* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With vasicine In ethylene glycol at 80℃; for 48 h;
General procedure: The mixture of nitrocompound (0.5 mmol) and vasicine (0.5 mmol) in ethylene glycol (2 mL) was stirred at 80°C for 24-48 h. Time was not optimized separately for all substrates. After completion of reaction as monitored by TLC, the reaction mixture was cooled to ambient temperature and extracted with ethyl acetate. The ethyl acetate layer was dried under reduced pressure using rotatory evaporator. The crude was chromatographed over silica gel to afford the desired product.
64%
With iron; acetic acid In ethanol at 0℃; for 0.666667 h; Inert atmosphere
To a solution of 4-bromo-2-nitrobenzaldehyde (10 g, 43.47 mmol) in EtOH (50 mL) andacetic acid (50 mL) was added Fe powder (7.28 g, 130.42 mmol). The mixture was stirred at0 °C for 40 mm under a nitrogen atmosphere. Insoluble solid was filtered off and the filtratewas adjusted to pH= 8 by progressively adding solid NaI-1C03. The resulting solution wasextracted with EtOAc (300 mL x 2), washed with saturated NaHCO3 (100 mL) and brine(100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The cruderesidue was purified by silica gel chromatography (petroleum ether EtOAc = 10: 1) to givethe title compound (6 g, 64 percent) as a yellow solid. ‘1-1 NMR (400 Mhz, DMSO-d6) 6 9.79 (s, IH), 7.48 (d,J= 8.4 Hz, IH), 7.27 (s, 2H), 6.99 (s, 1H), 6.78 (d,J 8.0 Hz, IH).
38%
With iron; acetic acid In ethanol at 20℃; for 1.5 h;
Step 3. 2-Amino-4-bromobenzaldehyde To a 0.2M solution of 4-bromo-2-nitrobenzaldehyde in acetic acid and ethanol (v/v 1:1) solvent system was added iron powder. The reaction mixture was stirred at ambient temperature under <n="335"/>PP028218.0002Argon for 1.5 h and LCMS showed the reaction was complete. Insoluble solid was filtered off and the filtrate was concentrated in vacuum. Residue was diluted with ethyl acetate and was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. Crude product was purified by Biotage using 15percent ethyl acetate in hexane to give desired product in 38percent yield. ES/MS m/z 200/202 (MH+).
Reference:
[1] Tetrahedron Letters, 2016, vol. 57, # 45, p. 5003 - 5008
[2] Patent: WO2016/86200, 2016, A1, . Location in patent: Page/Page column 219
[3] Patent: WO2007/117607, 2007, A2, . Location in patent: Page/Page column 333-334
[4] Chemische Berichte, 1909, vol. 42, p. 3697
[5] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 7, p. 2462 - 2467
[6] Synthesis, 2010, # 10, p. 1678 - 1686
[7] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6829 - 6833
[8] Patent: WO2016/30443, 2016, A1, . Location in patent: Page/Page column 99-100
2
[ 5551-12-2 ]
[ 59278-65-8 ]
Reference:
[1] Patent: US6599917, 2003, B1,
3
[ 60956-26-5 ]
[ 59278-65-8 ]
Reference:
[1] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 7, p. 2462 - 2467
4
[ 99474-21-2 ]
[ 59278-65-8 ]
Reference:
[1] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 7, p. 2462 - 2467
5
[ 99277-71-1 ]
[ 59278-65-8 ]
Reference:
[1] Patent: WO2007/117607, 2007, A2,
6
[ 22996-19-6 ]
[ 59278-65-8 ]
Reference:
[1] Patent: WO2007/117607, 2007, A2,
7
[ 5551-12-2 ]
[ 59278-65-8 ]
Reference:
[1] Chemische Berichte, 1909, vol. 42, p. 3697
With p-toluenesulfonic acid monohydrate In toluene for 3 h; Reflux
A mixture of 3,3-diethoxypropanenitrile (1.80 mL, 12.00 mmol), 2-amino-4- bromobenzaldehyde (2 g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (0.380 g, 2.000 mmol) in toluene (30 mL) was heated under reflux using Dean-Stark apparatus for 3 h. The reaction was cooled, evaporated under reduced pressure, and the residue was dissolved in a small amount of DMF, diluted with chloroform, and washed with aq. sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the combined extracts were washed with brine, dried (Na2S04), and concentrated in vacuo. Purification by flash chromatography (0-3percent methanol in dichloromethane) followed by trituration in diethyl ether provided the title compound (1.75 g, 75percent). 1H NMR (400 MHz, DMSO-de) δ ppm 7.95 (dd, J=8.72, 1.89 Hz, 1 H) 8.08 (d, J=8.84 Hz, 1 H) 8.38 (d, J=2.02 Hz, 1 H) 9.13 (d, J=1.52 Hz, 1 H) 9.21 (d, 1 H).
