* 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 pyridine; boron trifluoride diethyl etherate In N,N-dimethyl-formamide at 75℃; for 1.5 h; Stage #2: With phosphorus pentachloride In N,N-dimethyl-formamide at 55℃; for 0.5 h;
In the first reaction flask, resorcinol (0.72 g, 6.5 mmol), p-nitrophenylacetic acid (1.0 g, 6.0 mmol), BF 3 / Et 2 O (10 mL) was added and stirred at 75 ° C Reaction for 90 min. The reaction was completed, cooled to below 10 ° C, and DMF (10 mL) was added slowly with stirring. (0.72g6.5mmol)(1.0g6.0mmol)BF 3 /Et 2 O(10mL)75°C90min 10°CDMF(10mL) In a second reaction flask, DMF (20 mL) was added, cooled to below 10 ° C, and PCl 5 (2.0 g, 9 mmol) was added portionwise and stirred at 55 ° C for 30 min. The reaction was completed, cooled to below 10 ° C, slowly added to the first reaction flask, room temperature reaction 1h. After completion of the reaction, the reaction solution was poured into hot dilute hydrochloric acid (0.1 N) with stirring, and the solid was precipitated, suction filtered, washed with water and dried. The crude product was recrystallized from methanol to give 0.36 g of product, yield 16.4percent. MS (ESI): m / z = 284 [M + H] & lt; + & gt ;.
Stage #1: at 85℃; for 1.5 h; Stage #2: at 10 - 25℃; for 2 h;
4.1.2 7-Hydroxy-3-(4-nitrophenyl)-4H-benzopyran-4-one (9) A mixture of 4-nitrophenylacetic acid (7; 1.0 g, 6.0 mmol), resorcinol (8; 0.72 g, 6.5 mmol) and BF3/Et2O (10 ml) was heated at 85 °C for 1.5 h with stirring, then cooled down to 10 °C and 10 ml DMF was added slowly. In another flask, 10 ml DMF was added and cooled to 10 °C, PCl5 (2.0 g, 9 mmol) was added in batches, afterwards the mixture was heated to 55 °C and stirred for 0.5 h, after that cooled to 10 °C. Then the mixture was added by droplet into the first flask and stirred at 25 °C for 2 h. Then the reaction mixture was poured into heated dilute hydrochloric acid (0.5 mol/L). The product was filtered, and purified by recrystallization from methanol to yield 9 (0.36 g, 1.26 mmol, 21percent) as a white solid. 1H NMR (DMSO, 300 MHz): δ 8.48 (s, 1H, H-2), 8.28 (2H, J = 8.8 Hz, H-3', H-5'), 8.07 (d, 1H, J = 8.8 Hz, H-5), 7.96 (d, 2H, J = 8. 8 Hz, H-2', H-6'), 7.05 (dd, 1H, J = 8.8, 2.4 Hz, H-6), 6.97 (d, 1H, J = 2.4 Hz, H-8); MS (ESI): m/z = 282 [M-H]-.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 15, p. 4428 - 4433
3
[ 104-03-0 ]
[ 19733-56-3 ]
Reference：
[1] Patent: CN106883166, 2017, A,
4
[ 104-03-0 ]
[ 25026-34-0 ]
Reference：
[1] Biochemische Zeitschrift, 1910, vol. 27, p. 102
5
[ 104-03-0 ]
[ 100-27-6 ]
Yield
Reaction Conditions
Operation in experiment
96.5%
With lithium aluminium tetrahydride In diethyl ether at 50℃; for 3 h; Inert atmosphere
(1) Dissolve p-nitrophenylacetic acid in ether.Heat to 50°C under nitrogen protectionAfter adding lithium aluminum hydride and mixing evenly,Add water, continue stirring for 3h,After the reaction is completed,Reduce the temperature to 0 °C,Add sodium hydroxide solution and water,The concentration of sodium hydroxide solution is 12percent.After standing for 20 minutes, warm to room temperature and add anhydrous MgSO4.After stirring for 30min,The solvent in the filtrate is distilled off,Obtained p-nitrophenyl ethanol;(2) dissolving the obtained p-nitrophenyl ethanol in ethanol,The catalyst was added, nitrogen was introduced, and the temperature was raised to 80°C.Hydrogen gas is introduced under atmospheric pressureStir the reaction for 3h,Filter after cooling,Ethanol is distilled,After the resulting solid is recrystallized,Obtained p-aminophenyl ethanol;The catalyst is a mixture of CeO2, MnO, and ZnO.The mass ratio of lithium aluminum hydride used in step (1) to p-nitrophenylacetic acid is 1:2; the volume of water added dropwiseThe mass ratio to lithium aluminum hydride is 1:1; the mass ratio of sodium hydroxide to lithium aluminum hydride is 3:2 and the second additionThe mass ratio of water to lithium aluminum hydride is 5:2.The catalyst in step (2) is a mixture of CeO2, MnO and ZnO in a mass ratio of 1:2:5;The mass ratio of nitrobenzene ethanol is 3:167. The step (1)
Reference：
[1] Patent: CN108033888, 2018, A, . Location in patent: Paragraph 0019-0057
[2] European Journal of Organic Chemistry, 2011, # 17, p. 3178 - 3183
[3] Journal of Medicinal Chemistry, 1990, vol. 33, # 11, p. 3008 - 3014
[4] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1992, # 1, p. 109 - 114
[5] Patent: WO2004/29066, 2004, A2, . Location in patent: Page/Page column 302
[6] Patent: WO2007/18941, 2007, A2, . Location in patent: Page/Page column 63
[7] Synthesis, 2011, # 18, p. 2935 - 2940
[8] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 2, p. 131 - 134
6
[ 104-03-0 ]
[ 19910-33-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 1994, vol. 37, # 11, p. 1704 - 1711
7
[ 104-03-0 ]
[ 5339-26-4 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1992, # 1, p. 109 - 114
8
[ 104-03-0 ]
[ 1798-06-7 ]
Reference：
[1] Journal of the Chemical Society, 1934, p. 161,164
9
[ 104-03-0 ]
[ 1197-55-3 ]
Yield
Reaction Conditions
Operation in experiment
97.6%
With iron(III) chloride; hydrazine hydrate In water at 90℃; for 1 h; Inert atmosphere
The preparation method of p-aminophenylacetic acid comprises the following steps: mixing water, ferric chloride and p-nitrophenylacetic acid,Heating to 90 ° C in a nitrogen atmosphere, dropping hydrazine hydrate solution, incubating for 1 hour, cooling to 5 ° C, filtering the filter cake,Washing and drying to obtain p-aminophenylacetic acid, wherein the weight ratio of water, iron chloride, p-nitrophenylacetic acid and hydrazine hydrate is 10: 0.2:1: 1, where the amount of water used to wash the filter cake is not taken into account.
