* 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 N-Bromosuccinimide In neat (no solvent) at 20℃; for 1 h; Milling; Green chemistry
General procedure: 1-Methoxy-3,5-dimethylbenzene(100mg, 0.73 mmol), N-Bromosuccinimide (NBS,260 mg,1.46 mmol) and one ball (5 mmdiameter, stainless steel) were transferred to a milling jar (10 mL, stainlesssteel). The ball-milling operation was performed and the progress of reaction was monitored by TLC/1H NMR.[1]After completion, the reaction mixture was transferred into 30 mL ethyl acetate and cooled at 0 °C. The product was isolated as filtrate upon paper filtration and waste succinimide as precipitate. The resulting filtrate were concentrated in vacuo to isolate 250 mg (yield: 85percent) of 2b as colourless powder. To test the efficiency in large scale, the reaction was also performed for the mono-bromination of 1-methoxy-3,5-dimethylbenzene in 1.3 g scale for 1 h and the product was isolated in 87percent yield.[1] The milling apparatus was stopped and small portion of the sample was collected from the reaction jar to study either TLC/ proton NMR. Following, the reaction was started again andthis operation time was excluded for reporting the reaction timing.
87%
With N-Bromosuccinimide In neat (no solvent) at 20℃; for 1 h; Milling; Green chemistry
General procedure: 1-Methoxy-3,5-dimethylbenzene (100mg, 0.73 mmol), N-Bromosuccinimide (NBS,260 mg,1.46 mmol) and one ball (5 mmdiameter, stainless steel) were transferred to a milling jar (10 mL, stainlesssteel). The ball-milling operation was performed and the progress of reactionwas monitored by TLC/1H NMR.[1]After completion, the reaction mixture was transferred into 30 mL ethyl acetateand cooled at 0 °C. The product was isolated as filtrate upon paper filtrationand waste succinimide as precipitate. The resulting filtrate were concentrated in vacuoto isolate 250 mg (yield: 85percent) of 2bas colourless powder. To test the efficiency in largescale, the reaction was also performed for the mono-bromination of1-methoxy-3,5-dimethylbenzene in 1.3 g scale for 1 h and the product wasisolated in 87percent yield.[1] Themilling apparatus was stopped and small portion of the sample was collectedfrom the reaction jar to study either TLC/ proton NMR. Following, the reaction was started again andthis operation time was excluded for reporting the reaction timing.
87%
With N-Bromosuccinimide; iodine In acetonitrile for 12 h; Darkness; Inert atmosphere
General procedure: To a reaction tube charged with NBS (1.5 equiv, 0.3 mmol), catalyst (10 molpercent, 0.02 mmol) and CH3CN (1.0 mL),was added para-chloroanisole 1a (0.2 mmol). After being stirred at room temperature for 12 h in dark, the reaction was quenched by saturated aq. solution of Na2S2O3 (2 mL). The resulting mixture was extracted by ethyl acetate (3 5 mL). The combined organic extracts were washed by brine (10 mL), dried over Na2SO4 and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and the residuewas purified by flash chromatography on a silica gel column with petroleum ether/dichloromethane (5:1) as the eluent to give 4.3.1. 2-Bromo-4-chloroanisole (2a)
82%
With iodine pentoxide; potassium bromide In water at 20℃; for 20 h;
General procedure: A mixture of arene (0.5 mmol), I2O5 (334 mg, 1.0 mmol), and KBr (148 mg, 1.25 mmol) was dissolved in 2mL of H2O. The reaction was complete after stirring for the indicated time at room temperature. The mixture was extracted by ethyl acetate and concentrated under reduced pressure, and the mixture was purified by flash column chromatography (silica gel) to afford the desired product.
77%
With N-Bromosuccinimide; thioacetamide In acetonitrile at 20℃; for 20 h;
General procedure: Reaction conditions: Thiourea (5.1 molpercent, 2 mg, 0.026 mmol) was added to an acetonitrile solution (10 mL) containing NBS (1.15 equiv, 104.4 mg, 0.587 mmol). Anisole (56.3 mg, 0.51 mmol) was added immediately to the resulting stirred solution and allowed to stir at room temperature for 10 min. The reaction was quenched by the addition of 10percent aqueous solution of Na2S2O3 (10 mL) and extracted with ethyl acetate (70 mL). The organic solution was then washed with additional 10percent Na2S2O3 (2 * 10 mL), followed by deionized water (3 * 15 mL) and brine (2 * 10 mL). The organic solution was then dried over anhydrous Na2SO4 and the solvent was evaporated in vacuo. The major product of each reaction was isolated by centrifugal thin-layer chromatography using a 2 mm thick silica gel 60GF254 coated plate (5percent CH2Cl2/hexanes). The products reported herein are known compounds and were characterised by GC-MS, IR, 1H and 13C NMR. Their spectroscopic data are in agreement with those reported in the literature.
55%
With lithium bromide monohydrate; [bis(acetoxy)iodo]benzene In 2,2,2-trifluoroethanol at 20℃; for 0.166667 h;
General procedure: To a solution of alkoxybenzylalcohol 1 (0.2 mmol) in CF3CH2OH (1 mL) were added LiBr·H2O (0.2 mmol) and PhI(OAc)2 (0.2 mmol) atroom temperature. After completion of the reaction as indicated by TLC monitoring, saturated aq. Na2SO3 wasadded and the mixture was extracted with CH2Cl2. The combined organic layers were washed with brine, driedover anhydrous Na2SO4 and then concentrated in vacuo. The residue was purified by silica gel columnchromatography to afford pure monobrominated compounds 2.
42.1%
With bromine In 1,2-dichloro-ethane at 0 - 60℃;
To a stirred solution of 4-methoxybenzaldehyde (30.0 g, 220.4 mmol) taken in DOE (300 mL), at 0 00 bromine (38.7 g, 242.2 mmol) was added drop wise. It was heated at 60 00 over night. The reaction mixture was quenched with ice water, and then extracted with ethyl acetate. The organic layer was washed with sodium thiosulphate,water and brine solution, was dried over anhydrous Na2SO4 and concentrated. The product was purified by column chromatography to yield the title product (20.0 g, 42.1percent) as an off white solid.
42.1%
With bromine In 1,2-dichloro-ethane at 0 - 60℃;
To a stirred solution of 4-methoxybenzaldehyde (30.0 g, 220.4 mmol) was taken inDOE (300 mL), at 0 00 was added bromine (38.7 g, 242.2 mmol) drop wise. It washeated at 60 00 for over night. The reaction mixture was quenched with ice water,and then extracted with ethyl acetate. The organic layer was washed with sodium thiosulphate, water and brine solution, over anhydrous Na2SO4 and concentrated. The product was purified by column chromatography to yield the title product (20.0 g, 42.1percent) as an off white solid.
Reference：
[1] Journal of the Iranian Chemical Society, 2011, vol. 8, # 2, p. 531 - 536
[2] Tetrahedron Letters, 2014, vol. 55, # 13, p. 2154 - 2156
[3] Tetrahedron Letters, 2015, vol. 55, # 13, p. 2154 - 2156
[4] Tetrahedron, 2017, vol. 73, # 50, p. 7105 - 7114
[5] Synthetic Communications, 2014, vol. 44, # 2, p. 181 - 187
[6] Tetrahedron Letters, 2009, vol. 50, # 2, p. 158 - 160
[7] Tetrahedron, 2017, vol. 73, # 46, p. 6564 - 6572
[8] Journal of Chemical Research, 2015, vol. 39, # 6, p. 336 - 339
[9] Chemistry of Natural Compounds, 1993, vol. 29, # 6, p. 748 - 759[10] Khimiya Prirodnykh Soedinenii, 1993, # 6, p. 839 - 853
[11] Synlett, 2018, vol. 29, # 17, p. 2275 - 2278
[12] New Journal of Chemistry, 2016, vol. 40, # 10, p. 8198 - 8201
[13] Patent: WO2014/202580, 2014, A1, . Location in patent: Page/Page column 82
[14] Patent: WO2014/202528, 2014, A1, . Location in patent: Page/Page column 69
[15] Journal of the American Chemical Society, 1917, vol. 39, p. 1711
[16] Justus Liebigs Annalen der Chemie, 1928, vol. 460, p. 135
[17] Justus Liebigs Annalen der Chemie, 1928, vol. 460, p. 135
[18] Journal of the Chemical Society, 1924, vol. 125, p. 1062
[19] Justus Liebigs Annalen der Chemie, 1845, vol. 56, p. 308[20] Annales de Chimie (Cachan, France), 1845, vol. <3> 14, p. 486
[21] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1979, p. 829 - 837
[22] Journal of the Chemical Society [Section] C: Organic, 1970, p. 2234 - 2238
[23] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1984, # 11, p. 1797 - 1802
[24] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 2, p. 463 - 466
[25] Tetrahedron Letters, 2009, vol. 50, # 7, p. 831 - 833
[26] Indian Journal of Heterocyclic Chemistry, 2012, vol. 21, # 3, p. 281 - 288
2
[ 2973-78-6 ]
[ 77-78-1 ]
[ 34841-06-0 ]
Yield
Reaction Conditions
Operation in experiment
90.6%
With potassium carbonate In N,N-dimethyl-formamide at 0 - 25℃; for 2 h;
Dimethyl sulfate (6.6 g, 0.053 mol) was added dropwise at a ratethat maintained <0 C reaction temperature to a stirred solution of3-bromo-4-hydroxybenzaldehyde (10 g, 0.05 mol) and anhydrouspotassium carbonate (10.28 g, 0.075 mol) in DMF (40 mL). Uponcompletion of addition, the mixturewas stirred at 25 C for another2 h. The reaction mixture was slowly poured into cold water(100 mL) and stirred for 20 min. The solid was separated byfiltration as a gray powder (9.7 g) in 90.6percent yield, mp 40.1e41.0 C.1H NMR (300 MHz, CDCl3): d 9.84 (s, 1H, CHO), 8.08 (d, 1H,J 2.0 Hz, AreH), 7.80 (dd, 1H, J 2.0 & 8.5 Hz, AreH), 6.98 (d, 1H,J 8.5 Hz, AreH), 3.86 (s, 3H, OCH3).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 5, p. 1549 - 1553
[2] European Journal of Medicinal Chemistry, 2015, vol. 103, p. 343 - 353
[3] Archives of Pharmacal Research, 2018, p. 1 - 18
[4] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 7, p. 2464 - 2473
3
[ 38493-59-3 ]
[ 34841-06-0 ]
Yield
Reaction Conditions
Operation in experiment
98%
Stage #1: With oxalyl dichloride; dimethyl sulfate In dichloromethane at -78℃; for 1 h; Inert atmosphere Stage #2: With triethylamine In dichloromethane at -78 - 20℃; for 2 h; Inert atmosphere
To a solution of dimethyl sulfoxide (6.50 mL, 91.5 mmol) in CH2Cl2 (45 mL) was added oxalyl chloride (1.57 mL, 18.3 mmol) at -78 °C. The resulting mixture was stirred at the same temperature for 20 min. A solution of 13 (1.99 g, 9.15 mmol) in CH2Cl2 (10 mL) was added to the reaction flask. After stirring for 1 h, triethylamine (6.40 mL, 45.8 mmol) was then added. The reaction mixture was stirred at -78 °C for 1 h, warmed to room temperature, and then stirred for 1 h. The reaction was quenched with 1 N HCl, and the aqueous phase was then separated and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, and then concentrated in vacuo. Purification by silica gel column chromatography (hexane/EtOAc = 5/1) gave 15 (1.92 g, 8.93 mmol, 98percent) as a colorless powder;
With potassium carbonate In N,N-dimethyl-formamide at 0 - 5℃; Inert atmosphere
(2) In 4000mL reaction vessel, nitrogen protection,740.7 g of 3-bromo-4-hydroxybenzaldehyde was put into the reaction vessel.2000 g of N,N-dimethylformamide and558.0g potassium carbonate,Control temperature drop 0 ~ 5 °C drop775g iodomethane,After the control of raw materials is complete,Concentrate the reaction solution into ice water,Precipitation of solids,Recrystallization gave white crystalline product 3-bromo-4-methoxybenzaldehyde 752.7g, yield 95.0percent;
Reference：
[1] Patent: CN107118087, 2017, A, . Location in patent: Paragraph 0015; 0031; 0035; 0039; 0043; 0047
5
[ 105-13-5 ]
[ 34841-06-0 ]
Yield
Reaction Conditions
Operation in experiment
55 %Chromat.