75%
With toluene-4-sulfonic acid In toluene for 3 h; Dean-Stark; Reflux
A mixture of 3,3-diethoxypropanenitrile (1.80 mL, 12.00 mmol), 2-amino-4-bromobenzaldehyde (2g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (0.380 g, 2.000 mmol) in toluene (30 mL) was heated under reflux using Dean-Stark apparatusfor 3 h. The reaction was cooled, evaporated under reduced pressure, and the residue was dissolved in a small amount of N,N-dimethylformamide, diluted with chloroform, and washed with aq sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the combined extracts were washed with brine, dried (Na2504), and concentrated in vacuo. Purification of the residue by flash chromatography (0-3percentmethanol in dichloromethane) followed by trituration in diethyl ether provided the titlecompound (1.75 g, 75percent). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.95 (dd, J=8.72, 1.89Hz, 1H) 8.08 (d, J=8.84 Hz, 1H) 8.38 (d, J=2.02 Hz, 1H) 9.13 (d, J=1.52 Hz, 1H) 9.21(d, 1H).
75%
With toluene-4-sulfonic acid In toluene for 3 h; Reflux
a) 7-bromoquinoline-3 -carbonitrileA mixture of 3,3-diethoxypropanenitrile (1.801 mL, 12.00 mmol),2-amino-4-bromobenzaldehyde (2 g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (0.380 g, 2.000 mmol) in toluene (30 mL) was heated under reflux using Dean-Starkapparatus for 3 h. The reaction was cooled, evaporated under reduced pressure, and the residue was dissolved in a small amount of DMF, diluted with chloroform, and washed with aq. NaHCO3 solution. The aqueous layer was extracted with chloroform, and the combined extracts were washed with brine, dried (Na2504), and concentrated in vacuo. Purification by flash chromatography (0-3percent methanol in dichloromethane) followed by trituration in diethylether provided the title compound (1.75 g, 75percent). ‘H NMR (400 MHz, DMSO-d6) ö ppm7.95 (dd, J8.72, 1.89 Hz, 1 H) 8.08 (d, J8.84 Hz, 1 H) 8.38 (d, J2.02 Hz, 1 H) 9.13 (d, J1.52 Hz, 1 H) 9.21 (d, 1 H).
75%
With toluene-4-sulfonic acid In toluene for 3 h; Reflux; Dean-Stark
A mixture of 3,3-diethoxypropanenitrile (1.80 mL, 12.00 mmol), 2-amino-4- bromobenzaldehyde (2 g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (0.380 g, 2.000 mmol) in toluene (30 mL) was heated under reflux using Dean-Stark apparatus for 3 h. The reaction was cooled, evaporated under reduced pressure, and the residue was dissolved in a small amount of DMF, diluted with chloroform, and washed with aq. sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the combined extracts were washed with brine, dried (Na2S04), and concentrated in vacuo. Purification by flash chromatography (0-3percent methanol in dichloromethane) followed by trituration in diethyl ether provided the title compound (1.75 g, 75percent). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.95 (dd, J=8.72, 1.89 Hz, 1 H) 8.08 (d, J=8.84 Hz, 1 H) 8.38 (d, J=2.02 Hz, 1 H) 9.13 (d, J=1.52 Hz, 1 H) 9.21 (d, 1 H)
With toluene-4-sulfonic acid In toluene at 110℃; for 3 h; Dean-Stark
A mixture of 2-chloro-1 , 1-diethoxyethane (4.50 ml_, 30.0 mmol), 2-amino-4- bromobenzaldehyde (3.00 g, 15.0 mmol), and p-toluenesulfonic acid monohydrate (0.285 g, 1.500 mmol) in toluene (50 ml_) was heated at 110 °C for 3 hours using a Dean/Stark trap. The solvent was then evaporated and the residue partitioned between ethyl acetate and saturated aq NaHC03. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were evaporated onto silica gel and purified by flash chromatography (20-50percent dichloromethane/hexanes) to give the title product (1.97 g, 8.12 mmol, 54percent yield) as a yellow solid. MS (ES+) m/e 241.8/243.8 Br pattern [M+H]+; H NMR (400 MHz, DMSO-d6) δ ppm 7.85 (dd, J=8.84, 2.02 Hz, 1 H) 7.98 (d, J=8.59 Hz, 1 H) 8.29 (d, J=1.77 Hz, 1 H) 8.65 (d, J=2.02 Hz, 1 H) 8.94 (d, J=2.53 Hz, 1 H).
With potassium hydroxide In ethanol for 3 h; Inert atmosphere; Reflux
A solution of KOH (5.61 g, 100 mmol) dissolved in ethanol (50 mL) was added drop wise to a mixture of 2-amino-4-bromobenzaldehyde (60.6 g, 303 mmol) and propionaldehyde (17.6 g, 303 mmol) in absolute ethanol (200 mL) under nitrogen. The mixture was heated to reflux, and then maintained at reflux for 3 h. After cooling to room temperature, the reaction mixture was concentrated to remove the ethanol, then water was added and the mixture was extracted with methylene chloride (3 x 100 mL). The combined organic layers were washed with water, dried over sodium sulfate, and concentrated in vacuo. The crude material was triturated from diethyl ether to provide the title product (48.6 g, 219 mmol, 72percent yield) as a light brown solid. MS(ES) m/e 221.9, 223.9 [M+H]+ (bromine pattern).
