* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Synthetic Communications, 1991, vol. 21, # 7, p. 959 - 964
[2] Justus Liebigs Annalen der Chemie, 1937, vol. 527, p. 83,101
2
[ 6361-21-3 ]
[ 19301-35-0 ]
Reference：
[1] Synthetic Communications, 1991, vol. 21, # 7, p. 959 - 964
[2] Justus Liebigs Annalen der Chemie, 1937, vol. 527, p. 83,101
3
[ 2365-48-2 ]
[ 6361-21-3 ]
[ 4965-26-8 ]
Yield
Reaction Conditions
Operation in experiment
81%
With hydrogenchloride; sodium hydroxide; sodium methylate In quinoline; methanol; n-heptane; water
Step 1 Preparation of 5-nitrobenzo[b]thiophene Methyl thioglycolate (14.3 g, 135 mmol) in methanol (250 mL) at 40° C. is treated dropwise with 25percent sodium methoxide in methanol (37 mL, 160 mmol) and the resulting mixture mechanically stirred at 50° C. for 30 min. 2-chloro-5-nitrobenzaldehyde in methanol (250 mL) is added in a steady stream to give a heavy precipitate which is heated at 50° C. for 1 h. Sodium hydroxide (50percent aqueous, 15 mL) is added and heating continued for 2 h, then cooled to ice bath temperature and acidified with concentrated hydrochloric acid. An additional 200 mL of water is added during this process to facilitate stirring. The resulting solids are collected by filtration, washed with water, and dried in vacuo at 45° C. overnight. The dried solids are suspended in quinoline (120 mL), copper metal (7.2 g) is added and the mixture is heated at 190° C. for 2 hr. The mixture is allowed to cool, then poured onto 500 g of ice, 6 N hydrochloric acid (500 mL) is added and then extracted with of dichloromethane. The organic layers are combined and washed with 6 N hydrochloric acid, dried, and flash chromatographed on silica gel eluding with 10-40percent ethyl acetate in heptane to give 16.2 g (81percent) of the title compound. 1H NMR (CDCl3) δ8.75 (s, 1 H), 8.22 (dd, J=2.3, 10 Hz, 1 H), 8.0 (d, J=10 Hz, 1 H), 7.68 (d, J=6 Hz, 1 H), 7.53 (d, J=6 Hz, 1 H); MS (-ESI) m/z 221.8 (M-H)
Reference：
[1] Patent: US6387896, 2002, B1,
4
[ 6361-21-3 ]
[ 4965-26-8 ]
Reference：
[1] Synthetic Communications, 1991, vol. 21, # 7, p. 959 - 964
[2] Journal of Medicinal Chemistry, 1990, vol. 33, # 9, p. 2621 - 2629
[3] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 3, p. 403 - 427
5
[ 89-98-5 ]
[ 6361-21-3 ]
Reference：
[1] Journal of the Indian Chemical Society, 1989, vol. 66, # 2, p. 106 - 109
[2] Justus Liebigs Annalen der Chemie, 1893, vol. 272, p. 153
[3] Journal of the Chemical Society, 1926, p. 154[4] Journal of the Chemical Society, 1927, p. 2380
[5] Journal of the Chemical Society. Perkin transactions 1, 1965, p. 5976 - 5983
[6] Chinese Journal of Chemistry, 2012, vol. 30, # 7, p. 1571 - 1574
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
To a solution of 2-Chloro-5-nitrobenzaIdehyde (3.7 g, 0.020 mol) in N, N- Dimethylformamide (40 ml_) was added methyl thioglyocolate (1.82 ml_, 0.020 mol) followed by K2CO3 (3.3 g, 0.024 mol). The reaction mixture was stirred at rt overnight. Then, water was added to the reaction mixture and the suspension was filtered. The residue was subsequently washed with water to yield the product 6-Nitro- benzo[b]thiophene-2-carboxylic acid methyl ester as yellow solid. Yield: 95 percent.
94%
With potassium carbonate In water; N,N-dimethyl-formamide at 20℃;
Potassium carbonate (1.73 g, 12.5 mmol) was added to a solution of 2-chloro-5-nitrobenzaldehyde (1.94 g, 10.5 mmol) and methyl 2-mercapto acetate (1.11 g, 10.5 mmol) in DMF (21 mL), and the mixture was stirred at room temperature overnight. Water (100 mL) was added thereto, then the reaction solution was stirred at room temperature for 1 hour, and then the obtained precipitate was filtered out and dried to obtain the title compound (2.35 g, 94percent). 1H-NMR (d-DMSO): δ 9.00 (s, 1H), 8.47-8.42 (m, 1H), 8.40-8.28 (m, 2H), 3.92 (s, 3H).
66%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.166667 h; Stage #2: at 20 - 100℃; for 6 h;
Methyl thioglycolate (19.62 mL, 0.216 mol) was added dropwise, via syringe pump, to a stirred suspension of 95percent sodium hydride (5.99 g, 0.237 mol) in dry N,N-dimethyl- formamide (400 mL) at r.t. under nitrogen (CAUTION : hydrogen evolution). Upon complete addition, the reaction was stirred for 10 min and then a solution of 2-chloro-5- nitrobenzaldehyde (40.0 g, 0.216 mol) in DMF (120 mL) was added. The solution turned orange and a gentle exotherm was observed. After Ih, the now yellow mixture was heated to 100 °C for 5 h. The mixture turned amber in appearance. After cooling to r.t. the mixture was poured into 1 N aqueous hydrochloric acid (500 mL). The resulting yellow precipitate was filtered off and washed with water (250 mL). The solid was suspended in hot methanol / ethyl acetate (1:1) (1000 mL) and allowed to cool to r.t. The EPO <DP n="28"/>resulting solid was filtered off and air dried to yield methyl 5-nitrobenzo[b]thiophene-2- carboxylate (33.77 g, 66percent) as a tan amorphous solid. 1H NMR δ Cd6-DMSO, 400 MHz) 3.92 (s, 3 H), 8.32 (dd, / = 9, 2 Hz, 1 H), 8.37 (d, / = 9 Hz, 1 H), 8.45 (s, 1 H), 9.00 (d, / = 2 Hz, 1 H).
95%
With sodium methylate In methanol
Preparation of Methyl 5-Nitrobenzo[b]thiophene-2-Carboxylate A 2000 ml 3-necked round-bottomed flask, 250 ml pressure equalized dropping funnel, Teflon stirrer, and gas inlet were oven-dried for 12 hours at 160° C. The apparatus was rapidly assembled, fitted with a thermometer, flushed with dry nitrogen gas, and allowed to cool to room temperature. The cooled flask was charged with methanol (600 ml) and methyl thioglycolate (28.6 g, 0.27 mole). Sodium methoxide (19,98 g, 0.37 mole) in methanol (125 ml) was added to the reaction mixture over 10 minutes while stirring. The reaction mixture was then warmed to 40° C. and a solution of 2-chloro-5-nitrobenzaldehyde (28.6 g, 0.27 mole) in methanol (300 ml) was added over a period of about 20 minutes. The resulting slurry was stirred at 40° C. for 1 hour, cooled to room temperature, and acidified with 2M hydrochloric acid. The resulting white solid was filtered, washed with water (2*300 ml) and air-dried to give 61 g (95percent) of methyl 5-nitrobenzothiophene-2-carboxylate. See, R. A. Zambias, M. L. Hammond, Synthetic Communications, 21:959 (1991).