Reference：
[1] ChemCatChem, 2014, vol. 6, # 11, p. 3153 - 3159
[2] Patent: CN106083631, 2016, A, . Location in patent: Paragraph 0017; 0023; 0024
[3] Tetrahedron Letters, 1984, vol. 25, # 32, p. 3415 - 3418
[4] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1985, vol. 24, p. 1185
[5] Journal of the Chemical Society, 1934, p. 161,164
[6] Organic Syntheses, Coll. Vol. 1 <New York 1932>, S. 44,
[7] Journal of the Chemical Society, 1880, vol. 37, p. 91
[8] Chemische Berichte, 1869, vol. 2, p. 209[9] Chemische Berichte, 1870, vol. 3, p. 648
[10] Journal of the American Chemical Society, 1917, vol. 39, p. 1437
[11] Journal of the American Chemical Society, 1921, vol. 43, p. 180
[12] Journal of Organic Chemistry, 1963, vol. 28, p. 2347 - 2350
[13] J. Gen. Chem. USSR (Engl. Transl.), 1964, vol. 34, p. 1474 - 1477[14] Zhurnal Obshchei Khimii, 1964, vol. 34, # 5, p. 1469 - 1473
[15] Australian Journal of Chemistry, 1967, vol. 20, p. 1413 - 1428
[16] Patent: US2011/288329, 2011, A1, . Location in patent: Page/Page column 2
[17] European Journal of Medicinal Chemistry, 2015, vol. 94, p. 284 - 297
[18] Patent: CN106380413, 2017, A, . Location in patent: Paragraph 0012; 0013
10
[ 104-03-0 ]
[ 5438-70-0 ]
Reference：
[1] Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9199 - 9221
[2] European Journal of Medicinal Chemistry, 2015, vol. 94, p. 284 - 297
[3] ChemMedChem, 2018, vol. 13, # 1, p. 30 - 36
Reference：
[1] Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9199 - 9221
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 13, p. 5287 - 5307
13
[ 104-03-0 ]
[ 61367-39-3 ]
[ 76325-96-7 ]
Reference：
[1] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1980, vol. 29, p. 1689 - 1694[2] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1980, # 10, p. 2374 - 2379
14
[ 64-17-5 ]
[ 104-03-0 ]
[ 76308-26-4 ]
Yield
Reaction Conditions
Operation in experiment
40%
Stage #1: With hydrogen In water at 44 - 58℃; Inert atmosphere; Autoclave; Industry scale Stage #2: With hydrogenchloride In waterReflux; Industry scale
Preparation of trans 4-amino-cyclohexyl-acetic acid ethyl ester HClA 2500 1 enamelled autoclave is charged with 1000 kg of deionizated water and 210 kg (1.16 kM) of 4-nitrophenyl-acetic acid at room temperature under nitrogen atmosphere. After inertisation by nitrogen to the mixture obtained a suspension of 21 kg of 10percent Pd/C in 20 kg of deionized water is added and the catalyst measuring gauge is rinsed by additional 20 kg of deionizated water. After rinsing the reaction vessel by hydrogen gas the hydrogenation is carried out at a temperature between 44-46°C and under up to 0,6 bar overpressure until the hydrogen uptake is slowed. After reducing the nitro group the temperature is brought to 55- 58°C and the hydrogenation continued maintaining hydrogen pressure on max. 4.0 bar overpressures. After completion of the hydrogen uptake, the mixture is cooled to a temperature between 25-30°C, purged with nitrogen and the catalyst is filtered on a Spakler filter under pressurized nitrogen. The reaction vessel, the filter and the lines are washed additional 200 g of deionized water. The filtrates are combined and in a 2500 1 enamelled doubler 1200 kg of distillate is distilled at up to 80°C inner temperature in vacuum. The residue obtained is cooled to a temperature below 30°C and 430 kg of ethyl alcohol is added, then 500 1 of distillate is collected at up to 80°C under vacuum. After completion of the distillation the mixture is cooled to a temperature between 25-30°C, (water content is max. 10 wpercent, in terms of absolute value is about 32 kg), and 550 kg of ethyl alcohol, then 170 kg of 30percent hydrochloric ethyl alcohol are added and the reaction mixture is heated to reflux for approx. 2 hours. When the esterification is complete 800 1 of solvent is distilled off at up to 80°C, under vacuum. Additional 800 1 of ethyl alcohol is added and further 750-800 1 of solvent is distilled off at up to 80°C, under vacuum. To the residue obtained 700 kg of acetonitrile is added and 140 1 of distillate is collected at up to 80°C under vacuum. The vacuum is stopped by introducing nitrogen and the solution is cooled to a temperature between 0-(-)5°C. The crystals obtained is centrifuged, washed with 100 kg of acetonitrile in two portions during which the temperature is kept at 0-(-)5°C. The solid obtained is dried to a constant weight at up to 6O0C. In this manner 90 kg of title product is obtained. Yield: 40 percent. Melting point: 173-1760C.
Reference：
[1] Patent: WO2010/70368, 2010, A1, . Location in patent: Page/Page column 4
[2] Bulletin of the Academy of Sciences of the USSR, Division of Chemical Science (English Translation), 1980, vol. 29, p. 1689 - 1694[3] Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1980, # 10, p. 2374 - 2379
15
[ 110-91-8 ]
[ 104-03-0 ]
[ 144-55-8 ]
[ 262368-47-8 ]
Reference：
[1] Patent: US2003/199478, 2003, A1,
16
[ 104-03-0 ]
[ 890839-11-9 ]
Reference：
[1] Green Chemistry, 2017, vol. 19, # 20, p. 4798 - 4803
Compound 9-1 was refluxed in a solution of HCl in MeOH (500 ml) for 12 h, and then the resulting solution was concentrated to give compound 9-2 (brown solid, 53 g, Yield 100%). 1H NMR (400 MHz, CDCl3): delta ppm 8.21 (d, J=8 Hz, 2H), 7.48 (d, J=8 Hz, 2H), 3.77 (s, 2H), 3.75 (s, 3H).
98%
With thionyl chloride; at 0 - 23℃; for 2.16667h;
Step 1 : To a stirred MeOH (100 mL) solution of 2-(4-nitrophenyl)acetic acid (10.0 g, 55.202 mmol, 1 .0 eq) SOCl2 (6.7 mL, 1 10.045 mmol, 2.0 eq) was added at 0C for 10 min and the mixture was stirred at RT for 2 h, then excess of SOCl2 was removed under vacuum and the residue was dissolved in EtOAC (50 mL), washed with water, sat. (aq) NaHCO3, dried (Na2SO4) and the solvent was evaporated to get methyl 2-(4-nitrophenyl)acetate (10.5g, 98%, solid; TLC system: EtOAc/PE (3:7), Rf: 0.60).
97%
With sulfuric acid; for 18h;Inert atmosphere; Reflux;
(a) Synthesis of (4-nitro-phenyl)-acetic acid methyl ester To 4-nitrophenyl acetic acid (50.12 g, 276 mmol) dissolved in methanol (300 mL) was added concentrated sulfuric acid (8 mL). The reaction mixture was stirred at reflux for 18 h under nitrogen atmosphere. The methanol was removed in vacuo and the resulting residue was diluted with H2O. The reaction mixture was extracted two times with CH2Cl2, and then washed with 0.5% NaHCO3. The organic phase was dried over Na2SO4, filtered, and concentrated by rotary evaporation. The resulting solid was dried under vacuum for about 10-19 h. The title compound as pale yellow solid was used as such with no further purification (52.2 g, 97% yield).1H NMR (300 MHz, CDCl3, TMS): delta 3.72 (s, 3H), 3.74 (s, 2H), 7.43 to 7.48 (m, 2H), 8.17-8.21 (m, 2H).LC-MSD (ES+): (m/z) 196 [(M+H)+, 100].
