyde 2 (2.5 mmol, 0.26 mL in case of 2a) was added slowly and the mixture was stirred at room temperature until the reaction was completed (as monitored by TLC) (Table 3) . The reaction mixture was then poured into 20 mL of distilled water and extracted with ethyl acetate (3 × 10 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The resulting product isoflavone 3 was further purified either by recrystallizationor by column chromatography (Ethyl acetate:Hexane, 1:4v/v). All compounds were characterized by their mp and 1HNMR, 13CNMR and mass spectral data.
General procedure: To prepare catalyst, 0.21 g of thiamine hydrochloride (0.6 mmol) was dissolved in 0.64 mL of water and added 2.4 mLof 95% ethanol (water : 95% ethanol = ~1:4). The solution was cooled in an ice bath, then added 0.40 mL of 3 M NaOH(1.2 mmol) dropwise with stirring in a manner such that thetemperature remained below 20 C. Intense yellow coloured solution changed to pale yellow solution of thiamine (thiazolium ion)/N-heterocyclic carbene (Scheme 1).47 In a 25-mL round bottom flask, a mixture of phenacylbromide 1 (2.5 mmol, 0.5 g in case of 1a) and thiamine (0.6 mmol, 25 mol %) in ethanol (4 mL) was stirred at room temperature for 15 min. Then, salicylaldehyde 2 (2.5 mmol, 0.26 mL in case of 2a) was added slowly and the mixture was stirred at room temperature until the reaction was completed (as monitored by TLC) (Table 3) . The reaction mixture was then poured into 20 mL of distilled water and extracted with ethyl acetate (3 × 10 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The resulting product isoflavone 3 was further purified either by recrystallizationor by column chromatography (Ethyl acetate:Hexane, 1:4v/v). All compounds were characterized by their mp and 1HNMR, 13CNMR and mass spectral data.
5-hydroxy-3-(4-methoxyphenyl)-4H-1-benzopyran-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
General procedure: To prepare catalyst, 0.21 g of thiamine hydrochloride (0.6 mmol) was dissolved in 0.64 mL of water and added 2.4 mLof 95% ethanol (water : 95% ethanol = ~1:4). The solution was cooled in an ice bath, then added 0.40 mL of 3 M NaOH(1.2 mmol) dropwise with stirring in a manner such that thetemperature remained below 20 C. Intense yellow coloured solution changed to pale yellow solution of thiamine (thiazolium ion)/N-heterocyclic carbene (Scheme 1).47 In a 25-mL round bottom flask, a mixture of phenacylbromide 1 (2.5 mmol, 0.5 g in case of 1a) and thiamine (0.6 mmol, 25 mol %) in ethanol (4 mL) was stirred at room temperature for 15 min. Then, salicylaldehyde 2 (2.5 mmol, 0.26 mL in case of 2a) was added slowly and the mixture was stirred at room temperature until the reaction was completed (as monitored by TLC) (Table 3) . The reaction mixture was then poured into 20 mL of distilled water and extracted with ethyl acetate (3 × 10 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The resulting product isoflavone 3 was further purified either by recrystallizationor by column chromatography (Ethyl acetate:Hexane, 1:4v/v). All compounds were characterized by their mp and 1HNMR, 13CNMR and mass spectral data.
With potassium carbonate; In dimethyl sulfoxide; at 80℃; for 1h;
General procedure: A 4-mL screw capped reaction vial was charged successively with 2-mercaptonicotinic acid (100 mg, 0.65 mmol), phenacyl bromide (256 mg, 1.30 mmol) and potassium carbonate (180 mg, 1.30 mmol) in 2 ml DMSO. The solution was shaked at 80 C for 1 h. Complete disappearance of 2-mercaptonicotinic acid in LCMS confirms the completion of reaction. Upon completion of the reaction, the mixture was quenched with few drops of conc. HCl and 10 mL water. The mixture was extracted with DCM (3 10 mL), and the combined extract was dried with sodium sulfate and concentrated. The solid product obtained after the evaporation of solvent was further purified by filtration and washing with acetone. The combined yield of the isolated product 2a was 90%.