With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione In dichloromethane at 25℃; for 0.5 h;
General procedure: DBDMH (1 mmol) was added to a mixture of 1b (1 mmol) and dichloromethane (20ml). The reaction was kept at room temperature. After the mixture was stirred for0.5h, the mixture was washed with water (330 ml),dried with anhydrous MgSO4,filtered, and vacuum evaporated. The residue was purified by column chromatography (silica gel: petroleum ether/ethyl acetate, 30:1) to afford the product as light yellowsolid (93percent yield).
Reference：
[1] Journal of Medicinal Chemistry, 2013, vol. 56, # 14, p. 5917 - 5930
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 10, p. 4790 - 4799
22
[ 34841-06-0 ]
[ 38493-59-3 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 18, p. 6874 - 6885
[2] Patent: JP2005/120047, 2005, A, . Location in patent: Page/Page column 106
[3] Chemical Communications, 1999, # 3, p. 287 - 288
[4] Tetrahedron Letters, 2013, vol. 54, # 21, p. 2737 - 2739
[5] Journal of the Chemical Society, 1938, p. 1780,1782
[6] Journal of the Chemical Society [Section] C: Organic, 1970, p. 2234 - 2238
[7] Patent: US6582351, 2003, B1,
[8] Chemical Communications, 2014, vol. 50, # 40, p. 5254 - 5257
[9] Patent: CN106632070, 2017, A, . Location in patent: Paragraph 0024-0025
23
[ 34841-06-0 ]
[ 117572-79-9 ]
Reference：
[1] Synlett, 2009, # 20, p. 3378 - 3382
25.0 g (0.116 MOL) 3-BROMANISALDEHYD werden unter leichtem Erwaermen in 120 ml Pyridin geloest ; anschliessend werden 15.6 g (0.150 Mol) Malonsaeure und 5.75 ML (0.058 Mol) Piperidin zugesetzt. Danach wird 2 STUNDEN BEI 100C (GASENTWICKLUNG) und ueber Nacht bei Raumtemperatur geruehrt. Das Solvens wird abdestilliert, der Rueckstand mit 500 mi Eiswasser versetzt und mit Eisessig auf pH 4-5 gestellt. Das ausgefallene Produkt wird abgesaugt, mit Wasser gewaschen und getrocknet. Ausbeute : 29.7 g (99 % der Theorie) CYOHGBR03 (257.09) Massenspektrum: (M-H)+ = 255/57 (Bromisotope)
92%
With piperidine; pyridine; for 12h;Reflux;
3-Bromo-4-methoxybenzaldehyde (10) was subjected to Doebner-Knoevenagel condensation with malonic acid in the presence of pyridine and piperidine to afford cinnamic acid 11 as a yellow solid; yield 92%
1.2 g
With piperidine; pyridine; at 80 - 115℃; for 4h;
<strong>[34841-06-0]3-bromo-4-methoxy-benzaldehyde</strong> (1 g (0.0046 mmol)), malonic acid (0.93 g, 0.0092 mol), pyridine (9 mL), and piperidine (88 ul, 0.5 mmol) were mixed well, heated to 80-85 C. for 1 h and finally refluxed (110-115 C.) for an additional 3 h. The reaction mixture was poured into water and acidified with concentrated HCl. The precipitate obtained was filtered, and washed with cold water repeatedly. The residue was dissolved in NaOH, diluted, again acidified, the precipitate was collected washed with cold water and dried under high vacuum over P2O5 and used without further purifications. Yield=1.2 g.
With sodium borohydrid; In tetrahydrofuran; ethanol;
PREPARATION 31 To a solution of 3-bromo-4-methoxybenzaldehyde (4.98 g) in ethanol (50 mL) and tetrahydrofuran (10 mL) was added sodium borohydride (1.31 g) under ice-water cooling. The mixture was stirred at 0° C. for 2 hours. After evaporation of the solvent, the residue was partitioned between ethyl acetate and water. The separated organic layer was washed successively with water and brine, and dried over magnesium sulfate. The organic layer was evaporated in vacuo to give 3-bromo-4-methoxybenzyl alcohol as a colorless oil (4.98 g). NMR(CDCl3, delta): 1.73 (1H, t, J=7 Hz), 3.90 (3H, s), 4.60 (2H, d, J=7 Hz), 6.88 (1H, d, J=8 Hz), 7.25 (1H, dd, J=4, 8 Hz), 7.56 (1H, d, J=4 Hz).
With sodium tetrahydroborate; ethanol;
(1) 30 g of raw material A, 3-bromo-4-methoxybenzaldehyde was taken, and NaOH4 8-10 g was slowly added in batches and reacted in ethanol. The reaction was monitored by TLC. After completion of the reaction, the ethanol was removed, and the combined organic phases were dried over anhydrous sodium sulfate and dried to give 30.0 g of 3-bromo-4-methoxybenzyl alcohol as a white product. The product was subjected to the next step without further purification Rate> 98percent
With N-Bromosuccinimide; In neat (no solvent); at 20℃; for 1h;Milling; Green chemistry;
General procedure: 1-Methoxy-3,5-dimethylbenzene(100mg, 0.73 mmol), N-Bromosuccinimide (NBS,260 mg,1.46 mmol) and one ball (5 mmdiameter, stainless steel) were transferred to a milling jar (10 mL, stainlesssteel). The ball-milling operation was performed and the progress of reaction was monitored by TLC/1H NMR.[1]After completion, the reaction mixture was transferred into 30 mL ethyl acetate and cooled at 0 C. The product was isolated as filtrate upon paper filtration and waste succinimide as precipitate. The resulting filtrate were concentrated in vacuo to isolate 250 mg (yield: 85%) of 2b as colourless powder. To test the efficiency in large scale, the reaction was also performed for the mono-bromination of 1-methoxy-3,5-dimethylbenzene in 1.3 g scale for 1 h and the product was isolated in 87% yield.[1] The milling apparatus was stopped and small portion of the sample was collected from the reaction jar to study either TLC/ proton NMR. Following, the reaction was started again andthis operation time was excluded for reporting the reaction timing.
87%
With N-Bromosuccinimide; In neat (no solvent); at 20℃; for 1h;Milling; Green chemistry;
General procedure: 1-Methoxy-3,5-dimethylbenzene (100mg, 0.73 mmol), N-Bromosuccinimide (NBS,260 mg,1.46 mmol) and one ball (5 mmdiameter, stainless steel) were transferred to a milling jar (10 mL, stainlesssteel). The ball-milling operation was performed and the progress of reactionwas monitored by TLC/1H NMR.[1]After completion, the reaction mixture was transferred into 30 mL ethyl acetateand cooled at 0 C. The product was isolated as filtrate upon paper filtrationand waste succinimide as precipitate. The resulting filtrate were concentrated in vacuoto isolate 250 mg (yield: 85%) of 2bas colourless powder. To test the efficiency in largescale, the reaction was also performed for the mono-bromination of1-methoxy-3,5-dimethylbenzene in 1.3 g scale for 1 h and the product wasisolated in 87% yield.[1] Themilling apparatus was stopped and small portion of the sample was collectedfrom the reaction jar to study either TLC/ proton NMR. Following, the reaction was started again andthis operation time was excluded for reporting the reaction timing.
87%
With N-Bromosuccinimide; iodine; In acetonitrile; for 12h;Darkness; Inert atmosphere;
General procedure: To a reaction tube charged with NBS (1.5 equiv, 0.3 mmol), catalyst (10 mol%, 0.02 mmol) and CH3CN (1.0 mL),was added para-chloroanisole 1a (0.2 mmol). After being stirred at room temperature for 12 h in dark, the reaction was quenched by saturated aq. solution of Na2S2O3 (2 mL). The resulting mixture was extracted by ethyl acetate (3 5 mL). The combined organic extracts were washed by brine (10 mL), dried over Na2SO4 and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and the residuewas purified by flash chromatography on a silica gel column with petroleum ether/dichloromethane (5:1) as the eluent to give 4.3.1. 2-Bromo-4-chloroanisole (2a)
82%
With iodine pentoxide; potassium bromide; In water; at 20℃; for 20h;
General procedure: A mixture of arene (0.5 mmol), I2O5 (334 mg, 1.0 mmol), and KBr (148 mg, 1.25 mmol) was dissolved in 2mL of H2O. The reaction was complete after stirring for the indicated time at room temperature. The mixture was extracted by ethyl acetate and concentrated under reduced pressure, and the mixture was purified by flash column chromatography (silica gel) to afford the desired product.
77%
With N-Bromosuccinimide; thioacetamide; In acetonitrile; at 20℃; for 20h;
General procedure: Reaction conditions: Thiourea (5.1 mol%, 2 mg, 0.026 mmol) was added to an acetonitrile solution (10 mL) containing NBS (1.15 equiv, 104.4 mg, 0.587 mmol). Anisole (56.3 mg, 0.51 mmol) was added immediately to the resulting stirred solution and allowed to stir at room temperature for 10 min. The reaction was quenched by the addition of 10% aqueous solution of Na2S2O3 (10 mL) and extracted with ethyl acetate (70 mL). The organic solution was then washed with additional 10% Na2S2O3 (2 * 10 mL), followed by deionized water (3 * 15 mL) and brine (2 * 10 mL). The organic solution was then dried over anhydrous Na2SO4 and the solvent was evaporated in vacuo. The major product of each reaction was isolated by centrifugal thin-layer chromatography using a 2 mm thick silica gel 60GF254 coated plate (5% CH2Cl2/hexanes). The products reported herein are known compounds and were characterised by GC-MS, IR, 1H and 13C NMR. Their spectroscopic data are in agreement with those reported in the literature.
55%
With lithium bromide monohydrate; [bis(acetoxy)iodo]benzene; In 2,2,2-trifluoroethanol; at 20℃; for 0.166667h;
General procedure: To a solution of alkoxybenzylalcohol 1 (0.2 mmol) in CF3CH2OH (1 mL) were added LiBr·H2O (0.2 mmol) and PhI(OAc)2 (0.2 mmol) atroom temperature. After completion of the reaction as indicated by TLC monitoring, saturated aq. Na2SO3 wasadded and the mixture was extracted with CH2Cl2. The combined organic layers were washed with brine, driedover anhydrous Na2SO4 and then concentrated in vacuo. The residue was purified by silica gel columnchromatography to afford pure monobrominated compounds 2.
42.1%
With bromine; In 1,2-dichloro-ethane; at 0 - 60℃;
To a stirred solution of 4-methoxybenzaldehyde (30.0 g, 220.4 mmol) taken in DOE (300 mL), at 0 00 bromine (38.7 g, 242.2 mmol) was added drop wise. It was heated at 60 00 over night. The reaction mixture was quenched with ice water, and then extracted with ethyl acetate. The organic layer was washed with sodium thiosulphate,water and brine solution, was dried over anhydrous Na2SO4 and concentrated. The product was purified by column chromatography to yield the title product (20.0 g, 42.1%) as an off white solid.
42.1%
With bromine; In 1,2-dichloro-ethane; at 0 - 60℃;
To a stirred solution of 4-methoxybenzaldehyde (30.0 g, 220.4 mmol) was taken inDOE (300 mL), at 0 00 was added bromine (38.7 g, 242.2 mmol) drop wise. It washeated at 60 00 for over night. The reaction mixture was quenched with ice water,and then extracted with ethyl acetate. The organic layer was washed with sodium thiosulphate, water and brine solution, over anhydrous Na2SO4 and concentrated. The product was purified by column chromatography to yield the title product (20.0 g, 42.1%) as an off white solid.