97%
With sulfuric acid; for 3h;Reflux;
A single-neck RBFequipped with a magnetic stirrer and a reflux condenser was charged sequentiallywith 4-nitrophenyl acetic acid (1, 60.88 g, 336.08 mmol), MeOH (360 mL) and concentrated sulfuricacid (2.5 mL). The solution was heated to reflux for 3 h. After evaporation invacuo, the resulting residue was dissolved in ether (350 mL). The ether solution was then washed withsaturated sodium bicarbonate solution (50 mL x 2) and brine (50 mL x 2), driedover magnesium sulfate and filtered. The filtrate was concentrated under vacuumto afford white crystals as compound 2(63.80 g, 97%).
97%
With sulfuric acid; for 12h;Reflux;
S1. Add 626 g of methanol to a 1000 mL four-necked flask with a reflux condenser, and slowly add 67.5 g of concentrated sulfuric acid.And 414 g of p-nitrophenylacetic acid was heated to reflux for 12 h.S2. The above reaction solution was cooled to room temperature, poured into a 2000 mL beaker containing 72.2 g of sodium carbonate and 672 g of water, drained, washed with water until the wash was neutral.After draining and drying, methyl p-nitrophenylacetate (434 g, yield 97%, mp: 53-54 C) was obtained.
96%
With sulfuric acid; for 16h;Heating / reflux;
Methyl 2-(4-Nitrophenyl)acetate (1); A 1-L single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 4-nitrophenylacetic acid (14.1 g, 77.5 mmol), anhydrous methanol (130 mL) and concentrated sulfuric acid (12.0 mL, 216 mmol), and the reaction mixture was heated at reflux for 16 h. After this time, the reaction was concentrated to dryness under reduced pressure. The resulting residue was partitioned between water (500 mL) and diethyl ether (200 mL) and the layers separated. The aqueous phase was extracted with diethyl ether (100 mL). The combined organic phases were washed with saturated aqueous sodium carbonate and dried over magnesium sulfate, and the drying agent was removed by filtration. The filtrate was concentrated under reduced pressure and dried to a constant weight under vacuum to afford a 96% yield of 1 (14.6 g) as a white solid: mp 45-46 C.; 1H NMR (500 MHz, CDCl3) delta 8.19 (d, 2H, J=8.5 Hz), 7.46 (d, 2H, J=8.5 Hz), 3.75 (s, 2H), 3.73 (s, 3H). Reference: Tetrahedron 2002, 58, 10113.
96%
With sulfuric acid; for 16h;Reflux;
A l-L single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 2-(4-nitrophenyl)acetic acid (If) (14.1 g, 77.5 mmol), anhydrous methanol (130 mL) and concentrated sulfuric acid (12.0 mL, 216 mmol), and the reaction mixture was heated at reflux for 16 h. After this time, the reaction was concentrated to dryness under reduced pressure. The resulting residue was partitioned between water (500 mL) and diethyl ether (200 mL) and the layers separated. The aqueous phase was extracted with diethyl ether (100 mL). The combined organic phases were washed with saturated aqueous sodium carbonate and dried over magnesium sulfate, and the drying agent was removed by filtration. The filtrate was concentrated under reduced pressure and dried to a constant weight under <n="68"/>vacuum to afford a 96% yield of Ig (14.6 g) as a white solid: mp 45-46 0C; 1H NMR (500 MHz, CDCl3) 58.19 (d, 2H, J = 8.5 Hz), 7.46 (d, 2H, J = 8.5 Hz), 3.75 (s, 2H), 3.73 (s, 3H). Reference: Tetrahedron 2002, 58, 10113.
91%
With sulfuric acid; for 5h;Reflux;
To a solution of 4-nitrobenzene acetic acid (9.0?g, 50?mmol) in absolute methanol (60?mL), concentrated sulfuric acid (1?mL) was added. The reaction mixture was refluxed for 5?h. After the completion of the reaction, the residue was concentrated under vacuum, poured into deionized water (20?mL) and then extracted with ethyl acetate (3?*?10?mL). The organic layers were combined and washed with saturated aqueous NaCl (10?mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by silica gel column chromatography using ethyl acetate/hexane (1:8, v:v) as an eluent to afford 4 as yellow solid. Yield: 8.9?g (91%, 45.5?mmol). 1H NMR (400?MHz, CDCl3) delta [ppm]?=?8.21 (d, 3J(H,H)?=?8.8?Hz, 2H), 7.48 (d, 3J(H,H)?=?8.8?Hz, 2H), 3.76 (s, 2H), 3.75 (s, 3H). 13C NMR (100?MHz, CDCl3) delta [ppm]?=?170.6, 147.2, 141.3, 130.3, 123.8, 52.4, 40.8. GC-MS (M)+ calculated for C9H9NO4 195.05, found 195.0.
With sulfuric acid; for 3h;Reflux;
Concentrated sulfuric acid (1 mL) was added to a solution of 4-nitrophenylacetic acid (10.0 g, 55.2 mmol) in anhydrous MeOH and heated under reflux for 3 hours. After evaporation of solvent under reduced pressure the mixture was dissolved in ethyl acetate and washed sequentially with 5% sodium bicarbonate, water, and brine. The organic phase was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was solidified on standing at a temperature in the range of 15 C. to 40 C. to afford the title compound as a white solid.1HNMR (CDCl3, 300 MHz): delta 8.40 (d, J=9 Hz, 2H), 7.48 (d, J=9 Hz, 2H), 3.52 (s, 2H), 3.42 (s, 3H).LC-MSD (ES+): (m/z) 196 [(M+H)+, 100].
With sulfuric acid; for 2h;Reflux;
Example 101 Preparation of methyl 2-(4-nitrophenyl)acetate U [0385] A solution of 2-(4-nitrophenyl)acetic acid (10.0 g, 55.2 mmol) in methanol (50 mL) was treated with 18 M sulfuric acid (5 rriL) and the mixture stirred at reflux for 2 hours. After this time, the reaction was slowly cooled to 5C, let stand for 30 minutes and the resulting suspension filtered. The filter cake was washed with methanol and dried to a constant weight under vacuum to afford methyl 2-(4-nitrophenyl)acetate as an off-white solid: *H NMR (300 MHz, DMSO-i): delta 8.19 (d, 2H), 7.57 (d, 2H), 3.90 (s, 2H), 3.64 (s, 3H).