2.5 g
With potassium hydroxide In ethanol; water at 95℃;
To a solution of 4-bromo-2-nitrobenzaldehyde (5 g, 21.7 mmol) in ethanol (50 mL), iron powder (4.85 g, 86.9 mmol ) was added followed by HCl aqueous solution (0.1 N, 15 mL) . The resulting reaction mixture was vigorously stirred at 95 °C for 2 h. The reaction progression was followed by TLC. When the reduction was completed, propionaldehyde (1 .5 mL, 21.7 mmol) and KOH (1.46 g, 26.0 mmol, in two portions) were added at rt. The reaction mixture was stirred at 95 °C overnight. It was cooled to rt, diluted with DCM (30 mL) and filtered through celite. The filtrate was washed with water (50 mL) and the aqueous layer was extracted with DCM (2 x 100 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography, affording the title compound. Yield: 52percent (2.5 g, Pale yellow solid). 1 H NMR (400 MHz, DMSO-d6): δ 8.81 (s, 1H), 8.18-8.17 (m, 2H), 7.89 (d, J = 8.7 Hz, 1H), 7.72 (dd, J = 1.9, 8.7 Hz, 1H), 2.50 (s, 3H). LCMS: (Method D) 223.9 (M+H), Rt. 2.48 min, 99.58percent (Max).
With toluene-4-sulfonic acid In toluene for 18 h; Reflux; Inert atmosphere
To a solution of 2-amino-4-bromobenzaldehyde (6 g, 28.2 mmol) in toluene (50 mE) was added (E)- 1 -ethoxyprop- 1 -ene (6.07g, 70.49mmol) and 4-methylbenzcnesulfonic acid (0.49 g, 2.82 mmol). The mixture was heated to reflux for 18 h under a nitrogen atmosphere. Aftercooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether EtOAc = 5 : 1) to give the title compound (4 g, 57 percent) as a yellow solid. ‘H NMR (400 MHz, DMSO-d6) 6 8.80 (s, IH), 8.19-8.17 (m, 2H), 7.88 (d,J= 8.8 Hz, 1H). 7,73 -7.70 (m, 11-1), 2.47 (s, 3H).
With p-toluenesulfonic acid monohydrate; sodium sulfate In chloroformReflux
A I L round bottom flask fitted with a stirbar, a Dean-Stark trap for solvents heavier than water, and a condenser was charged with 2-amino-4-bromobenzaldehyde (20 g, 100 mmol), sodium sulfate (71.0 g, 500 mmol), and /?-toluenesulfonic acid monohydrate (4.75 g, 25.00 mmol). The solids were taken up in anhydrous chloroform (498 mL) and the suspension treated with 1-ethoxyprop-l-ene (14.39 mL, 130 mmol). The mixture was then heated to reflux with stirring overnight. The reaction mixture was cooled to room temperature and transferred to a 2L separatory funnel. The solution was extracted twice with 200 mL saturated aq sodium bicarbonate and once with 200 mL water. The organic layer was isolated and the aqueous layers were combined and re-extracted twice with an additional 100 mL dichloromethane. The organics were then pooled, dried over sodium sulfate, filtered, and concentrated to a residue. The residue was purified by flash chromatography (0.2-1.9percent methanol: dichloromethane). Fractions containing the desired material were pooled and concentrated to afford the title compound as a bright orange solid (5.603 g, 25.2 mmol, 25percent yield). MS(ES)+ m/e 221.8 [M+H]+.
With vasicine; In ethylene glycol; at 80℃; for 48h;
General procedure: The mixture of nitrocompound (0.5 mmol) and vasicine (0.5 mmol) in ethylene glycol (2 mL) was stirred at 80C for 24-48 h. Time was not optimized separately for all substrates. After completion of reaction as monitored by TLC, the reaction mixture was cooled to ambient temperature and extracted with ethyl acetate. The ethyl acetate layer was dried under reduced pressure using rotatory evaporator. The crude was chromatographed over silica gel to afford the desired product.
64%
With iron; acetic acid; In ethanol; at 0℃; for 0.666667h;Inert atmosphere;
To a solution of 4-bromo-2-nitrobenzaldehyde (10 g, 43.47 mmol) in EtOH (50 mL) andacetic acid (50 mL) was added Fe powder (7.28 g, 130.42 mmol). The mixture was stirred at0 C for 40 mm under a nitrogen atmosphere. Insoluble solid was filtered off and the filtratewas adjusted to pH= 8 by progressively adding solid NaI-1C03. The resulting solution wasextracted with EtOAc (300 mL x 2), washed with saturated NaHCO3 (100 mL) and brine(100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The cruderesidue was purified by silica gel chromatography (petroleum ether EtOAc = 10: 1) to givethe title compound (6 g, 64 %) as a yellow solid. ?1-1 NMR (400 Mhz, DMSO-d6) 6 9.79 (s, IH), 7.48 (d,J= 8.4 Hz, IH), 7.27 (s, 2H), 6.99 (s, 1H), 6.78 (d,J 8.0 Hz, IH).