2-(2-(4-methoxyphenyl)-2-oxoethoxy)anthracene-9,10-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
General procedure: General Procedure. 2-Hydroxyanthraquinone (4)/2-hydroxyxanthone (5)/2-hydroxycarbazole(6) (10 mmol), K2CO3 (10 mmol), and dry N,N-dimethylformamide (DMF) (50 mL) were stirred at room temperature (r.t.) for 30 min. To this soln. was added 2-(bromoacetyl) naphthalene/different substituents 2-bromoacetophenone (10 mmol) in dry DMF (10 mL) in one portion. The resulting mixture was stirred at r.t. for 24 h (TLC monitoring)and then poured into ice-water (100 mL). The yellow solid thus obtained was collected and purified by column chromatography on silica gel using CH2Cl2/MeOH 20:1. The proper fractions were combined and evaporated to furnish a residual solid which was crystallized from Et2O and CH2Cl2.
General procedure: Absolute EtOH (20 mL), ketoacid (10 mmol), 0.2 g activated KSF, and thiosemicarbazide(10 mmol) were added to a 100-ml round-bottom flask equipped withcondenser and magnetic stir bar. The reaction mixture was refluxed for the requiredreaction time (about 7 h). The progress of reaction was monitored by thin-layer chromatography(TLC) (EtOAc-petroleum ether 2:1). After completion of the reaction,phenacyl bromide (10 mmol) was added and refluxed for the required reaction time(about 2 h). The progress of the reaction was monitored by TLC (EtOAc-petroleumether 1:2). The catalyst was removed by filtration. The reaction solution was cooledto rt. The product was isolated by filtration and purified by washing with EtOH.
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 1.75h;
Step 1 [0263] N,N-dimethylformamide (23 mL) was added to <strong>[13466-43-8]3-bromopyridin-2-ol</strong> (V-4) (2.0 g, 11.49 mmol) and cesium carbonate (4.49 g, 13.79 mmol), and then compound (II-2) (2.90 g, 12.64 mmol) was added, and the resultant mixture was stirred for 1.75 hours at room temperature. Water was added to the reaction solution, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resultant product was purified by silica gel column chromatography to obtain compound (IV-53) (amount 2.09 g, yield 56%).
56%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 1.75h;
Step 1 N,N-dimethylformamide (23 mL) was added to <strong>[13466-43-8]3-bromopyridin-2-ol</strong> (V-4) (2.0 g, 11.49 mmol) and cesium carbonate (4.49 g, 13.79 mmol), and then compound (II-2) (2.90 g, 12.64 mmol) was added, and the resultant mixture was stirred for 1.75 hours at room temperature. Water was added to the reaction solution, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resultant product was purified by silica gel column chromatography to obtain compound (IV-53) (amount 2.09 g, yield 56%).
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3.5h;
Step 1 [0101] Cesium carbonate (745 mg, 2.3 mmol) and 4'-methoxyphenacyl bromide (II-2) (500 mg, 2.2 mmol) were added to a solution of compound (III-1) (227 mg, 2.1 mmol) in N,N-dimethylformamide (10 mL), and the resultant mixture was stirred for 3.5 hours at room temperature. Water was added under ice cooling to stop the reaction, and then the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over magnesium sulfate. The solvent was removed under reduced pressure to obtain compound (IV-2) (amount 440 mg, yield 82%) as a light yellow solid.
82%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3.5h;
Cesium carbonate (745 mg, 2.3 mmol) and 4?-methoxyphenacyl bromide (II-2) (500 mg, 2.2 mmol) were added to a solution of compound (III-1) (227 mg, 2.1 mmol) in N,N-dimethylformamide (10 mL), and the resultant mixture was stirred for 3.5 hours at room temperature. Water was added under ice cooling to stop the reaction, and then the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over magnesium sulfate. The solvent was removed under reduced pressure to obtain compound (IV-2) (amount 440 mg, yield 82%) as a light yellow solid.
