* 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 triphenylphosphine In diphenylether at 260℃; for 1 h;
General procedure: In a 50 ml round bottom flask containing magnetic stir bar was charged with o-nitro benzaldehydes (2 mmol), phosphorane (2.2 mmol), triphenyl phosphine (4.6 mmol) and diphenyl ether (10 mL) and heated at 260 oC for 1 h. The reaction mass was then cooled to room temperature and poured on silica column. Products were isolated by eluting with petrolium ether to 3:1 pet ether: ethyl acetate.
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 6, p. 2649 - 2658
4
[ 20357-25-9 ]
[ 22608-87-3 ]
Yield
Reaction Conditions
Operation in experiment
99%
With 5%-palladium/activated carbon; hydrogen In tetrahydrofuran at 20℃; for 0.25 h;
Pd/C (5percent, 0.5 g) was suspended in a solution of 4,5-dimethoxy-2-nitrobenzaldehyde (3, 1.0 g, 4.74 mmol) in dry THF (10 mL), and the reaction mixture was stirred at room temperature for 15 min in hydrogen atmosphere under 50 psi pressure. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (0.85 g, 99percent).
92%
With hydrogenchloride; iron In ethanol; water at 80℃; for 2.5 h;
4,5-dimethoxy-2-nitrobenzaldehyde (5.00 g, 23.7 mmol), 0.1 mol / L hydrochloric acid (10 mL)A suspension of iron powder 150 μm (5.17 g, 92.6 mmol) in ethanol (70 mL) was stirred at 80 ° C. for 2.5 hours.The reaction solution was cooled to room temperature, filtered through Celite (Kanto Chemical Co., Celite 545), and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue and the mixture was filtered through silica gel. The filtrate was concentrated under reduced pressure and dried to give the target compound (3.96 g, 21.9 mmol, yield 92percent) as a red solid.
Reference：
[1] Bulletin of the Korean Chemical Society, 2013, vol. 34, # 8, p. 2480 - 2486
[2] European Journal of Medicinal Chemistry, 2017, vol. 127, p. 413 - 423
[3] Tetrahedron Letters, 2015, vol. 56, # 25, p. 3954 - 3960
[4] Patent: JP2018/52878, 2018, A, . Location in patent: Paragraph 0149
[5] Canadian Journal of Chemistry, 2004, vol. 82, # 3, p. 461 - 478
[6] Heteroatom Chemistry, 2008, vol. 19, # 3, p. 229 - 233
[7] Tetrahedron, 2001, vol. 57, # 15, p. 3087 - 3098
[8] Organic Letters, 2010, vol. 12, # 23, p. 5502 - 5505
[9] Chemische Berichte, 1943, vol. 76, p. 1011,1015
[10] Journal of the American Chemical Society, 1935, vol. 57, p. 1329
[11] Zhurnal Obshchei Khimii, 1941, vol. 11, p. 647[12] Chem.Abstr., 1941, p. 5869,6937
[13] Journal of Heterocyclic Chemistry, 1980, vol. 17, # 7, p. 1489 - 1495
[14] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 3, p. 641 - 647
[15] Journal of Heterocyclic Chemistry, 2006, vol. 43, # 3, p. 623 - 628
[16] Heterocycles, 2005, vol. 65, # 9, p. 2095 - 2105
[17] Tetrahedron, 2004, vol. 60, # 13, p. 2937 - 2942
[18] Helvetica Chimica Acta, 1922, vol. 5, p. 548
[19] Organic Letters, 2008, vol. 10, # 2, p. 173 - 175
[20] Organic Letters, 2010, vol. 12, # 12, p. 2841 - 2843
[21] Chemical Communications, 2010, vol. 46, # 29, p. 5244 - 5246
[22] ACS Combinatorial Science, 2012, vol. 14, # 5, p. 316 - 322
[23] Patent: US2012/184548, 2012, A1, . Location in patent: Page/Page column 18
[24] Synthetic Communications, 2014, vol. 44, # 3, p. 346 - 351
With sodium tetrahydroborate In methanol; dichloromethane at 0 - 20℃; for 12 h;
Step (a): To a solution of a 6-nitroveratraldehyde (20.0 g, 95 mmol) in a mixture of MeOH/CH2Cl2 (800 mL; 3:1), NaBH4 (7.6 g, 199 mmol) was slowly added at 0 °C. After stirring overnight at room temperature, the reaction was quenched by addition of water. The organic layer was washed with water and brine, dried over Na2SO4, filtered off and concentrated under reduced pressure. After purification by column chromatography on silica gel (CH2Cl2), the pure product (4,5-dimethoxy-2-nitrophenyl)methanol (19.7 g, 92 mmol) was obtained as a yellow solid. Yield, 99percent.
76%
With sodium tetrahydroborate In methanol at 0℃; for 13 h;
To 6-nitroveratraldehyde (3.0 g, 14 mmol) in dry methanol (40 mL) was added sodium tetrahydroborate (NaBH4, 0.60 g, 16 mmol) at 0 °C. The mixture was stirred for 13 h. Thereafter, the reaction was quenched with brine, and extraction performed with dichloromethane. After removal of the solvent, the residue was washed with hexane, and filtered. Drying in vacuo afforded 2-OH as a brownish solid in 76percent yield (2.3 g).
56.5%
With sodium borohydrid In ethanol; water
EXAMPLE 1 Preparation of 2-nitro-4,5-dimethoxybenzyl alcohol 1011 g of 2-nitro-4,5-dimethoxybenzaldehyde in 10 l of ethanol with 94.8 ml water added was stirred, and a solution of 57 g sodium borohydride in 2 l absolute ethanol was added over 1 hour. The mixture was heated to 40° C. for 2.5 hours, cooled to 5° C. and the mixture filtered. The solid was washed with 4 l of cold 2B alcohol (denatured ethanol) and 8 l cold water, and dried in a 50° C. vacuum oven to yield 570 g, 56.5percent yield.
Reference：
[1] European Journal of Medicinal Chemistry, 2016, vol. 115, p. 453 - 462
[2] Journal of Organic Chemistry, 1998, vol. 63, # 8, p. 2434 - 2441
[3] Tetrahedron, 1997, vol. 53, # 39, p. 13449 - 13472
[4] Journal of Organic Chemistry, 2002, vol. 67, # 16, p. 5567 - 5577
[5] Chemical Communications, 2017, vol. 53, # 68, p. 9470 - 9473
[6] Angewandte Chemie - International Edition, 2017, vol. 56, # 15, p. 4356 - 4360[7] Angew. Chem., 2017, vol. 129, # 15, p. 4421 - 4425,5
[8] Chemistry Letters, 2015, vol. 44, # 9, p. 1194 - 1196
[9] Journal of Organic Chemistry, 1990, vol. 55, # 5, p. 1585 - 1589
[10] Patent: US4477556, 1984, A,
[11] Journal of the Chemical Society, 1965, p. 1080 - 1087
[12] Photochemical and Photobiological Sciences, 2012, vol. 11, # 3, p. 548 - 555
[13] European Journal of Medicinal Chemistry, 2012, vol. 55, p. 125 - 136
[14] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 18, p. 5971 - 5975
8
[ 20357-25-9 ]
[ 5392-10-9 ]
Reference：
[1] Helvetica Chimica Acta, 1922, vol. 5, p. 548
9
[ 20357-25-9 ]
[ 4998-07-6 ]
Yield
Reaction Conditions
Operation in experiment
93%
With sodium chlorite; dihydrogen peroxide; acetic acid In methanol; water at 50℃;
In 3,4-dimethoxy-6-nitrobenzaldehyde (10 g)The reaction medium (20 mL of water, 30 mL of methanol)Acetic acid (3.5 mL), 30percent hydrogen peroxide (9 mL)Stir well and add sodium chlorite (content 80percent, 9g) in water (5mL);Stirring warming to about 50 , monitoring the reaction,After the reaction was completed, sodium bisulfite (10.5 g) was added to quench the reaction,The solvent was evaporated to dryness, the product was dissolved in a solution of sodium hydroxide (6g × 10mL)Filtered to remove impurities, the filtrate was added sulfuric acid to pH 1 precipitated product,Filter and dry.Obtained product 10g (93percent yield, high performance liquid chromatography 99.5percent purity).
83%
for 7 h;
Compound 2 (33.0 g, 156.3 mmol) was suspended in 0.6MNaOH (500 mL) under stirring, KMnO4(19.7 g, 125.0 mmol) was slowly added to the reaction mixture. After 7 h of stirring, the initial purplecolor went black, then a yellow solution was got after filtration. The pH value of the solution wasadjusted to 2–3 by 10percent HCl and large amounts of yellow solid was got. 4,5-Dimethoxy-2-nitro-benzoicacid (Compound 3) was obtained after filtration as a yellow solid, yield: 83.0percent, m.p. 193.2–195.0 °C.
Reference：
[1] Patent: CN106854161, 2017, A, . Location in patent: Paragraph 0023; 0024; 0025; 0026; 0027; 0028; 0029-0039
[2] Molecules, 2018, vol. 23, # 1,
[3] RSC Advances, 2016, vol. 6, # 81, p. 77717 - 77734
[4] Chemische Berichte, 1899, vol. 32, p. 3407
[5] Indian Journal of Chemistry - Section B Organic Chemistry Including Medicinal Chemistry, 1989, vol. 28, # 5, p. 431 - 434
10
[ 20357-25-9 ]
[ 53413-67-5 ]
Reference：
[1] Journal of Organic Chemistry, 1990, vol. 55, # 5, p. 1585 - 1589
[2] Photochemical and Photobiological Sciences, 2012, vol. 11, # 3, p. 548 - 555
[3] European Journal of Medicinal Chemistry, 2012, vol. 55, p. 125 - 136
[4] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 18, p. 5971 - 5975
[5] Chemical Communications, 2017, vol. 53, # 68, p. 9470 - 9473
With ammonium carbonate In methanol for 0.25h; Microwave irradiation;
Synthesis of 4-(4,5-dimethoxy-2-nitrophenyl)-2,6-dimethyl-3,5-dicarbethoxy-1,4-dihydropyridine (C21H26N2O8)
A fusion mixture of 4,5-dimethoxy-2-nitrobenzaldehyde (10 mmol), ethyl 3-oxobutanoate(0.025 mol), and ammonium carbonate (0.015 mol) in 10 mL methanol was transferred intoa 25mL round bottom flask and was then irradiated at 400Win a domestic microwave ovenfor 15 min. The progress of reaction was monitored by TLC using benzene:acetone (7:3)solvent system. After completion of reaction, the resulting reaction mixture was cooledto room temperature and treated with little quantity of methanol and then poured into the crushed ice followed by filtration through suction. The solid thus obtained was washed withsmall amount of water and dried in air under vacuum to give the product as lemon yellowcolor powder (Scheme 1).