38%
With iron; acetic acid; In ethanol; at 20℃; for 1.5h;
Step 3. 2-Amino-4-bromobenzaldehyde To a 0.2M solution of 4-bromo-2-nitrobenzaldehyde in acetic acid and ethanol (v/v 1:1) solvent system was added iron powder. The reaction mixture was stirred at ambient temperature under <n="335"/>PP028218.0002Argon for 1.5 h and LCMS showed the reaction was complete. Insoluble solid was filtered off and the filtrate was concentrated in vacuum. Residue was diluted with ethyl acetate and was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. Crude product was purified by Biotage using 15% ethyl acetate in hexane to give desired product in 38% yield. ES/MS m/z 200/202 (MH+).
With hydrogenchloride; iron; In ethanol; water; at 95℃; for 2h;
To a solution of 4-bromo-2-nitrobenzaldehyde (5 g, 21.7 mmol) in ethanol (50 mL), iron powder (4.85 g, 86.9 mmol ) was added followed by HCl aqueous solution (0.1 N, 15 mL) . The resulting reaction mixture was vigorously stirred at 95 C for 2 h. The reaction progression was followed by TLC. When the reduction was completed, propionaldehyde (1 .5 mL, 21.7 mmol) and KOH (1.46 g, 26.0 mmol, in two portions) were added at rt. The reaction mixture was stirred at 95 C overnight. It was cooled to rt, diluted with DCM (30 mL) and filtered through celite. The filtrate was washed with water (50 mL) and the aqueous layer was extracted with DCM (2 x 100 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography, affording the title compound. Yield: 52% (2.5 g, Pale yellow solid). 1 H NMR (400 MHz, DMSO-d6): delta 8.81 (s, 1H), 8.18-8.17 (m, 2H), 7.89 (d, J = 8.7 Hz, 1H), 7.72 (dd, J = 1.9, 8.7 Hz, 1H), 2.50 (s, 3H). LCMS: (Method D) 223.9 (M+H), Rt. 2.48 min, 99.58% (Max).
Step 4. 7-Bromoquinazolin-2-olA mixture of <strong>[59278-65-8]2-amino-4-bromobenzaldehyde</strong> (leq) and urea (14eq) was heated to 180 0C in an oil bath under Argon for 1 h. Water was added to after cooling to ambient temperature. The solid was collected by filtration and air dried to give product in 95% yield. ES/MS m/z 225/227 (MH+).
93%
at 180℃; for 2h;
A mixture of <strong>[59278-65-8]2-amino-4-bromo-benzaldehyde</strong> (13g, 65 mmol) and urea ( 54.6 g, 910 mmol ) was heated to 180C in an oil bath for 2 hours. Then the reaction was cooled to room temperature and H20 (500 mL ) was added. The reaction mixture was stirred at room temperature for 1 hour. The solid was collected by filtration to obtain 1 5 intermediate 412 ( 16 g, 93% yield ) as white solid.
With hydrogenchloride; ammonia; In methanol; water;
c 2-Amino-4-bromobenzaldehyde 16.1 ml of an aqueous 29% ammonia solution was added to a mixture of 5.0 g of 2-nitro-4-bromobenzaldehyde, 60.4 g of iron (II) sulfate heptahydrate, 200 ml of methanol, 100 ml of water and 335 mul of concentrated hydrochloric acid in an oil bath kept at 90 C., followed by heating under stirring for 10 minutes. After cooling as it was, insoluble matters were filtered through Celite and the filtrate was extracted with ethyl acetate. The organic phase was washed with brine and the solvent was removed, to give 3.9 g of the target compound. 1H-NMR (CDCl3) delta=6.17 (2H, br.s), 6.84-6.89 (2H, m), 7.33 (1H, d, J=8 Hz), 9.82 (1H, s).
With toluene-4-sulfonic acid; In toluene; for 4h;Reflux;
intermediate 395 intermediate 396 A mixture of intermediate 395 (22. 1 g, 84.0 mmol ), 4-bromo-2-amino-benzaidehyde ( 14 g, 70.0 mmol) and p-MeC6H SO ,H.H:0 (13.3 g, 70.0 mmol) in PhMe (200 niL) was reflu ed for 4 hours. The mixture was cooled and filtered. The solid was washed with toluene to give the crude PTSA-salt of the product as a brown sol id. The solid w as stirred in saturated aq. sodium bicarbonate and extracted w ith dichloromethane The solvent was evaporated and the residual solid was slurried in ethanol and collected to obtain intermediate 396 ( 14.2 g, 56% yield ).