General procedure: n-Butyl lithium (1 equiv., 2.5 M in THF) was added dropwise to a 0.12 M solution of methyltriphenylphosphonium bromide (1 equiv.) in THF. The yellow solution was allowed to stir for 15 minutes before addition of aldehyde (1 equiv.), upon which, the mixture turned white or pale yellow. After 2 hours (or observed completion of the reaction by TLC), saturated ammonium chloride was added and the mixture extracted with CH2Cl2. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification of the crude residue with column chromatography (ethyl acetate/petroleum ether or petroleum ether only was used as the eluent) afforded the substituted styrene.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 5.16667h;Heating / reflux;
To a round-bottom flask was charged 3-bromo-4~methoxybenzaldehyde (12.23 g, 56.87 mmol), thiophene-2-boronic acid (8.38 g, 65.5 mmol), ethylene glycol dimethyl ether (310 niL), and 2M aq. Na2CO3 (120 mL). The mixture was purged subsurface with nitrogen as tetrakis (triphenylphosphine) palladium(O) (6.58 g, 5.69 mmol) was added. The mixture was purged another 10 min. with nitrogen, then heated at reflux for 5 h. HPLC analysis indicated the reaction was complete. After cooling, the mixture was diluted with H2O (300 mL) and extracted with EtOAc. The organics were washed with brine, dried over Na2SO4, filtered, concentrated, and dried. The crude material was purified by silica gel chromatography (20- 25% EtOAc in hexanes) to provide 11.31 g (91%) of pure product as an orange oil. 1H-NMR (CDCl3) delta 9.94 (s, IH), 8.16 (d, J= 2.4 Hz, IH), 7.80 (dd, J= 8.8, 2.4 Hz, IH), 7.57 (dd, J = 3.7, 1.5 Hz, IH), 7.38 (d, J= 5.4 Hz, IH), 7.12 (dd, J= 5.4, 3.7 Hz, IH), 7.09 (d, J= 8.8 Hz, IH) , 4.03 (s, 3H).
91%
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 5h;Heating / reflux;
[0223] Ex-IB: In a 1 L round-bottom flask <strong>[34841-06-0]3-bromo-4-methoxy-benzaldehyde</strong> (12.23 g, 56.87 mmol) was combined with thiophene 2-boronic acid (8.38 g, 65.5 mmol) and dimethoxyethane (310 mL). The resulting solution was purged subsurface with nitrogen while adding 2 M Na2CO3 (120 mL, 240 mmol) and tetrakis (triphenylphospine) palladium (0) (6.58 g, 5.69 mol). The solution was purged another 10 min, then heated to reflux; HPLC indicated the reaction was complete after 5 h. The cooled reaction mixture was diluted with H2O and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered, concentrated, and dried. The crude material was purified by silica gel chromatography (20-25% EtOAc in hexanes) to provide 11.31 g (91%) of 4-methoxy-3-thien-2-yl-benzaldehyde as an orange oil. 1H-NMR (CDCl3) delta 9.94 (s, IH), 8.16 (d, J= 2.4 Hz, IH), 7.80 (dd, J= 8.8, 2.4 Hz, IH), 7.57 (dd, J= 3.7, 1.5 Hz, IH), 7.38 (d, J= 5.4 Hz, IH), 7.12 (dd, J= 5.4, 3.7 Hz, IH), 7.09 (d, J= 8.8 Hz, IH), 4.03 (s, 3H).
87%
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; for 3h;Heating / reflux;
Tetrakis(triphenylphosphine)palladium(0) (0.24 g, 0.21 mmol) was added to a solution of 4-methoxy-3-bromobenzaldehyde (1.5 g, 6.98 mmol) in toluene (15 mL) and ethanol (15 mL), followed by a 2 M aqueous solution of sodium carbonate (14 mL, 28 mmol). To this mixture was added thiophene-2-boronic acid (0.98 g, 7.68 mmol), and the mixture was heated to reflux. After 3 hours, the reaction was partitioned between water (100 mL) and ethyl acetate (250 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (75 mL) and brine (75 mL), dried with magnesium sulfate and concentrated. Chromatography (silica, 20% ethyl acetate/hexanes) afforded 1.3 g (87%) of 4-methoxy-3-thiophen-2-yl-benzaldehyde as a yellow oil. 1H NMR (360 MHz, DMSO-d6) delta 9.92 (s, 1H, CHO), 8.2 (d, 1H, J=3 Hz, 1*Ar-H), 7.8 (dd, 1H, J=10 and 10 Hz, SCHCHCH), 7.65 (m, 1H, Ar-H), 7.60 (dd, 1H, J=2 and 6 Hz, Ar-H), 7.32 (d, 1H, J=10 Hz, SCHCHCH), 7.13 (d, 1H, J=10 and 6 Hz, SCHCHCH), 3.99 (s, 3H, OCH3).
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; for 12h;Heating / reflux;
Tetrakis(triphenylphosphine)palladium(0) (1.35 g, 1.17 mmol) was added to a solution of 4-methoxy-3-bromobenzaldehyde (6.72 g, 31.26 mmol) dissolved in toluene (45 mL) and ethanol (45 mL). To the solution was added 2M aqueous sodium carbonate (80 mL, 78 mmol). Thiophene-3-boronic acid (5 g, 39.07 mmol) was then added to the mixture. The mixture was refluxed for 12 hours after which it was poured into water (200 mL) and extracted with ethyl acetate (2*150 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (150 mL) and brine (150 mL), dried over anhydrous magnesium sulfate and concentrated. Chromatography (silica, 20% ethyl acetate/hexanes) afforded 6 g (88%) of 3-(3-thiophene)-4-methoxybenaldehyde as a yellow oil. 1H NMR (360 MHz, DMSO-d6) delta 9.92 (s, 1H, CHO), 8.04 (d, 1H, J=2.4 Hz, 1*Ar-H), 7.8 (m, 2H, Ar-H), 7.58 (dd, 1H, J=3.1 and 5.5 Hz, thiophene and Ar-H), 7.50 (dd, 1H, J=1.6 and 5.1 Hz, Ar-H), 7.28 (d, 1H, J=8.7 Hz, thiophene), 3.94 (s, 3H, OCH3). MS m/z: 219.2 [M+1]+.
With potassium carbonate; In methanol; at 20 - 80℃; for 0.583333h;
The mixed solution of <strong>[34841-06-0]3-bromo-4-methoxybenzaldehyde</strong> (200 mg, 0.93 mmol) in methanol (4 mL) was added tosylmethyl isocyanide (200 mg, 1.02 mmol) and K2CO3 (260 mg, 1.88 mmol). The reaction was stirred at room temperature for 5 min before heated to 80 C. in the sealed tube. After 30 min, the solution was cooled to room temperature and concentrated. Column chromatography afforded 5-(3-bromo-4-methoxyphenyl)oxazole (o) (190 mg, 80%).
2-(3-bromo-4-methoxy-phenyl)-[1,3]dithiane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With boron trifluoride diethyl etherate; sodium sulfate; In chloroform; at 0 - 20℃; for 3.33333h;
Example 15: 4-[l-(4-Methoxy-3-thien-2-yl-benzoyl)-vinyl]-benzoic acid[0282] Ex-15A: In a 100 mL round-bottom flask <strong>[34841-06-0]3-bromo-4-methoxy-benzaldehyde</strong> (2.09 g, 9.72 mmol) was combined with CHCl3 (10 mL), 1,3-propane dithiol (1.02 mL, 10.16 mmol), and Na2SO4 (0.90 g). The mixture was cooled in a 0 0C bath and boron trifluoride diethyletherate (0.62 mL, 4.89 mmol) was added dropwise. After 5 min, the reaction was allowed to warm to room temperature. HPLC indicated the reaction was complete in 3 h 15 min. The reaction was diluted with CH2Cl2 and washed with H2O. The organic phase was dried over Na2SO4, filtered, concentrated, and dried. The crude material was purified by silica gel chromatography (10-25% EtOAc in hexanes) to provide 2.15 g (73%) of 2-(3-bromo-4-methoxy-phenyl)-[l,3]dithiane as a crystalline, white solid. 1H-NMR (CDCl3) delta 7.67 (d, J= 2.1 Hz, IH), 7.38 (dd, J= 8.1, 2.1 Hz, IH), 6.85 (d, J = 8.1 Hz, IH), 5.08 (s, IH), 3.89 (s, 3H), 3.04 (td, J= 14.7, 3.0 Hz, 2H), 2.89 (dt, J = 14.7, 3.0 Hz, 2H), 2.17 (dp, J = 12.3, 2.7 Hz, IH), 1.93 (qt, J = 12.3, 2.76 Hz, IH).
2-(3-bromo-4-methoxy-phenyl)-5,5-dimethyl-1,3-dioxan[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With Amberlyst-15; In toluene; for 2h;Reflux;
A) 2-(3-Bromo-4-methoxyphenyl)-5,5-dimethyl-[1,3]dioxane3-Bromo-4-methoxybenzaldehyde (60.0 g, 279 mmol) was dissolved in toluene (600 mL), and after addition of neopentyl glycol (32.0 g, 306 mmol) and Amberlyst-15 (3.6 g) the reaction mixture was heated under reflux for 2 hours on a water separator. After cooling, the reaction mixture was filtered, washed twice with water, and then concentrated under reduced pressure. The oil residue was combined with heptane, and the product which precipitated was filtered off and washed with heptane.Yield: 57.3 g (68% of theoretical). MS (API-ES, pos) m/z=301, 303 [M+H]+
With pyridinium p-toluenesulfonate; In benzene;
a. 2-(3-Bromo-4-methoxyphenyl)-5,5-dimethyl-1,3-dioxane. A solution of <strong>[34841-06-0]3-bromo-4-methoxybenzaldehyde</strong> (74.65 g, 0.347 mol), neopentyl glycol (43.35 g, 0.416 mol), pyridinium p-toluenesulfonate (0.87 g, 0.035 mol), and benzene (1.8 L) was refluxed with azeotropic removal of water for 6 hours. The cooled reaction mixture was diluted with water. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried (Na2SO4), charcoaled, filtered through a short column of Florisil, and concentrated in vacuo. There was obtained 102.8 g (98%) of ketal as a peach colored solid.
With toluene-4-sulfonic acid; In toluene; for 1.33333h;Reflux; Dean-Stark water trap;
A mixture of <strong>[34841-06-0]3-bromo-4-methoxy-benzaldehyde</strong> (10.0 mmol), 2,2-dimethyl-propane- 1,3-diol (12.0 mmol) and PTSA (0.20 mmol) in toluene (25 mL) is heated to reflux in the presence of a Dean-Stark water trap for 80 min. TEA (0.5 mmol) is added and the mixture is cooled to RT. The mixture is washed three times with water, diluted with EtOAc (25 mL), washed additional two times with water, dried over Na2SO4 and concentrated in vacuo to give the desired product as a white solid. LC-MS (^4): tR = 1.02 min; [M+H]+ = 301.1.
With potassium carbonate;tetrakis(triphenylphosphine)palladium (0); In 1,2-dimethoxyethane; water;
b. 3-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4-methoxybenzaldehyde A mixture of <strong>[34841-06-0]3-bromo-4-methoxybenzaldehyde</strong> (19.0 g, 88.4 mmol), (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)boronic acid (23.8 g, 97.2 mmol) and potassium carbonate (48.8 g, 353.6 mmol) in 1,2-dimethoxyethane (500 mL) and water (40 mL) was degassed with argon for 60 minutes. Tetrakis(triphenylphosphine)palladium(0) (5.0 g, 4.3 mmol) was added and the mixture heated at reflux under argon for 16 hours. The solution was cooled to room temperature, diluted with ethyl acetate (200 mL) and washed successively with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (eluent: ethyl acetate/hexane, 1:9) to give 26.8 g of 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4-methoxy-benzaldehyde (90%). 1H NMR (500 MHz; CDCl3): delta1.26 (s, 6H); 1.32 (s, 6H); 1.70 (s, 4H); 2.08 (s, 3H); 3.89 (s, 3H); 7.06 (d, J=8.5 Hz, 1H); 7.09 (s, 1H); 7.16 (s, 1H); 7.71 (d, J=2.0 Hz, 1H); 7.88 (dd, J1=2.0 Hz, J2=8.5H (s, 1H).
With hydrogenchloride; sodium hydroxide; In ethyl acetate; tert-butyl alcohol;
PREPARATIVE EXAMPLE 31 3-Bromo-4-methoxybenzaldehyde (15 g, 70 mmol), t-butanol (140 ml), 2-methyl-2-butene (50 ml, 469 mmol) were mixed, and to this solution was added dropwise a solution prepared by mixing sodium chlorite (10.42 g, 91 mmol), sodium dihydrogenphosphate dihydrate (14.2 g, 91 mmol) and water (70 nil). The mixture was stirred at room temperature for 16 hours. A 1N aqueous sodium hydroxide solution (50 ml) was added, and t-butanol was evaporated under reduced pressure. Conc. hydrochloric acid was added to make the mixture acidic. The precipitated crystals were collected by filtration and washed with hexane. The obtained crystals were dissolved in ethyl acetate (200 ml), and this solution was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give 3-bromo-4-methoxybenzoic acid (10.5 g, 65%) as colorless crystals. 1 H-NMR (CDCl3)delta: 12.9(1H, bs), 8.06(1H, s), 7.94(1H, d, J=8.5 Hz), 7.20(1H, d, J=8.5 Hz), 3.93(3H, s). FABMS (m/z): 232[M+ H+ ] (800),233(90),231(100).