With acetic anhydride; sodium hydrogencarbonate In ethyl acetate at 100℃; for 6h;
71.A Diethyl 2-(4,5-dimethoxy-2-nitrobenzylidene)malonate
In a 100 mL pear-shaped flask, 4,5-dimethoxy-2-nitro-benzaldehyde (4.02 g, 19.0 mmol, 1.00 eq) (Aldrich) was suspended in acetic anhydride (10.0 mL) (Aldrich). Diethyl malonate (4.22 g, 4.0 mL, 26.3 mmol, 1.38 eq) (Aldrich) and sodium bicarbonate (3.35 g, 39.9 mmol, 2.09 eq) were added and the mixture was heated at 100° C. and stirred for 6 hours. After cooling to room temperature, the reaction mixture was partitioned between water and EtOAc. The organic phase was removed, washed with saturated sodium bicarbonate and brine, dried over Na2SO4 and concentrated. The crude material was purified by flash chromatography (Analogix; SF65-300, Si50; 30-100% EtOAc in hexanes). The product-containing fractions were combined, concentrated and re-crystallized to give diethyl 2-(4,5-dimethoxy-2-nitrobenzylidene)malonate. (Yield 3.476 g, 9.84 mmol, 51.7%).
With sodium chlorite; dihydrogen peroxide; acetic acid In methanol; water at 50℃;
1 Example 1
In 3,4-dimethoxy-6-nitrobenzaldehyde (10 g)The reaction medium (20 mL of water, 30 mL of methanol)Acetic acid (3.5 mL), 30% hydrogen peroxide (9 mL)Stir well and add sodium chlorite (content 80%, 9g) in water (5mL);Stirring warming to about 50 , monitoring the reaction,After the reaction was completed, sodium bisulfite (10.5 g) was added to quench the reaction,The solvent was evaporated to dryness, the product was dissolved in a solution of sodium hydroxide (6g × 10mL)Filtered to remove impurities, the filtrate was added sulfuric acid to pH 1 precipitated product,Filter and dry.Obtained product 10g (93% yield, high performance liquid chromatography 99.5% purity).
88%
Stage #1: 6-nitroveratraldehyde With potassium dihydrogenphosphate In water; acetonitrile
Stage #2: With sodium chlorite In water; acetonitrile at 25 - 35℃;
2 Preparation of a compound of formula III:
370 g (1.75 mol) of a compound of the formula II was added to a 5 L three-necked flask, and 1.75 L of acetonitrile, 0.7 L of water, and 64.4 g of potassium dihydrogen phosphate (0.47 mol) were added, and the mixture was stirred to obtain a cloudy liquid. 2.38 kg (2.63 mol) of a 10% sodium chlorite solution was added dropwise, and the dropping temperature was controlled at 25-35 ° C. After the completion of the dropwise addition, stirring was continued for 1 hour, and the reaction was monitored by HPLC. 36% hydrochloric acid was added dropwise to pH=2, a large amount of solid was precipitated, and the solid was collected by filtration. The mixture was dried at 50 ° C to obtain 350.5 g of a yellow compound of formula III, the molar yield was 88%, and the purity was 97%.
83%
With potassium permanganate; sodium hydroxide for 7h;
3.1.2. 4,5-Dimethoxy-2-nitrobenzoic acid (3)
Compound 2 (33.0 g, 156.3 mmol) was suspended in 0.6MNaOH (500 mL) under stirring, KMnO4(19.7 g, 125.0 mmol) was slowly added to the reaction mixture. After 7 h of stirring, the initial purplecolor went black, then a yellow solution was got after filtration. The pH value of the solution wasadjusted to 2-3 by 10% HCl and large amounts of yellow solid was got. 4,5-Dimethoxy-2-nitro-benzoicacid (Compound 3) was obtained after filtration as a yellow solid, yield: 83.0%, m.p. 193.2-195.0 °C.
79%
With potassium permanganate In water; acetone
With potassium hydroxide; potassium permanganate
With potassium permanganate
350.5 g
With sodium chlorite; potassium dihydrogenphosphate In water; acetonitrile at 25 - 35℃; for 1h;
2 Preparation of a compound of formula III:
370 g (1.75 mol) of the compound of the formula II was added to a 5 L three-necked flask, and 1.75 L of acetonitrile, 0.7 L of water, and 64 g of 4 g (0.47 mol) of potassium dihydrogen phosphate were added thereto, followed by stirring to obtain a cloudy liquid.Add 10% sodium chlorite solution 2·38kg (2.63mol), and control the dropping temperature to 25-35°C.Stirring was continued for 1 hour after the completion of the dropwise addition, and the reaction was monitored by HPLC. 36% hydrochloric acid was added dropwise to ρΗ=2, a large amount of solid was precipitated, and the solid was collected by filtration. The mixture was dried at 50 ° C to obtain 350.5 g of a yellow compound of formula III. The molar yield was 88%, and the purity was 97%.
With iron(0); ammonia hydrochloride In lithium hydroxide monohydrate; ethyl acetate at 20℃; for 120h;
2-Amino-4,5-dimethoxybenzaldehyde (10)
A suspension of S2 (2.00 g, 9.47 mmol), Fe powder(2.10 g, 37.5 mmol) and NH4Cl (3.34 g, 62.5 mmol) in EtOAc (100 mL) and H2O (60 mL) was stirredfor 5 d at room temperature. The reaction mixture was filtered through Celite and rinsed with EtOAc(100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 50 mL). Thecombined organic layers were washed with brine (100 mL), dried (Na2SO4) and the solvent was removedunder reduced pressure to give 10 (1.70 g, 9.4 mmol, quant.) as a brown solid, mp. 85 °C.
99%
With 5%-palladium/activated carbon; hydrogen In tetrahydrofuran at 20℃; for 0.25h;
2-Amino-4,5-dimethoxybenzaldehyde (4)
Pd/C (5%, 0.5 g) was suspended in a solution of 4,5-dimethoxy-2-nitrobenzaldehyde (3, 1.0 g, 4.74 mmol) in dry THF (10 mL), and the reaction mixture was stirred at room temperature for 15 min in hydrogen atmosphere under 50 psi pressure. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound (0.85 g, 99%).
99%
With palladium on activated charcoal; hydrogen at 20℃; for 0.0833333h;
93%
With palladium on activated charcoal; hydrogen at 20℃; for 2h;
92%
With hydrogenchloride; iron(0) In ethanol; lithium hydroxide monohydrate at 80℃; for 2.5h;
8-1 2-amino-4,5-dimethoxybenzaldehyde
4,5-dimethoxy-2-nitrobenzaldehyde (5.00 g, 23.7 mmol), 0.1 mol / L hydrochloric acid (10 mL)A suspension of iron powder 150 μm (5.17 g, 92.6 mmol) in ethanol (70 mL) was stirred at 80 ° C. for 2.5 hours.The reaction solution was cooled to room temperature, filtered through Celite (Kanto Chemical Co., Celite 545), and the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue and the mixture was filtered through silica gel. The filtrate was concentrated under reduced pressure and dried to give the target compound (3.96 g, 21.9 mmol, yield 92%) as a red solid.
77%
With iron(0); ammonia hydrochloride In lithium hydroxide monohydrate; ethyl acetate at 20℃; for 20h;
62%
With hydrogenchloride; lithium hydroxide monohydrate; iron(0) In ethanol; glacial acetic acid for 0.5h; Heating;
50%
With hydrogenchloride; iron(0) In ethanol; lithium hydroxide monohydrate at 20℃; for 1.5h; Reflux;
35%
With sodium dihydrosulfite; anhydrous sodium carbonate In methanol; lithium hydroxide monohydrate at 20℃; for 1.5h;
35%
With hydrogenchloride; iron(0) In ethanol; lithium hydroxide monohydrate; glacial acetic acid at 20℃; for 0.916667h; Reflux;
With methanol; palladium(0) Hydrogenation;
With ammonium hydroxide; FERROUS SULFATE
With hydrogen In ethanol Ambient temperature;
With hydrogenchloride; iron(0); glacial acetic acid In ethanol; lithium hydroxide monohydrate for 1h; Heating;
With iron(0); glacial acetic acid In lithium hydroxide monohydrate; ethyl acetate for 0.5h; Heating;
With iron(0); glacial acetic acid In ethanol Heating;
With hydrogenchloride; iron(0) In ethanol; ethyl acetate for 0.25h; Heating;
With hydrogenchloride; iron(0) In ethanol; lithium hydroxide monohydrate for 1h; Reflux;
With hydrogenchloride; lithium hydroxide monohydrate; iron(0) In ethanol Reflux;
With hydrogenchloride
Stage #1: 6-nitroveratraldehyde With hydrogenchloride; iron(0); glacial acetic acid In ethanol; lithium hydroxide monohydrate for 0.5h; Reflux;
Stage #2: With Sodium hydrogenocarbonate In ethanol; lithium hydroxide monohydrate; ethyl acetate
12.A 2-Amino-4,5-dimethoxybenzaldehyde
6-Nitroveratraldehyde (tech, 80%, 5.28 g, 20 mmol) (Aldrich) was dissolved in mixture of ethanol (50 mL) and acetic acid (50 mL) with warming. Water (30 mL) was then added followed by conc. hydrochloric acid (0.12 g). Iron powder (4.2 g, 75 mmol) was added with vigorous stirring and mixture was heated at reflux for 30 minutes. Mixture was filtered through Celite while hot. Filter cake was washed with ethanol. Combined filtrate and washing was diluted with water (300 mL) and extracted with ethyl acetate (3*300 mL). Organic layers were washed with saturated aqueous sodium bicarbonate solution (2*200 mL), water (200 mL) and brine (200 mL) and then combined. Combined organic layer was dried (MgSO4), filtered, and concentrated to give crude 2-amino-4,5-dimethoxybenzaldehyde as brown oil which was used in next step without further purification.