With thionyl chloride; for 3h;Reflux;
General procedure: To a mixture of LiAlH4 (15 mmol) in anhydrous THF (25 mL) in an ice-bath was added dropwise a solution of phenylacetic acids (15 mmol) in THF (8 mL). This mixture was stirred at room temperature for 30 min, and then heated to reflux for 4 h. After it was cooled to room temperature, water (0.5 mL) was added, and then NaOH (15%, 0.5 mL) and water (1.5 mL) were added in sequence. After stirring for another 30 min, the mixture was filtered, dried over anhydrous Na2SO4 and concentrated to give crude products. Pure phenylethyl alcohols were obtained in 50-85% yield by column chromatography. Alternative method: To a solution of phenylacetic acids (15 mmol) in MeOH (30 mL) was added SOCl2 (30 mmol). This mixture was heated to reflux for 3 h before evaporation. The residue was dissolved in DCM (30 mL), washed with aqueous NaHCO3, water and brine, dried over anhydrous Na2SO4, and concentrated to give 100% yield of crude methyl phenylacetates which were used to next step without further purification. To a solution of the methyl phenylacetates in THF (30 mL) was added NaBH4 (60 mmol). When the mixture was heated to gently reflux, MeOH (1.0 mL) was added dropwise from a syringe over 5 min. After refluxing for another 6 h, the mixture was cooled to room temperature and poured into 30 mL ice water, and extracted with EtOAc (30 mL × 2). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated to give crude products. Pure phenylethyl alcohols were obtained in 70-85% yield by column chromatography.
With sulfuric acid; for 2h;Reflux;
20 g (0.11 mol)Nitrobenzoic acid was dissolved in 300ml of methanol, 2ml of concentrated sulfuric acid was added,Plus warming to reflux, the reaction 2 hours. A portion of the solvent was distilled off under reduced pressure,The residue was added with saturated aqueous sodium bicarbonate to adjust the pH to 7-8, 200 ml of water was added and extracted with ethyl acetate (100 ml × 3). The combined organic phases were washed with brine (100 ml × 2), dried over anhydrous sodium sulfate, Concentration under reduced pressure gave 21.2 g of pale yellow needles. The crude product is used in the next step without purification.
With acetic anhydride; triethylamine for 0.0833333h; Microwave irradiation; Neat (no solvent);
52%
Stage #1: 4-nitrobenzeneacetic acid; salicylaldehyde With acetic anhydride; triethylamine at 90℃;
Stage #2: In diethyl ether at 20℃;
1 2.1.2.1 3-(4-Nitrophenyl)coumarin (9a)
General procedure: To a mixture of 2-hydroxybenzaldehyde (7a) [or 2-hydroxyacetophenone(7b), 2,3,4-trihydroxy benzaldehyde (7c), 2-hydroxy-4-methoxybenzophenone (7d) or 2-hydroxy- benzophenone (7e)] (7.4 mmol) and 4-nitrophenylacetic acid (8) (8 mmol) in aceticanhydride (3 ml) was added triethylamine (99%, 1 ml). The reactionmixture was then refluxed overnight at 90 C, allowed to coolto r.t. and 10 ml of ether was added with occasional stirring foranother 2-3 h to afford the desired product as a precipitate thatwas collected using vacuum filtration.
With piperidine at 130℃;
With acetic anhydride; triethylamine
at 220℃; Im geschlossenen Rohr;
With acetic anhydride; triethylamine Microwave irradiation;
Preparation of trans 4-amino-cyclohexyl-acetic acid ethyl ester HClA 2500 1 enamelled autoclave is charged with 1000 kg of deionizated water and 210 kg (1.16 kM) of 4-nitrophenyl-acetic acid at room temperature under nitrogen atmosphere. After inertisation by nitrogen to the mixture obtained a suspension of 21 kg of 10% Pd/C in 20 kg of deionized water is added and the catalyst measuring gauge is rinsed by additional 20 kg of deionizated water. After rinsing the reaction vessel by hydrogen gas the hydrogenation is carried out at a temperature between 44-46C and under up to 0,6 bar overpressure until the hydrogen uptake is slowed. After reducing the nitro group the temperature is brought to 55- 58C and the hydrogenation continued maintaining hydrogen pressure on max. 4.0 bar overpressures. After completion of the hydrogen uptake, the mixture is cooled to a temperature between 25-30C, purged with nitrogen and the catalyst is filtered on a Spakler filter under pressurized nitrogen. The reaction vessel, the filter and the lines are washed additional 200 g of deionized water. The filtrates are combined and in a 2500 1 enamelled doubler 1200 kg of distillate is distilled at up to 80C inner temperature in vacuum. The residue obtained is cooled to a temperature below 30C and 430 kg of ethyl alcohol is added, then 500 1 of distillate is collected at up to 80C under vacuum. After completion of the distillation the mixture is cooled to a temperature between 25-30C, (water content is max. 10 w%, in terms of absolute value is about 32 kg), and 550 kg of ethyl alcohol, then 170 kg of 30% hydrochloric ethyl alcohol are added and the reaction mixture is heated to reflux for approx. 2 hours. When the esterification is complete 800 1 of solvent is distilled off at up to 80C, under vacuum. Additional 800 1 of ethyl alcohol is added and further 750-800 1 of solvent is distilled off at up to 80C, under vacuum. To the residue obtained 700 kg of acetonitrile is added and 140 1 of distillate is collected at up to 80C under vacuum. The vacuum is stopped by introducing nitrogen and the solution is cooled to a temperature between 0-(-)5C. The crystals obtained is centrifuged, washed with 100 kg of acetonitrile in two portions during which the temperature is kept at 0-(-)5C. The solid obtained is dried to a constant weight at up to 6O0C. In this manner 90 kg of title product is obtained. Yield: 40 %. Melting point: 173-1760C.
With lithium aluminium tetrahydride; In diethyl ether; at 50℃; for 3h;Inert atmosphere;
(1) Dissolve p-nitrophenylacetic acid in ether.Heat to 50C under nitrogen protectionAfter adding lithium aluminum hydride and mixing evenly,Add water, continue stirring for 3h,After the reaction is completed,Reduce the temperature to 0 C,Add sodium hydroxide solution and water,The concentration of sodium hydroxide solution is 12%.After standing for 20 minutes, warm to room temperature and add anhydrous MgSO4.After stirring for 30min,The solvent in the filtrate is distilled off,Obtained p-nitrophenyl ethanol;(2) dissolving the obtained p-nitrophenyl ethanol in ethanol,The catalyst was added, nitrogen was introduced, and the temperature was raised to 80C.Hydrogen gas is introduced under atmospheric pressureStir the reaction for 3h,Filter after cooling,Ethanol is distilled,After the resulting solid is recrystallized,Obtained p-aminophenyl ethanol;The catalyst is a mixture of CeO2, MnO, and ZnO.The mass ratio of lithium aluminum hydride used in step (1) to p-nitrophenylacetic acid is 1:2; the volume of water added dropwiseThe mass ratio to lithium aluminum hydride is 1:1; the mass ratio of sodium hydroxide to lithium aluminum hydride is 3:2 and the second additionThe mass ratio of water to lithium aluminum hydride is 5:2.The catalyst in step (2) is a mixture of CeO2, MnO and ZnO in a mass ratio of 1:2:5;The mass ratio of nitrobenzene ethanol is 3:167. The step (1)
a. 4-nitro-phenylethanol; A solution of 4-nitrophenyl acetic acid (150 g, 0.829 mole) in THF (1.5 L) was cooled to 0 0C. Borane dimethyl sulfide (94.5 g, 118 ml_, 1.24 mole) was added slowly over 60 minutes. The reaction was allowed to warm to room temperature and stirred at room temperature for 17 hours. The reaction was quenched by the addition of 1.5 N HCI (350 mL) and concentrated to a viscous liquid. The liquid was dissolved in DCM (1.5 L), washed with water (2 x 1 L) and brine (1 x 1L), dried (Na2SO4), filtered and concentrated to provide the desired product as a pale yellow solid (130 g).