Reference：
[1] Synthetic Communications, 1991, vol. 21, # 7, p. 959 - 964
[2] Organic and Biomolecular Chemistry, 2015, vol. 13, # 24, p. 6814 - 6824
[3] Patent: WO2006/101454, 2006, A1, . Location in patent: Page/Page column 45
[4] Patent: EP2876105, 2015, A1, . Location in patent: Paragraph 0945; 0946
[5] Heterocycles, 2008, vol. 75, # 8, p. 1913 - 1929
[6] Journal of the American Chemical Society, 2000, vol. 122, # 27, p. 6382 - 6394
[7] Patent: WO2006/66172, 2006, A1, . Location in patent: Page/Page column 26-27
[8] Journal of Medicinal Chemistry, 1990, vol. 33, # 9, p. 2621 - 2629
[9] Patent: US5863936, 1999, A,
[10] Journal of Medicinal Chemistry, 2006, vol. 49, # 24, p. 7108 - 7118
[11] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 3, p. 403 - 427
12
[ 96-35-5 ]
[ 6361-21-3 ]
[ 20699-86-9 ]
Yield
Reaction Conditions
Operation in experiment
69%
With potassium carbonate In N,N-dimethyl-formamide
Step 1: Methyl-5-nitro-benzo[b]thiophene-2-carboxylate (584) A stirring suspension of 5-nitro-2-chloro-benzaldehyde (4.0 g, 21.6 mmol) in DMF (40 ml) at 5° C. was treated with K2CO3(3.52 g, 25.5 mmol) followed by methylglycolate (1.93 ml, 21.6 mmol). The resulting solution was warmed to 25° C. and stirred for 20 h. The solution was then poured into 250 ml of ice H2O and the white precipitate that formed was collected by filtration. Crystallization from EtOAc afforded fine pale orange needles of 584 (3.54 g, 69percent). LRMS: 237.0 (Calc.); 238.1 (found). 1H NMR: (DMSO) δ (ppm): 9.00 (d, J=2.2 Hz, 1H), 8.45 (s, 1H), 8.39-8.30 (m, 2H), 3.93 (s, 3H).
69%
With potassium carbonate In N,N-dimethyl-formamide
Step 1: Methyl-5-nitro-benzo[b]thiophene-2-carboxylate (584) A stirring suspension of 5-nitro-2-chloro-benzaldehyde (4.0 g, 21.6 mmol) in DMF (40 ml) at 5° C. was treated with K2CO3(3.52 g, 25.5 mmol) followed by methylglycolate (1.93 ml, 21.6 mmol). The resulting solution was warmed to 25° C. and stirred for 20h. The solution was then poured into 250 ml of ice H2O and the white precipitate that formed was collected by filtration. Crystallization from EtOAc afforded fine pale orange needles of 584 (3.54 g, 69percent). LRMS: 237.0 (Calc.); 238.1 (found). 1H NMR: (DMSO) δ (ppm): 9.00 (d, J=2.2 Hz, 1H), 8.45 (s, 1H), 8.39-8.30 (m, 2H), 3.93 (s, 3H).
69%
With potassium carbonate In N,N-dimethyl-formamide
Step 1: Methyl-5-nitro-benzo[b]thiophene-2-carboxylate (584) A stirring suspension of 5-nitro-2-chlorobenzaldehyde (4.0 g, 21.6 mmol) in DMF (40 ml) at 5° C. was treated with K2CO3(3.52 g, 25.5 mmol) followed by methylglycolate (1.93 ml, 21.6 mmol). The resulting solution was warmed to 25° C. and stirred for 20 h. The solution was then poured into 250 ml of ice H2O and the white precipitate that formed was collected by filtration. Crystallization from EtOAc afforded fine pale orange needles of 584 (3.54 g, 69percent). LRMS: 237.0 (Calc.). 238.1 (found). 1H NMR: (DMSO) δ (ppm): 9.00 (d, J=2.2 Hz, 1H), 8.45 (s, 1H), 8.39-8.30 (m, 2H), 3.93 (s, 3H).
With potassium hydroxide In N,N-dimethyl-formamide at 100℃; for 0.25h;
In sodium hydroxide; ethanol; water
4 EXAMPLE 4
The 10-chloro-10,11-dihydro-2-nitro-dibenzo[b,f]thiepin used as starting material can be prepared as follows: A solution of 480 g of 2-chloro-5-nitro-benzaldehyde in 3.2 litres of ethanol is treated dropwise under a nitrogen atmosphere at 30°-40° C with stirring within 4 hours with a solution of 320 g of thiophenol in 120 g of sodium hydroxide, 2 litres of ethanol and 440 ml of water. The mixture is stirred for a further 30 minutes at 60° C, then cooled to 0° C and filtered. There is obtained crude crystalline 3-nitro-6-(phenylthio)-benzaldehyde of melting point 96°-100° C.
With methanol; sodium tetrahydroborate In tetrahydrofuran at 20℃; for 1h; Cooling with ice;
1 (2-Chloro-5-nitrophenyl)methanol
(2-Chloro-5-nitrophenyl)methanol To a solution of 2-chloro-5-nitrobenzaldehyde (20 g, 108 mmol) in MeOH:THF (10:1, 220 mL) cooling with an ice-water bath, sodium borohydride (8.0 g, 216 mmol) was added in portions. After completion of addition, the resulting reaction mixture was stirred at room temperature for 1 hour. The solvents were removed by roto-vap and the residue was carefully mixed with water (150 mL). The aqueous mixture was extracted with EA (200 mL*2). The combined extracts were washed with brine (100 mL*2), dried over NaSO4, and concentrated to provide the title compound (20.2 g, yield 100%) as a white solid, which was directly used in the next reaction. 2-(Bromomethyl)-1-chloro-4-nitrobenzene
94%
With sodium tetrahydroborate In methanol at 0 - 25℃; for 24h;
94%
With methanol; sodium tetrahydroborate at 20℃; for 3h;
92%
With methanol; sodium tetrahydroborate In water at -10 - 0℃; for 1.5h;
13
[00226] 2-Chloro-5-nitrobenzaldeyhde (10 g, mmol) was dissolved in 150 ml of MeOH and cooled to 0° C. A solution of NaBH4 (3.33 g, mmol) in 30 ml of water was then added dropwise over 90 minutes while maintaining the temperature below 10 °C. The resultant reaction mixture was then stirred for one hour, acidified with 2N HC1 and left to stir overnight. Then, the mixture was concentrated in vacuo, and the resulting solids were filtered then washed with water and dried in vacuo to give (2-chloro-5-nitrophenyl)methanol (9.3 g, 92%) as a white solid. XH NMR (400 MHz, OMSO-d6) δ 8.35 (d, J= 2.8 Hz, 1H), 8.14 (dd, J= 8.8 Hz, 2.8 Hz, 1H), 7.73 (d, J= 8.8 Hz, 1H), 5.81 (bs, 1H), 4.63 (s, 2H). LC-MS Purity (254 nm): > 98%; tR = 1.60 min.