5-(4-methoxyphenyl)-2-(4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
In ethanol; at 80 - 85℃; for 24h;
General procedure: 4.2.3.1. 6-(4-Chlorophenyl)-2-methyl imidazo[2,1-b][1,3,4]thiadiazole(3a). A mixture of 2a (2 g, 17.39 mmol) and 4-chloro phenacyl bromide (4.032 g, 17.39 mmol) was refluxed in dry ethanol (20 mL)for 24 h. The excess of solvent was removed under reduced pressureand the solid hydrobromide salt was suspended in water, and neutralized by the aqueous sodium carbonate solution to get free base. It was then filtered, washed with water, dried, and recrystallized from ethanol to get compound 3a as light yellow solid. Yield: 3.4 g, 80%
2-(2-chlorophenyl)-5-(4-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
In ethanol; at 80 - 85℃; for 24h;
General procedure: 4.2.3.1. 6-(4-Chlorophenyl)-2-methyl imidazo[2,1-b][1,3,4]thiadiazole(3a). A mixture of 2a (2 g, 17.39 mmol) and 4-chloro phenacyl bromide (4.032 g, 17.39 mmol) was refluxed in dry ethanol (20 mL)for 24 h. The excess of solvent was removed under reduced pressureand the solid hydrobromide salt was suspended in water, and neutralized by the aqueous sodium carbonate solution to get free base. It was then filtered, washed with water, dried, and recrystallized from ethanol to get compound 3a as light yellow solid. Yield: 3.4 g, 80%
6-(4-methoxyphenyl)-2-m-tolylimidazo[2,1-b][1,3,4]thiadiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
In ethanol; for 24h;Reflux;
General procedure: A mixture of equimolar quantities of <strong>[76074-47-0]5-m-tolyl-1,3,4-thiadiazol-2-amine</strong> 8 (0.01mol) and substituted phenacyl bromides (0.01mol) was refluxed in dry ethanol (50mL) for 24h. The excess of solvent was distilled off and the solid hydrobromide salt that separated out was collected by filtration, suspended in water and neutralized by sodium carbonate to get free base 9(a-i). The product was filtered, washed with water, dried and crystallized from carbon tetrachloride.
2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-7-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
With sodium hydrogencarbonate; In methanol; for 4h;Reflux;
Example 12-(4-Methoxyphenyl)imidazo[1,2-a]pyridin-7-amineA microwave vial was charged with <strong>[461-88-1]pyridine-2,4-diamine</strong> (400 mg, 3.67 mmol), 2-bromo-1-(4- methoxyphenyl)ethanone (882 mg, 3.85 mmol), sodium bicarbonate (329 mg, 3.92 mmol) and methanol (3.5 mL). The reaction mixture was stirred at reflux for 4 h. The reaction mixture was cooled to room temperature, diluted with water and ethyl acetate, sonicated and stirred at room temperature for -15 min. The suspension was filtered, rinsed with water and ethyl acetate. Theresulting pale yellow solid was put under high vacuum to afford 2-(4- methoxyphenyl)imidazo[l,2-a]pyridin-7-amine hydrobromide. It was suspended in ~5 mL saturated aqueous NaHCO3 solution, sonicated, filtered and rinsed with water. The residue was suspended in ~5 mL aqueous 2M NaOH- solution, sonicated, filtered and rinsed with water. The resulting residue was put under high vacuum to afford the title compound as a light brown solid (310 mg, 1.3 mmol, 35 % yield). MS m/z: 240.1 [M+H]+.
With triethylamine; In 1,4-dioxane; for 72h;Reflux; Inert atmosphere;
General procedure: The starting materials 1 and 2 (10 mmol each) were mixed with 40 ml of 1, 4-dioxane. Et3N (10 mmol), was added all at once at room temperature. The reaction was stirred vigorously to ensuremixing, and subsequently refluxed at high heat. Note: Thick slurry might form initially at the bottom of theflask. Regardless, continue heating at reflux for the indicated amount of time, to ensure completion of the reaction. The reaction mixture was removed from the heat and allowed to reach room temperature. It was evaporated under vacuum to remove the solvent. The residue was quenched with 50 ml of cold water, andmaintained at room temperature for one hour. Subsequently, it was stirred vigorously until a fine precipitate was formed. The precipitate was filtered under vacuum, washed well with 3 x 50 ml of water, and dried under vacuum overnight. In most cases, this procedure gives a product that is pure for all practical synthetic and analytical purposes. Procedures for 3k and 3l required chromatographic purification, and are described indetails.