45%
With p-toluenesulfonic acid monohydrate; In toluene;Reflux;
mixture of 2-(2,2-diethoxyethyl)isoindoline-l,3-dione (3.16 g, 12.00 mmol), 2- amino-4-bromobenzaldehyde (2 g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (1.902 g, 10.00 mmol) in toluene (60 mL) was heated under reflux using Dean-Stark apparatus overnight. A very dark/black solid precipitated overnight and was collected, washed with toluene and hexanes, then dissolved in chloroform fortified with DMF. The mixture was washed with aq. NaHC03 solution (x 2), ensuring any precipitate was dissolved in additional chloroform during separation. The organic layer was dried (sodium sulfate) and evaporated onto silica gel. Purification by flash chromatography (0-2% methanol in dichloromethane) afforded the title compound (1.6 g, 45%). 1H NMR (400MHz, DMSO-d6) delta ppm 9.05 (d, 1 H), 8.57 (d, J= 2.3 Hz, 1 H), 8.35 (d, J= 1.8 Hz, 1 H), 8.11 (d, J= 8.6 Hz, 1 H), 8.09 - 8.02 (m, 2 H), 8.02 - 7.93 (m, 2 H), 7.87 (dd, J= 1.9, 8.7 Hz, 1 H).
45%
With toluene-4-sulfonic acid; In toluene;Reflux; Dean-Stark;
A mixture of 2-(2,2-diethoxyethyl)isoindoline-1 ,3-dione (3.16 g, 12.00 mmol), 2- amino-4-bromobenzaldehyde (2 g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (1.902 g, 10.00 mmol) in toluene (60 mL) was heated under reflux using Dean-Stark apparatus overnight. A very dark/black solid precipitated overnight and was collected,washed with toluene and hexanes, then dissolved in chloroform fortified with N,Ndimethylformamide. The mixture was washed with aq NaHCO3 solution (x2), ensuring any precipitate was dissolved in additional chloroform during separation. The organic layer was dried (sodium sulfate) and evaporated onto silica gel. Purification of the solid by flash chromatography (0-2% methanol in dichloromethane) afforded the titlecompound (1.6 g, 45%). 1H NMR (400MHz, DMSO-d6) delta ppm 9.05 (d, 1H), 8.57 (d, J =2.3 Hz, 1H), 8.35 (d, J = 1.8 Hz, 1H), 8.11 (d, J = 8.6 Hz, 1H), 8.09-8.02 (m, 2H),8.02 - 7.93 (m, 2H), 7.87 (dd, J = 1.9, 8.7 Hz, 1H).
45%
With toluene-4-sulfonic acid; In toluene;Reflux;
a) 2-(7-bromoquinolin-3 -yl)isoindoline- 1,3 -dioneA mixture of 2-(2,2-diethoxyethyl)isoindoline- 1,3 -dione (3.16 g, 12.00 mmol), <strong>[59278-65-8]2-amino-4-bromobenzaldehyde</strong> (2 g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (1.902 g, 10.00 mmol) in toluene (60 mL) was heated under reflux using Dean-Starkapparatus overnight. A very dark/black solid precipitated overnight and was collected, washed with toluene and hexanes, then dissolved in chloroform fortified with DMF. The mixture was washed with aq. NaHCO3 solution (x2), ensuring any precipitate was dissolved in additional chloroform during separation. The organic layer was dried (sodium sulfate) and evaporated onto silica gel. Purification by flash chromatography (0-2% methanol in dichioromethane) afforded the title compound (1.6 g, 45%). ?H NMR (400MHz, DMSO-d6)o ppm 9.05 (d, 1 H), 8.57 (d, J= 2.3 Hz, 1 H), 8.35 (d, J= 1.8 Hz, 1 H), 8.11 (d, J 8.6 Hz, 1H), 8.09 - 8.02 (m, 2 H), 8.02 - 7.93 (m, 2 H), 7.87 (dd, J= 1.9, 8.7 Hz, 1 H).
45%
With toluene-4-sulfonic acid; In toluene;Reflux; Dean-Stark;
A mixture of 2-(2,2-diethoxyethyl)isoindoline-l,3-dione (3.16 g, 12.00 mmol), 2- amino-4-bromobenzaldehyde (2 g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (1.902 g, 10.00 mmol) in toluene (60 mL) was heated under reflux using Dean-Stark apparatus overnight. A very dark/black solid precipitated overnight and was collected, washed with toluene and hexanes, then dissolved in chloroform fortified with DMF. The mixture was washed with aq. NaHC03 solution (x2), ensuring any precipitate was dissolved in additional chloroform during separation. The organic layer was dried (sodium sulfate) and evaporated onto silica gel. Purification by flash chromatography (0-2% methanol in dichloromethane) afforded the title compound (1.6 g, 45%). 1H NMR (400MHz, DMSO-d6) delta ppm 9.05 (d, 1 H), 8.57 (d, J= 2.3 Hz, 1 H), 8.35 (d, J= 1.8 Hz, 1 H), 8.11 (d, J= 8.6 Hz, 1 H), 8.09 - 8.02 (m, 2 H), 8.02 - 7.93 (m, 2 H), 7.87 (dd, J= 1.9, 8.7 Hz, 1 H).