92%
With sodium tetrahydroborate In 1,2-dimethoxyethane; water at 0 - 10℃; for 2.5h;
31
2-Chloro-5-nitrobenzaldeyhde (10 g, mmol) was dissolved in 150 ml of MeOH and cooled to 0° C. A solution of NaBH4 (3.33 g, mmol) in 30 ml of water was then added dropwise over 90 minutes while maintaining the temperature below 10 C. The resultant reaction mixture was then stirred for one hour, acidified with 2N HCl and left to stir overnight. Then, the mixture was concentrated in vacuo, and the resulting solids were filtered then washed with water and dried in vacuo to give (2-chloro-5-nitrophenyl)methanol (9.3 g, 92%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 2.8 Hz, 1H), 8.14 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 5.81 (bs, 1H), 4.63 (s, 2H). LC-MS Purity (254 nm): > 98%; tR = 1.60 min.
92%
With sodium tetrahydroborate In methanol; water at 0 - 10℃; for 1h;
58 EXAMPLE 58- PREPARATION OF 7V-{4-CHLORO-3-[(PYRIDIN-3-YLOXY)METHYL]PHENYL}- 5,7-DIMETHYLPYRAZOLO[L,5-A]PYRIMIDINE-3-CARBOXAMIDE
2-Chloro-5-nitrobenzaldeyhde (10 g, mmol) was dissolved in 150 ml of methanol and cooled to 0° C. A solution of NaBH4(3.33 g, mmol) in 30 ml of water was then added dropwise over 90 minutes while maintaining the temperature below 10 °C. The resultant reaction mixture was then stirred for one hour, acidified with 2N HC1 and left to stir overnight. The mixture was concentrated in vacuo, and the resulting solids were filtered then washed with water and dried in vacuo to give (2-chloro-5-nitrophenyl)methanol (9.3 g, 92%) as a white solid.XH NMR (400 MHz, DMSO-i) δ 8.35 (d, J= 2.8 Hz, 1H), 8.14 (dd, J= 8.8 Hz, 2.8 Hz, 1H), 7.73 (d, J= 8.8 Hz, 1H), 5.81 (bs, 1H), 4.63 (s, 2H). LC-MS Purity (254 nm): > 98%; tR= 1.60 min.
88%
Stage #1: 2-chloro-5-nitrobenzaldehyde With 7% w/w Pd/C In water Green chemistry;
Stage #2: With sodium tetrahydroborate; water Reflux; Green chemistry;
General procedure for the reduction of nitroarenes to arylamines catalyzedby Pd/C
General procedure: For example, in a round-bottom flask (15 mL) equipped with a magnetic stirrer, a mixture of PhNO2 (1 mmol, 0.123 g) and H2O (2 mL) was prepared. Then, (7wt%) Pd/C (30 mg) was added, and the mixture was stirred. At the next step, NaBH4 (2 mmol, 0.076 g) was added, and the resulting mixture continued to stir at reflux for 7 min. After completion of the reaction (monitored by thin-layer chromatography (TLC) using CCl4:ether (5:2) as an eluent), the mixture was cooled to room temperature, and the mentioned catalytic system was separated by filtration. The reaction mixture was extracted with dichloromethane (DCM)(3 × 5 mL) and then dried over anhydrous sodium sulfate (Na2SO4). Finally, the solvent was evaporated under reduced pressure to afford the pure liquid aniline in 93% yield.
79%
With diisobutylaluminum borohydride In tetrahydrofuran at 25℃; for 1h; Inert atmosphere;
With methanol; sodium tetrahydroborate; water
With methanol; sodium hydroxide; formaldehyd
With sodium tetrahydroborate In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere;
With pyridine; hydrogen at 80℃; for 12h; chemoselective reaction;
With sodium tetrahydroborate In tetrahydrofuran; methanol at 0℃; for 1h;
With pentamethylcyclopentadienyl(iridium(4-cyano-N-(2-(pyridin-2-yl)ethyl)benzenesulfonamide))chloride In isopropyl alcohol at 85℃; for 0.5h;
4.4 Catalytic transfer hydrogenation
General procedure: The precatalyst (0.005mmol) was massed into three different 1 dram vials. If the substrate was liquid, a standard solution containing the substrate (0.500mmol), and the internal standard 1,4-dimethoxybenzene (0.050mmol) was prepared using 2-propanol as the solvent. If the substrate was solid it was massed directly into the vial with the precatalyst and the standard solution was prepared from 1,4-dimethoxybenzene (0.050mmol) using 2-propanol as the solvent. A 500μL aliquot of the standard solution was added via syringe to each of the vials containing precatalyst. The vials were then heated to 85°C in an OptiMag-ST aluminum heating plate containing wells fit for the vials for the time indicated. The product yield was determined using 1H NMR spectroscopy (sample spectra in Supporting Information). Each run was conducted in triplicate and the values are reported as an average with standard deviation in the tree trials.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
To a solution of 2-Chloro-5-nitrobenzaIdehyde (3.7 g, 0.020 mol) in N, N- Dimethylformamide (40 ml_) was added methyl thioglyocolate (1.82 ml_, 0.020 mol) followed by K2CO3 (3.3 g, 0.024 mol). The reaction mixture was stirred at rt overnight. Then, water was added to the reaction mixture and the suspension was filtered. The residue was subsequently washed with water to yield the product 6-Nitro- benzo[b]thiophene-2-carboxylic acid methyl ester as yellow solid. Yield: 95 %.
94%
With potassium carbonate; In water; N,N-dimethyl-formamide; at 20℃;
Potassium carbonate (1.73 g, 12.5 mmol) was added to a solution of 2-chloro-5-nitrobenzaldehyde (1.94 g, 10.5 mmol) and methyl 2-mercapto acetate (1.11 g, 10.5 mmol) in DMF (21 mL), and the mixture was stirred at room temperature overnight. Water (100 mL) was added thereto, then the reaction solution was stirred at room temperature for 1 hour, and then the obtained precipitate was filtered out and dried to obtain the title compound (2.35 g, 94%). 1H-NMR (d-DMSO): delta 9.00 (s, 1H), 8.47-8.42 (m, 1H), 8.40-8.28 (m, 2H), 3.92 (s, 3H).