With hydrogenchloride; iron(0) In ethanol
With hydrogenchloride; iron(0) Inert atmosphere; Schlenk technique;
With hydrogenchloride; iron(0) In ethanol; lithium hydroxide monohydrate for 1.5h; Reflux;
With hydrogenchloride; iron(0) In ethanol; lithium hydroxide monohydrate at 80℃; for 0.5h;
With hydrogenchloride; iron(0) In ethanol; lithium hydroxide monohydrate at 80℃; for 1h;
With hydrogenchloride; iron(0) In ethanol; lithium hydroxide monohydrate at 70℃; for 1h; chemoselective reaction;
2.2 Representative procedure for the synthesis of 2-aminoaldehyde (6-Aminopiperonal as example)
General procedure: Step 1 3 mL of concentrated HNO3 was added to piperonal (7) (6.66 mmol; 1g) and mixed in a round-bottom flask under ice bath. The mixture was allowed to vigorous magnetic agitate in r.t. It is observed immediate change of color (colorless to yellow). TLC reveals the end of reaction in 2h. The isolation is performed through ice-bath cooling of reactional medium, observing immediate precipitation, which was vacuum filtered, washed with around 200mL of cold distilled water and recrystallized in ethanol/water. Light yellow solid, 1.171g, 90%. Step 2 The synthesis of 6-aminopiperonalAdd 6-nitropiperonal (780 mg) to a 30 ml solution of EtOH/water (3:1) with eletrolytic iron powder (1600 mg) and concentrated HCl (1 drop). The mixture was heated at 70 °C for 1 h until the completion was detected by TLC. The reaction mixture was allowed to cool to ambient temperature. Then the reaction mass was diluted with ethyl acetate and filtered through a plug of celite. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel with ethyl acetate/petroleum ether (2:5) as eluent to afford 6-aminopiperonal(430 mg65%).
With hydrogenchloride; iron(0) In ethanol; lithium hydroxide monohydrate at 78℃; for 3.5h; Inert atmosphere;
With hydrogenchloride; iron(0) In ethanol; lithium hydroxide monohydrate at 85℃; for 0.666667h;
With nitric acid at 0 - 20℃; for 3h; Inert atmosphere; Green chemistry;
90%
With nitric acid 0 deg C -> room temperature, 1 h;
89%
With nitric acid
89%
With sulfuric acid; nitric acid at 0 - 20℃; for 2h;
89%
With nitric acid In 1,2-dichloro-ethane at 25 - 40℃; for 7h;
1 Preparation of a compound of formula II:
2 g of 3,4-dimethoxybenzaldehyde 200 g (1.2 mol) was added to a 2 L three-necked flask, and 1 L of dichloroethane was added thereto, and the mixture was stirred at 25 ° C until completely dissolved. To the reaction flask, 200 mL of nitric acid (200 mL) (2.93 mol) was added dropwise. The dropping temperature was controlled between 25 and 40 ° C, and the addition was completed in about 1 hour. Stirring was continued for 6 hours at 35 ° C and the reaction was monitored by HPLC. After adding water (1.5 L), the organic phase is collected, washed once with 4 saturated sodium bicarbonate solution, once with saturated brine, and then dried over anhydrous sodium sulfate. After being beaten with n-hexane, it was filtered to obtain 226.2 g of a compound of the formula II, with a molar yield of 89% and a purity of 98%.
84%
With nitric acid at 20℃;
78.2%
With nitric acid at 20 - 25℃; for 1h;
3.1.1. 4,5-Dimethoxy-2-nitrobenzaldehyde (2)
4,5-Dimethoxy benzaldehyde (16.6 g, 0.1 mol) was slowly added to 65% (g/g) nitric acid (100 mL)under stirring at a temperature range of 20-25 C. The mixture was stirred for another 1 h and slowly added to 400 mL of ice water, a large amount of yellow solid was formed. The crude product was got by filtration and recrystallized in ethanol to get 4,5-Dimethoxy-2-nitrobenzaldehyde (Compound 2)16.0 g as a yellow solid, yield 78.2%, m.p. 133-135 °C.
73%
With nitric acid; acetic anhydride at 0℃; for 2h;
73%
With nitric acid at 0 - 20℃; for 2h;
70.86%
With sulfuric acid; nitric acid at 20℃; Cooling with ice;
65%
With nitric acid at 0 - 20℃; for 2h;
4,5-Dimethoxy-2-nitrobenzaldehyde (S2)
3,4-Dimethoxybenzaldehyde S1 (4.00 g, 24.1 mmol) wasadded at 0 °C to a stirred solution of 65%ic HNO3 (22 mL, 343 mmol). After stirring at roomtemperature for 2 h, the reaction mixture was poured onto a mixture of H2O/ice (200 mL). Theprecipitated crude product was filtered off, washed with cold H2O and EtOH and recrystallized fromEtOH to give S2 (3.29 g, 65%) as a yellow solid, mp 130 °C.
61%
With conc. nitric acid; sodium hydrogencarbonate In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; ethyl acetate; toluene
R.88 4,5-Dimethoxy-2-nitrobenzaldehyde STR230
REFERENTIAL EXAMPLE 88 4,5-Dimethoxy-2-nitrobenzaldehyde STR230 After reacting 135 g of 3,4-dimethoxybenzaldehyde and 500 ml of conc. nitric acid at 10° C. for 20 hours, the reaction mixture was poured in 3 l of ice water and the resultant crystals were collected by filtration. The crystals were dissolved in a mixed solvent of 8 l of toluene and 500 ml of ethyl acetate. After washing the resultant solution once with a saturated aqueous solution of sodium bicarbonate, three times with water and then once with saturated saline, the solution was concentrated to about 500 ml under reduced pressure. The concentrate was cooled to room temperature and the resultant yellowish crystals (77.71 g) were then collected by filtration (yield: 61%).
55%
With nitric acid at 6℃;
23%
With aluminium trinitrate In acetonitrile at 50℃; regioselective reaction;
With water; nitric acid unter Ausschluss von Tageslicht;
With water; nitric acid; acetic acid
With nitric acid at 5 - 10℃;
With nitric acid; acetic anhydride
With nitric acid; acetic anhydride
With nitric acid
With nitric acid In water
With nitric acid at 18 - 22℃; for 0.5h;
With nitric acid
226.2 g
With nitric acid In 1,2-dichloro-ethane at 25 - 40℃; for 7h;
1 Preparation of a compound of formula II:
Add 2,4-dimethoxybenzaldehyde 200g (1.2mol) to a 2L three-necked flask, add 1L of dichloroethane, stir at 25 ° C until completely dissolved, and add 65% nitric acid 200 mL (2.93 mol) to the reaction flask. , control the dropping temperature between 25-40 ° C, about 1 hour, the addition is completed. Stirring was continued for 6 hours at 35 ° C, and the reaction was monitored by HPLC. Add water (1.5 L) for extraction, collect the organic phase, wash once with saturated sodium bicarbonate solution, and wash once with saturated brine.The organic phase is dried over anhydrous sodium sulfate, and the organic layer is filtered and evaporated to drynessFiltration gave 226.2 g of a yellow hydrazine compound with a molar yield of 89% and a purity of 98%.
With nitric acid at 0 - 20℃; for 2h; regioselective reaction;
2.2 Representative procedure for the synthesis of 2-aminoaldehyde (6-Aminopiperonal as example)
General procedure: Step 1 3 mL of concentrated HNO3 was added to piperonal (7) (6.66 mmol; 1g) and mixed in a round-bottom flask under ice bath. The mixture was allowed to vigorous magnetic agitate in r.t. It is observed immediate change of color (colorless to yellow). TLC reveals the end of reaction in 2h. The isolation is performed through ice-bath cooling of reactional medium, observing immediate precipitation, which was vacuum filtered, washed with around 200mL of cold distilled water and recrystallized in ethanol/water. Light yellow solid, 1.171g, 90%. Step 2 The synthesis of 6-aminopiperonalAdd 6-nitropiperonal (780 mg) to a 30 ml solution of EtOH/water (3:1) with eletrolytic iron powder (1600 mg) and concentrated HCl (1 drop). The mixture was heated at 70 °C for 1 h until the completion was detected by TLC. The reaction mixture was allowed to cool to ambient temperature. Then the reaction mass was diluted with ethyl acetate and filtered through a plug of celite. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel with ethyl acetate/petroleum ether (2:5) as eluent to afford 6-aminopiperonal(430 mg65%).
Stage #1: Methyltriphenylphosphonium bromide With n-butyllithium In tetrahydrofuran at -78℃; for 2h;
Stage #2: 6-nitroveratraldehyde In tetrahydrofuran at -78 - 20℃;
Compounds 20 and 21:
General procedure: To a suspension of pre-dried methyltriphenylphosphonium bromide (3.5 mmol) in THF (10 mL) at -78 °C was added dropwise a solution of n-BuLi (2.5 M, 1 equiv). The resultant mixture was stirred at -78 °C for 2 h before a solution of 14 or 11 (2.71 mmol) in THF was added. The mixture was allowed to warm to room temperature and stirring was continued for 16 h. Saturated NH4Cl solution (15 mL) was added and the mixture was extracted with EtOAc (3 × 50 mL), the organic phase was dried over Na2SO4 and concentrated in vacuo. Flash chromatographic purification of the residue (n-hexane-EtOAc) afforded 20 or 21.
65%
Stage #1: Methyltriphenylphosphonium bromide With sodium hexamethyldisilazane In tetrahydrofuran for 1h;
Stage #2: 6-nitroveratraldehyde In tetrahydrofuran at 20℃; for 12h;
62%
With sodium hexamethyldisilazane In tetrahydrofuran
43%
Stage #1: Methyltriphenylphosphonium bromide With sodium hexamethyldisilazane In tetrahydrofuran at 0℃; for 1h;
Stage #2: 6-nitroveratraldehyde In tetrahydrofuran at 20℃; Further stages.;
With sodium tetrahydridoborate In methanol; dichloromethane at 0 - 20℃; for 12h;
a 1-(Chloromethyl)-4,5-dimethoxy-2-nitrobenzene (1)
Step (a): To a solution of a 6-nitroveratraldehyde (20.0 g, 95 mmol) in a mixture of MeOH/CH2Cl2 (800 mL; 3:1), NaBH4 (7.6 g, 199 mmol) was slowly added at 0 °C. After stirring overnight at room temperature, the reaction was quenched by addition of water. The organic layer was washed with water and brine, dried over Na2SO4, filtered off and concentrated under reduced pressure. After purification by column chromatography on silica gel (CH2Cl2), the pure product (4,5-dimethoxy-2-nitrophenyl)methanol (19.7 g, 92 mmol) was obtained as a yellow solid. Yield, 99%.