7-(2-(4-methoxyphenyl)-2-oxoethoxy)-4-(trifluoromethyl)-2H-chromen-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With triethylamine; In tetrahydrofuran; at 20℃; for 24h;
General procedure: The appropriate bromoketone (6a-o) (1.7 mmol) and triethylamine (1.6 mmol) were added to as olution of either7-hydroxy-4-methyl-2H-chromen-2-one 4 (1.4 mmol)or <strong>[575-03-1]7-hydroxy-4-(trifluoromethyl)-2H-chromen-2-one</strong> 5 (1.4 mmol) in THF (20 mL). The mixture was stirred at room temperature for 24h, filtered and the solvent was evaporated under reduced pressure.The solid residue was purified by column chromatography eluting with DCM/MeOH 9:1 to afford (7a-n) and (8a-o).
tert-butyl 4-(4-(4-methoxyphenyl)thiazol-2-yl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In 1,4-dioxane; at 90℃; for 20h;
Example 5, Step 1, 1.0 g, 4.0 mmol) in dioxane (20 mL), triethyl amine (0.6 mL, 8.3 mmol) and 2- bromo-1-(4-methoxyphenyl)ethan-1-one (1.2 g, 5.3 mmol) was added at rt and stirred at 90 C for 20 h. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 25 mL). The organic layer was separated, dried over anhydrous Na2SO4. After evaporation of the solvents, the resulting crude product was taken as such for the next step. Yield: 53% (0.8 g, pale yellow liquid).
With triethylamine; In 1,4-dioxane; at 90℃; for 20h;
To a stirred solution of <strong>[196811-66-2]tert-butyl 4-carbamothioylpiperazine-1-carboxylate</strong> (synthesized according to Example 5, Step 1, 1 .0 g, 4.0 mmol) in dioxane (20 mL), triethyl amine (0.6 mL, 8.3 mmol) and 2-bromo-1-(4-methoxyphenyl)ethan-1-one (1.2 g, 5.3 mmol)was added at rt and stirred at 90 C for 20 h. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2 x 25 mL). The organic layer was separated, dried over anhydrous Na2504. After evaporation of the solvents, the resulting crude product was taken as such for the next step. Yield: 53% (0.8 g, pale yellow liquid).
2-(3,4-dimethoxybenzyl)-6-(4-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
In ethanol;Reflux;
General procedure: In a two-necked flask, 2-amino-1,3,4-thiadiazole derivatives2a-b (0.004 mol) were dissolved in absolute ethanol (30mL). Phenacyl bromide derivatives 3a-i (0.04 mol) werealso dissolved in absolute ethanol (20 mL) and then addeddrop by drop to this solution at room temperature with theassistance of a dropping funnel. The mixture was thenrefluxed and stirred for 12-16 h. The progress of reactionwas monitored by thin layer chromatographyat appropriatetime intervals. The excess solvent was removed underreduced pressure and neutralized by an aqueous sodiumcarbonate (Na2CO3) solution. The solution was filtered andwashed with deionized water. The solid matter wasrecrystallized from acetone. The synthesized compoundswere dried with P2O5 in a vacuum oven. The physicalproperties and spectral data derived from the obtainedproducts are listed below.
2-(4-methoxy-phenyl)-5,6,7,8-tetrahydroimidazo[2,1-b]benzothiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
23%
In ethanol; at 150℃; for 0.333333h;Microwave irradiation;
46.3 mg (0.3 mmol) of 4,5,6,7-tetrahydrobenzo [d] thiazol-2-amine 68.7 mg (0.3 mmol) of 2-bromo-4'-methoxyacetophenone were dissolved in 3 ml of ethanol and stirred in a microwave reactor at 150 C for 20 minutes. The residue was concentrated under reduced pressure and subjected to column chromatography (EtOAc: Hex = 1: 5) to obtain Compound 2d (19.8 mg, 23%).
With triethylamine; In tetrahydrofuran; at 20℃; for 24h;Inert atmosphere;
General procedure: A substituted 2-bromoketone (1mmol) and a substituted phenylacetic acid (1mmol) were dissolved in dry THF (15mL) and triethylamine (1mmol) under Ar. The reaction mixture was stirred for 24h at room temperature; sodium hydride (60% oil suspension, 1mmol) was then added, and the resultant mixture stirred for 1h. Finally, concentrated aqueous hydrochloric acid was added (to adjust pH to approx. 1), and the mixture stirred for 15min. The reaction mixture was quenched with water (15mL), and extracted with ethyl acetate (3×20mL). The organic layers were dried over sodium sulfate, and concentrated under reduced pressure. The product was purified by column chromatography using hexane: ethyl acetate 7:3 mixture as a mobile phase.