66%
Methyl thioglycolate (19.62 mL, 0.216 mol) was added dropwise, via syringe pump, to a stirred suspension of 95% sodium hydride (5.99 g, 0.237 mol) in dry N,N-dimethyl- formamide (400 mL) at r.t. under nitrogen (CAUTION : hydrogen evolution). Upon complete addition, the reaction was stirred for 10 min and then a solution of 2-chloro-5- nitrobenzaldehyde (40.0 g, 0.216 mol) in DMF (120 mL) was added. The solution turned orange and a gentle exotherm was observed. After Ih, the now yellow mixture was heated to 100 C for 5 h. The mixture turned amber in appearance. After cooling to r.t. the mixture was poured into 1 N aqueous hydrochloric acid (500 mL). The resulting yellow precipitate was filtered off and washed with water (250 mL). The solid was suspended in hot methanol / ethyl acetate (1:1) (1000 mL) and allowed to cool to r.t. The EPO <DP n="28"/>resulting solid was filtered off and air dried to yield methyl 5-nitrobenzo[b]thiophene-2- carboxylate (33.77 g, 66%) as a tan amorphous solid. 1H NMR delta Cd6-DMSO, 400 MHz) 3.92 (s, 3 H), 8.32 (dd, / = 9, 2 Hz, 1 H), 8.37 (d, / = 9 Hz, 1 H), 8.45 (s, 1 H), 9.00 (d, / = 2 Hz, 1 H).
61 g (95%)
With sodium methylate; In methanol;
Preparation of Methyl 5-Nitrobenzo[b]thiophene-2-Carboxylate A 2000 ml 3-necked round-bottomed flask, 250 ml pressure equalized dropping funnel, Teflon stirrer, and gas inlet were oven-dried for 12 hours at 160 C. The apparatus was rapidly assembled, fitted with a thermometer, flushed with dry nitrogen gas, and allowed to cool to room temperature. The cooled flask was charged with methanol (600 ml) and methyl thioglycolate (28.6 g, 0.27 mole). Sodium methoxide (19,98 g, 0.37 mole) in methanol (125 ml) was added to the reaction mixture over 10 minutes while stirring. The reaction mixture was then warmed to 40 C. and a solution of 2-chloro-5-nitrobenzaldehyde (28.6 g, 0.27 mole) in methanol (300 ml) was added over a period of about 20 minutes. The resulting slurry was stirred at 40 C. for 1 hour, cooled to room temperature, and acidified with 2M hydrochloric acid. The resulting white solid was filtered, washed with water (2*300 ml) and air-dried to give 61 g (95%) of methyl 5-nitrobenzothiophene-2-carboxylate. See, R. A. Zambias, M. L. Hammond, Synthetic Communications, 21:959 (1991).
With hydrogenchloride; sodium methylate; In methanol; at 40 - 50℃; for 1.5h;Inert atmosphere;
To a solution of methyl thioglycolate (530 mg, 5 mmol) in absolute methanol (20 mL) at 40 C was added a solution of sodium methoxide (320 mg, 6 mmol) in methanol (5 mL). The reaction mixture was heated to 50 C and treated drop wise a solution of 2-chloro-5-nitro benzaldehyde (49) (1 g, 5 mmol) in methanol (10 mL) was added drop wise. A precipitate was formed during the addition. The resulting suspension was heated at 60 C for 1.5 h and cooled to RT. A solution of sodium hydroxide (2 mL, 2.5 N solution) was added and the reaction mixture was refluxed for 2 h, cooled to 0 C and acidified with conc. hydrochloric acid (pH 4). The resulting solid was isolated by filtration, redissolved in hot sodium hydroxide solution, and acidified with drop wise addition of conc. hydrochloric acid. The solid obtained was isolated by filtration, washed with water, co-evaporated with toluene, and dried to get 880 mg 5-nitrobenzothiophene-2-carboxylic acid (50) (74%).
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 4h;
88%
With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃;
85%
With potassium carbonate In ethanol at 20℃; for 10h;
General procedure for preparation of benzo[b]thiophene-2-carboxylate derivatives (11a and 11b)
General procedure: To a stirred solution of 2-chloro-5-nitrobenzaldehyde 9 or 1-(2-chloro-5-nitrophenyl)ethanone 10 (27 mmol) in ethanol(30mL), were added ethyl 2-mercaptoacetate (27mmol) andK2CO3 (36 mmol). Stirring was continued at room temperatureovernight and monitored by TLC (EA: n-Hex=7:3) (Xuet al. 2017). After completion of the reaction, the precipitatewas filtered and recrystallized from ethyl acetate to obtaincompounds 11a and 11b. Ethyl 5-nitrobenzo[b]thiophene-2-carboxylate (11a).Time = 10 h, Yield: 85%, m.p. 162-163 °C; lit.165 °C.(Prez-Silanes et al. 2001). IR (KBr, cm-1): 3085, 2987,2921, 1718, 1541, 1515.
85%
With potassium carbonate In ethanol at 20℃;
4.2.1 General procedure for preparation of benzo[b]thiophene-2-carboxylate derivative (3)
To a stirred solution of 2-chloro-5-nitrobenzaldehyde 2 (10mmol, 1,85gr) in ethanol (30mL), were added ethyl 2-mercaptoacetate (12mmol, 1.09gr) and K2CO3 (15mmol, 2.07gr). Stirring was continued at room temperature overnight and monitored by TLC (EA: n-Hex=7:3) [34]. After completion of the reaction, the precipitate was filtered and recrystallized from the ethyl acetate to obtain compounds 3. Ethyl 5-nitrobenzo[b]thiophene-2-carboxylate (3) m.p. 162-163°C; lit. 165°C [35]. Yield: 85%. IR (KBr): 3085, 2987, 2921, 1718, 1541, 1515cm-1.
With sodium ethanolate In ethanol
With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃;
To a solution of 2-chloro-5-nitro- benzaldehyde (31.01 g, 167.1 mmol) in 330 mL of anhydrous DMF at 00C was added K2CO3 (27.80 g, 201.1 mmol), followed by slow addition of mercapto-acetic acid ethyl ester (18.5 mL, 168.7mmol). After stirring at 00C for 20 min, the resulting mixture was allowed to warm to rt and stir at it overnight. The reaction mixture was then poured into 1.5 L of water. The solid formed was filtered and washed with 600 mL of water. After drying, 5-nitro-benzo[b]thiophene-2-carboxylic acid ethyl ester was obtained as pale solid. MS (EI): cal'd 252.0 (MH+), exp 252.1 (MH+).