99%
With sodium tetrahydridoborate In tetrahydrofuran; methanol at 0 - 20℃;
96%
With sodium tetrahydridoborate In ethanol
96%
With sodium tetrahydridoborate In ethanol at 0℃; for 2h;
90%
With sodium tetrahydridoborate In tetrahydrofuran at 0 - 5℃; for 6h;
82%
With sodium tetrahydridoborate In methanol at 20℃; for 1h;
82%
With sodium tetrahydridoborate In ethanol at 20℃; for 4h;
77%
With methanol; sodium tetrahydridoborate at 20℃; for 1h; Inert atmosphere;
76%
With sodium tetrahydridoborate In methanol at 0℃; for 13h;
3.1. Synthesis of (4,5-dimethoxy-2-nitro-phenyl)methanol (2-OH).
To 6-nitroveratraldehyde (3.0 g, 14 mmol) in dry methanol (40 mL) was added sodium tetrahydroborate (NaBH4, 0.60 g, 16 mmol) at 0 °C. The mixture was stirred for 13 h. Thereafter, the reaction was quenched with brine, and extraction performed with dichloromethane. After removal of the solvent, the residue was washed with hexane, and filtered. Drying in vacuo afforded 2-OH as a brownish solid in 76% yield (2.3 g).
70%
With sodium tetrahydridoborate In methanol at 20℃; for 1h; Inert atmosphere;
69%
With sodium tetrahydridoborate In methanol for 1h;
56.5%
With sodium borohydride In ethanol; water monomer
1 Preparation of 2-nitro-4,5-dimethoxybenzyl alcohol
EXAMPLE 1 Preparation of 2-nitro-4,5-dimethoxybenzyl alcohol 1011 g of 2-nitro-4,5-dimethoxybenzaldehyde in 10 l of ethanol with 94.8 ml water added was stirred, and a solution of 57 g sodium borohydride in 2 l absolute ethanol was added over 1 hour. The mixture was heated to 40° C. for 2.5 hours, cooled to 5° C. and the mixture filtered. The solid was washed with 4 l of cold 2B alcohol (denatured ethanol) and 8 l cold water, and dried in a 50° C. vacuum oven to yield 570 g, 56.5% yield.
With potassium borohydrate
With sodium tetrahydridoborate In methanol at 20℃; for 2h;
With sodium tetrahydridoborate In dichloromethane at 20℃; for 0.5h;
General procedure for the preparation of 4-aminomethyl-3-(substituted benzyloxyimino)pyrrolidine dimesylates (8a-w)
General procedure: To a solution of various benzaldehydes 4aew (10 mmol) dissolved in methanol (50 mL) was added sodium borohydride (20 mmol) at room temperature, and the mixturewas stirred at the same temperature for 30 min and concentrated under reduced pressure. The residue was diluted with methylene chloride (500 mL) and washed with water, and dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the corresponding crude phenylmethanols 5a-w
With methanol; sodium tetrahydridoborate at 0℃; for 2.5h;
General procedure: To a stirring solution of 2,5-dimethoxyl benzaldehyde 1a (0.67 g, 4 mmol) dissolved in anhydrous methanol (30 mL) was added NaBH4 (0.84 g, 22 mmol) in batches at 0 ºC over a period of 0.5 h. The reaction mixture was stirred at the same temperature for 2 h. After removal of the methanol under reduced pressure, the residue was diluted with methylene chloride (30 mL), washed with distilled water (3 Χ 10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product 2a.
With K[18F]-4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane complex; potassium carbonate In N,N-dimethyl-formamide at 140℃; for 0.166667h;
1.1 Preparation of 2-[18F]fluoro-4,5-dimethoxybenzaldehyde ([18F] fluorination reaction)
The process for the preparation of 2-[18F]fluoro-4,5-dimethoxybenzaldehyde (Compound 2) is shown in step (1) of Scheme 1 above. Specifically, a quaternary ammonium salt support (Chromafix or QMA) is passed through [18F] fluoride to adsorb [18F] fluoride on the quaternary ammonium salt support by anion exchange, [18F] fluoride was eluted into the reaction vessel using an eluent containing potassium carbonate and cryptopix (K222). After the elution, the eluent was completely removed by azeotropic mixed distillation while injecting nitrogen gas at 100 °C. 0.5 mL of dimethylformamide in which 5-10 mg of 4,5-dimethoxy-2-nitrobenzaldehyde (Compound 1) was dissolved was placed in the reaction vessel, and the mixture was reacted at 140 °C for 10 minutes to prepare Compound 2.
23%
With [18F]-potassium fluoride; [2.2.2]cryptande In dimethyl sulfoxide at 120℃; for 0.166667h;
With K[18F]F-4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane complex In N,N-dimethyl-formamide at 140℃;
With K[18F]-4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]-hexacosane complex In water; dimethyl sulfoxide at 140℃; for 0.25h;
4.3.1. Labeling step
General procedure: 600-800 mL of the ammonium substrate or nitro precursor inMe2SO (water content 3000 ppm, 15-20 mg/mL) were added tothe dry KryptofixK222/[18F]fluoride complex (111-370 MBq),prepared as previously described [30]. The mixture was thenallowed to react at 140 °C for 2.5 min. The nitro starting precursorwas labeled at the same temperature but for 15 min. After labeling,the Me2SO solution was diluted with water (20-30 mL) and thewhole solution passed through a previously activated tC18 Sep-Pak1 cartridge. An environmental tC18 cartridge (1 g) was used forthe trapping of aldehydes 2, 3, 7-9 (Table 1). For compounds 4-6 acartridge containing 400 mg of phase material was more suitable.The [18F]fluorobenzaldehyde trapped on the support was thenwashed with 10 mL of water. For analytical purposes, the activityretained on the cartridge was eluted with 2 mL of CH3CN and wasanalyzed by TLC and HPLC (see above). Radiolabeling yields aresummarized in Table 1.
With barium hydroxide octahydrate In water at 20℃; for 3h; Inert atmosphere; Green chemistry;
81%
With Daucus carota root enzyme In aq. phosphate buffer at 28℃; for 10h; Enzymatic reaction;
Experimental procedure
General procedure: An aliquot (10μL, 0.7μg) of enzyme solution of concentration 0.07mg/mL was taken in 1mL of phosphate buffer of pH 7. Then 2-nitrobenzaldehyde (1a; 100mg, 0.66mmol) and nitromethane (2, 35μL, 0.66mmol) were added to the reaction mixture and it was stirred at 28°C for 8h. The reaction was monitored by TLC on silica gel G using 15% ethyl acetate in petroleum ether as mobile phase. The reaction mass was then diluted with 50mL of diethylether. The organic layer was separated and passed through anhydrous Na2SO4. The solvent was removed in rotary evaporator to obtain a yellow sticky mass (152mg). The product was purified by column chromatography using 60-120 mesh silica gel and eluting with 10-12% of ethyl acetate in petroleum ether. A sticky mass obtained which was washed with diethyl ether to get a yellow solid 3a (130mg, yield 93%).
With sodium azide In N,N,N,N,N,N-hexamethylphosphoric triamide at 60℃; for 9h;
25%
With N,N,N,N,N,N-hexamethylphosphoric triamide; sodium azide at 20 - 25℃;
STEP 1 - NUCLEOPHILIC AROMATIC SUBSTITUTION REACTION
General procedure: In a dry scintillation vial were successively added 2-nitrobenzaldehyde (1.0 equiv.), sodiumazide (2.0 equiv.) and HMPA (3 mL/mmol). After stirring overnight at room temperature,the mixture was diluted with Et2O (12 mL/mmol) and the resulting organic phase waswashed with cold water, dried over Na2SO4, filtered and evaporated. Purification of the soobtainedresidue by column chromatography, eluting with cyclohexane/EtOAC (95:5),furnished the desired 2-azidobenzaldehydes 1’a-d in pure form.
With N,N,N,N,N,N-hexamethylphosphoric triamide; sodium azide Schlenk technique; Inert atmosphere;
With N,N,N,N,N,N-hexamethylphosphoric triamide; sodium azide
1-(4,5-dimethoxy-2-nitro-phenyl)-2-(4-nitro-phenyl)-ethanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
With Tetrakis(dimethylamino)ethylen In N,N-dimethyl-formamide at -20 - 20℃; for 3h;
36%
Stage #1: 4-nitrobenzyl chloride; 6-nitroveratraldehyde With Tetrakis(dimethylamino)ethylen In N,N-dimethyl-formamide at -20 - 20℃; for 3h; Inert atmosphere;
Stage #2: With water
4.1.1. General procedure for TDAE reaction with various electrophiles
General procedure: All materials were dried for one day at 120 °C. Chloride and carbonyl derivatives were introduced into a Schlenk of 30 mL. Products were put in vacuo, then under nitrogen. An appropriate volume of anhydrous DMF was added after 10 min of nitrogen bubbling. The solution was vigorously stirred for 20 min at -20 °C. TDAE was added slowly under inert atmosphere. The reaction was stirred for one hour. The second reaction phase was performed at rt or at temperature according to procedure of synthesis. The reaction was hydrolysed with distilled water after TLC analysis clearly showed that the chloride 1 had been totally consumed. The aqueous solution was extracted with dichloromethane and the combined organic layers washed with brine then dried on MgSO4.
(4,5-dimethoxy-2-nitro-phenyl)-(3-methoxy-phenyl)-methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
Stage #1: (3-methoxyphenyl)magnesium bromide; 6-nitroveratraldehyde In tetrahydrofuran at -78 - -15℃; for 0.416667h;
Stage #2: With hydrogenchloride In tetrahydrofuran; dichloromethane for 0.333333h; Further stages.;
Stage #1: 6-nitroveratraldehyde; phenylmagnesium bromide In tetrahydrofuran at -78 - -15℃; for 0.416667h;
Stage #2: With hydrogenchloride In tetrahydrofuran; dichloromethane for 0.333333h; Further stages.;
Stage #1: 6-nitroveratraldehyde With 3-chloro-benzenecarboperoxoic acid; trifluoroacetic acid In dichloromethane at 20℃; for 18h;
Stage #2: With sodium hydroxide In dichloromethane at 20℃; for 1h;
13 Example 13; 4,5-Dimethoxy-2-nitro-phenol
To a solution of 4,5-dimethoxy-2-nitro-benzaldehyde (3.75 g, 14.2 mmol) in dichloromethane (75 mL) at 0C under a nitrogen atmosphere was added meta-chloroperoxybenzoic acid (75 % purity, 4.90 g, 28.4 mmol), then trifluoroacetic acid (1.05 mL, 14.2 mmol). The reaction was stirred at room temperature for 18h, then recooled to 0C. Excess reagent was quenched with 5% sodium bisulfite solution and the precipitate was removed by filtration, washing with dichloromethane. The organic phase of the filtrate was washed with sodium bicarbonate and brine, was dried (sodium sulfate), and was evaporated to provide a yellow solid. This intermediate was suspended in methanol (50 mL), treated with 2N NaOH (16 mL, 32 mmol), and was stirred at room temperature for 1h. The reaction was acidified with 1N HC1 and was filtered, washing with methanol to provide 4,5-dimethoxy-2-nitro-phenol (2.00 g, 71% yield) as a bright yellow solid. 1H-NMR (CDCl3, 500 MHz) 11.0 (s, 1H), 7.39 (s, 1H), 6.48 (s, 1H), 3.90 (s, 3H), 3.83 (s, 3H) ppm; MS (FIA) 197.9 (M-H); HPLC (Method A) 3.357 min.