7-(4-methoxyphenyl)imidazo[2,1-c][1,2,4]triazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With potassium carbonate; In ethanol; for 4h;Inert atmosphere; Reflux;
Under an argon atmosphere, <strong>[1120-99-6]3-amino-1,2,4-triazine</strong> (100mg, 1,04mmol) and K2CO3 (173mg, 1,25mmol) were added to a solution of 2-bromo(substituted)acetophenone (1,14mmol) in EtOH (2mL). The resulting solution was heated to reflux for 4h and then cooled down to r.t. After concentration under reduced pressure, the residue was diluted with CH2Cl2 (10mL), the CH2Cl2 layer was washed with H2O (2×10mL), and dried (MgSO4). After filtration and concentration under reduced pressure, the crude was purified by flash chromatography on silica gel (EtOAc-PE, 1:9 to 4:6). 4.2.1 7-(4-Methoxyphenyl)imidazo[2,1-c][1,2,4]triazine (1) The product 1 was prepared following the General Procedure for the preparation of compounds 1-8 with 2-bromo-4?-acetophenone (262mg, 1.14mmol). Yellow solid (214mg, 91%), mp: 122-124C; 1H NMR (400MHz, CDCl3) delta 8.36 (d, J=2.0Hz, 1H), 8.27 (d, J=2.0Hz, 1H), 8.17 (s, 1H), 8.00 (d, J=8.9Hz, 2H), 6.99 (d, J=8.9Hz, 2H), 3.86 (s, 3H); 13C NMR (101MHz, CDCl3) delta 160.8, 148.5, 142.8, 140.6, 137.6, 127.9 (2C), 125.3, 114.5 (2C), 110.0, 55.5; HRMS (ESI): calcd. for C12H11N4O 227.09274 [M+H]+ found 227.09292 [M+H]+.
1-(2-(4-methoxyphenyl)-2-oxoethyl)-1H-pyrrole-2-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In acetonitrile; at 20℃; for 12h;
To a cold solution of hydroxylamine hydrochloride (0.38 g, 5.5 mmol, 1.1 equiv.) in anhydrous acetonitrile (50 mL), triethylamine (0.77 mL, 5.5 mmol, 1.1 equiv.) and 1H-pyrrole-2-carboxaldehyde (5.0 mmol, 1.0 equiv.) were added and stirred for around 30 mins. Then phthalic anhydride (0.75 g, 5.05 mmol, 1.01 equiv.) was slowly added under nitrogen protection. The resulting mixture was stirred at 80 C for about 8 h. After concentration, the resulting residue was added cold CH2Cl2 (30 ml × 3) and stirred. The combined filtrates were washed with 5% ammonia water to remove phthalic acid completely. The separated organic layer was dried over anhydrous Na2SO4, and then concentrated under reduced pressure. Finally the residue was purified by passing it through a short silica gel column using CHCl3 as eluent to give pure <strong>[4513-94-4]1H-<strong>[4513-94-4]pyrrole-2-carbonitrile</strong></strong> as yellow oil (80%).3 A mixture of <strong>[4513-94-4]1H-<strong>[4513-94-4]pyrrole-2-carbonitrile</strong></strong> (3.0 mmol, 1.0 equiv.), substituted methyl bromide (3.3 mmol, 1.1 equiv.) and K2CO3 (3.6 mmol, 1.2 equiv.) was stirred in CH3CN (20 mL) at room temperature. After being stirred for 12 h, the reaction mixture was concentrated under reduced pressure, diluted with EtOAc (30 mL), and washed with H2O (30 mL). The water layer was extracted with EtOAc (30 mL) one more time. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane: EtOAc = 10:1) to afford 1b as white solid.
methyl 8-methoxy-3-(4-methoxybenzoyl)-2-(trifluoromethyl)pyrrolo[2,1-a]isoquinoline-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
General procedure: Under air, isoquinoline derivatives 1 (2.0 mmol) and bromoacetyl derivatives 2 (2.2 mmol) were mixed and stirred in THF (5 mL) at r.t. for 4 h; then THF was removed under vacuum and EtOH (5 mL), methyl perfluoroalk-2-ynoates 3 (1.0 mmol), and DIPEA (1.0 mmol) were added. The resulted mixture continued to be stirred at r.t. for another 7 h. EtOH was removed as before and the residue was purified by column chromatography on silica gel by eluting with petroleum ether / ethyl acetate 20:1) to afford the desired product 4.