With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃;
1
5-Nitro-benzo[b]thiophene-2-carboxylic acid ethyl ester. To a solution of 2-chloro-5-nitro- benzaldehyde (31.01 g, 167.1 mmol) in 330 mL of anhydrous DMF at 00C was added K2CO3 (27.80 g, 201.1 mmol), followed by slow addition of mercapto-acetic acid ethyl ester (18.5 mL, 168.7mmol). After stirring at 00C for 20 min, the resulting mixture was allowed to warm to it and stir at rt overnight. The reaction mixture was then poured into 1.5 L of water. The solid formed was filtered and washed with 600 mL of water. After drying, 5-nitro-benzo[b]thiophene-2-carboxylic acid ethyl ester was obtained as pale solid. MS (EI): cal'd 252.0 (MH+), exp 252.1 (MH+)
With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃;
A1
To a solution of 2-chloro-5-nitro- benzaldehyde (31.01 g, 167.1 mmol) in 330 mL of anhydrous DMF at 00C was added K2CO3 (27.80 g, 201.1 mmol), followed by slow addition of mercapto-acetic acid ethyl ester (18.5 mL, 168.7mmol). After stirring at 00C for 20 min, the resulting mixture was allowed to warm to rt and stir at it overnight. The reaction mixture was then poured into 1.5 L of water. The solid formed was filtered and washed with 600 mL of water. After drying, 5-nitro-benzo[b]thiophene-2-carboxylic acid ethyl ester was obtained as pale solid. MS (EI): cal'd 252.0 (MH+), exp 252.1 (MH+).
With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃;
1
5-Nitro-benzo [blthiophene-2-carboxylic acid ethyl ester. To a solution of 2-chloro-5-nitro- benzaldehyde (31. 01 g, 167. 1 mmol) in 330 mL of anhydrous DMF at 0 °C was added K ; C03 (27.80 g, 201.1 mmol), followed by slow addition of mercapto-acetic acid ethyl ester (18. 5 mL, 168.7mmol). After stirring at 0 °C for 20 min, the resulting mixture was allowed to warm to rt and stir at rt overnight. The reaction mixture was then poured into 1.5 L of water. The solid formed was filtered and washed with 600 mL of water. After drying, 5-nitro-benzo [b] thiophene-2-carboxylic acid ethyl ester was obtained as pale solid. MS (El) : cal'd 252.0 (MH+), exp 252.1 (MH+).
Stage #1: 2-chloro-5-nitrobenzaldehyde With sodium sulfide In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 12h;
Stage #2: (S)-(9H-fluoren-9-yl)methyl 1-chloro-3-methyl-1-oxobutan-2-ylcarbamate In tetrahydrofuran; N,N-dimethyl-formamide at -78 - -50℃; for 3h;
Stage #1: 2-chloro-5-nitrobenzaldehyde With 7% w/w Pd/C In water Green chemistry;
Stage #2: With sodium tetrahydroborate; water for 0.233333h; Reflux; Green chemistry;
General procedure for the reduction of nitroarenes to arylamines catalyzedby Pd/C
General procedure: For example, in a round-bottom flask (15 mL) equipped with a magnetic stirrer, a mixture of PhNO2 (1 mmol, 0.123 g) and H2O (2 mL) was prepared. Then, (7wt%) Pd/C (30 mg) was added, and the mixture was stirred. At the next step, NaBH4 (2 mmol, 0.076 g) was added, and the resulting mixture continued to stir at reflux for 7 min. After completion of the reaction (monitored by thin-layer chromatography (TLC) using CCl4:ether (5:2) as an eluent), the mixture was cooled to room temperature, and the mentioned catalytic system was separated by filtration. The reaction mixture was extracted with dichloromethane (DCM)(3 × 5 mL) and then dried over anhydrous sodium sulfate (Na2SO4). Finally, the solvent was evaporated under reduced pressure to afford the pure liquid aniline in 93% yield.
Multi-step reaction with 2 steps
1: 94 percent / NaBH4 / methanol / 24 h / 0 - 25 °C
2: 72 percent / Fe; AcOH / ethanol / 4 h / Heating
Multi-step reaction with 2 steps
1: sodium tetrahydroborate / tetrahydrofuran; methanol / 1 h / 0 °C
2: acetic acid; iron / 3 h / 70 °C / Inert atmosphere
With hydrogenchloride; sodium hydroxide; sodium methylate; In quinoline; methanol; n-heptane; water;
Step 1 Preparation of 5-nitrobenzo[b]thiophene Methyl thioglycolate (14.3 g, 135 mmol) in methanol (250 mL) at 40 C. is treated dropwise with 25% sodium methoxide in methanol (37 mL, 160 mmol) and the resulting mixture mechanically stirred at 50 C. for 30 min. 2-chloro-5-nitrobenzaldehyde in methanol (250 mL) is added in a steady stream to give a heavy precipitate which is heated at 50 C. for 1 h. Sodium hydroxide (50% aqueous, 15 mL) is added and heating continued for 2 h, then cooled to ice bath temperature and acidified with concentrated hydrochloric acid. An additional 200 mL of water is added during this process to facilitate stirring. The resulting solids are collected by filtration, washed with water, and dried in vacuo at 45 C. overnight. The dried solids are suspended in quinoline (120 mL), copper metal (7.2 g) is added and the mixture is heated at 190 C. for 2 hr. The mixture is allowed to cool, then poured onto 500 g of ice, 6 N hydrochloric acid (500 mL) is added and then extracted with of dichloromethane. The organic layers are combined and washed with 6 N hydrochloric acid, dried, and flash chromatographed on silica gel eluding with 10-40% ethyl acetate in heptane to give 16.2 g (81%) of the title compound. 1H NMR (CDCl3) delta8.75 (s, 1 H), 8.22 (dd, J=2.3, 10 Hz, 1 H), 8.0 (d, J=10 Hz, 1 H), 7.68 (d, J=6 Hz, 1 H), 7.53 (d, J=6 Hz, 1 H); MS (-ESI) m/z 221.8 (M-H)
1 Preparation of N-3-((2-chlorophenoxy)methyl)-4-chlorophenyl-2-methyl-3-furancarbothioamide STR10 Step 1:
Preparation of 2-chloro-5-nitrobenzoyl alcohol 30 g of 2-chloro-5-nitrobenzaldehyde was dissolved in 500 ml of methanol and cooled to 0° C. A solution of 10 g of sodium borohydride in 100 ml of water was then added dropwise over 90 minutes while maintaining the temperature below 10° C. The resultant reaction mixture was then stirred for one hour, then acidified with 2N HCl and left stirring overnight. The solids were then, washed with water and dried, to produce 27 g of 2-chloro-5-nitrobenzyl alcohol as a white solid.
With sodium borohydrid In methanol; water
6.1 UC781-like Phosphonate NNRTI Compounds
Step 1: Preparation of 2-chloro-5-nitrobenzoyl alcohol 30 g of 2-chloro-5-nitrobenzaldehyde was dissolved in 500 mL of methanol and cooled to 0° C. A solution of 10 g of sodium borohydride in 100 mL of water was then added dropwise over 90 minutes while maintaining the temperature below 10° C. The resultant reaction mixture was then stirred for one hour, then acidified with 2N HCl and left stirring overnight. The solids were then, washed with water and dried, to produce 27 g of 2-chloro-5-nitrobenzyl alcohol as a white solid.