With sodium cyanoborohydride; acetic acid; In methanol; at 20℃; for 12h;
EXAMPLE 26Synthesis of (R)-N-(4-Methoxy-3-(pyrrolidin-1-yl)benzyl)-1-(3-fluorophenyl)ethanamine Step 1. (R)-1-(3-Fluorophenyl)ethanamine 115 (1.24 g, 8.92 mmol) and 3-bromo-4-methoxybenzaldehyde 114 (1.92 g, 8.92 mmol) were mixed in 100 mL anhydrous methanol in a round bottom flask. After the mixture was stirred at 20 C. for 10 min, the flask was cooled in an ice-water bath. To this flask was added sodium cyanoborohydride (0.56 g, 8.92 mmol) followed by acetic acid (0.54 g, 8.92 mmol). The resulting mixture was stirred for 12 h and allowed to warm to 20 C. After removing most of the methanol, the remaining residue was dissolved in 200 mL ethyl ether and washed with saturated sodium bicarbonate, 3 times. The organic phase was dried over sodium sulfate. After removing the solvent under reduced pressure, the remaining residue was subjected to a silica gel column using 50% ethylacetate in hexane as the eluant to yield a colorless oil as the pure product (R)-N-(3-bromo-4-methoxybenzyl)-1-(3-fluorophenyl)ethanamine 116 (2.3 g, yield=93%). LCMS (M+1) 338, calc. for C16H17BrFNO 338; 1H NMR (400 MHz, CHLOROFORM-d) ? ppm 1.34 (d, J=6.26 Hz, 3H) 3.46-3.60 (m, 2H) 3.78 (q, J=6.39 Hz, 1H) 6.84 (d, J=8.22 Hz, 1H) 6.90-6.98 (m, 1H) 7.09 (t, J=9.00 Hz, 2H) 7.16 (dd, J=8.41, 2.15 Hz, 1H) 7.27-7.34 (m, 1H) 7.48 (d, J=1.96 Hz, 1H).
With 2,6-bis[(3aR,8aS)-3a,8a-dihydro-8H-indeno[1,2-d]oxazolin-2-yl]pyridine; scandium tris(trifluoromethanesulfonate); In dichloromethane; at 20℃;Molecular sieve;
General procedure: In an oven dried flask pybox ligand 10 (7.5 mumol) and Sc(OTf)3 (3 mumol) were taken in 1 mL of anhydrous dichloromethane. 50mg of 4A molecular sieves was added to the solution and the resulting mixture was stirred further. After 3 h, Anthranilamide (1a) (300 mumol) solubilized in 1 mL of dichloromethane was added at the indicated temperature, followed by aldehyde (360 mumol) and stirred until the reaction was completed. Completion of the reaction was ascertained by TLC, and the product was purified by using a small pad of silica gel 60-100 mesh with an eluent of (PEEA, 1:1) to afford dihydroquinazolinones as colourless solids.
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 25℃; for 2h;
Dimethyl sulfate (6.6 g, 0.053 mol) was added dropwise at a ratethat maintained <0 C reaction temperature to a stirred solution of3-bromo-4-hydroxybenzaldehyde (10 g, 0.05 mol) and anhydrouspotassium carbonate (10.28 g, 0.075 mol) in DMF (40 mL). Uponcompletion of addition, the mixturewas stirred at 25 C for another2 h. The reaction mixture was slowly poured into cold water(100 mL) and stirred for 20 min. The solid was separated byfiltration as a gray powder (9.7 g) in 90.6% yield, mp 40.1e41.0 C.1H NMR (300 MHz, CDCl3): d 9.84 (s, 1H, CHO), 8.08 (d, 1H,J 2.0 Hz, AreH), 7.80 (dd, 1H, J 2.0 & 8.5 Hz, AreH), 6.98 (d, 1H,J 8.5 Hz, AreH), 3.86 (s, 3H, OCH3).
With copper(II) bis(trifluoromethanesulfonate); In dichloromethane; at 20℃; for 2.5h;
To a flame-dried 200 mL round bottom flask (rbf) was added compound 6 (1.28 g, 5.95 mmol, 1.0 equiv.) and Cu(OTf)2 (127 mg, 0.04 mmol, 8 mol%) in CH2Cl2 (50 mL). Compound 7 (5.98 g, 1.19 mmol, 2 equiv.) in CH2Cl2 (20 mL) as added via syringe over 1 h. The reaction was stirred for another 1.5 h at which time aldehyde 6 was completely consumed as observed by TLC. The purple solution was concentrated to dryness and then dissolved in a 93:5:1 hexane:EtOAc:triethylamine (TEA) solution containing silica gel. The slurry was evaporated to dryness and added to a column of silica gel pre-treated with 93:5:1 hexane:EtOAc:TEA. The crude mixture was subjected to flash chromatography (gradient elution, 90:10:1 to 50:50:1 hexane:EtOAc:TEA) to afford 8 (4.24 g, 99% yield) as an inseparable mixture of diastereomers. Compound 7 (1.40 g) and 5 (634 mg) were recovered and recycled.
[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl) palladium(II) dichloride; In tetrahydrofuran; at 25℃; for 2h;
(4-Fluorobenzyl)zinc pivalate (11) shows a clean coupling reaction with 3-bromo-4- methoxybenzaldehyde (5m) and afford 3-(4-fluorobenzyl)-4-methoxybenzaldehyde (6s) in 82 % yield without observance of any addition products towards the aldehyde functionality (entry 19).
With barium hydroxide octahydrate; In methanol; at 20℃; for 2h;
General procedure: example: synthesis of 2,6-bis(3-bromo-4-methoxybenzylidene)cyclohexanone (9) Cyclohexanone (1.15 mmol, 0.12 mL) was added to a suspension of barium hydroxide octahydrate (4.6 mmol, 1.45 g) in methanol (20 mL), and the mixture was stirred for 5 min. Then a solution of <strong>[34841-06-0]3-bromo-4-methoxybenzaldehyde</strong> (2.3 mmol, 0.5 g) in methanol (10 mL) was added, and the resultant mixture was stirred for 2 h at room temperature. The precipitate was filtered, washed with water, dried and recrystallized by acetonitrile to afford the pure product. Melting point: 170-172 C; yield: 82%; 1H NMR (400 MHz, DMSO-d6) delta 1.72-1.75 (m, 2H, cyclohexanone protons), 2.86-2.89 (m, 4H, cyclohexanone protons), 3.90 (s, 6H, OCH3), 7.19-7.21(d, 2H, benzene protons), 7.55-7.59 (m, 4H, benzene protons and PhCH = CCO), 7.78 (s, 2H, benzene protons) ppm; 13C NMR (400 MHz, DMSO-d6) delta 25.1, 26.1 (2C), 55.1 (2C), 112.1 (2C), 112.2 (2C), 128.4 (2C), 129.2 (2C), 130.9 (2C), 132.2 (2C), 137.1 (2C), 156.2 (2C), 190.4 ppm; m/z [M]+: 491.9759.
To a solution of dimethyl sulfoxide (6.50 mL, 91.5 mmol) in CH2Cl2 (45 mL) was added oxalyl chloride (1.57 mL, 18.3 mmol) at -78 °C. The resulting mixture was stirred at the same temperature for 20 min. A solution of 13 (1.99 g, 9.15 mmol) in CH2Cl2 (10 mL) was added to the reaction flask. After stirring for 1 h, triethylamine (6.40 mL, 45.8 mmol) was then added. The reaction mixture was stirred at -78 °C for 1 h, warmed to room temperature, and then stirred for 1 h. The reaction was quenched with 1 N HCl, and the aqueous phase was then separated and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, and then concentrated in vacuo. Purification by silica gel column chromatography (hexane/EtOAc = 5/1) gave 15 (1.92 g, 8.93 mmol, 98percent) as a colorless powder;
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In dimethyl sulfoxide; at 80℃; for 24h;Inert atmosphere;
To a mixture of [1,1?-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (68.0 mg, 92.9 mumol), bis(pinacolato)diboron (283 mg, 1.11 mmol), and potassium acetate (274 mg, 2.79 mmol) was added 15 (202 mg, 0.939 mmol) in DMSO (3 mL). The reaction mixture was stirred at 80 C for 24 h. After addition of water, the aqueous layer was extracted with toluene. The combined organic layers were washed with water, dried over Na2SO4, and then concentrated in vacuo. Purification by silica gel column chromatography (hexane/EtOAc=3:1) gave 9 (182 mg, 0.693 mmol, 74%) as a colorless solid; Rf 0.26 (hexane/EtOAc=3:1); mp 98-101 C; IR (neat, cm-1) 2979, 1688, 1490, 1427, 1362, 1266, 1201, 1065, 1020, 854, 808; 1H NMR (300 MHz, CDCl3) delta 9.90 (1H, s, H13), 8.20 (1H, d, J=2.4 Hz, H18), 7.96 (1H, dd, J=6.4, 2.3 Hz, H15), 6.97 (1H, d, J=8.7 Hz, H16), 3.92 (1H, s, OMe), 1.37 (12H, s, Bpin); 13C NMR (75 MHz, CDCl3) delta 191.2, 169.0, 140.1, 134.2, 129.5, 110.7, 84.1, 56.2, 25.0; EI-HRMS (m/z) calcd for C14H19BO4 [M]+ 261.1412, found 261.1383.
73.76%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90℃;Inert atmosphere;
To a stirred solution of intermediate 8a (9.0 g, 41.9 mmol) taken in 1,4 dioxane (90 mL), bis(pinocalato)diboran (12.7 g, 50.0 mmol) and potassium acetate (8.28 g, 2.0 eq) was added, degasified using nitrogen. Then, Pd(dppf)C12 (1 .7 g, 0.05 eq) was added and the resultant was heated at 90 00 over night. The reaction mixture wasdiluted with water and extracted with ethyl acetate; the organic layer was washed with water, brine solution, dried over anhydrous Na2SO4 and concentrated. The product was purified by combi-flash to yield the title product (9.0 g, 73.76%) as an off white solid. LCMS: (M+H)+ = 263.2; 1H NMR: (ODd3, 300MHz) 6 9.83(s, 1H), 8.13- 8.14 (d, 1H), 7.87-7.91 (m, 1H), 1 6.89-6.92 (d, 1H), 3.85 (5, 3H), 1.30 (5, 12H).
73.76%
To a stirred solution of intermediate 8a (9.0 g, 41.9 mmol) ,1,4 dioxane (90 mL), bis(pinocalato)diboran (12.7 g, 50.0 mmol) and potassium acetate (8.28 g, 2.0 eq)was added and was degasified using nitrogen. Then, Pd(dppf)012 (1.7 g, 0.05 eq)was added and was heated at 90 00 over night. The reaction mixture was dilutedwith water and extracted with ethyl acetate; the organic layer was washed with water,brine solution, dried over anhydrous Na2SO4 and concentrated. The product waspurified by combi-f lash to yield the title product (9.0 g, 73.76%) as an off white solid.LOMS: (M+H)+ = 263.2;1H NMR: (0D013, 300MHz) 69.83(s, 1H), 8.13-8.14 (d, 1H),7.87-7.91 (m, 1H), 1 6.89-6.92 (d, 1H), 3.85 (5, 3H), 1.30 (5, 12H).
53.76%
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; In 1,4-dioxane; at 0℃;Inert atmosphere; Microwave irradiation;
4-Methoxy-3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)benzaldehyde To a stirred solution of <strong>[34841-06-0]3-bromo-4-methoxybenzaldehyde</strong> (2.0 g, 9.3 mmol) in dioxane (5 mL), bis(pinacolato)diboron (2.82 g, 11.1 mmol) in 1, 4 dioxane (10.0 mL) and potassium acetate (2.73 g, 27.9 mmol) was added at 0 C. under argon atmosphere. Then (PPh3)2PdCl2 (0.38 g, 0.465 mmol) was added and the reaction was allowed to be completed under Microwave condition. The reaction mixture thus obtained was diluted with ethyl acetate, washed with water and brine solution dried over anhydrous Na2SO4 and concentrated in vacuum. The resulting crude product was purified by combiflash, to give the title compound as a pale pink solid (1.3 g, yield: 53.76%): 1H NMR (300 MHz, CDCl3): delta 9.83 (s, 1H), 8.13 (s, 1H), 7.88-7.91 (d, 1H), 6.89-6.92 (d, 1H), 3.86 (s, 3H), 1.3 (s, 12H).