45%
With toluene-4-sulfonic acid; In toluene;Dean-Stark; Reflux;
A mixture of 2-(2,2-diethoxyethyl)isoindoline-1 ,3-dione (3.16 g, 12.00 mmol), 2- amino-4-bromobenzaldehyde (2 g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (1.902 g, 10.00 mmol) in toluene (60 ml_) was heated under reflux using Dean-Stark apparatus overnight. A very dark/black solid precipitated overnight and was collected, washed with toluene and hexanes, then dissolved in chloroform fortified with DMF. The mixture was washed with aq. NaHC03 solution (2x), ensuring any precipitate was dissolved in additional chloroform during separation. The organic layer was dried (sodium sulfate) and evaporated onto silica gel. Purification by flash chromatography (0- 2% methanol in dichloromethane) afforded the title compound (1.6 g, 45%). H NMR (400MHz, DMSO-d6) delta ppm 9.05 (d, 1 H), 8.57 (d, J = 2.2, Hz, 1 H), 8.35 (d, J = 1.8 Hz, 1 H), 8.11 (d, J = 8.6 Hz, 1 H), 8.09 - 8.02 (m, 2 H), 8.02 - 7.93 (m, 2 H), 7.87 (dd, J = 1.9, 8.7 Hz, 1 H).
With p-toluenesulfonic acid monohydrate; In toluene; for 3h;Reflux;
A mixture of 3,3-diethoxypropanenitrile (1.80 mL, 12.00 mmol), 2-amino-4- bromobenzaldehyde (2 g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (0.380 g, 2.000 mmol) in toluene (30 mL) was heated under reflux using Dean-Stark apparatus for 3 h. The reaction was cooled, evaporated under reduced pressure, and the residue was dissolved in a small amount of DMF, diluted with chloroform, and washed with aq. sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the combined extracts were washed with brine, dried (Na2S04), and concentrated in vacuo. Purification by flash chromatography (0-3% methanol in dichloromethane) followed by trituration in diethyl ether provided the title compound (1.75 g, 75%). 1H NMR (400 MHz, DMSO-de) delta ppm 7.95 (dd, J=8.72, 1.89 Hz, 1 H) 8.08 (d, J=8.84 Hz, 1 H) 8.38 (d, J=2.02 Hz, 1 H) 9.13 (d, J=1.52 Hz, 1 H) 9.21 (d, 1 H).
75%
With toluene-4-sulfonic acid; In toluene; for 3h;Dean-Stark; Reflux;
A mixture of 3,3-diethoxypropanenitrile (1.80 mL, 12.00 mmol), <strong>[59278-65-8]2-amino-4-bromobenzaldehyde</strong> (2g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (0.380 g, 2.000 mmol) in toluene (30 mL) was heated under reflux using Dean-Stark apparatusfor 3 h. The reaction was cooled, evaporated under reduced pressure, and the residue was dissolved in a small amount of N,N-dimethylformamide, diluted with chloroform, and washed with aq sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the combined extracts were washed with brine, dried (Na2504), and concentrated in vacuo. Purification of the residue by flash chromatography (0-3%methanol in dichloromethane) followed by trituration in diethyl ether provided the titlecompound (1.75 g, 75%). 1H NMR (400 MHz, DMSO-d6) delta ppm 7.95 (dd, J=8.72, 1.89Hz, 1H) 8.08 (d, J=8.84 Hz, 1H) 8.38 (d, J=2.02 Hz, 1H) 9.13 (d, J=1.52 Hz, 1H) 9.21(d, 1H).
75%
With toluene-4-sulfonic acid; In toluene; for 3h;Reflux;
a) 7-bromoquinoline-3 -carbonitrileA mixture of 3,3-diethoxypropanenitrile (1.801 mL, 12.00 mmol),<strong>[59278-65-8]2-amino-4-bromobenzaldehyde</strong> (2 g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (0.380 g, 2.000 mmol) in toluene (30 mL) was heated under reflux using Dean-Starkapparatus for 3 h. The reaction was cooled, evaporated under reduced pressure, and the residue was dissolved in a small amount of DMF, diluted with chloroform, and washed with aq. NaHCO3 solution. The aqueous layer was extracted with chloroform, and the combined extracts were washed with brine, dried (Na2504), and concentrated in vacuo. Purification by flash chromatography (0-3% methanol in dichloromethane) followed by trituration in diethylether provided the title compound (1.75 g, 75%). ?H NMR (400 MHz, DMSO-d6) oe ppm7.95 (dd, J8.72, 1.89 Hz, 1 H) 8.08 (d, J8.84 Hz, 1 H) 8.38 (d, J2.02 Hz, 1 H) 9.13 (d, J1.52 Hz, 1 H) 9.21 (d, 1 H).