With sodium borohydrid In methanol; water
N.4.1 Pyrimidine Example 6
Step 1: Preparation of 2-chloro-5-nitrobenzoyl alcohol 30 g of 2-chloro-5-nitrobenzaldehyde was dissolved in 500 mL of methanol and cooled to 0° C. A solution of 10 g of sodium borohydride in 100 mL of water was then added dropwise over 90 minutes while maintaining the temperature below 10° C. The resultant reaction mixture was then stirred for one hour, then acidified with 2N HCl and left stirring overnight. The solids were then, washed with water and dried, to produce 27 g of 2-chloro-5-nitrobenzyl alcohol as a white solid.
With sodium chloride; In chloroform; ethyl acetate; benzene;
(8) A mixture of 2-chloro-5-nitrobenzaldehyde (3.73 g), <strong>[10495-09-7]ethyl 4,4-diethoxyacetoacetate</strong> (4.365 g) and piperidine (272.5 mg) in benzene (10 ml) was refluxed under azeotropic dehydration for 1.5 hours. To the mixture was added ethyl acetate, and the resultant mixture was washed three times with water and then with an aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvent was removed under reduced pressure to give a reddish brown oil (7.87 g) of ethyl 2-(2-chloro-5-nitrobenzylidene)-4,4-diethoxyacetoacetate. The mixture of thus obtained reddish brown oil and ethyl 3-aminocrotonate (3.48 g) was heated with stirring at 105 to 107 C. in an oil bath for 4.5 hours. The resultant mixture was extracted with ethyl acetate, and the extract was washed with water three times and then with an aqueous solution of sodium chloride, and dried over magnesium sulfate. After removal of the solvent from the extract, the obtained residue (10.87 g) was subjected to column chromatography on silica gel with an eluent (a mixture of 20 parts of chloroform and one part of ethyl acetate by volume). The fractions were checked with thin-layer chromatography and crystals (6.02 g) were obtained by removing the solvent from the fraction containing the designated substance. The crystals were recrystallized from a mixture of diethyl ether and n-hexane to give crystals of diethyl 2-methyl-4-(2-chloro-5-nitrophenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate, m.p. 117 to 118 C.
With potassium fluoride; In N-methyl-acetamide; water;
EXAMPLE 6 18.6 g (0.1 mol) of 2-chloro-5-nitrobenzaldehyde and 11.6 g (0.2 mol) of dry potassium fluoride in 50 ml of dimethylformamide are stirred for 12 hours at 100 C. The solvent is then distilled off in vacuo and the residue is stirred in 100 ml of water. The crude 2-fluoro-5-nitrobenzaldehyde is filtered off under suction, washed with water and dried. 16.7 g of 2-fluoro-5-nitrobenzaldehyde with a content of 96% are obtained. Yield: 94.8% of the theoretical yield.
With potassium fluoride; In N,N-dimethyl-formamide; at 20 - 160℃;
Production Example 28-1 2-Fluoro-5-nitrobenzaldehyde At room temperature, potassium fluoride (15.7 g) was added to a DMF solution (100 mL) of 2-chloro-5-nitrobenzaldehyde (25.0 g). The reaction liquid was stirred at 160 C. for 1.5 hours, then poured into water with ice. After extracted with ethyl acetate, the organic layer was washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1 to 3:1) to obtain the entitled compound (17.1 g).
(2S)-N-methyl-1-phenylpropan-2-amine hydrate[ No CAS ]
[ 96-35-5 ]
[ 6361-21-3 ]
[ 20699-86-9 ]
Yield
Reaction Conditions
Operation in experiment
69%
With potassium carbonate; In N,N-dimethyl-formamide;
Step 1: Methyl-5-nitro-benzo[b]thiophene-2-carboxylate (584) A stirring suspension of 5-nitro-2-chloro-benzaldehyde (4.0 g, 21.6 mmol) in DMF (40 ml) at 5 C. was treated with K2CO3(3.52 g, 25.5 mmol) followed by methylglycolate (1.93 ml, 21.6 mmol). The resulting solution was warmed to 25 C. and stirred for 20 h. The solution was then poured into 250 ml of ice H2O and the white precipitate that formed was collected by filtration. Crystallization from EtOAc afforded fine pale orange needles of 584 (3.54 g, 69%). LRMS: 237.0 (Calc.); 238.1 (found). 1H NMR: (DMSO) delta (ppm): 9.00 (d, J=2.2 Hz, 1H), 8.45 (s, 1H), 8.39-8.30 (m, 2H), 3.93 (s, 3H).
69%
With potassium carbonate; In N,N-dimethyl-formamide;
Step 1: Methyl-5-nitro-benzo[b]thiophene-2-carboxylate (584) A stirring suspension of 5-nitro-2-chloro-benzaldehyde (4.0 g, 21.6 mmol) in DMF (40 ml) at 5 C. was treated with K2CO3(3.52 g, 25.5 mmol) followed by methylglycolate (1.93 ml, 21.6 mmol). The resulting solution was warmed to 25 C. and stirred for 20h. The solution was then poured into 250 ml of ice H2O and the white precipitate that formed was collected by filtration. Crystallization from EtOAc afforded fine pale orange needles of 584 (3.54 g, 69%). LRMS: 237.0 (Calc.); 238.1 (found). 1H NMR: (DMSO) delta (ppm): 9.00 (d, J=2.2 Hz, 1H), 8.45 (s, 1H), 8.39-8.30 (m, 2H), 3.93 (s, 3H).
69%
With potassium carbonate; In N,N-dimethyl-formamide;
Step 1: Methyl-5-nitro-benzo[b]thiophene-2-carboxylate (584) A stirring suspension of 5-nitro-2-chlorobenzaldehyde (4.0 g, 21.6 mmol) in DMF (40 ml) at 5 C. was treated with K2CO3(3.52 g, 25.5 mmol) followed by methylglycolate (1.93 ml, 21.6 mmol). The resulting solution was warmed to 25 C. and stirred for 20 h. The solution was then poured into 250 ml of ice H2O and the white precipitate that formed was collected by filtration. Crystallization from EtOAc afforded fine pale orange needles of 584 (3.54 g, 69%). LRMS: 237.0 (Calc.). 238.1 (found). 1H NMR: (DMSO) delta (ppm): 9.00 (d, J=2.2 Hz, 1H), 8.45 (s, 1H), 8.39-8.30 (m, 2H), 3.93 (s, 3H).