1-(4,5-dimethoxy-2-nitrobenzylidene)-2-(p-tosyl)hydrazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99.6%
In ethanol at 80℃; for 6h; Industry scale;
2 Step 2) 4,5-dimethoxy-2-nitro-p-toluenesulfonlhydrazone
Step 2) 4,5-dimethoxy-2-nitro-p-toluenesulfonlhydrazone 12.5 L of ethanol, p-toluenesulfonylhydrazide (1 kg, 5.37 mol) and 6-nitroveratraldehyde (1.2 kg, 5.907 mol) were added to a reactor, and then heated to 80°C, followed by stirring for 6 hours. After checking completion of the reaction by thin layer chromatography (eluent: chloroform/methanol = 15/1), the reaction mixture was cooled to room temperature. The resulting mixture was filtered, washed with 12.5 L of ethanol, and then dried with hot air at 40°C in an oven to obtain the title compound (1.47 kg, 99.6%). 1H-NMR(CDCl3) d: 8.48(s, 1H), 8.08(s, 1H), 7.89(d, 2H), 7.59(s, 1H), 7.42(s, 1H), 7.33(d, 2H), 4.02(s, 3H), 3.98(s, 3H), 2.44(s, 3H).
99.6%
In ethanol at 80℃; for 6h;
2
Step 2) 4,5-dimethoxy-2-nitro-p-toluenesulfonylhydrazone12.5 L of ethanol, p-toluenesulfonylhydrazide (1 kg, 5.37 mol) and 6-nitroveratraldehyde (1.2 kg, 5.907 mol) were added to a reactor, and then heated to 80° C., followed by stirring for 6 hours. After checking completion of the reaction by thin layer chromatography (eluent: chloroform/methanol=15/1), the reaction mixture was cooled to room temperature. The resulting mixture was filtered, washed with 12.5 L of ethanol, and then dried with hot air at 40° C. in an oven to obtain the title compound (1.47 kg, 99.6%).1H-NMR(CDCl3) d: 8.48 (s, 1H), 8.08 (s, 1H), 7.89 (d, 2H), 7.59 (s, 1H), 7.42 (s, 1H), 7.33 (d, 2H), 4.02 (s, 3H), 3.98 (s, 3H), 2.44 (s, 3H).
85%
In ethanol at 80℃; for 0.5h;
1.2
Step 2 : Preparation OF 4, 5-DIMETHOXY-2-NITRO-P-TOLUENESULFONYLHYDRAZONE 6. 90 G of P-TOLUENESULFONYL hydrazide was dissolved in 40 ML of ethanol, and 7. 90 G of 6-NITROVERATRALDEHYDE dissolved in A small amount of ethanol was added thereto. The mixture was stirred at 80°C for 30 min, cooled to room temperature, and mixed with 100 ML of water. The solid formed therein was filtrated, washed with 100 ML of ethanol, and dried under A reduced pressure, to obtain 12. 0 G of the title compound (yield 85%).
84%
In ethanol at 80℃; for 1h;
1 Synthesis of Intermediate IC (Scheme 1; General Procedure CC)
General procedure: A clean 40 mL vial was charged with aldehyde (3.15 mmol, 1.05 eq.), p-toluenesulfonohydrazide (558 mg, 3.0 mmol, 1.0 eq.), and EtOH (20 mL). The reaction mixture was heated at 80° C. and stirred for 1 h. The reaction mixture was then cooled to room temperature and diluted with water (200 mL). The solid was then filtered, washed with 50% EtOH, and dried under vacuum to afford Intermediate IC, which was used without further purification.
84%
In ethanol at 80℃; for 1h;
1 Synthesis of Intermediate IC (Scheme 1; General Procedure CC)
General procedure: A clean 40 mL vial was charged with aldehyde (3.15 mmol, 1.05 eq.), p-toluenesulfonohydrazide (558 mg, 3.0 mmol, 1.0 eq.), and EtOH (20 mL). The reaction mixture was heated at 80° C. and stirred for 1 h. The reaction mixture was then cooled to room temperature and diluted with water (200 mL). The solid was then filtered, washed with 50% EtOH, and dried under vacuum to afford Intermediate IC, which was used without further purification.
84%
In ethanol at 80℃; for 1h;
1 Synthesis of Intermediate IC (Scheme 1; General Procedure CC)
General procedure: A clean 40 mL vial was charged with aldehyde (3.15 mmol, 1.05 eq.), p-toluenesulfonohydrazide (558 mg, 3.0 mmol, 1.0 eq.), and EtOH (20 mL). The reaction mixture was heated at 80° C. and stirred for 1 h. The reaction mixture was then cooled to room temperature and diluted with water (200 mL). The solid was then filtered, washed with 50% EtOH, and dried under vacuum to afford Intermediate IC, which was used without further purification.
(E)-3-(4,5-dimethoxy-2-nitro-phenyl)-propenal[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With hydrogenchloride; NaOCH3 In tetrahydrofuran; ethyl acetate; N,N-dimethyl-formamide
164.a (E)-2-[2-(1E,3E)-4-[4,5-Dimethoxy-2-nitro-phenyl)-buta-1,3-dienyl]-phenyl]-3-methoxy-acrylic acid methyl ester
a) At room temperature, NaOCH3 (335 mg, 6.19 mmol) was added to a solution of 1,3-dioxan-2-ylmethyltributylphosphoniumbromide (C. Spangler; R. McCoy, Synthetic communications, 18, 51, (1988)) (5.17 ml, 1 M in DMF, 5.71 mmol) and 4,5-dimethoxy-2-nitro-benzaldehyde (1.25 g, 4.76 mmol) in DMF (20 ml). After heating the mixture at 50° for overnight, the mixture was poured over water, and extracted with ether, washed with brine and dried over MgSO4. The solvent was evaporated and the residue was dissolved in THF (100 ml) and treated with 2 N HCl (50 ml). After stirring the mixture at room temperature for 2 h, the THF was evaporated, and the yellow solid was filtered, and suspended in ether/ethylacetate 4:1. The suspension stirred at room temperature for 1 h, filtered and washed with ether to afford (E)-3-(4,5-dimethoxy-2-nitro-phenyl)-propenal (624 mg, 55%) as a yellow solid, m.p. 103-105°. IR (KBr): 1689, 1605 cm-1. MS (EI): 237 (M).
R.89 6,7-Dimethoxy-2-hydroxyquinazoline STR231
REFERENTIAL EXAMPLE 89 6,7-Dimethoxy-2-hydroxyquinazoline STR231 Dissolved in a mixed solvent of 30 ml of dichloromethane and 30 ml of methanol were 3.17 g of the 4,5-dimethoxy-2-nitrobenzaldehyde synthesised in Referential Example 88, followed by an addition of 0.16 g of 5% Pd-C. The resultant mixture was stirred for 4 hours in a hydrogen atmosphere. Pd-C was filtered off and the solvent was distilled off under reduced pressure. The residue was dissolved in 30 ml of acetic acid, followed by an addition of potassium cyanate. After reacting the contents overnight at room temperature, they were heated and reacted for further 1 hour under reflux. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography (silica gel; eluent: 5:1 mixed solvent of dichlromethane and MeOH), thereby obtaining 1.51 g of the above-identified compound as colorless crystals (yield: 49%). Melting point: 260°-263° C.
With perchloric acid In 1,4-dioxane; water at 70℃;
4.2. General procedure for synthesis of nitroarenes 1a-n
General procedure: Aq. HClO4 (70%, 0.3 mL) was added to solution of 2-nitrobenzaldehyde 6 (5 mmol) and compound 7 (12.5 mmol) in 1,4-dioxane (15 mL). The reaction mixture was stirred at 70 °C for 40-60 min (TLC control), then poured into cold water (200 mL). The product was extracted with ethyl acetate (3×50 mL). The combined organic fractions were dried with Na2SO4 and evaporated to dryness under reduced pressure. The product was purified by flash chromatography using CH2Cl2/petroleum ether (1:9) mixture as an eluent. Compounds 1b-g,j,k,m,n were obtained as light-yellow oils and used without additional purification.
With perchloric acid In 1,4-dioxane; water at 65 - 70℃;
With triphenylphosphine In 1,2-dichloro-ethane at 0 - 20℃; for 1h;
With triphenylphosphine In dichloromethane at 0 - 20℃;
With triphenylphosphine In dichloromethane at 0 - 20℃; for 1.5h;
(II) General Experimental Procedures for the Synthesis of Starting Material
General procedure: o-gem-dibromovinyl aniline were synthesized according to the traditional procedure [1]: To a solution of 2-nitrobenzaldehyde (5.0 g, 33 mmol) and CBr4 (21.9 g, 66 mmol) in DCM (200 mL) at 0 _C was added dropwise a solution of PPh3 (34.6 g, 132 mmol) in DCM (100 mL) by an addition funnel. The addition rate was controlled so that the internal temperature was at 1-5 °C. After addition, the mixture was stirred for another 0.5 h before warmed to r.t., and stirred for an additional 1 h. The reaction mixture was filtered through a short plug of silica gel (80 g), and was washed with a copious amount of DCM until no product was found. Solvent was removed under vacuum to give a mixture of the desired intermediate and triphenylphosphine oxide. To the mixture was added EtOH (95%, 200 mL) and SnCl2_H2O (37.2 g, 165 mmol). The suspension was heated at 100 °C (reflux) for 1 h, and then cooled to rt. After most of the ethanol was removed under vacuum, H2O (100 mL) and EtOAc (150 mL) were added. To the resulting mixture, solid K2CO3 was added carefully until pH >10. The EtOAc layer was separated from the heterogeneous mixture, and the aqueous phase was extracted with EtOAc until it was free of the product (3×100 mL). The combined organic solution was washed with brine and dried over Na2SO4/K2CO3. Solvent was removed under vacuum and the residue was redissolved in Et2O. The resulting precipitated Ph3P(O) was removed. The residue was subjected to silica gel chromatography using using 10% EtOAc in petroleum ether giving 2-(2, 2-dibromovinyl)-phenylamine (7.3 g, 80%). The substrates 2-(1, 1-dibromoprop-1-en-2-yl) aniline were synthesized according to Posner G. H. procedure [2].