With oxalyl dichloride; Triphenylphosphine oxide; In chloroform; at 45℃; for 2h;
General procedure: Method a: To a solution of triphenylphosphine oxide (21.0 mg, 75.5 mumol) in CHCl3 (1.0 mL) was added the appropriate aldehyde (1.00 equiv, 1.00 mmol). Oxalyl chloride (110 muL, 1.30 mmol) as a solution in CHCl3 (1.0 mL) was then added over 2 h via syringe pump at 55 C after which time the solvent was removed in vacuo. Purification by flash chromatography (silica, 0-10% Et2O/pet. ether) gave the pure 1,1-dichlorides. Method b: As general method a, with the exception that the reaction was conducted at 45 C. Method c: To a solution of triphenylphosphine oxide (21.0 mg, 75.5 mumol) in DCE (1.0 mL) was added the appropriate aldehyde (1.00 equiv, 1.00 mmol). Oxalyl chloride (110 muL, 1.30 mmol) as a solution in DCE (1.0 mL) was then added over 8 h via syringe pump at 75 C after which time solvent was removed in vacuo. Purification by flash chromatography (silica, 0-10% Et2O/pet. ether) gave the pure 1,1-dichlorides. Method d: Same as general method c, with the exception that a 2 h slow addition time was employed. 4.3.5 2-Bromo-4-(dichloromethyl)-1-methoxybenzene 4e The following reagents were combined in the amounts indicated below in accordance with method b. 3-Bromo-4-methoxybenzaldehyde (215 mg, 1.00 mmol), oxalyl chloride (110 muL, 1.30 mmol) and triphenylphosphine oxide (21.0 mg, 75.5 mumol) gave 2-bromo-4-(dichloromethyl)-1-methoxybenzene 4e (243 mg, 90%) by 1H NMR. Purification by flash column chromatography (silica, 10% Et2O/pet. ether) afforded 2-bromo-4-(dichloromethyl)-1-methoxybenzene 4e as a colourless oil (243 mg, 90%). 1H NMR (270 MHz, CDCl3) delta 7.79 (d, J=2.3 Hz, 1H, ArH), 7.49 (dd, J=8.7 and 2.3 Hz, 1H, ArH), 6.90 (d, J=8.7 Hz, 1H, ArH), 6.65 (s, 1H, CHCl2), 3.93 (s, 1H, CH3); 13C NMR (68 MHz, CDCl3) delta 157.0 (Cq), 134.0 (Cq), 131.4 (CH), 126.6 (CH), 111.8 (CH), 111.5 (CH), 70.6 (CH), 56.5 (CH3); IR numax (CHCl3) 3011, 2971, 2946, 2910, 2841, 1602, 1572, 1498, 1462, 1441, 1407, 1309, 1289, 1281, 1263, 1190, 1151, 1055, 1020, 908, 893, 660 cm-1; HRMS (EI+) [M+] C8H8OBrCl2 calcd 267.9057, found 267.9052.
With HCNC-4; In neat (no solvent); at 20℃; for 0.416667h;UV-irradiation; Green chemistry;
General procedure: A mixture of an aldehyde (1 equiv), malononitrile (1 equiv), triethylphosphite (1.5 equiv), and the catalyst (0.1 equiv) was taken in a 5 ml glass test tube with a total reaction volume of 0.4-0.5 ml approximately. The reaction mixture was placed at room temperature for appropriate time period under ultrasonic irradiation, performed in a Bandelin Sonorex Super RK 510 H ultrasonic bath with inner tank dimensions; l × w × d: 300 × 240 × 150 mm, exterior dimensions; l × w × h: 325 × 265 × 305 mm, frequency: 35 kHz and ultrasonic peak output: 640 W. After completion of the reaction (monitored by TLC), the mixture was dissolved in ethyl acetate and filtered to separate the catalyst. The catalyst was subsequently washed with ethyl acetate, dried, and reused several times under same reaction conditions. Filtrate was worked up in ethyl acetate: water (1:1) system. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude products were purified by the crystallization technique and no column purification was followed.
With dipotassium peroxodisulfate; In water; dimethyl sulfoxide; at 100℃;Sealed tube; Microwave irradiation;
General procedure: We intended to synthesize compounds based on 1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one scaffold by using microwave assisted protocol (Scheme 1). In this direction we started the studies for optimization of synthesis of 5-(2-ethoxyphenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one 3a. The optimization studies were initiated by screening of different oxidizing agents as depicted in Table1, see Supplementary data using DMSO:Water in 1:1 proportion to see the conversion in desired product. Amongst all oxidants, the best result was observed with K2S2O8, in equivalence studies for catalyst, 3eq. of catalyst has given maximum yields (Table1, see Supplementary data). Therefore, all reactions were conducted using this condition after optimization of catalyst. However, oxone has also given the product 3a with minor yields. After screening of the catalyst we started study of selectivity for solvent that could affect the formation of 5-(2-ethoxyphenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one 3a. The solvent screening was carried out to find out the best conversion, the mixture of DMSO:H2O in 1:1 proportion has given the best results with excellent yields (Table2, see Supplementary data). The microwave protocols were optimized for this reaction as mentioned in Table 3, see Supplementary data; the reactions carried under different microwave Watt powers have given varied results. Wherein, entry 3(b) (Table3, see Supplementary data) was found to be the best condition for maximum conversion. A series of compounds based on 1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one scaffold was synthesized using these optimized conditions, wherein, all kind of substrates with diversity around aryl ring were chosen for conversion and in all cases products obtained in good to excellent yields (Table1).
85%
Synthesis of Ba; Step 7. 4-amino-1-methyl-3-propyl-1H-pyrazole-5-carboxamide (1 eq) and 3-Bromo-4-methoxybenzaldehyde (1.1 eq) were suspended in ethanol 5 ml and the mixture heated at 70 C for 2 hours after conformation of forming of imine by TLC. Added CuC12 (3 eq) and the reaction mixture heated at 75 C under 02 for 3 hours. After completion of the reaction, the ethanol was removed under vacuum. Then workupwith ethyl acetate and water. Separate the organic layer and Water layer re-extracted with 2x25 ml ethyl acetate. The combined organic layers are washed with brine solution, concentrated under vacuum. The residue was purified by column chromatography on silica the desired product Ba as a white solid; yield 85%. 1H NMR (400 MHz DMSO): 8.31(d J = 2.0Hz 1H),8.29(s 1H),8.14(dd J = 8.8,2.0Hz1H),7.24(dJ= 8.8Hz) 4.14(s 3H),3.93(s 3H)2.8(tJ 7.3Hz 2H),1.76(m 2H),0.95(tJ=7.3Hz 3H). MASS: ESI [M+2 + H] + 377.05; Elemental anal. calcd. for C16H17BrN4O2C, 50.94; H, 4.54; Br, 21.18; N, 14.85; 0, 8.48; found C, 50.89; H, 4.56; Br, 21.21; N,14.83; 0, 8.50.
N-((3-bromo-4-methoxyphenyl)(1-(2,6-dimethylphenyl)-1H-tetrazol-5-yl)methyl)-2-(1H-indol-3-yl)ethanamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With trimethylsilylazide; In methanol; at 20℃; for 6h;Inert atmosphere;
General procedure: In a round-bottomed flask equipped with a magnetic stirring bar, tryptamine (7) (1.0equiv.), aldehyde 8 (1.0 equiv.), isocyanide 9 (1.0 equiv.) and azidotrimethylsilane (10) (1.0equiv) in MeOH (1.0 M) were placed. The resulting mixture was stirred for 6 h under inertatmosphere (N2) at room temperature. The solvent was evaporated under reduced pressure.Then, the crude reaction was diluted with CH2Cl2 (20 mL) and washed with brine (10 mL).The aqueous layer was extracted with CH2Cl2 (2 × 10 mL). The combined organic layerwas dried over anhydrous Na2SO4, evaporated to dryness and purified on a silica gelcolumn chromatography using a mixture (Hex-AcOEt 3:1 V/V) as eluent.
With titanium tetrachloride; triethylamine; In dichloromethane; at 0 - 25℃;Inert atmosphere;
General procedure: To a mixture of an aldehyde (0.1 mol) and alkyl acetate (0.1 mol) in dichloromethane (15 mL) was added Et3N (0.3 mol). The resulting reaction mixture was cooled to 0 C under nitrogen atmosphere. To this was added TiCl4 (0.12 mol) dropwise over a period of 15 min and the mixture was stirred for further 2-4 h at room temperature. When the reaction was complete as confirmed by TLC, the mixture was diluted with water (25 mL) and the dichloromethane layer was separated. The organic phase was washed with 0.5 M aqueous HCl, water and brine. It was then dried over anhydrous Na2SO4 and evaporated under reduced pressure to afford the corresponding alkyl (E)-alpha,beta-unsaturated carboxylate (2) in excellent yield and purity.
General procedure: In a general procedure, an oven-dried round-bottom flask was charged with DABCO-IL 25 and HBD (PEG-300) in a ratio of 1:2, respectively. The reaction content was heated at 90 C to homogenize it, and then to this mixture aromatic aldehyde 26 (2 mmol), dimedone 27 (4 mmol), NH 4 OAc (2.4 mmol) were added. Next, reaction content was stirred and heated at reflux (78-80 C) for 10-12 h. The reaction progress was observed through TLC by comparison with the starting materials (20% EtOAc in n-hexane). Upon starting material complete consumption, the reaction content was cooled to RT and then crashed ice was added to the reaction flask. The resulting mixture was stirred to get precipitates that were filtered carefully and washed with cold distilled H 2 O to get the desired product in crude form (28a-28j). Silica gel column chromatography with the gradient eluent mixture of EtOAc and hexane (1:9 to 9:1) was used to purify the product.
89%
With ammonium acetate; In ethanol; at 80℃; for 2h;
General procedure: A mixture of dimedone (2 mmol), aromatic aldehyde (1 mmol) and ammonium acetate (1 mmol) was taken in ethanol (1.5 mL), mixed well and then SiO2-I (0.1 g) was added. The reaction mixture was stirred at 80 C for 2-3 h. The course of the reaction was monitored on TLC (3:7::EtOAc/hexane). After completion of the reaction, water (10 mL) was added and the separated solid was filtered along with the catalyst. The residue was washed with ether and the solid catalyst was recovered and kept aside for reuse. The crude product thus obtained from the ether extract after the evaporation of ether was subjected to silica gel column chromatography (3:7::EtOAc/light petrol) to get the pure products.
88%
With gamma-maghemite; ammonium acetate; In neat (no solvent); at 120℃; for 0.116667h;Green chemistry;
General procedure: A mixture of 5,5-dimethyl-1,3-cyclohexanedione (2 eq) (1), substituted aromatic aldehydes (1eq) (2), Ammonium acetate (1 eq) (3) and Fe2O3 nano particles (15 mol %) are stirred at 120 C in an oil bath for the prescribed time. The completion of the reaction is monitored by TLC. After completion of the reaction, the reaction mixture is cooled to room temperature to attain a solid product. Then the product is dissolved in methanol and the catalyst is recovered by magnetization. The crude products are further purified by recrystallization from ethanol. All the synthesized products are characterized by IR, NMR and Mass spectroscopic data and their melting points are compared with authentic samples.
With nickel(II) chloride tetrahydrate; ammonium acetate; In ethanol; at 78 - 80℃; for 1.5h;
General procedure: In a typical reaction, an oven dried round bottomed flask was cooled to room temperature and charged with 8 dimedone (10mmol, 1.40g), corresponding benzaldehyde (0.50mL, 5mmol), 10 ammonium acetate (0.57g, 7.5mmol), 11 nickel (II) fluoride tetrahydrate (25mol%) as catalyst and 12 ethanol (3mL). The resulting reaction mixture was heated at reflux (78-80C) for 1.5h, cooled, dissolved in 52 methanol and poured into the crushed ice in a beaker. The mixture was further stirred to dissolve catalyst and to precipitate out corresponding acridine-based product 2 which was filtered, dried and washed in n-hexane to remove the un-reacted 9 benzaldehyde to afford pure corresponding acridine 13 2 in 86% yield (1.50g) [32].