75%
With toluene-4-sulfonic acid; In toluene; for 3h;Reflux; Dean-Stark;
A mixture of 3,3-diethoxypropanenitrile (1.80 mL, 12.00 mmol), 2-amino-4- bromobenzaldehyde (2 g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (0.380 g, 2.000 mmol) in toluene (30 mL) was heated under reflux using Dean-Stark apparatus for 3 h. The reaction was cooled, evaporated under reduced pressure, and the residue was dissolved in a small amount of DMF, diluted with chloroform, and washed with aq. sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the combined extracts were washed with brine, dried (Na2S04), and concentrated in vacuo. Purification by flash chromatography (0-3% methanol in dichloromethane) followed by trituration in diethyl ether provided the title compound (1.75 g, 75%). 1H NMR (400 MHz, DMSO-d6) delta ppm 7.95 (dd, J=8.72, 1.89 Hz, 1 H) 8.08 (d, J=8.84 Hz, 1 H) 8.38 (d, J=2.02 Hz, 1 H) 9.13 (d, J=1.52 Hz, 1 H) 9.21 (d, 1 H)
With p-toluenesulfonic acid monohydrate; sodium sulfate; In chloroform;Reflux;
A I L round bottom flask fitted with a stirbar, a Dean-Stark trap for solvents heavier than water, and a condenser was charged with <strong>[59278-65-8]2-amino-4-bromobenzaldehyde</strong> (20 g, 100 mmol), sodium sulfate (71.0 g, 500 mmol), and /?-toluenesulfonic acid monohydrate (4.75 g, 25.00 mmol). The solids were taken up in anhydrous chloroform (498 mL) and the suspension treated with 1-ethoxyprop-l-ene (14.39 mL, 130 mmol). The mixture was then heated to reflux with stirring overnight. The reaction mixture was cooled to room temperature and transferred to a 2L separatory funnel. The solution was extracted twice with 200 mL saturated aq sodium bicarbonate and once with 200 mL water. The organic layer was isolated and the aqueous layers were combined and re-extracted twice with an additional 100 mL dichloromethane. The organics were then pooled, dried over sodium sulfate, filtered, and concentrated to a residue. The residue was purified by flash chromatography (0.2-1.9% methanol: dichloromethane). Fractions containing the desired material were pooled and concentrated to afford the title compound as a bright orange solid (5.603 g, 25.2 mmol, 25% yield). MS(ES)+ m/e 221.8 [M+H]+.
With toluene-4-sulfonic acid; sodium sulfate; In chloroform;Reflux; Dean-Stark;
A 1 L round bottom flask fitted with a stirbar, a Dean-Stark trap for solvents heavier than water, and a condenser was charged with <strong>[59278-65-8]2-amino-4-bromobenzaldehyde</strong> (20 g, 100 mmol), sodium sulfate (71.0 g, 500 mmol), and p-toluenesulfonic acidmonohydrate (4.75 g, 25.00 mmol). The solids were taken up in anhydrous chloroform (498 mL) and the suspension treated with 1-ethoxyprop-1-ene (14.39 mL, 130 mmol). The mixture was then heated to reflux with stirring overnight. The reaction mixture was cooled to room temperature and transferred to a 2L separatory funnel. The solution was extracted twice with 200 mL saturated aq sodium bicarbonate and once with 200 mLwater. The organic layer was isolated and the aqueous layers were combined and reextracted twice with an additional 100 mL dichloromethane. The organics were then pooled, dried over sodium sulfate, filtered, and concentrated to a residue. The residue was purified by flash chromatography (0.2-1.9% methanol:dichloromethane). Fractions containing the desired material were pooled and concentrated to afford the titlecompound as a bright orange solid (5.603 g, 25.2 mmol, 25% yield). MS(ES) me 221.8 [M+H]+.
With toluene-4-sulfonic acid; In toluene; for 18h;Reflux;
a) ethyl 7-bromoquinoline-3 -carboxylateA mixture of <strong>[59278-65-8]2-amino-4-bromobenzaldehyde</strong> (1 g, 5.00 mmol), ethyl(2E)-3-(ethyloxy)-2-propenoate (0.862 mL, 5.97 mmol) and p-toluenesulfonic acidmonohydrate (0.095 g, 0.500 mmol) in toluene (80 mL) was heated under reflux over inbath for 18 h. The mixture was cooled, evaporated under reduced pressure, and then dissolved in chloroform and washed with sodium hydrogen carbonate solution. The organic solution was dried (Na2504) and evaporated under reduced pressure to a solid thatrecrystallized from ethanol to afford the title compound (720 mg, 51%). MS (ES)+ mle282.1 [M+H] ?H NMR (400MHz, CDC13) oe ppm 9.47 (d, 1 H), 8.84 (d, J= 1.5 Hz, 1 H),8.38 (d, J 1.5 Hz, 1 H), 7.92 - 7.79 (m, 1 H), 7.74 (dd, J= 1.9, 8.7 Hz, 1 H), 4.50 (q, J= 7.1Hz,2H), 1.49(t,J7.2Hz,3H).
With potassium hydroxide; In ethanol; for 3h;Inert atmosphere; Reflux;
A solution of KOH (5.61 g, 100 mmol) dissolved in ethanol (50 mL) was added drop wise to a mixture of <strong>[59278-65-8]2-amino-4-bromobenzaldehyde</strong> (60.6 g, 303 mmol) and propionaldehyde (17.6 g, 303 mmol) in absolute ethanol (200 mL) under nitrogen. The mixture was heated to reflux, and then maintained at reflux for 3 h. After cooling to room temperature, the reaction mixture was concentrated to remove the ethanol, then water was added and the mixture was extracted with methylene chloride (3 x 100 mL). The combined organic layers were washed with water, dried over sodium sulfate, and concentrated in vacuo. The crude material was triturated from diethyl ether to provide the title product (48.6 g, 219 mmol, 72% yield) as a light brown solid. MS(ES) m/e 221.9, 223.9 [M+H]+ (bromine pattern).