With triphenylphosphine In dichloromethane at 0 - 20℃; for 1.5h;
General experimental procedure for synthesis of 1-(2,2-dibromovinyl)-2- nitrobenzene derivatives (II)
General procedure: To a 100 mL three neck round bottom flask were added o-nitrobenzaldehyde (6.62 mmol, 1.0 equiv), PPh3 (16.54 mmol, 2.5 equiv) and CH2Cl2 (30 mL), and the solution was cooled to 0 °C in an ice bath. CBr4 (15.55 mmol, 2.35 equiv) was dropping into the solution and the mixture was stirred at 0 °C for 0.5 h. Then the reaction was warmed to room temperature, and monitored by TLC visualized with UV short wavelengths. After completion, a mixture of the desired product and triphenylphosphine oxide was obtained by column chromatography (silica gel) using dichloromethane as eluent without further purification. And the mixture was directly used for next step.
With triphenylphosphine In dichloromethane at 0℃; for 1h;
A flame-dried round-bottomed flask under N2 atmosphere was charged with 5-iodo- 1,2, 3-trimethoxybenzene (2.92g, 9.93 mmol) and THF (31mL) was added. The solution was cooled down to-78C and 1.5 M solution of t-BuLi in pentane (13.6mL, 20.57 mmol) was added dropwise. The mixture was stirred for lh and transferred via canula to a precooled (-78C) solution of 6-nitroveratraldehyde (2.02g, 9.57 mmol) in THF (12mL) under N2 atmosphere. The resulting mixture was stirred for 2 h and slowly warmed up to 0C, quenched with saturated aqueous solution of NH4CI and allowed to warm-up to rt. Solvent was removed in vacuo and the residue was partitioned between water and DCM. Organic layer was collected and washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography using EtOAc/DCM (9: 91) affording the title compound 241 (1.46g, 40% yield) 1H NMR (CDCI3) 6 (ppm): 7.61 (s, 1H), 7.16 (s, 1H), 6.58 (s, 2H), 6.45 (s, 1H), 6.09 (s, 1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.84 (s, 3H), 3.83 (s, 6H). m/z : 402.4 (MH+).
With potassium fluoride; N-benzyl-N,N,N-triethylammonium chloride In acetonitrile at 20℃;
9
Reference Example 9: 5-(4,5-Dimethoxy-2-nitrophenyl)oxazole-2-thiol 4,5-Dimethoxy-2-nitrobenzaldehyde (1.52 g, 7.19 mmol), 353.0 mg (6.07 mmol) of potassium fluoride, and 134.8 mg (0.59 mmol) of benzyltriethylammonium chloride were added to a solution of 1.51 g (5.97 mmol) of phenylthio(trimethylsilyl)methyl isothiocyanate, synthesised according to a document (J. Chem. Soc., Perkin Trans 1 1984, 435.), in acetonitrile (36 ml), and the mixture was stirred at room temperature overnight. The solvent was removed from the reaction solution by distillation, and the water and chloroform were then added to the residue. The aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (n-hexane: ethyl acetate = 5: 1 → 1: 1) to give 302.4 mg (yield 18%) of the title compound.
ethyl 5,6-dimethoxylbenzo[b]thiophene-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere;
30.1 Step 1: Synthesis of compound 5
Under the protection of nitrogen, compound 3 (10g, 47.4mmol) was dissolved in anhydrous DMF, anhydrous potassium carbonate (13g, 94.8mmol) was added, placed at 0°C, compound 4 (6.9g, 57.8mmol) was added dropwise to In the above suspension, stir at 0°C for 30 min. Then, the temperature was raised to 80°C and reacted overnight.After the reaction is complete, cool to room temperature, evaporate DMF under reduced pressure, add water, extract with DCM (100mL×3), combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography. Compound 5 (9.1 g, 72%).
63%
With potassium carbonate In N,N-dimethyl-formamide at 60 - 100℃;
With sodium hydride In tetrahydrofuran; mineral oil for 1h; Reflux;
General procedure for Horner-Wadsworth-Emmons reaction:
To a solution of methyl diethylphosphonoacetate (10 mmol) in dry THF (100 mL) at 0 °C was added NaH (1 equiv, 60% dispersion in mineral oil). When the evolution of H2 had ceased (5 min), the appropriate o-nitrobenzaldehyde (11, 13, 14 or 15) was added and the reaction mixture was heated at reflux for 1 h. After cooling, the solvent was removed in vacuo and the residue was partitioned between EtOAc (100 mL) and H2O (30 mL). The organic phase was separated, dried (MgSO4), filtered and the solvent removed in vacuo. The residue was triturated with n-hexane containing a few drops of EtOAc and filtered to afford the corresponding cinnamates 16-19.
Compound 15:
To a solution of 14 (1.23 g, 5.83 mmol) in concentrated H2SO4 (5 mL), NBS (3.11 g, 17.48 mmol) was added portion wise over a period of 30 min and the reaction vessel was stoppered and wrapped in aluminium foil to exclude light. The reaction mixture was stirred for 16 h, poured onto cold H2O (20 mL) and the resultant precipitate filtered and dried. The crude product was triturated with n-hexane containing a few drops of EtOAc and filtered to afford 15 as a light yellow solid (1.81 g, 84%).
84%
With N-Bromosuccinimide; sulfuric acid
With N-Bromosuccinimide; sulfuric acid at 20℃; for 16.5h;
Stage #1: diethyl {3-[1-(methoxycarbonyl)prop-1-en-2-yl]-1-(phenylsulfonyl)-indol-2-yl}methylphosphonate With sodium hydride In tetrahydrofuran at -10℃; for 0.25h; Inert atmosphere;
Stage #2: 6-nitroveratraldehyde In tetrahydrofuran at -10℃; for 2h; Inert atmosphere;
80%
Stage #1: diethyl {3-[1-(methoxycarbonyl)prop-1-en-2-yl]-1-(phenylsulfonyl)-indol-2-yl}methylphosphonate With sodium hydride In tetrahydrofuran; hexane at -10 - 0℃; for 0.25h; Inert atmosphere;
Stage #2: 6-nitroveratraldehyde In tetrahydrofuran; hexane for 2h; Inert atmosphere;
7.1.2. General procedure for the preparation of the Schiff bases 9a-d and benzoxazoles 10a-d
General procedure: A mixture of 2-hydroxyaniline 8 (1 equiv) and the appropriate 2-nitrobenzaldehyde derivative 5 (1 equiv) in ethanol (30 mL) was heated at reflux for 3-4 h. After cooling to room temperature the resulting precipitate 9a-d was collected and dried. To a stirred solution of the Schiff’s base 9a-d (1 equiv) in CH2Cl2 (30 mL) at room temperature, DDQ (1 equiv) was added over a 1 min. The reaction mixture was stirred at room temperature for 1-2 days, filtered and evaporated giving the crude product 10a-d.
With triethylamine In acetic anhydride at 90℃; for 15h; Inert atmosphere;
1.A
Compound i (10 mmol) and compound ii (10 mmol) were condensed in 10 mL acetic anhydride in the presence of Et3N (10 mmol) under N2 at 90° C. for 15 hr. After extraction with CH2Cl2 and cryastallization in EtOAc, compound iii was obtained at the yield of 86%. Compound iii (9.5 mmol) was treated with FeSO4.7H2O (95 mmol) in 97 mL NH4OH under N2 at 100° C. for 2 hr, followed by addition of H3PO4 and extraction with CHCl3: 2-propanol (3:1), to afford compound iv at the yield of 87%. Compound iv (5.8 mmol) was reacted with isoamyl nitrite (11.6 mmol) in the presence of H2SO4 (11.6 mmol), NaI (58 mmol) and Acetone 330 mL to form phenanthrene-9-carboxylic acid compound v, which was purified by extraction with CH2Cl2 and washing with EtOAc to give the pure compound at a yield of 72%.
With perchloric acid supported on silica gel In dichloromethane; acetonitrile at 20℃; for 0.25h;
Typical experimental procedure for HClO4-SiO218 catalysed Hosomi-Sakurai reaction of aldehydes:
General procedure: To a solution of benzaldehyde 1 (100 mg, 0.942 mmol). in acetonitrile:dichloromethane (7:3) 2 mL was added 10 wt % HClO4-SiO2 (0.018 mg, 0.018 mmol) followed by the addition of benzyl alcohol (0.195 mL, 1.88 mmol) and allyltrimethylsilane (0.449 mL, 2.82 mmol) dropwise at ambient temperature. The reaction was stirred for a further 5 min. After the completion of reaction (TLC), brine (10 mL) was added and the reaction mixture was extracted with ether (2 × 10 mL). The combined ether layer was dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the crude product by column chromatography afforded pure homoallylic benzyl ether 1a as colorless oil (217 mg, 97%).
Stage #1: 6-methoxybenzothiazol-2-ylamine; 6-nitroveratraldehyde at 110℃;
Stage #2: With sodium tetrahydroborate In methanol at 20℃;
(a) Preparation of 18a-c
General procedure: Equimolar amounts of o-nitrobenzaldehyde derivatives 16a [or b or c] and 2-amino-6-methoxybenzothiazole (17) were mixed thoroughly and heated at 110 °C. The Schiff base, initially a viscous red liquid, solidified upon cooling and was dissolved in the minimal volume of methanol for reduction with NaBH3 at room temperature. The pure (TLC) o-nitobenzylamine derivatives 18a [b or c] precipitated as yellow a solid, which was collected and washed with cold methanol. The structures of 18a-c were supported by IR, 1H NMR, 13C NMR and MS.
With mercury dichloride In ethanol at 60℃; for 2h;
General procedure for the preparation of2,3-dihydroquinizolin-4(1H)-ones
General procedure: To a mixture of anthralinamide (1 mmol) and aromaticaldehyde (1 mmol) in ethanol (5 mL), catalytic amount ofmercuric chloride was added and the reaction mixture wasstirred at 60 °C in water bath for about 60-120 min and thereaction was monitored by TLC. After completion of thereaction the ethanol was distilled off from the reactionmixture and the solid mass poured into cold water (25 mL),filtered off and the product was washed with conc. KIsolution 5-6 times to remove remaining mercuric salts, ifany, then further purified using recrystallization fromethanol. Finally, the dried compounds were confirmed bytheir physical constants or spectral data.