General procedure: Diselenide was added to a solution of thiol (equivalents are given in table) in 2 mL of anhydrous solvent under a N2 atmosphere. The reaction mixture was stirred for 30 min at a given temperature in table. The haloaryl aldehyde (100 mg) was added to the reaction mixture in a portion and the mixture was stirred at a given temperature for 15 min. A base (equivalents are given in table) was added to the reaction mixture and stirring was continued for an additional 15 min. The progress of the reaction was followed by TLC analysis. When the starting material was disappeared, the mixture was concentrated in vacuo and the residue was extracted with CH2Cl2 (3 × 25 mL). The combined organic layer was dried over anhydrous MgSO4 and the solvent was removed in vacuo. The crude product was purified by silica-gel column chromatography, eluting with an ethyl acetate-hexane solution. Yields are given in table.
69%
With 1,4-dithio-D,L-threitol; potassium carbonate; In N,N-dimethyl-formamide; at 80℃;
In Experimental Example 3, in order to prepare a selenyl-substituted aromatic aldehyde-based compound,As the reducing agent, dithiothreitol (DTT) was used,Dimethylformaldehyde (DMF) was used as the solvent.A diselenide compound represented by the above general formula A-Se-Se-A,The aromatic aldehyde-based starting material,And the base was experimented while varying the base without being fixed. Specifically, as the above-mentioned diselenide compound, dimethyldiselenide whose functional group A is methyl group (Me)Diphenyldiselenide wherein the functional group A is a phenyl group (Ph), Or dibenzyldiselenide in which the functional group A is a benzyl group (Bn). As the aromatic aldehyde-based starting material,Having an electron-donating substituent or an electron-withdrawing substituent Various aromatic aldehyde-based materials were used,These more specific formulas are shown in Table 3 below.As the base, K2CO3 which is weak base or DBU which is strong base was used, The bases were used in 2.5 equivalents in all cases. The difference in% yield of the product due to the difference in the reaction conditions is as shown in Table 3 below.In the following Table 3, the reaction condition A is K2CO3 And the reaction temperature was maintained at 80 C, The reaction condition A' was carried out using K2CO3 as the baseWhen the reaction temperature is maintained at room temperature,Reaction condition B is the case where DBU is used as the base, the reaction temperature is maintained at room temperature, and reaction condition C is the case where DBU is used as the base and the reaction temperature is maintained at 80C.
(E)-ethyl α-cyano-2-(heptamethyleneimin-1-yl)-5-nitrocinnamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
In N,N-dimethyl-formamide at 90℃; for 1h; stereoselective reaction;
Typical Experimental Procedure
General procedure: Cyclic secondary amine (2.5 equiv) was treated with 2-halobenzaldehyde (1 mmol) and active methylidene compound (1 mmol) in EtOH (2 mL) or DMF (2 mL). The mixture was stirred and heated to reflux. After the reaction was completed, the mixture was cooled down to r.t. and poured into H2O (10 mL). Crude products were filtered off and purified by recrystallization in EtOH or by column chromatography on silica gel; 52-88% yield.
(E)-α-cyano-3-[5-nitro-2-(heptamethyleneimin-1-yl)phenyl]acrylamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
In N,N-dimethyl-formamide at 90℃; for 0.833333h; stereoselective reaction;
Typical Experimental Procedure
General procedure: Cyclic secondary amine (2.5 equiv) was treated with 2-halobenzaldehyde (1 mmol) and active methylidene compound (1 mmol) in EtOH (2 mL) or DMF (2 mL). The mixture was stirred and heated to reflux. After the reaction was completed, the mixture was cooled down to r.t. and poured into H2O (10 mL). Crude products were filtered off and purified by recrystallization in EtOH or by column chromatography on silica gel; 52-88% yield.
(E)-5-(2-chloro-5-nitrophenyl)-1,1-bis(methylthio)penta-1,4-dien-3-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With sodium hydroxide In ethanol at 0 - 20℃; for 1.5h;
General procedure for the synthesis of 1,1-bis(methylthio)-5-arylpenta-1,4-dien-3-one (2a-y)
General procedure: To a solution of 4,4-bis(methylthio)but-3-en-2-one (1mol) in ethanol (10 ml) were added NaOH (1.5mol) and aryl aldehyde (1.1 mol) under constant stirring. After the starting material was consumed as indicated by TLC, the reaction mixture was poured into ice water and the resulting solid was filtered, washed well with water (20 ml). The solid material obtained was crystallized from ethanol to furnish 81-99% of 1,1-bis(methylthio)-5-arylpenta-1,4-dien-3-one as a yellow solid.
2-(4-isopropylpiperazin-1-yl)-5-nitrobenzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 4h;
A mixture of 2?chloro?5?nitrobenzaldehyde (2 g, 10.8 mmol), 1?isopropylpiperazine (2.07 g, 16.2 mmol) and potassium carbonate (2.68 g, 19.4 mmol) in DMF (10 mL) was heated at 90 °C for 4 h. The reaction mixture wascooled to room temperature and diluted with water. The resulting precipitate was collected by filtration, then washed on the filter with water and dried in a vacuum oven to give the title compound (2.8 g, 96percent) . LCMS (Method A) : = 0.49 mi m/z = 278 [M+H].
2-(2-(2-chloro-5-nitrobenzylidene)hydrazino)-6-fluorobenzothiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With acetic acid; In ethanol; at 80℃; for 0.166667h;Microwave irradiation;
General procedure: 2-(2-Arylidenehydrazino)-6-fluorobenzothiazoles 6a-r. General Procedure D. A mixture of compound 2 (0.0549 g, 0.0003 mol), the appropriate aromatic aldehyde (0.00033 mol) and glacial acetic acid (0.1 mL) in ethanol (5 mL) was heated under microwave (20 W) at 80 °C for 10 min. On cooling, the precipitated solid was collected by filtration, washed with water, dried and crystallized from the appropriate solvent to give the desired compounds 6a-r.
(4H-3,5-dipyridin-2-yl-1,2,4-triazole-4-ylamino) (2-chloro,5-nitrophenyl)methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With hydrazine hydrate In acetonitrile at 50℃; for 9h;
2.4.2. Synthesis of hemiaminals 4-12
General procedure: Compounds 4-6 were synthesized according to the followinggeneral procedure. The corresponding aldehyde (0.34 mmol) in acetonitrile (2 mL) was added to a solution of compound 1(0.34 mmol) in 2.5 ml of acetonitrile and the mixture was then stirred and heated at 50 C for 9 h. After removing volatile components,raw solid products washed with cold acetonitrile, methanol and dried in air. Crystals of hemiaminals were obtained upon slow evaporation of the solvent from the reaction mixtures.