2.5 g
With potassium hydroxide; In ethanol; water; at 95℃;
To a solution of 4-bromo-2-nitrobenzaldehyde (5 g, 21.7 mmol) in ethanol (50 mL), iron powder (4.85 g, 86.9 mmol ) was added followed by HCl aqueous solution (0.1 N, 15 mL) . The resulting reaction mixture was vigorously stirred at 95 C for 2 h. The reaction progression was followed by TLC. When the reduction was completed, propionaldehyde (1 .5 mL, 21.7 mmol) and KOH (1.46 g, 26.0 mmol, in two portions) were added at rt. The reaction mixture was stirred at 95 C overnight. It was cooled to rt, diluted with DCM (30 mL) and filtered through celite. The filtrate was washed with water (50 mL) and the aqueous layer was extracted with DCM (2 x 100 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography, affording the title compound. Yield: 52% (2.5 g, Pale yellow solid). 1 H NMR (400 MHz, DMSO-d6): delta 8.81 (s, 1H), 8.18-8.17 (m, 2H), 7.89 (d, J = 8.7 Hz, 1H), 7.72 (dd, J = 1.9, 8.7 Hz, 1H), 2.50 (s, 3H). LCMS: (Method D) 223.9 (M+H), Rt. 2.48 min, 99.58% (Max).
With toluene-4-sulfonic acid; In toluene; at 110℃; for 3h;Dean-Stark;
A mixture of 2-chloro-1 , 1-diethoxyethane (4.50 ml_, 30.0 mmol), 2-amino-4- bromobenzaldehyde (3.00 g, 15.0 mmol), and p-toluenesulfonic acid monohydrate (0.285 g, 1.500 mmol) in toluene (50 ml_) was heated at 110 C for 3 hours using a Dean/Stark trap. The solvent was then evaporated and the residue partitioned between ethyl acetate and saturated aq NaHC03. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were evaporated onto silica gel and purified by flash chromatography (20-50% dichloromethane/hexanes) to give the title product (1.97 g, 8.12 mmol, 54% yield) as a yellow solid. MS (ES+) m/e 241.8/243.8 Br pattern [M+H]+; H NMR (400 MHz, DMSO-d6) delta ppm 7.85 (dd, J=8.84, 2.02 Hz, 1 H) 7.98 (d, J=8.59 Hz, 1 H) 8.29 (d, J=1.77 Hz, 1 H) 8.65 (d, J=2.02 Hz, 1 H) 8.94 (d, J=2.53 Hz, 1 H).
N'-(2-amino-4-bromobenzylidene)-4-methylbenzenesulfonohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With acetic acid; In methanol; at 20 - 65℃; for 1h;
General procedure: To a screw cap vial was added 2-amino aryl aldehyde (1.0 mmol) in ethanol (5.0 mL). Thencharged "osylhydrazide (1.2 mmol) followed by the addition of glacial acetic acid (0.5 mmol) atroom temperature. The mixture was heated to 65 C for 1.0 h. The reaction progress wasmonitored by using TLC. After consumption of starting material the reaction mixture wasconcentrated and triturated with diethyl ether to get desired "osylhydrazone.
With toluene-4-sulfonic acid; In toluene; for 18h;Reflux; Inert atmosphere;
To a solution of <strong>[59278-65-8]2-amino-4-bromobenzaldehyde</strong> (6 g, 28.2 mmol) in toluene (50 mE) was added (E)- 1 -ethoxyprop- 1 -ene (6.07g, 70.49mmol) and 4-methylbenzcnesulfonic acid (0.49 g, 2.82 mmol). The mixture was heated to reflux for 18 h under a nitrogen atmosphere. Aftercooling the reaction to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (petroleum ether EtOAc = 5 : 1) to give the title compound (4 g, 57 %) as a yellow solid. ?H NMR (400 MHz, DMSO-d6) 6 8.80 (s, IH), 8.19-8.17 (m, 2H), 7.88 (d,J= 8.8 Hz, 1H). 7,73 -7.70 (m, 11-1), 2.47 (s, 3H).
General procedure: A mixture of o-aminobenzaldehyde 7a-7r (0.5 mmol) and 1,1-dimethoxy-2-nitroethene 6 (1.5 mmol) in H2O (1 mL) and AcOH (1 mL)was stirred at 70 C for 7h-12h, and the progress was monitored by TLC. Upon completion, the reaction mixture was allowed to cool to room temperature, and the precipitate from the reaction mixture was separated by filtration. At last the product was got by recrystallization from DMSO/H2O.
(2S,3R)-methyl 3-((R)-2-(1-(2,5-bis(trifluoromethyl)benzyl)piperidin-4-yl)-1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)3-cyclopropyl-2-methylpropanoate[ No CAS ]
(2S,3R)-3-((R)-2-(1-(2,5-bis(trifluoromethyl)benzyl)piperidin-4-yl)-1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)3-cyclopropyl-2-methylpropanoic acid[ No CAS ]