With Tetrakis(dimethylamino)ethylen In N,N-dimethyl-formamide at -50 - 60℃; for 3.5h; Inert atmosphere;
32%
Stage #1: 1-(3-chloroprop-1-ynyl)-4-nitrobenzene; 6-nitroveratraldehyde With Tetrakis(dimethylamino)ethylen In N,N-dimethyl-formamide at -50 - 60℃; for 3h; Inert atmosphere;
Stage #2: With water
4.1.1. General procedure for TDAE reaction with various electrophiles
General procedure: All materials were dried for one day at 120 °C. Chloride and carbonyl derivatives were introduced into a Schlenk of 30 mL. Products were put in vacuo, then under nitrogen. An appropriate volume of anhydrous DMF was added after 10 min of nitrogen bubbling. The solution was vigorously stirred for 20 min at -20 °C. TDAE was added slowly under inert atmosphere. The reaction was stirred for one hour. The second reaction phase was performed at rt or at temperature according to procedure of synthesis. The reaction was hydrolysed with distilled water after TLC analysis clearly showed that the chloride 1 had been totally consumed. The aqueous solution was extracted with dichloromethane and the combined organic layers washed with brine then dried on MgSO4.
General procedure: All materials were dried for one day at 120 C. Chloride and carbonyl derivatives were introduced into a Schlenk of 30 mL. Products were put in vacuo, then under nitrogen. An appropriate volume of anhydrous DMF was added after 10 min of nitrogen bubbling. The solution was vigorously stirred for 20 min at -20 C. TDAE was added slowly under inert atmosphere. The reaction was stirred for one hour. The second reaction phase was performed at rt or at temperature according to procedure of synthesis. The reaction was hydrolysed with distilled water after TLC analysis clearly showed that the chloride 1 had been totally consumed. The aqueous solution was extracted with dichloromethane and the combined organic layers washed with brine then dried on MgSO4.
With toluene-4-sulfonic acid In tetrahydrofuran at 20℃; for 0.166667h;
Quinazolinones 3; General Procedure
General procedure: To a soln of amide 1 (1 mmol) and p-TsOH (0.05 mmol) in THF (10mL) was added aldehyde 2 (1.1 mmol). The mixture was stirred at r.t. for 10 min (1 h for the reaction in entry 20, Table 2), and then PIDA (1.5 mmol) was added portionwise over 5 min. After stirring at r.t. for 1 h, the mixture was diluted with EtOAc (20 mL), quenched with sat. aq NaHCO3 soln (20 mL), and then extracted with EtOAc (3 × 20 mL). The combined organic layer was washed with brine (3 × 30 mL), dried over anhyd Na2SO4 and concentrated using a rotary evaporator. The crude residue was purified by flash column chromatography (EtOAc-PE) to give the desired product.
With potassium carbonate; sodium hydroxide In neat (no solvent) at 20℃; for 0.166667h; Schlenk technique;
63%
With montmorillonite KSF In neat (no solvent) at 150℃; for 1h; Sealed tube; Microwave irradiation; Green chemistry;
3.2. General Procedure for Cross Aldol Condensations
General procedure: A mixture of the suitable aldehyde (1.0 mmol), acetophenone (1.0 mmol) and clay catalyst(240 mg) was warmed at 150 °C in a sealed tube under microwave irradiation, for 1 h. In the reactions involving solid starting materials, they were thoroughly mixed by grinding in a mortar before irradiation. The reaction mixture was diluted with hot ethanol (20 mL), the catalyst was filtered off, the solvent was evaporated and the residue was purified by crystallization (EtOH) for solid chalcones(compounds 3a-3d, 3f-3m, 3p-3ar) or by column chromatography (silica gel, ethyl acetate/hexanes) for oily chalcones (compounds 3e, 3o), to afford the pure final products. All yields were calculated from isolated products. Characterization data for previously unknown compounds are given below. For full characterization data, see the Supporting Information.
With montmorillonite KSF In neat (no solvent) at 150℃; for 1h; Sealed tube; Microwave irradiation; Green chemistry;
3.2. General Procedure for Cross Aldol Condensations
General procedure: A mixture of the suitable aldehyde (1.0 mmol), acetophenone (1.0 mmol) and clay catalyst(240 mg) was warmed at 150 °C in a sealed tube under microwave irradiation, for 1 h. In the reactions involving solid starting materials, they were thoroughly mixed by grinding in a mortar before irradiation. The reaction mixture was diluted with hot ethanol (20 mL), the catalyst was filtered off, the solvent was evaporated and the residue was purified by crystallization (EtOH) for solid chalcones(compounds 3a-3d, 3f-3m, 3p-3ar) or by column chromatography (silica gel, ethyl acetate/hexanes) for oily chalcones (compounds 3e, 3o), to afford the pure final products. All yields were calculated from isolated products. Characterization data for previously unknown compounds are given below. For full characterization data, see the Supporting Information.
3-(4,5-dimethoxy-2-nitrophenyl)-3-hydroxypropionic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
Stage #1: acetic acid tert-butyl ester With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.25h; Inert atmosphere;
Stage #2: 6-nitroveratraldehyde In tetrahydrofuran at -78℃; for 0.0833333h;
2.1. Synthesis of 3-(4,5-dimethoxy-2-nitro-phenyl)-3-hydroxy-propionic acid tert-butyl ester (1-OH).
tert-Butyl acetate (17 g, 150 mmol) was dissolved in dry THF (100 mL) and cooled to -78 °C under a N2 atmosphere. A THF solution of lithium bis(trimethylsilyl)amide (LiHMDS, 85 mL, ca. 1.3 mol/L, 110 mmol) was slowly added, followed by stirring at -78 °C for 15 min. A THF solution of 6-nitroveratraldehyde (130 mL, 0.73 mol/L, 95 mmol) was then added. This mixture was vigorously stirred for 5 min. The reaction was quenched by the addition of 10 wt% HCl aqueous solution at room temperature. Chloroform was added, the organic layer was washed with brine, and then dried over MgSO4. Purification of the residue was performed by column chromatography with ethyl acetate/chloroform (1/20, v/v) to afford 1-OH as a dark orange viscous liquid, in 86% yield (27 g).
N'-(4,5-dimethoxy-2-nitrobenzylidene)-2-(trifluoromethyl)benzohydrazide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With potassium hydroxide; In ethanol; at 20℃; for 3.0h;
General procedure: To a mixture of 2-(trifluoromethyl) (1 mmol) and aromatic aldehyde (1 mmol) in ethanol (5 mL), was added (4 mmol) of 50 % of potassium hydroxide. Stirred the reaction mass for 2-3 h reaction was monitored by TLC. After completion of the reaction the ethanol was distilled off from the reaction mass, the solid mass poured in to cold water (25 mL) filtered off the product then washed with cold water and the compounds were confirmed by their spectral data.
2-(4,5-dimethoxy-2-nitrobenzylidene)-1-(pthalazin-4-yl)hydrazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With 1,2,3-trimethylimidazolium methylsulphate at 50℃; for 1h;
General procedure for the synthesis of Schiff base derivatives of 1-(Phthalazin-4-yl)hydrazine (6a-j)
General procedure: To a solution of 1-(Phthalazin-4-yl) hydrazine (1mmol) in 1,2,3-Trimethylimidazoliummethylsulphate (5ml), added aldehydes (5a-j) (1.1mmol) and heatedat 50 °C for one hour .The solid precipitated out were filtered and recystalized in acetonitrile. 2-(4,5-dimethoxy-2-nitrobenzylidene)-1-(pthalazin-4-yl)hydrazine (6a)mp 284-286 °C ; IR (KBr) v/cm-1: 3281.02 (N-H str), 1616.40 (C=N str), 1510.31 (C-N str). 1H NMR (400 MHz, DMSO-d6) δ: 12.41 (s , 1H), 8.9 (s , 1H ), 8.4 (d,1H), 8.25 (s,1H ), 8.15(s,1H), 7.7-7.9 (m,3H), 7.65 (s, 1H), 4.1 (s, 3H), 3.9 (s , 3H ). 13C NMR: 152.17, 150.20,138.8, 134.62, 133.10, 132.39, 130.13, 128.92, 127.60, 125.99, 124.24, 60.10, 59.24. (MM:ES+APCI) 322.2(M+H)+. Anal.Calcd for C17H15N5O2 : C 63.54; H 4.71; N 21.79; Found: C,63.58; H, 4.81; N, 21.83.
With enzyme from root of Daucus carota In aq. phosphate buffer at 28℃; for 10h; Enzymatic reaction;
Typical procedure for the synthesis of chiral 4-hydroxy-4-(substituted phenyl)-butan-2-one
General procedure: 3-Nitrobenzaldehyde (1a; 100 mg, 0.66 mmol) was taken in 1 mL of phosphate buffer of pH 7.5 and treated with 73 μL (1 mmol) of acetone (2) and 10 μL (0.7 μg) of enzyme (isolated from Daucus carota roots) of concentration 0.07 mg/mL. Then the whole reaction mixture was stirred at 28 °C for 8 h. The reaction was monitored by TLC using 20% ethyl acetate in petroleum ether as mobile phase. The reaction mass was diluted with 25 mL of ethyl acetate and washed with 25 mL of water (twice) followed by brine (25 mL). The organic layer was passed through anhyd. Na2SO4 and the solvent was removed in rotary evaporator to obtain a yellow sticky mass (154 mg). The product was purified by column chromatography using 60-120 mesh silica gel. It was eluted with 10-12% ethyl acetate in petroleum ether. The sticky mass was washed with diethyl ether to get an yellow solid (131 mg, yield 95%). Enantiomeric excess was determined by Chiral HPLC using DAICEL CHIRALPAK AS-H column (5 μm, 4.6 mm x 250 mm) with the solvent system Hexane/Isopropanol = 90:10 with 1 mL/min flow rate at 20 °C.