With molecualar sevies 4A In toluene at 120℃; for 18h;
3.11 Example 3 [Scope of Substrate Application]
By combining diversely the carboxylic acid of various structure and alcohol, the scope of substrate application of the tetravalent hafnium compound was examined. A Soxhlet tube filled with dried molecular sieves 4A (about 1.5 g) was connected to the top of a 5 ml eggplant flask contained with a teflon coated magnetic stirrer, and a cooling tube was further attached over said Soxhlet tube. Unless there is a particular point of concern, toluene solvent (2 ml) and 0.1 mol %, 0.2 mol % or 1 mol % of hafnium chloride (IV)•(THF)2 were added to carboxylic acid (10 mmol) and alcohol (10 mmol), and heating reflux was conducted in the argon for several hours at 120°C. After the reaction, the mixture solution was purified by direct silica gel column chromatography (eluant hexane:ethyl acetate=4:1 to 8:1), and the solution was dried under reduced pressure. The results are shown in Table 2. In Table 2, the following are shown: for the experiment of Entry 3, toluene solvent (5 ml) was used; for the experiment of Entry 4, 4-phenyl butanoic acid (36 mmol) and toluene solvent (4 ml) were used; for the experiment of Entry 5, the numerical value of yield showed in parenthesis is the value in the case the inventors wanted to use the catalyst; for the experiment of Entry 9, o-xylene solvent (2 ml) was used; for the experiment of Entry 14, enantiomer of carboxylic acid was used and at a yield of 84%, the enantiomer of ester was obtained; for the experiment of Entry of 17, 1,3,5-mesitylene solvent(2 ml) was used; for the experiments of Entry 18 and 19, the lactone value is shown for the yield. [TABLE-US-00002] TABLE 2 [CHEMMOL-00003] HfCl4.(THF)2 reaction entryRCO2H ROH (1 mol %) time (h) yield (%) 1 [CHEMMOL-00004] [CHEMMOL-00005] 0.2 6 97 2 [CHEMMOL-00006] [CHEMMOL-00007] 0.2 24 92 3 [CHEMMOL-00008] [CHEMMOL-00009] 0.1 18 >99 4 [CHEMMOL-00010] EtC(CH2OH)3 0.2 24 >99 5 [CHEMMOL-00011] [CHEMMOL-00012] 0.2 5 94 (36) 6 [CHEMMOL-00013] l-menthol 0.2 36 >99 7 [CHEMMOL-00014] [CHEMMOL-00015] 0.2 13 >99 8 [CHEMMOL-00016] Et3COH 1.0 24 0 9 [CHEMMOL-00017] PhOH 0.2 36 91 10 [CHEMMOL-00018] [CHEMMOL-00019] 0.2 10 92 11 [CHEMMOL-00020] [CHEMMOL-00021] 0.1 18 98 12 [CHEMMOL-00022] [CHEMMOL-00023] 0.2 7 96 13Et2CHCO2H [CHEMMOL-00024] 0.2 60 98 14 [CHEMMOL-00025] [CHEMMOL-00026] 0.2 13 98 15PhCO2H [CHEMMOL-00027] 0.2 15 92 16 [CHEMMOL-00028] [CHEMMOL-00029] 0.2 10 92 17PhCO2H3,5-Me2C5H3OH 1.0 24 95 18 [CHEMMOL-00030] 0.2 10 98 19 [CHEMMOL-00031] 0.2 10 94 [0022] As it is also shown in Table 2, every carboxylic acid reacted with primary and secondary alcohol, under the presence of the catalyst of 0.2 mol % and under, and produced ester quantitatively, but as it is shown from the experiment of Entry 8, it did not react with tertiary alcohol. Furthermore, as it is shown from the experiment of Entry 17, the aromatic substrates (benzoic acid and phenol) showed lower reactivity compared to aliphatic substrates, and when carboxylic acid and alcohol are both aromatics, the ester could be obtained at a high yield, by increasing the catalyst amount up to 1 mol %. Moreover, when the reactivity is low, it is also effective to use a benzene solvent of higher boiling point, for example, o-xylene of the experiment of Entry 9 or 1,3,5-mesitylene of the experiment of Entry 17 and to conduct heating reflux.
With dmap; N-cyclohexyl-N'-β-(4-methylmorpholinium)ethylcarbodiimide p-toluenesulfonate In dichloromethane for 4h; Ambient temperature;
With iron(III) trifluoromethanesulfonate; sodium nitrite In dimethyl sulfoxide at 50℃; for 10h; Inert atmosphere; Sealed tube;
Nitriles 2a-r: General Procedure
General procedure: A tube of approximate volume 45 mL was charged with theappropriate arylacetic acid (0.5 mmol), NaNO2 (3 mmol),Fe(OTf)3 (1 mmol), and undried DMSO (2 mL), and the air in thetube was replaced by argon gas. The tube was sealed and themixture was heated with magnetic stirring at 50 °C for 10 h,then cooled to r.t. The solvent was evaporated, and the residuewas purified by column chromatography (silica gel).
56%
With oxygen; copper(II) trifluoroacetate; urea In dimethyl sulfoxide at 150℃; for 16h; Green chemistry;
22%
With trifluoroacetic acid; trifluoroacetic anhydride; sodium nitrite at 20℃;
With hydrogenchloride; thionyl chloride; sodium bicarbonate; sulfuric acid; acetic acid; In ethanol; water; ethyl acetate; toluene;
Reference Example 1 Preparation of 4-nitrophenylacetone t-butyl methyl ether (290 ml), ethanol (40 ml) and ethyl malonate (70.04 g, 0.437 mol) were added to magnesium ethoxide (50.00 g, 0.437 mol), which was heated to reflux for 30 minutes and returned to room temperature (hereinafter, abbreviated as Solution A). Thionyl chloride (104.04 g, 0.875 mol) was added to 4-nitrophenylacetic acid (66.00 g, 0.364 mol), which was stirred at 70-75 C. for 45 minutes. Thionyl chloride was distilled off under reduced pressure, followed by azeotropy with toluene (66 ml) two times. t-butyl methyl ether (132 ml) was added to the azeotropic residue to dissolve it, which was added dropwise to Solution A. After stirred at 65 C. for 30 minutes, the mixture was cooled to room temperature, and 2N hydrochloric acid (264 ml) was added thereto dropwise under cooling. The organic layer was separated, the aqueous layer was reverse-extracted with t-butyl methyl ether (132 ml), the organic layers were combined, and the solvent was distilled off under reduced pressure. Acetic acid (111 ml), water (74 ml) and concentrated sulfuric acid (14 ml) were added to the concentrated residue, and the mixture was refluxed at an outer temperature of 125 C. for 5 hours while stirring vigorously. After completion of the reaction, the mixture was ice-cooled, returned to room temperature, and t-butyl methyl ether (264 ml) and water (264 ml) were added thereto, followed by extraction. An aqueous saturated sodium hydrogen carbonate solution (264 ml) and ethyl acetate (80 ml) were added to the organic layer to wash the layer, followed by further washing with an aqueous saturated sodium bicarbonate solution (264 ml). After washed with brine (264 ml) twice, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 4-nitrophenylacetone (48.96 g, 0.273 mol, 75%).