N-(2-formyl-4-nitrophenyl)-2-methoxyacetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
242 mg
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In toluene at 100℃; for 1h; Inert atmosphere;
1.1 1 ) N-(2-formyl-4-nitro-phenyl)-2-methoxy-acetamide
1 ) N-(2-formyl-4-nitro-phenyl)-2-methoxy-acetamide [0184] 2-Methoxyacetamide (196 mg) was dissolved in toluene (7 mL) and under argon were added caesium carbonate (912 mg), 2-chloro-5-nitro-benzaldehyde (371 mg), Xantphos (35.8 mg) and Pd2(dba)3 (18.3 mg). The reaction mixture was heated at 100°C for lh, then cooled to room temperature, poured on a mixture ice/water and extracted twice with ethyl acetate. The organic layers were combined, washed once with water, brine, dried over Na2S04 and concentrated under reduced pressure. The resulting crude product was purified by chromatography to give 242 mg of N-(2-formyl-4-nitro-phenyl)-2-methoxy-acetamide 1H NMR (CDC13, 400 MHz) δ = 12.11 (m, 1H), 10.05 (s, 1 H), 9.02 (d, 1H), 8.63 (d, 1H), 8.46 (dd, 1H), 3.61 (s, 3H), 4.11 (s, 2H) .
(E)-2-((2-chloro-5-nitrobenzylidene)amino)isoindoline-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With acetic acid In ethanol at 60℃; for 1.5h;
11 General method of synthesis of compounds (5a-j)
General procedure: To a solution of the compound 2 (mLeq) in ethanol (10 mL), thecorresponding aromatic aldhyde or sugar aldhyde (mLeq) wasadded and 0.5 mL of acetic acid (33%). The reaction mixture washeated under reflux for 1.5 h and then left to cool to room temperature.The solid that separated out was filtered off, washed withethanol, and dried.
1,1'-((2-chloro-5-nitrophenyl)methylene)bis(3-methylurea)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With silica-bonded N-(propylsulfonyl)piperazine-N-sulfamic acid In toluene for 2.5h; Reflux;
General procedure for synthesis of 1,1'-(arylmethylene) diurea derivatives
General procedure: A mixture of aldehyde (1 mmol), urea (2 mmol), and catalyst (0.07 g) in toluene (10 mL) was heated under reflux, and the reaction was followed by thin-layer chromatography (TLC) analysis. After vigorously stirring for the appropriate time, a white solid was obtained. The mixture was filtered, the residue was diluted with hot ethanol (30 mL) or dimethylformamide (DMF, 5 mL), and the catalyst was filtered using a sintered glass funnel. The catalyst was washed with hot ethanol and the combined solution concentrated under vacuum to afford the product, which was purified by recrystallization. All yields refer to isolated products after purification. All products were characterized by 1H and 13C NMR spectra and melting point. The analytical data for these compounds are presented below.
1,1'-((2-chloro-5-nitrophenyl)methylene)bis(3-phenylurea)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With silica-bonded N-(propylsulfonyl)piperazine-N-sulfamic acid In toluene for 2.5h; Reflux;
General procedure for synthesis of 1,1'-(arylmethylene) diurea derivatives
General procedure: A mixture of aldehyde (1 mmol), urea (2 mmol), and catalyst (0.07 g) in toluene (10 mL) was heated under reflux, and the reaction was followed by thin-layer chromatography (TLC) analysis. After vigorously stirring for the appropriate time, a white solid was obtained. The mixture was filtered, the residue was diluted with hot ethanol (30 mL) or dimethylformamide (DMF, 5 mL), and the catalyst was filtered using a sintered glass funnel. The catalyst was washed with hot ethanol and the combined solution concentrated under vacuum to afford the product, which was purified by recrystallization. All yields refer to isolated products after purification. All products were characterized by 1H and 13C NMR spectra and melting point. The analytical data for these compounds are presented below.
diethyl (2-chloro-5-nitrophenyl)(4-(4-chlorophenoxy)phenylamino)methylphosphonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With ZnBr2/SiO2; In neat (no solvent); for 0.1h;Microwave irradiation; Green chemistry;
General procedure: The mixture of 4-(4-chlorophenoxy)aniline (2) (220 mg,1.0 mmol), 3-nitrobenzaldehyde (3e) (155mg, 1.03 mmol),diethyl phosphite (4) (0.13 mL, 1.0 mmol) and SiO2-ZnBr2 (17.1 mg, 6 molpercent) were taken into a flask. Thereaction mass was irradiated with microwave radiationsfor 4 min using Catalyst systems (CATA-4R,), percentpower is 65percent and 465Watts. Ethyl acetate (10 mL) wasadded to the reaction mixture and stirred for 10 min,after completion of the reaction as checked by TLC.The catalyst, SiO2-ZnBr2 was separated by filtrationas residue, washed with ethyl acetate (2×5mL) andcollected residue was dried under vacuum at 100°C toutilize in further reactions. The combined organic layerwas washed with water (10 mL), dried over anhydrousNa2SO4 and concentrated under vacuum at 50°C toobtain crude mass. The pure compound, diethyl (4-(4-chlorophenoxy)phenylamino)(3-nitrophenyl)methylphosphonate (5e) was isolated by column chromatographyusing 20?60percent ethyl acetate:n-hexane as a mobilephase.
12,12-dimethyl-2-nitro-12,13-dihydroimidazo[4,5,1-de]quinolino[4,3,2-mn]acridin-14(11H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With copper(l) iodide; caesium carbonate; L-proline; In 1,4-dioxane; for 10h;Reflux;
General procedure: A dry 50 mL flask was charged with 2-halogenated aromatic aldehyde 1 (1.0 mmol), 1H-benzo[d]imidazol-5-amine (0.133 g,1.0 mmol), cyclohexane-1,3-diones (1.0 mmol), CuI (10 mg), L-proline(6 mg), Cs2CO3 (650 mg) and dioxane (10 mL). The reaction mixture was stirred at reflux for 10-18 h. After completion of the reaction, as indicated by TLC, the solid was filtered off by a fast and hot filtration, and the products of 4 were obtained as pale yellow powder or crystals, when the mixture was allowed to cool down to room temperature.
2-[allyl(methyl)amino]-5-nitrobenzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h;
General procedure: A stirred solution of compound 9a,d,e (13 mmol) in DMF(20 ml) was treated with N-methylprop-2-en-1-amine (1.11 g,15.6 mmol), followed by K2CO3 (2.70 g, 19.5 mmol). Theresulting solution was stirred for 2 h at 120C. Aftercooling to room temperature, water (120 ml) was added,and the mixture was extracted with EtOAc (2×40 ml). Thecombined organic layers were washed with water (30 ml),dried over anhydrous Na2SO4, and concentrated in vacuo.Purification by flash column chromatography (20:1 petroleum ether-EtOAc, v/v) afforded the desired product 10a,e,f.
With potassium hydroxide In ethanol at 20℃; for 24h;
1-(2,5-Dimethyl thiophen-3-yl)-3-(aryl substituted) prop-2-en-1-ones (3a-m)
General procedure: A solution of 3-acetyl-2,5-dimethyl thiophene (0.01 mol) in ethanol (10 ml) was added to 10% KOH (10 ml) solution and substituted aromatic aldehyde (0.01 mol) was added to the mixture, the mixture was kept at room temperature for 24 hr. On acidification with 1:1 HCl, the chalcone precipitated out which was filtered and recrystallized from ethanol. The physical data of compounds (3a-m) are given in Table-1.
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