N-(3-bromo-4-methoxybenzylidene)quinolin-3-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With acetic acid; In ethanol; at 60℃; for 3h;
General procedure: Substituted aromatic aldehyde (2 mmol) was dissolved in10 mL ethanol and few drop of glacial acetic acid wereadded and reaction mixture was refluxed at 60 C. Then 5-aminoquinoline or 3 -aminoquinoline (1 mmol), were addedwith constant refluxing, and completion of reaction waschecked by TLC analysis. After 3 h, when reaction completed,reaction mixture was poured on to water then a solidappeared. The resultant solid product was filtered andwashed with hexanes. Recrystallization from methanol affordedthe desired solid Schiff bases 1-19
(Z)-5-(3-bromo-4-hydroxybenzylidene)-3-(4-hydroxybenzoyl)-4-(4-hydroxyphenyl)furan-2(5H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39%
Stage #1: 3-bromo-4-methoxybenzylaldehyde; p-methoxybenzoylmethanol; 6-(4-methoxyphenyl)-2,2-dimethyl-4H-1,3-dioxin-4-one With triethylamine In toluene at 150℃; for 0.0833333h; Inert atmosphere; Sealed tube; Microwave irradiation; Molecular sieve;
Stage #2: With boron tribromide In dichloromethane at -78 - 20℃; for 20h; Inert atmosphere;
General procedure for the synthesis of cadiolide analogues 5-10
General procedure: Toluene (for a solution of 1.0 mol L1), Et3N (2.0 equiv) and the appropriate a-hydroxy-ketone 1a-c (1 equiv), dioxinone 2a-d (2 equiv) and aldehyde 3a-c (1 equiv) were added to a 15 mL tube flushed with argon. The tube was sealed and then heated in a microwave reactor. Over 1.5 min, the temperature was raised to 150 C, held for 5 min, and then cooled for 10 min. The reaction was quenched at room temperature with 1 M HCl and the mixture extracted with EtOAc. The combined organic layers were thendried with Na2SO4, filtered and concentrated under vacuum. Filtration through a plug of silica and elution with (cyclohexane/EtOAc, 80:20) afforded a mixture of bis-methoxylated and monomethoxylated acylfuranones 4, which was used directly without further purification (partial de-methoxylation resulted during them icrowave-assisted multi-component recation). To a stirred solution of bis-methoxylated and mono-methoxylatedacylfuranones 4 (obtained above) in CH2Cl2 (5 mL) was added BBr3 (10 equiv) at -78 C. The mixture was then slowly warmed to room temperature over 20 h. The reaction was quenched at -78 C with MeOH then at room temperature with H2O and the mixture extracted twice with EtOAc. The combined organic layers were then dried with Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography on silicagel using a gradient of EtOAc/MeOH (100:0 to 95:5) to give cadiolide analogues 5-10.
6-(3-bromo-4-methoxyphenyl)-2,2-dimethyl-4H-1,3-dioxin-4-one[ No CAS ]
(Z)-3-(3-bromo-4-hydroxybenzoyl)-5-(3-bromo-4-hydroxybenzylidene)-4-(4-hydroxyphenyl)furan-2(5H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%
Stage #1: 3-bromo-4-methoxybenzylaldehyde; p-methoxybenzoylmethanol; 6-(3-bromo-4-methoxyphenyl)-2,2-dimethyl-4H-1,3-dioxin-4-one With triethylamine In toluene at 150℃; for 0.0833333h; Inert atmosphere; Sealed tube; Microwave irradiation; Molecular sieve;
Stage #2: With boron tribromide In dichloromethane at -78 - 20℃; for 20h; Inert atmosphere;
General procedure for the synthesis of cadiolide analogues 5-10
General procedure: Toluene (for a solution of 1.0 mol L1), Et3N (2.0 equiv) and the appropriate a-hydroxy-ketone 1a-c (1 equiv), dioxinone 2a-d (2 equiv) and aldehyde 3a-c (1 equiv) were added to a 15 mL tube flushed with argon. The tube was sealed and then heated in a microwave reactor. Over 1.5 min, the temperature was raised to 150 C, held for 5 min, and then cooled for 10 min. The reaction was quenched at room temperature with 1 M HCl and the mixture extracted with EtOAc. The combined organic layers were thendried with Na2SO4, filtered and concentrated under vacuum. Filtration through a plug of silica and elution with (cyclohexane/EtOAc, 80:20) afforded a mixture of bis-methoxylated and monomethoxylated acylfuranones 4, which was used directly without further purification (partial de-methoxylation resulted during them icrowave-assisted multi-component recation). To a stirred solution of bis-methoxylated and mono-methoxylatedacylfuranones 4 (obtained above) in CH2Cl2 (5 mL) was added BBr3 (10 equiv) at -78 C. The mixture was then slowly warmed to room temperature over 20 h. The reaction was quenched at -78 C with MeOH then at room temperature with H2O and the mixture extracted twice with EtOAc. The combined organic layers were then dried with Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash chromatography on silicagel using a gradient of EtOAc/MeOH (100:0 to 95:5) to give cadiolide analogues 5-10.
With bis(tri-t-butylphosphine)palladium(0); sodium carbonate In 1,4-dioxane; water at 70℃; for 24h; Inert atmosphere;
Dialdehyde 16
Two step method: To a schlenk tube of 11 (1.0 g, 4.65 mmol, 1.0 equiv) in p-dioxane (18.6 ml) was added KOAc (1.37 g, 13.95 mmol, 3.0 equiv) and bis-pinacolatodiboron (1.18 g, 4.65 mmol, 1.0 equiv). The reaction mixture was then degassed by bubbling nitrogen through the solution for about 5 minutes before adding Pd(dppf)Cl2 (0.21 g, 0.028 mmol, 6 mol%) and then stirring at 90 °C for 24 hours. The reaction mixture was then cooled to room temperature before filtering through celite and concentrating in vacuo. To the boronate ester 15 thus obtained in p-dioxane (18.6 ml) was added 10 (0.80 g, 3.72 mmol, 1.0 equiv) and Pd(tBu3P)2 (0.36 g, 0.7 mmol, 15 mol%) followed by the addition of the solution of Na2CO3 (1.48 g, 13.95 mmol, 3.0 equiv) in H2O (2 ml). The reaction was stirred at 70 °C for 24 hours and then quenched with H2O and extracted three times with EtOAc. The organic extracts were dried over MgSO4, filtered over celite, and concentrated in vacuo. Purification by column chromatography on silica (10:1 hexanes:ethyl acetate) gave 16 (0.887 g, 73.5 %) as a pale yellow crystalline solid. 1H NMR (500 MHz, CDCl3) δ 10.50 (t, J = 0.9 Hz, 1H), 9.92 (t, J = 0.9 Hz, 1H), 8.00 (dt, J = 2.3, 0.9 Hz, 1H), 7.89 - 7.80 (m, 2H), 7.73 (ddd, J = 8.6, 2.4, 0.8 Hz, 1H), 7.07 (dd, J = 12.0, 8.6 Hz, 2H), 3.98 (t, J = 0.8 Hz, 3H), 3.90 (d, J = 1.0 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 190.82, 190.80, 189.63, 161.37, 161.27, 161.24, 136.88, 131.96, 131.52, 131.47, 129.95, 129.77, 129.62, 129.55, 129.52, 124.50, 111.54, 111.10, 77.22, 76.96, 76.55, 56.03, 56.02, 55.90, 55.83, 29.06.
N'-[(Z)-(3-bromo-4-methoxyphenyl)methylidene]-2-hydroxybenzohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With hydrogenchloride; In ethanol; water; at 20℃;
General procedure: The synthesis of hydrazide based Schiff bases were carried out in two steps. First methyl salicylate (1 mmol) was mixed with hydrazine hydrate (1 mmol) in methanol (10 ml) as solvent with 2-3 drops of acetic acid under continuous stirring for 4 h to obtain hydrazide. The reaction completion was monitored by TLC through depletion of starting material spot and formation of hydrazide fluorescent spot established the reaction completion. After completiondistilled water was added into the reaction mixture whichgives white precipitate. The product obtained was then further purified by washing with n-hexane. In step-2, the hydrazide was mixed with different aldehydes (1:1) in EtOH with 1-2 drops of HCl and stirred for 2-3 h to obtain various Schiff bases of hydrazones (1-28). The reaction completion was checked by TLC. The Schiff bases obtained were then washed with ethanol and n-hexane. 4.7.17 N'-[(Z)-(3-bromo-4-methoxyphenyl)methylidene]-2-hydroxybenzohydrazide (17) Yield: 0.23 g (85%);m.p. 216-218 C; 1H NMR (300 MHz, DMSO-d6) delta (ppm): 11.82 (s, 2H, -OH, -NH), 8.36 (s, 1H, N=C-H), 7.96 (s, 1H, H-2'), 7.87 (d, 1H, J6,5 = 7.5 Hz, H-6), 7.72 (d, 1H, J6',5' = 7.2 Hz, H-6'), 7.43 (t, 1H, J4(3,5) = 7.2 Hz, H-4), 7.21 (d, 1H, J5',6' = 8.4 Hz, H-5'), 6.94 (m, 2H, H-3/5), 3.90 (s, 3H, -OCH3); EI-MS: m/z (rel. abund.%), 351 ([M+2]+, 3.8), 350 ([M+1]+, 9.2), 349 (M+, 3.4), 230 (76.3), 228 (65), 137 (64), 121 (100), 120 (35), 93 (19), 65 (40).
1-ethyl-7-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid (3-bromo-4-methoxybenzylidene)hydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In methanol; at 20℃; for 3h;
General procedure: Compounds (3-16) were prepared according to a literature procedure reported earlier by our group10. Compound 2 (2.46 g,10 mmol) was dissolved in methanol (15 mL). The mixture wasstirred until a clear solution was obtained. After that, the appropriate (hetero)aromatic aldehydes were added (11 mmol) andthe solution was stirred at room temperature for 3 h. The precipitate obtained was fltered o, dried, and recrystallized fromethanol.The analytical and spectral data of compounds (3-16) werereported earlier10.
2-methylthio-5-(3-bromo-4-methoxyphenyl)-5,12-dihydro-4-amino-benzo[g]pyrimido[4,5-b]quinoline-6,11-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55.7%
With acetic acid; for 2.0h;Reflux;
Will be 1.56 g<strong>[1005-39-6]2-methylthio-4,6-diaminopyrimidine</strong>, 2.13 g 3-bromo-4-methoxybenzaldehyde,1.74 g of 2-hydroxy-1,4-naphthoquinone and 10 mL of acetic acid were added to a 50 mL reaction flask.Heat to reflux for 2 hours. After the reaction is complete, the resulting mixture is cooled to room temperature.The solvent was distilled off, dissolved in 20 mL of dichloromethane, and saturated with 20 mL of sodium bicarbonate solution in that order.The solution was washed twice with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The solvent was evaporated and purified by column chromatography to give a red-brown solid.2-Methylthio-4-amino-5-(3-bromo-4-methoxyphenyl)-5,12-dihydro-benzo[g]pyrimido[4,5-b]quinoline -6,11-Dione 2.83 g, yield 55.7%.
methyl (2Z)-3-(3-bromo-4-methoxyphenyl)-2-[(tert-butoxycarbonyl)amino]acrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
Example 24A Methyl (2Z)-3-(3-bromo-4-methoxyphenyl)-2-[(tert-butoxycarbonyl)amino]acrylate Under an argon atmosphere, methyl [(tert-butoxycarbonyl)amino](dimethoxyphosphoryl)acetate (7129 mg, 23 mmol) was initially charged in dichloromethane (150 ml), 1,8-diazabicyclo[5.4.0]undec-7-ene (7129 mg, 25 mmol) was added and the mixture was stirred at RT for 10 min. A solution of <strong>[34841-06-0]3-bromo-4-methoxybenzaldehyde</strong> (5000 mg, 23 mmol) in dichloromethane (40 ml) was added and stirred at RT for 90 min. Ethyl acetate was added to the reaction mixture and the solution was adjusted to pH 4 using 1N hydrochloric acid solution. The mixture was washed with saturated aqueous sodium chloride solution. The organic phase was dried with sodium sulphate and the solvent was removed. The crude product was applied to silica gel and purified chromatographically (silica gel, cyclohexane/ethyl acetate 7.5:1, then 5:1, then 3:1), and the solvent was removed. This gave 7300 mg (83% of theory) of the title compound. 1H NMR (400 MHz, DMSO-d6): delta=ppm 1.43 (br. s., 9H), 3.72 (s, 3H), 3.88 (s, 3H), 7.17 (d, 2H), 7.66 (d, 1H), 7.96 (d, 1H), 8.67 (br. s, 1H). LC-MS (Method 1): Rt=1.11 min; MS (ESIneg): m/z=384 [M-H]-.