4-(2-Morpholin-4-yl-ethyl)-phenylamine is prepared from (4-nitro-phenyl)-acetic acid by the following method: A room temperature solution of 1.8839 gms. (4-Nitro-phenyl)-acetic acid in tetrahydrofuran (5 mL) is treated with 1.8069 gms. 1',1'-carbonyl-diimidizole. The reaction mixture is stirred for 1 h. The reaction mixture is then treated with 1.0 mL morpholine. The reaction is heated overnight at 35 C. The reaction is then allowed to cool to room temperature, and is made basic with the addition of saturated aqueous sodium bicarbonate. The resulting mixture is extracted with ethyl acetate. The aqueous layer is re-extracted four more times with ethyl acetate. The combined organics are evaporated to dryness in vacuo. The crude product residue is then chromatographed by flash silica gel chromatography using 60% ethyl acetate in hexanes as the eluant.
With 1,1'-carbonyldiimidazole; In tetrahydrofuran;
(1) Carbonyldiimidazole (8.7 g, 30.4 mmol) was added to a solution of 4-nitrophenylacetic acid (10 g, 55.2 mmol) in tetrahydrofuran (100 ml) at room temperature. After stirred at room temperature for 6 hours, a magnesium salt of malonic acid monoethyl ester (4.4 g, 15.2 mmol) was added. This mixture was stirred at 60 C. for 1.5 hours, The reaction solution was diluted with ethyl acetate (100 ml), washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution and saturated brine, dried with sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent:hexane-ethyl acetate (3:1)] to obtain ethyl 4-(4-nitrophenyl)-3-oxobutanoate (10.3 g, 41.0 mmol, 74%) as a pale yellow powder. IR numax (KBr) cm-1: 1738, 1722 (C=O). 1H-NMR (CDCl3) delta: 1.280 ({fraction (1/7)}*3H, t, J=7.0 Hz), 1.289 ({fraction (6/7)}*3H, t, J=7.0 Hz), 3.529 ({fraction (6/7)}*2H, s), 3.603 ({fraction (1/7)}*2H, s), 4.000 ({fraction (6/7)}*2H, s), 4.194 ({fraction (1/7)}*2H, q, J=7.0 Hz), 4.216 ({fraction (6/7)}*2H, q, J=7.0 Hz), 4.973 ({fraction (1/7)}*1H, s), 7.36-7.46 (2H, m), 8.17-8.24 (2H, m). Elemental Analysis (C12H13NO5) Cal'd: C, 57.37; H, 5.22; N, 5.58. Found: C, 57.42; H, 5.13; N, 5.72.
3-(4-bromo-1-methylpyrazole-3-yl)phenylamine[ No CAS ]
[ 104-03-0 ]
[ 94790-37-1 ]
[ 80029-43-2 ]
[ 7087-68-5 ]
N-[3-(4-bromo-1-methylpyrazol-3-yl)phenyl]-2-(4-nitrophenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
18%
In chloroform;
N-[3-(4-bromo-1-methylpyrazol-3-yl)phenyl]-2-(4-nitrophenyl)acetamide A mixture of 3-(3-aminophenyl)-4-bromo-1-methylpyrazole (30 mg, 0.12 mmol), 4-nitrophenylacetic acid (22 mg, 0.12 mmol), 1-hydroxybenzotriazole hydrate (16 mg, 0.12 mmol) and <strong>[94790-37-1]2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate</strong> (46 mg, 0.12 mmol) were dissolved in chloroform (1.5 ml). N,N-Diisopropylethylamine (0.02 ml, 0.13 mmol) was added and the mixture stirred at room temperature for 16 h. The reaction mixture was then poured into brine and the organic layer washed with further brine, dried over magnesium sulphate and then concentrated in vacuo. The crude product was purified by column chromatography (ethyl acetate-toluene, 1:1), giving the title compound (9 mg, 18%). Rf 0.19 (ethyl acetate-toluene, 1:1). HPLC (Method B): retention time 7.22 min (94.30%). deltaH (CDCl3) 3.83 (3H, s), 3.87 (2H, s), 7.18-7.23 (1H, m), 7.42-7.65 (7H, m), 8.22-8.30 (2H, m). MS (AP+): m/z (%)=417 (M+H 81 Br, 100), 415 (M+H 79 Br, 100).
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC)[ No CAS ]
Et2 O-pentane[ No CAS ]
EtOAc-SSB[ No CAS ]
[ 66793-76-8 ]
[ 104-03-0 ]
N-Ethyl-N-heptyl-4-nitrophenylacetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With benzotriazol-1-ol; In N-methyl-acetamide; ethyl acetate;
PREPARATION 18 N-Ethyl-N-heptyl-4-nitrophenylacetamide, Chart IV; Step I A mixture of p-nitrophenylacetic acid (7.14 g, 0.0394 mol), ethylheptylamine (5.64 g, 0.0394 mol) and 1-hydroxybenzotriazole (6.0 g, 0.044 mol) in 35 ml of dimethylformamide (DMF), under nitrogen, is cooled in an ice bath. The mixture is then treated with the 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (7.68 g, 0.04 mol) in portions over 15 min. The mixture is stirred in the cold for 1 hr and at room temperature overnight. The mixture is diluted with 400 ml of ethyl acetate and washed twice with saturated NaHCO3. (Each wash is back extracted with ethyl acetate.) The pooled organic extract is washed sequentially with water (50 ml), 1N KHSO4 solution (3*50 ml), water (50 ml) and finally brine (50 ml). It is dried (Na2 SO4) and concentrated in vacuo to yield the title compound. This residue is treated with Et2 O-pentane, a solid filtered off and the filtrate concentrated in vacuo. The residue is chromatographed over 1400 ml of silica gel with 25percent EtOAc-SSB with 42 ml fractions being collected. Fractions at approximately 70-104 yield the title compound as an oil.
Step A (Scheme 1): Preparation of trans-1-Chloro-2-trifluoromethyl-4-[2-(4-nitrophenyl)ethenyl]benzene A mixture of p-nitrophenylacetic acid (51.85 g, 0.29 mol) and <strong>[34328-46-6]4-chloro-3-trifluoromethylbenzaldehyde</strong> (47.85 g, 0.23 mol) in piperidine (19.5 g, 0.23 mol) was heated under N2 atmosphere to 150 C. to 160 C. for 1 hour. The reaction mixture was cooled to 80 C. to 100 C. and refluxing i-PrOH (150 mL) was added. The mixture was continued to cool to room temperature and then placed under refrigeration for 5 hours. The crystalline precipitate was filtered off, rinsed with cold i-PrOH, and dried at room temperature in a vacuum oven overnight to yield trans-1-chloro-2-trifluoromethyl-4-[2-(4-nitrophenyl)ethenyl]benzene as an orange solid, 22.53 g (68.75 mmol, 30%). mp 173-174 C. MS: 327.0 (M+)
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;
General procedure: trans-Cinnamic acid (1.49, 10.0 mmol) and HOBt (2.263 g, 15 mmol) were dissolved in DMF (50 mL). EDC.HCl (2.865 g, 15 mmol) was added, followed by beta-alanine ethyl ester hydrochloride (1.53 g, 10 mmol) and DIPEA (5.3 mL, 30 mmol) and the solution was stirred at RT for 16 h. The solvent was removed in vacuo and the residual oil was re-dissolved in EtOAc (100 mL), the organic phase was washed with 5percent w/v aqueous sodium hydrogen carbonate solution (2 ×100 mL) then 5percent w/v citric acid solution (2× 30 mL) and brine, before being dried on MgSO4. The solvent was evaporated in vacuo to afford the product (1.48 g, 59.8percent yield).
2.4 General procedure for the synthesis of complexes 1 and 2
General procedure: Sodium bicarbonate (0.504g, 6mmol) was treated with equimolar quantity of the corresponding phenyl acetic acid derivatives (1.086g of 4-nitro phenyl acetic acid for complex 1 and 0.90g of 4-methyl phenyl acetic acid for 2, 6mmol each) in distilled water at 60°C.
Stage #1: 4-nitrobenzeneacetic acid With thionyl chloride In benzene at 80℃; for 3h;
Stage #2: 2-(4-aminophenyl)benzothiazole With sodium hydrogencarbonate In diethyl ether; water at 20℃;
General procedure for the synthesis of compounds(6a-6w)
General procedure: General procedure for the synthesis of compounds(6a-6w)The result products, 2-[4-(4-substitutedbenzamido/phenylacetamido/3-phenyl propionamido)benzyl/phenyl]-benzothiazole derivatives (6a-6w) were synthesized by heating thionyl chloride (0.3 ml) and appropriate carboxylicacid (4) (1 mmol) in benzene (0.5 ml) at 80 Cfor 3h, and then excess thionyl chloride was removed invacuo (Scheme 2). The residue was dissolved in ether (1ml) and solution added during 1h to a stired, ice-coldmixture of 2-(4-aminobenzyl/phenyl)benzothiazole (1mmol), sodium bicarbonate (2 mmol), diethylether (1ml) and water (1 ml).26 The mixture was kept stirredovernight at room temperature and then filtered. Afterthe precipitate was washed with water, 2N HCl andwater. Ethanol was used for recrystallization and crystalsare dried in vacuo.
Stage #1: 4-nitrobenzeneacetic acid; 2,3,4-trihydroxybenzylaldehyde With acetic anhydride; triethylamine at 90℃;
Stage #2: In diethyl ether at 20℃;
3 2.1.2.3 7,8-Diacetoxy-3-(4-nitrophenyl)coumarin (9c)
General procedure: To a mixture of 2-hydroxybenzaldehyde (7a) [or 2-hydroxyacetophenone(7b), 2,3,4-trihydroxy benzaldehyde (7c), 2-hydroxy-4-methoxybenzophenone (7d) or 2-hydroxy- benzophenone (7e)] (7.4 mmol) and 4-nitrophenylacetic acid (8) (8 mmol) in aceticanhydride (3 ml) was added triethylamine (99%, 1 ml). The reactionmixture was then refluxed overnight at 90 C, allowed to coolto r.t. and 10 ml of ether was added with occasional stirring foranother 2-3 h to afford the desired product as a precipitate thatwas collected using vacuum filtration.
7-methoxy-3-(4-nitrophenyl)-4-phenylcoumarin[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
General procedure: To a mixture of 2-hydroxybenzaldehyde (7a) [or 2-hydroxyacetophenone(7b), 2,3,4-trihydroxy benzaldehyde (7c), 2-hydroxy-4-methoxybenzophenone (7d) or 2-hydroxy- benzophenone (7e)] (7.4 mmol) and 4-nitrophenylacetic acid (8) (8 mmol) in aceticanhydride (3 ml) was added triethylamine (99%, 1 ml). The reactionmixture was then refluxed overnight at 90 C, allowed to coolto r.t. and 10 ml of ether was added with occasional stirring foranother 2-3 h to afford the desired product as a precipitate thatwas collected using vacuum filtration.
Stage #1: 2-Hydroxybenzophenone; 4-nitrobenzeneacetic acid With acetic anhydride; triethylamine at 90℃;
Stage #2: In diethyl ether at 20℃;
5 2.1.2.5 3-(4-Nitrophenyl)-4-phenyl-coumarin (9e)
General procedure: To a mixture of 2-hydroxybenzaldehyde (7a) [or 2-hydroxyacetophenone(7b), 2,3,4-trihydroxy benzaldehyde (7c), 2-hydroxy-4-methoxybenzophenone (7d) or 2-hydroxy- benzophenone (7e)] (7.4 mmol) and 4-nitrophenylacetic acid (8) (8 mmol) in aceticanhydride (3 ml) was added triethylamine (99%, 1 ml). The reactionmixture was then refluxed overnight at 90 C, allowed to coolto r.t. and 10 ml of ether was added with occasional stirring foranother 2-3 h to afford the desired product as a precipitate thatwas collected using vacuum filtration.
With acetic anhydride; at 20℃; for 6h;Inert atmosphere;
In a stirred solution of 4-nitrophenyl acetic acid (0.05 mol,1 equiv) in acetic anhydride (25 mL, 5 equiv), N-methylimidazole(0.025 mol, 0.5 equiv) was added at room temperature. After stirringfor 6 h in nitrogen atmosphere, the reaction was quenchedby adding water (20 mL). The mixture was extracted (EtOAc),washed (NaHCO3 and subsequently with H2O), dried (Na2SO4), filteredand concentrated to give the product as a yellow solid (yield:70%). 1H NMR (400 MHz, CDCl3): d 8.18 (d, J = 8.4 Hz, 2H), 7.35 (d,J = 8.4 Hz, 2H), 3.84 (s, 2H), 2.23 (s, 3H).