Multi-step reaction with 3 steps
1.1: toluene / 6 h / Reflux; Dean-Stark
2.1: tetrahydrofuran / 0.08 h / 0 °C
2.2: 18 h / 20 °C
3.1: titanium(IV) tetrachloride / chloroform / 16 h / Reflux
Multi-step reaction with 3 steps
1: toluene / 6 h / Reflux; Dean-Stark
2: triethyl phosphite / tetrahydrofuran / 18 h / 0 - 20 °C
3: titanium(IV) tetrachloride / chloroform / 48 h / Reflux
Multi-step reaction with 2 steps
1.1: toluene / 6 h / Reflux
2.1: tetrahydrofuran / 0.08 h / 0 °C
2.2: 18 h / 0 - 20 °C
2.3: 48 h / Reflux
Multi-step reaction with 2 steps
1.1: toluene / 6 h / 120 °C / Dean-Stark
2.1: isopropyl carbonochloridate / tetrahydrofuran / 0.08 h / 0 °C
2.2: 18.33 h / 20 °C
2-(3'-bromo-4'-methoxybenzylidene)-6-methyl-2,3,4,9-tetrahydrocarbazol-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With potassium hydroxide; In ethanol; at 20℃; for 24h;
General procedure: An equimolar mixture of the 2,3,4,9-tetrahydrocarbazol-1-one(1, 0.005 mol) and <strong>[34841-06-0]3-bromo-4-methoxybenzaldehyde</strong> (2, 0.005 mol) was treated with 5% ethanolic KOH (25 mL)solution andstirred for 24 h at room temperature. The completion of the reactionwasmonitored by TLC. After the completion of the reaction, thereaction mixture was cooled to room temperature and poured intoice cold water and neutralized with 1:1 HCl. The precipitated solidwas filtered and purified by column chromatography over silica gelusing petroleum ether: ethyl acetate (99:1) mixture as eluant toafford the respective product, 2-(3'-bromo-4'-methoxybenzylidene)-2,3,4,9-tetrahydrocarbazol-1-one 3.
2-(3'-bromo-4'-methoxybenzylidene)-8-methyl-2,3,4,9-tetrahydrocarbazol-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With potassium hydroxide; In ethanol; at 20℃; for 24h;
General procedure: An equimolar mixture of the 2,3,4,9-tetrahydrocarbazol-1-one(1, 0.005 mol) and <strong>[34841-06-0]3-bromo-4-methoxybenzaldehyde</strong> (2, 0.005 mol) was treated with 5% ethanolic KOH (25 mL)solution andstirred for 24 h at room temperature. The completion of the reactionwasmonitored by TLC. After the completion of the reaction, thereaction mixture was cooled to room temperature and poured intoice cold water and neutralized with 1:1 HCl. The precipitated solidwas filtered and purified by column chromatography over silica gelusing petroleum ether: ethyl acetate (99:1) mixture as eluant toafford the respective product, 2-(3'-bromo-4'-methoxybenzylidene)-2,3,4,9-tetrahydrocarbazol-1-one 3.
2-(3'-bromo-4'-methoxybenzylidene)-6-chloro-2,3,4,9-tetrahydrocarbazol-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With potassium hydroxide; In ethanol; at 20℃; for 24h;
General procedure: An equimolar mixture of the 2,3,4,9-tetrahydrocarbazol-1-one(1, 0.005 mol) and <strong>[34841-06-0]3-bromo-4-methoxybenzaldehyde</strong> (2, 0.005 mol) was treated with 5% ethanolic KOH (25 mL)solution andstirred for 24 h at room temperature. The completion of the reactionwasmonitored by TLC. After the completion of the reaction, thereaction mixture was cooled to room temperature and poured intoice cold water and neutralized with 1:1 HCl. The precipitated solidwas filtered and purified by column chromatography over silica gelusing petroleum ether: ethyl acetate (99:1) mixture as eluant toafford the respective product, 2-(3'-bromo-4'-methoxybenzylidene)-2,3,4,9-tetrahydrocarbazol-1-one 3.
(E)-3-(3-bromo-4-methoxyphenyl)-1-(2,5-dichlorothiophen-3-yl)prop-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With potassium hydroxide; In methanol; at 20℃; for 10h;
General procedure: An equimolar mixture of the aryl aldehyde, KOH were dissolved in MeOH (50 mL). To this solution 3-acetyl-2,5-dichlorothiophene, 3, in MeOH (10 mL) was added dropwise. After theaddition was completed, the reaction mixture was stirred at r.t.for 10 h. The precipitate formed was fltered o, washed withMeOH and dried without any further purifcation.
General procedure: A 25 mL two-necked round-bottom flask was charged with a solution of 7k (100 mg, 0.57 mmol) in anhydrous CH2Cl2 (5 mL) at 0 C. To this solution were successively added i-Pr2NEt (0.3 mL, 1.70 mmol) and TBDMSOTf (0.5 mL, 2.28 mmol) under nitrogen atmosphere. The mixture was stirred for 15 min at 0 C, and then 4-methoxybenzaldehyde 8a (0.08 mL, 0.68 mmol) was added. After stirring at 0 C for 1 h, the reaction mixture was left for 3 h at room temperature. Then DBU (0.25 mL, 1.71 mmol) was added and the resulting solution was allowed to stir for an additional 6 h before quenching with an aqueous solution of HCl (1M, 5 mL). Then CH2Cl2 was removed under reduced pressure in a rotary evaporator and the aqueous phase was extracted with ethyl acetate (3×10 mL. The combined organic layers were washed with saturated brine solution (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluted with hexane/ethyl acetate (8:2 v/v) to afford rubrolide F 10 as a yellow solid in 69% yield (116 mg, 0.39 mmol).
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 5℃;Inert atmosphere;
(2) In 4000mL reaction vessel, nitrogen protection,740.7 g of 3-bromo-4-hydroxybenzaldehyde was put into the reaction vessel.2000 g of N,N-dimethylformamide and558.0g potassium carbonate,Control temperature drop 0 ~ 5 C drop775g iodomethane,After the control of raw materials is complete,Concentrate the reaction solution into ice water,Precipitation of solids,Recrystallization gave white crystalline product 3-bromo-4-methoxybenzaldehyde 752.7g, yield 95.0%;
With tetrabutylammomium bromide; copper(l) chloride; sodium hydroxide; In water; at 120℃;
(3) In a 4000 mL reaction vessel,752.7 g of <strong>[34841-06-0]3-bromo-4-methoxybenzaldehyde</strong> and1400g pure water into the reaction vessel,Then put 1400.0g of 30% liquid caustic soda,6.9g of cuprous chloride and11.3g tetrabutylammonium bromide,Warm up to 120C,After the raw material is fully reacted, it is filtered, acidified, and solids precipitated.Recrystallization yields 399.4 g of the product, isovanillin.The yield was 75.0%, and the three-step total yield was 64.1%.
N'-(1E)-(3-bromo-4-methoxybenzylidene)-4-nitrobenzohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81.4%
With hydrazine hydrate; In ethanol; at 85℃; for 5h;
Take a 25ml three-vial bottle, add 8ml of absolute ethanol, 0.1g in order 4-Nitrobenzoyl hydrazide, refluxed at 85C until dissolved, 0.13 g3-Bromo-4-methoxybenzaldehyde, refluxed for 5 h. After the TLC monitoring reaction is over,After cooling to room temperature, it was filtered by suction on an ice bath for 15 minutes, and the filter cake was washed with anhydrous ethanol.The filtrate was columned (dichloromethane:methanol=30:1).Combine filter cake and column product to produce white product(E)-N'-(3-bromo-4-methoxybenzylidene)-4-nitrobenzoic acid hydrazide, 0.17 g,Yield 81.4%.
2-amino-N'-(1E)-(3-bromo-4-methoxyphenylmethylidene)-5-nitrobenzohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84.8%
With hydrazine hydrate; In ethanol; at 85℃; for 4h;
Take a 25ml three bottle, add 8ml of anhydrous ethanol,0.1 g of 2-amino-5-nitrobenzoylhydrazone was refluxed at 85C until dissolved, 0.12 g of <strong>[34841-06-0]3-bromo-4-methoxybenzaldehyde</strong> was added, and the reaction was refluxed for 4 hours. After the TLC monitoring reaction is over,After cooling to room temperature, it was filtered by suction on an ice bath for 15 minutes, and the filter cake was washed with anhydrous ethanol.The filtrate was columned (dichloromethane:methanol=30:1). Combine the filter cake and the product of the column to obtain the white product (E)-2-amino-N'-(3-bromo-4-methoxybenzylidene)-5-nitrobenzoylhydrazone.0.17 g, yield 84.8%.
N'-(1E)-(3-bromo-4-methoxyphenylmethylidene)-3-nitrobenzohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86.2%
With hydrazine hydrate; In ethanol; at 85℃; for 6h;
Take a 25ml three-necked bottle, add 8ml of absolute ethanol and 0.1g of 3-nitrobenzoylhydrazine in order, and dissolve it at 85C to add 0.13g of <strong>[34841-06-0]3-bromo-4-methoxybenzaldehyde</strong>.The reaction was refluxed for 6 h. TLC monitored the reaction and cooled to room temperature.After 15min ice bath, the filter cake was washed with anhydrous ethanol.The filtrate was columned (dichloromethane:methanol=30:1). Combine the filter cake and the column product to obtain the white product (E)-N'-(3-bromo-4-methoxybenzylidene)-3-nitrobenzoyl hydrazide 0.18 g, yield 86.2% .
2-(3-bromo-4-methoxybenzylidene)hydrazinecarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With sodium acetate; In ethanol; water; at 20℃;
General procedure: A round bottom oven dried flask was charged with aqueous solution of sodium acetate and semicarbazide hydrochloride. Sequentially, the solution of different substituted aldehydes or acetophenones in ethanol was added dropwise to the flask at room temperature. The resulting mixture was stirred until the complete consumption of starting materials. Precipitates of semicarbazones were formed within 5-10 min in case of aldehydes, while in 10-30 min in case of ketones. Progress of reaction was monitored through TLC analysis (Scheme 1). The obtained material was purified via recrystallization from ethanol.
2-(3-bromo-4-methoxyphenyl)quinazolin-4(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
General procedure: 2-Aminobenzamide (1, 0.44 mmol, 1.0 equiv), aldehyde (2, 0.44 mmol, 1.0 equiv), 60 mg silica gel (only for liquid aldehydes) and a stainless-steel milling ball were added into a 10 mL stainless-steel jar. Milling was carried out for 30 min and then IBX (0.484 mmol, 1.1 equiv) was added to the mixture and milling was continued for 1 h. The progress of the reaction was monitored by TLC after taking a small portion of the reaction mixture and dissolving it in DCM (with the appropriate solvent as eluent). After completion of the reaction, dichloromethane was used for extracting the compound from the solid reaction mixture. The solvent was evaporated to dryness and the crude reaction mixture was purified by silica gel column chromatography using an appropriate hexane/ethyl acetate mixture.
6-amino-4-(3-bromo-4-methoxyphenyl)-3-(thiophen-2-yl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With triethylamine; In ethanol; at 20℃; for 2h;
[0116] Pyrazolone (12 mmol, 1.1 equiv.) was suspended in absolute ethanol (typical (0188) concentration c = 0.3 mM) and malononitrile (1.1 equiv.), aldehyde (1 equiv.), and triethyl amine (0.11 equiv.) were added sequentially. The resulting suspension was stirred at room temperature (or at the temperature indicated) for 2 h, unless noted otherwise. Generally, the suspension clarified (due to the formation of polar intermediates), and as the reaction progressed, the product precipitated. The solid was isolated by filtration under vacuum and washed with cold ethanol.
With selenium; copper; potassium hydroxide In dimethyl sulfoxide at 120℃;
12
Under anhydrous and anaerobic conditions, 0.1 mmol of 2-iodo-4-methoxyaniline was added.0.12 mmol of 3-bromo-4-methoxybenzaldehyde, 0.3 mmol of selenium powder,0.005 mmol of copper, 0.2 mmol of potassium hydroxide and 10 ml of DMSO solution,The reaction was refluxed at 120 ° C in a single-neck round bottom flask, and the reaction was monitored by TLC.Separation of pure methoxy-containing benzoselenazole compounds by column chromatographyThe reaction product was obtained by demethylation of boron tribromide (6 eq.). The product was obtained as pale yellow solid.The yield was 23%.