4.1.2 7-Hydroxy-3-(4-nitrophenyl)-4H-benzopyran-4-one (9) A mixture of 4-nitrophenylacetic acid (7; 1.0 g, 6.0 mmol), resorcinol (8; 0.72 g, 6.5 mmol) and BF3/Et2O (10 ml) was heated at 85 C for 1.5 h with stirring, then cooled down to 10 C and 10 ml DMF was added slowly. In another flask, 10 ml DMF was added and cooled to 10 C, PCl5 (2.0 g, 9 mmol) was added in batches, afterwards the mixture was heated to 55 C and stirred for 0.5 h, after that cooled to 10 C. Then the mixture was added by droplet into the first flask and stirred at 25 C for 2 h. Then the reaction mixture was poured into heated dilute hydrochloric acid (0.5 mol/L). The product was filtered, and purified by recrystallization from methanol to yield 9 (0.36 g, 1.26 mmol, 21%) as a white solid. 1H NMR (DMSO, 300 MHz): delta 8.48 (s, 1H, H-2), 8.28 (2H, J = 8.8 Hz, H-3', H-5'), 8.07 (d, 1H, J = 8.8 Hz, H-5), 7.96 (d, 2H, J = 8. 8 Hz, H-2', H-6'), 7.05 (dd, 1H, J = 8.8, 2.4 Hz, H-6), 6.97 (d, 1H, J = 2.4 Hz, H-8); MS (ESI): m/z = 282 [M-H]-.
2-(4-nitrophenyl)-N-((4-(trifluoromethyl)phenyl)sulfonyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26%
General procedure: All solid chemicals used were dried in vacuum over P2O5 overnight.The acid derivative and CDI were dissolved in dry THF underN2 atmosphere and the mixture was allowed to stir at 66-68 C for2 h. The sulfonamide and DBU dissolved in THF were added to thereaction mixture and stirring was continued at room temperature(4 h-overnight).Method B1: The solvent was removed in vacuo, water was addedand pH was adjusted to 2 by addition of 1 M HCl aq. The aqueousphase was extracted with EtOAc (2 40 ml), dried with MgSO4, filteredand evaporated in vacuo. For most of the compounds, a silicagel column was first run, followed by purification on aluminumoxide.
<i>N</i>,<i>N</i>-dibenzyl-2-(4-nitro-phenyl)-acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
Stage #1: tribenzylamine With iodine; triphenylphosphine In dichloromethane at 0℃; for 0.166667h;
Stage #2: 4-nitrobenzeneacetic acid In dichloromethane at 25℃; for 2h;
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;Inert atmosphere;
General procedure: An oven-dried 50 mL round-bottom flask containing a magnetic stirrer bar was sealed with a septum, charged with Ar and tared on a balance. KH (~0.5 g, 30% mineral oil dispersion) was then added to the flask and the mineral oil removed by trituration under Ar with pet. spirit (2 x 30 mL) using a syringe. The flask containing dry KH was purged with Ar and reweighed to obtain an accurate mass of KH. Dry THF (10 mL) was added to the flask containing KH (0.15 g, 3.7 mmol, under Ar) and the mixture cooled to 0 oC. 3,5-Dimethyl-1H-pyrrole-2-carbaldehyde 5 (0.23 g, 1.9 mmol) was dissolved in dry THF (5 mL) under Ar and added dropwise to the stirring KH solution (Caution - flask requires outlet needle to release evolving H2 gas). After complete addition the mixture was stirred for a further 5 minutes at 0 oC. The phenylacetic acid derivative (1.9 mmoles) was added to a separate dry 50 mL round-bottom flask under Ar along with HBTU (0.71 g, 1.9 mmoles) and dry CH2Cl2 (10 mL). DIPEA (0.65 mL, 3.7 mmoles) was added dropwise to the stirring solution and upon complete addition the mixture was stirred for a further 5 minutes or until the HBTU was completely dissolved. The HBTU solution was then cooled to 0 oC and added in a single portion to the K+ pyrrolate salt solution at 0 oC and the combined mixture allowed to warm slowly to room temperature. A dark red colour observed in each reaction indicated formation of the desired 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-one. The reaction was quenched after ~ 2 h with ice-cold water (100 mL) and extracted with Et2O (2 x 50 mL). The combined organic phase was washed with 1 M HCl (2 x 50 mL), saturated NaHCO3 (2 x 50 mL) and brine (2 x 50 mL), dried over anhydrous MgSO4 and concentrated. The crude residue was purified by silica gel column chromatography using a gradient from 100% pet. spirit to 1:9 acetone:pet. spirit to afford the 5,7-dimethyl-2-aryl-3H-pyrrolizin-3-one as a deep red solid.
5 Preparation of 2-hexyldecyl 4-nitrophenylacetate
Example 5 Preparation of 2-hexyldecyl 4-nitrophenylacetate To a 3-neck 1000 ml round-bottomed flask was added 2-hexyl-1-decanol (200.0 g, 824.93 mmol, 1.0 equiv.), 4-nitrophenylacetic acid (186.79 g, 1031.15 mmol, 1.25 equiv.), toluene (240 ml) and p-toluenesulfonic acid monohydrate (1.5692 g, 8.2494 mmol, 0.010 equiv.) at room temperature. The resulting mixture was heated at reflux with stirring in an oil bath at 134° C. under a nitrogen atmosphere for 10 hours. The water produced in the reaction was collected in a Dean-Stark trap. The cooled mixture was diluted with hexanes, washed with dilute aqueous Na2CO3 solution, water, brine, dried (MgSO4), filtered, and concentrated in vacuo to afford a crude product. Excess solvent was further removed by heating the crude product with stirring in an oil bath under high vacuum for 3 hours to afford a dark brown liquid (363.0 g). This crude product was further purified by column chromatography on silica gel using hexane/EtOAc as eluent to afford a light yellow liquid (313.0 g, 93%).
In the first reaction flask, resorcinol (0.72 g, 6.5 mmol), p-nitrophenylacetic acid (1.0 g, 6.0 mmol), BF 3 / Et 2 O (10 mL) was added and stirred at 75 C Reaction for 90 min. The reaction was completed, cooled to below 10 C, and DMF (10 mL) was added slowly with stirring. (0.72g6.5mmol)(1.0g6.0mmol)BF 3 /Et 2 O(10mL)75C90min 10CDMF(10mL) In a second reaction flask, DMF (20 mL) was added, cooled to below 10 C, and PCl 5 (2.0 g, 9 mmol) was added portionwise and stirred at 55 C for 30 min. The reaction was completed, cooled to below 10 C, slowly added to the first reaction flask, room temperature reaction 1h. After completion of the reaction, the reaction solution was poured into hot dilute hydrochloric acid (0.1 N) with stirring, and the solid was precipitated, suction filtered, washed with water and dried. The crude product was recrystallized from methanol to give 0.36 g of product, yield 16.4%. MS (ESI): m / z = 284 [M + H] & lt; + & gt ;.
With piperidine; pyridine; at 100℃; for 6h;Reflux;
General procedure: The substituted ethenyl indoles were synthesized by the condensation of p-substituted phenyl acetic acid with the corresponding 3-formylindole or its derivatives in presence of pyridine-pipridine mixture. For this purpose, 3-formylindole was taken in freshly distilled pyridine (10 mL), pipiridine (0.6 mL) and p-nitrophenyl acetic acid (2 molar equivalent with respect to 3-formylindole) in a round bottom flask fitted with a reflux condenser. The reaction mixture was heated at 100C for 6 h. The reaction mixture was cooled to RT and treated with 100 mL of diluted hydrochloric acid to remove excess of pyridine from the reaction mixture. The product was extracted with diethyl ether and purified by column chromatography using 2-10% ethyl acetate in petroleum ether as the eluting solvent.
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