3-(m-chlorophenyl)-4-methoxybenzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With potassium dihydrogenphosphate; tetrakis(triphenylphosphine) palladium(0); In methanol; 1,2-dimethoxyethane; water; at 20 - 80℃; for 12h;Schlenk technique; Inert atmosphere; Sealed tube;
<strong>[34841-06-0]3-bromo-4-methoxybenzaldehyde</strong> (0.40 g, 1.86 mmol) was added sequentially to a Slecnck reaction flask.m-Chlorobenzeneboronic acid (0.36g, 2.3mmol)And potassium phosphate(0.51g, 1.92mmol), sealed with a rubber stopper,After vacuum pumping (10 seconds), nitrogen is introduced again.After repeating this three times, an argon balloon was inserted into the rubber stopper. then,Inject DME/MeOH/H2O mixed solvent with stirring(30 mL, VDME: VMeOH: VH2O = 4:1:1).The mixture is stirred at room temperature until all solids have dissolved.Injection of catalyst tetrakistriphenylphosphine palladium (0.18 g, 0.16 mmol)A suspension of DME/MeOH/H 2 O (2 mL) was suspended. then,The mixture was heated to 80 C, stirred for 12 h, and the progress of the reaction was examined by thin layer chromatography (TLC).After the reaction is complete,The reaction mixture was evaporated under reduced pressure to remove solvent and then distilled water (40 mL).Ethyl acetate (30 mL × 3) was extracted and the organic layers were combined.Dry over anhydrous sodium sulfate.The obtained ethyl acetate extract is further demineralized by filtration through a short silica gel layer.Ethyl acetate elutes the silica gel layer.After combining all the organic solutions, the obtained crude product was concentrated under reduced pressure.The obtained crude product was separated and purified by silica gel column chromatography.(V petroleum ether: V ethyl acetate = 10:1)4-methoxy-3-m-chlorophenylbenzaldehyde Z2a(Light yellow solid, 0.38 g, yield 83%).
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In methanol; 1,2-dimethoxyethane; water; at 80℃; for 12h;Schlenk technique;
General procedure: To a slecnck flask was added 3-bromo-4-alkoxybenzaldehyde (0.96mmol), 3- substituted phenylboronic acid (1.15 mmol) and potassium phosphate (510 mg, 1.92mmol) at room temperature. Then, the slecnck flask was gently flushed with argon of ordinarypurity using a balloon. After this, a mixed solvent (20 mL) of DME, MeOH and H2O (VDME :VMeOH : VH2O = 4:1:1) was added to the vessel. The mixture was stirred at room temperature.After all solids dissolve, a turbid liquid (2 mL) of DME/MeOH/H2O containingTetrakis(triphenylphosphine)palladium(0) (92 mg, 0.08 mmol) was added to reaction flask.The resulting mixture was heated to 80 oC for about 12 h, monitored by TLC. After completionof the reaction, the reaction mixture was cool down to room temperature. To the reactionmixture was added water (40 mL). The mixture was then extracted with EtOAc (20 mL × 3).The combined organic layer was dried over dry sodium sulfate and evaporated under reducedpressure. The crude product was purified by flash chromatography on silica gel (petroleumether/EtOAc = 10:1).
2-((3-bromo-4-methoxyphenyl)(hydroxy)methyl)-1,4-dihydroxyanthracene-9,10-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
Add 0.5 kg of 1,4-dihydroxyanthraquinone and 1 kg of potassium hydroxide in the glass-lined reaction tank.Add 50L of methanol and 10L of water as solvent.Protected by nitrogen and reacted under ice bath conditions.After 30 minutes, 1.5 kg of sodium dithionite was dissolved in 5 L of water to be added dropwise to the reaction system.After changing the color of the solution, slowly add 1 kg of the excess reaction material <strong>[34841-06-0]3-bromo-4-methoxybenzaldehyde</strong>.After the reaction was completed, 20 L of a 3% hydrogen peroxide solution diluted 5 times was added, and stirring was continued for 120 min.Finally, 10 L of a 1 mol/L hydrochloric acid solution was added for acidification, and the solid powder product was obtained after filtration.The solid yield was 90%.
76%
General procedure: In an ice bath,the solution of quinizarin (1 mmol) in MeOH (20 ml) and aqueous KOH (1 N, 6 ml) was added a solution of Na2S2O4 (1.0 mmol) in water under N2. After 15 min, the aldehyde (4 mmol) was added via syringe. The reaction mixture was stirred for 4 h at 0 C. The solution was poured into 20 ml of cold water, which contained 4 ml of 30% H2O2 and stirred for 20 min. The mixture was acidified by addition of HCl (3 N, 2 ml) and extracted with CH2Cl2, dried and concentrated. The residue was purified by flash column chromatography to afford A1-14 as an orange solid. The yields of the derivatives (A1-A14) were 20-80%.
3,3′-((3′′-bromo-4′′-methoxyphenyl)methylene)bis(6-fluoro-4-hydroxy-2H-chromen-2-one)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With tetraethylammonium bromide; In water; for 2h;Reflux;
General procedure: 6-Fluoro-4-hydroxy /6-chloro-4-hydroxy /4-hydroxy coumarin(1 mmol), and a variety of aromatic aldehydes (0.5 mmol), as well as 10 mol% of tetraethylammonium bromide (TEAB) were dissolved indistilled water (15 mL) in a 100 mL round-bottommed flask. The reactionmixture was refluxed for 2 h. Periodic TLC was taken to check theprogress of reaction. Resulting precipitates were filtered, and washedwith distilled water. This afforded products 1-44 in high yields.
3,3′-((3′′-bromo-4′′-methoxyphenyl)methylene)bis(6-chloro-4-hydroxy-2H-chromen-2-one)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With tetraethylammonium bromide In water for 2h; Reflux;
4.2. General procedure for the syntheses of bis-coumarin derivatives 1-44
General procedure: 6-Fluoro-4-hydroxy /6-chloro-4-hydroxy /4-hydroxy coumarin(1 mmol), and a variety of aromatic aldehydes (0.5 mmol), as well as 10 mol% of tetraethylammonium bromide (TEAB) were dissolved indistilled water (15 mL) in a 100 mL round-bottommed flask. The reactionmixture was refluxed for 2 h. Periodic TLC was taken to check theprogress of reaction. Resulting precipitates were filtered, and washedwith distilled water. This afforded products 1-44 in high yields.
6-methoxy-2'-methylbiphenyl-3-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 110℃; for 1h;Microwave irradiation;
A mixture of <strong>[34841-06-0]3-bromo-4-methoxybenzaldehyde</strong> (200 mg, 0.93 mmol), o-tolylboronic acid (190 mg, 1.4 mmol), PdCl2(dppf) (34 mg, 0.05 mmol) and K2CO3 (386 mg, 2.79 mmol) in 1,4-Dioxane (2 mL) and H2O (0.2 mL) was stirred in a microwave at 110 C. for 1 hour. Water was added and the solution was extracted with EtOAc (30 mL*2). The combined organic layers were concentrated under reduced pressure, and the residue was purified by silica gel column (pet. ether:EtOAc=5:1) to give the desired product 6-methoxy-2'-methylbiphenyl-3-carbaldehyde as a colorless oil (245 mg), Yield 99% (96% purity, UV=214 nm, ESI 227 (M+H)+).
Step A:Add 1,4-dioxane (8 mL) to a three-necked flask A,Benzyl mercaptan (866 mg, 6.97 mmol) and diisopropylethylamine (1.20 mg, 9.29 mmol), and the mixture was stirred at room temperature under nitrogen for 40 min.To another three-necked flask B was added 1,4-dioxane (10 mL),<strong>[34841-06-0]3-bromo-4-methoxybenzaldehyde</strong> (1.0 g, 4.65 mmol),Pd2(dba)3 (213mg, 0.233mmol) and4,5-bisdiphenylphosphino-9,9-dimethoxyxanthene (267 mg, 0.461 mmol), the mixture was stirred at room temperature under nitrogen for 20 min.The mixture in the three-necked flask A was then transferred to the above-mentioned three-necked flask B by a syringe.The resulting mixture was stirred at reflux overnight. Cool to room temperature and add water (40 mL).Extracted with ethyl acetate (40 mL×3).The combined organic phases were washed with saturated brine (30 mL×2).Dry over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel,Ethyl acetate: petroleum ether = 1:40 to 1:20 elution),3-Benzylthio-4-methoxybenzaldehyde (91) (1.25 g) was obtained.The yield was 100%.
(E)-2-(3-bromo-4-methoxystyryl)-5-methyl-6-nitrobenzo[d]thiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With sulfuric acid; In 1,4-dioxane; at 20 - 100℃; for 3h;Inert atmosphere;
To a solution of 2 (23.9 g, 114.9 mmol) and <strong>[34841-06-0]3-bromo-4-methoxybenzaldehyde</strong> (19.1 g, 184 mmol) in dioxane (720 mL) was added concentrated H2SO4 (18.0 g, 12.9 mmol) at room temperature. The result mixture was stirred at 100 C for 3 days under nitrogen atmosphere. After the reaction was completed, the reaction mixture was cooling down to room temperature. The precipitate was collected by filtration and the filter cake was washed with saturated NaHC03 aqueous solution (3 x 300 mL) and water (2 x 300 mL). The solid was dried under high vacuum to afford 3 as a yellow solid (40.0 g, 86% yield). MS (ESI) m/z 404.8, 406.8 [M + H]+
With potassium hydroxide In methanol at 20℃; for 10h;
3.3. Synthesis
General procedure: Synthesis of chalcones 4a-i, went according to the reported procedure [19]. A solution of 3-acetyl-2,5-dichlorothiophene, 2, in MeOH (10 mL) was added dropwise to an equimolar mixture ofthe corresponding aldehydes 3a-I and KOH in MeOH (50 mL). After the addition was completed,the reaction mixture was stirred at RT for 10 h. The precipitate formed was filtered off, washed withMeOH and dried without any further purification.
Stage #1: allyltriphenylphosphonium bromide With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 20℃; for 0.5h;
Stage #2: 3-bromo-4-methoxybenzylaldehyde In tetrahydrofuran at 20℃; Overall yield = 0.42 g;
1
Cooling a solution of triphenylallylphosphonium bromide (1.72 g, 4.5 mmol) in THF (50 mL) to 0 ° C, adding potassium tert-butoxide (0.50 g, 4.5 mmol),The solution turned yellow. The reaction mixture was stirred at room temperature for 30 minutes,A solution of 2-methoxybenzaldehyde (0.65 g, 3 mmol) in THF (10 mL) was added. The reaction mixture was further stirred at room temperature overnight.A saturated solution of NH4Cl (20 mL) was added to the reaction mixture,It was then extracted with Et2O (3 x 100 mL). The combined organic phases were washed with brine (100 mL), dried over MgSO4, and the crude product was purified by silica gel column chromatography (petroleum ether: EtOAc = 100: 1) to give the desired product as a colorless liquid (0.42 g, 58%) .
Stage #1: 3-bromo-4-methoxybenzylaldehyde; 2,2-dimethoxyethylamine With sodium sulfate In toluene for 6h; Reflux; Dean-Stark;
Stage #2: With acetyl hypochlorite In tetrahydrofuran at 0℃; for 0.0833333h; Further stages;
B1.1; B12.1a Step 1: Synthesis of 7-bromo-6-methoxyisoquinoline.
2,2-dimethoxyethanamine (3.7 g, 34.9 mmol) and Na2SO4 (3.3 g, 23.3 mmol) were added to a stirred solution of 3-bromo-4-methoxybenzaldehyde (5 g, 23.3 mmol) in 50 mL of toluene. The reaction mixture was heated to reflux for 6 h using a Dean-stark apparatus. Solvent and excess reagents were distilled off. The crude product was dissolved in THF (50 mL). ClCOOCH3 (2.2 g, 23.3 mmol) was added dropwise at 0 °C. After stirring for 5 min, P(OEt)3 (4.6 g, 27.9 mmol) was added dropwise. The mixture was stirred for 18 h at room temperature. Then the solvents were distilled off. Excess reagents were removed by repeated addition of toluene and evaporation of the solvents. TiCl4 (17.6 g, 93.0 mmol) and CHCl3 (25 mL) were added. The mixture was heated to reflux for 48 h. The mixture was poured on ice and the pH was adjusted to 9 by using aqueous ammonia. The resulting mixture was extracted with EtOAc followed by removal off the solvents. The residue was purified by flash silica gel column chromatography (0-70% EtOAc/petroleum ether) to give the title compound (1.3 g, 16% yield) as a white solid. LCMS: m/z 240.0 [M+H]+; tR = 1.38 min.
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