(4,5-dimethoxy-2-nitrobenzylidene)hydrazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With hydrazine hydrate; acetic acid In ethanol; acetonitrile at 20 - 80℃;
4.2 Bis(4,5-dimethoxy-2-nitrobenzyl) butylphosphonate (2)
In a 100 mL round bottom flask containing anhydrous acetonitrile (20 mL) and ethanol (20 mL) was added 4,5-dimethoxy-2-nitrobenzaldehyde (3.168 g, 15.0 mmol) followed by hydrazine monohydrate (5.9 mL, 120.0 mmol). The reaction mixture was cooled in an ice bath. To the cold solution was added glacial acetic acid (4.8 mL). The reaction mixture was stirred first at room tempetature for 5 min and then at 80 °C for 30 min. The solvents were removed and the resulting residue was resuspended in ethylacetate, and washed sequentially with saturated NaHCO3 solution (2*), water (3*) and brine. The organic layer was dried over Na2SO4 and the solvent was evaporated to yield the desired hydrazone as yellow crystalline material (2.87 g, 85%). 1H NMR (400 MHz, CDCl3): δ 8.43 (s, 1H), 7.57 (s, 1H) 7.49 (s, 1H), 5.82 (s, 2H), 3.99 (s, 3H), 3.96 (s, 3H). Next, (E/Z)-(4,5-dimethoxy-2-nitrobenzylidene)hydrazine (5 mg, 0.022 mmol) and CH2Cl2 (0.5 mL) were added to a scintillation vial with a stirr bar. MnO2 (29 mg, 0.333 mmol) was then added and the resulting reaction mixture was stirred at room temperature for 45 min before filtered through a plug of celite. The eluant was concentrated under reduced pressure to obtain 2 (4.8 mg, 98%) as an orange solid. 1H NMR (400 MHz, CDCl3): δ 7.77 (s, 1H), 6.76 (s, 1H) 6.39 (s, 1H), 3.95 (s, 3H), 3.92 (s, 3H).
With hydrazine hydrate In ethanol Reflux;
With hydrazine hydrate In ethanol at 80℃; for 5h; Inert atmosphere;
3-(4,5-dimethoxy-2-nitrobenzylidene)indolin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With piperidine In ethanol for 1h; Reflux;
General procedure for aldol product 2a-d
General procedure: in a dry 100-mL round-bottom flask, 2-oxindole 3a-b (1 mmol), o-nitrobenzaldehydes 4a-c (1.2 mmol), and EtOH (25 mL) were mixed with stirring, and piperidine (0.85 mg, 0.01 mmol) in EtOH (2 mL) was added dropwise while stirring at RT. Mixture was then refluxed with stirring for 1 h. On completion of the reaction (monitored by thin layer chromatography (TLC)), solvent was removed under vacuum and Et2O was added, insoluble solid aldol product 2a-d was separated out and was isolated by filtration.
With 1,4-diaza-bicyclo[2.2.2]octane In N,N-dimethyl-formamide at 100 - 110℃; for 1.36667h;
Preparation of cinnamic acids:
General procedure: To aromatic aldehyde (500 mg, 1.0 equiv) and malonic acid (981 mg, 2.0 equiv) was added DABCO (105 mg, 2 equiv) in dimethyl formamide (5 mL) and the reaction mixture was stirred at 100-110 °C for 60-90 min. After completion of the reaction (TLC monitoring), reaction mixture was poured in water and then extracted with ethyl acetate. Crude product was recrystallized from chloroform/hexane system to provide cinnamic acids in good yield.
N-[(anthracen-9-yl)methyl]-1-(4,5-dimethoxy-2-nitrophenyl)methanimine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
In isopropyl alcohol Reflux;
N-[(Anthracen-9-yl)methyl]-1-(4,5-dimethoxy-2-nitrophenyl)methanimine (3a).
To a solution of 0.42 g(2 mmol) of aldehyde 1a in 10 mL of 2-PrOH was added 0.42 g (2 mmol) of amine 2, and the obtained mixture was boiled for 34 h. The solvent was distilled off, the cooled residue was crystallized from BuOH. Yield 0.73 g (87%), mp 192193°. IR spectrum, ν,cm-1: 1647 (C=N), 1464 (=). 1 NMR spectrum, δ,ppm: 3.94 s (6, 2OMe), 5.88 d (2, C2, J 2.8 Hz),7.427.64 m (6arom), 8.06 d (2arom, J 8.6 Hz), 8.38 d(2arom, J 8.6 Hz), 8.49 s (1arom), 8.83 t (1, CH, J2.8 Hz). Found, %: 72.06; 5.10; N 6.94. [M]+ 400.C24H20N2O4. Calculated, %: 71.99; 5.03; N 7.00.M 400.44.
With triphenylphosphine In diphenylether at 260℃; for 1h;
General procedure for synthesis of indoles from nitrobenzaldehyde
General procedure: In a 50 ml round bottom flask containing magnetic stir bar was charged with o-nitro benzaldehydes (2 mmol), phosphorane (2.2 mmol), triphenyl phosphine (4.6 mmol) and diphenyl ether (10 mL) and heated at 260 oC for 1 h. The reaction mass was then cooled to room temperature and poured on silica column. Products were isolated by eluting with petrolium ether to 3:1 pet ether: ethyl acetate.
With triphenylphosphine; In diphenylether; at 260℃; for 1h;
General procedure: In a 50 ml round bottom flask containing magnetic stir bar was charged with o-nitro benzaldehydes (2 mmol), phosphorane (2.2 mmol), triphenyl phosphine (4.6 mmol) and diphenyl ether (10 mL) and heated at 260 oC for 1 h. The reaction mass was then cooled to room temperature and poured on silica column. Products were isolated by eluting with petrolium ether to 3:1 pet ether: ethyl acetate.
ethyl 3-(4,5-dimethoxy-2-nitrophenyl)-3-hydroxypropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
Stage #1: ethyl acetate With sodium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5h;
Stage #2: 6-nitroveratraldehyde In tetrahydrofuran at -78 - 20℃;
2 4.1.2. Ethyl 3-(4,5-dimethoxy-2-nitrophenyl)-3-hydroxypropanoate (5)
To an argon-purged flask was added THF (25 mL) and sodiumhexamethyldisilazide solution (2 M, 2.6 mL). A solution of ethyl acetate(0.463 g, 5.25 mmol) in THF (5 mL) was then added dropwise at-78 °C. The mixture was stirred for 0.5 h, after which a solution of 4, 5-dimethoxy-6-nitrobenzaldehyde (1.025 g, 4.84 mmol) in THF (20 mL)was added dropwise. The reaction was allowed to warm to room temperatureand then quenched by saturated NaCl solution (50 mL). Themixture was extracted by ethyl acetate (2×50 mL). The combinedorganic phase was dried over MgSO4 and concentrated by vacuum. Theresidue was purified by chromatography (ethyl acetate/hexane=1:2)to give the product as a white solid (0.911 g), yield 63%. 1H NMR(300 MHz, CDCl3, δ) 7.63 (s, 1H), 7.38 (s, 1H), 5.80 (dt, J=9.3 Hz,2.7 Hz, 1H), 4.22 (q, J=7.2 Hz, 2H), 4.00 (s, 3H), 3.95 (s, 3H), 3.85 (d,J=3.0 Hz, 1H), 2.98 (dd, J=16.5 Hz, 2.7 Hz, 1H), 2.58 (dd,J=16.5 Hz, 9.3 Hz, 1H), 1.30 (t, J=7.2 Hz, 3H). 13C NMR (75 MHz,CDCl3, δ): 172.79, 154.00, 148.09, 139.42, 133.83, 109.13, 107.87,66.31, 61.26, 56.60, 56.50, 42.42, 14.29. HRMS (ESI): calculated forC13H17NO7 [M+Na]+ 322.0903, found 322.0904.
Stage #1: 6-nitroveratraldehyde With 5%-palladium/activated carbon; hydrogen In tetrahydrofuran at 25 - 30℃; for 4h; Autoclave;
Stage #2: 2-oxo-propionic acid ethyl ester With sodium ethanolate In water at 60 - 65℃; for 6h;
1 Example 1 Preparation of 6,7-dimethoxy-2-carboxy-quinoline (formula VII)
1000mL hydrogenation autoclave replaced with nitrogen gas into6-nitro-veratraldehyde (63.4g, 0.3mol)And THF (380 mL),After stirring and dissolving,Add 5% Pd/C (6.34g, moisture content 63.5%),After the nitrogen is replaced, the hydrogen pressure is introduced to 0.1 to 0.2 MPa.The reaction was kept at 25-30 ° C for 4 hours.Vent to atmospheric pressure,The catalyst was filtered off by filtration.The filtrate was transferred to a 1000 mL four-neck bottle.Add ethyl pyruvate (38.3 g, 0.33 mol),Warming up to 60 ° C,Sodium ethoxide solid (30.6 g, 0.45 mol) was added in portions.After the addition, the reaction was kept at 60-65 ° C for 4 hours.Add water (200mL),The reaction was continued at 60-65 ° C for 2 hours.After cooling, the mixture was evaporated to remove most of the THF.The residue was extracted with water (300 mL) and tert-ether (200 mL).Collect the water layer,Adjust the pH to 6-7 with 10% hydrochloric acid.A large amount of solid precipitated.Filter and filter the filter cake with water (100 mL).The filter cake was dried at 70 ° C overnight to obtain 6,7-dimethoxy-2-carboxy-quinoline.(Formula VII, yellow solid, 57.8 g, 82.6%)
1-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-4,5-dimethoxy-2-nitrobenzene[ No CAS ]
1-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-4,5-dimethoxy-2-nitrobenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60 % de
Stage #1: 6-nitroveratraldehyde With hydrazine hydrate In dimethyl sulfoxide for 3h;
Stage #2: 1,1,1-Trichloro-2,2,2-trifluoroethane With ethylenediamine; copper(l) chloride In ethylene glycol at 20℃; Overall yield = 47 percent; Overall yield = 0.374 g;
Synthesis of styrenes 2 by catalytic olefination reaction in EtOH or DMSO (generalprocedure I, 5 mmol scale) [90].
General procedure: One neck 100 mL round bottomed flask was charged withN2H4H2O (0.265 g, 5.25 mmol), and solution of corresponding benzaldehyde (5 mmolin 25 mL of EtOH or DMSO) was added and stirred for 3 h until aldehyde disappearedMolecules 2021, 26, 7365 8 of 21(TLC control). Next, 1,2-ethylenediamine (0.65 mL, 7.5 mmol), CuCl (0.050 g, 0.5 mmol)were added and stirred for 1-2 min. After that CF3CCl3 (1.78 mL, 15 mmol) was addedin one portion at cooling by cold water bath. Reaction mixture stirred overnight at roomtemperature, poured into water (100 mL) and extracted with CH2Cl2 (3 20 mL). Combinedextract was washed with water (20 mL) and dried over Na2SO4. Solvents wereevaporated in vacuo, the residue was purified by passing through a short silica gel padusing 3:1 mixture of hexane and CH2Cl2 as an eluent.
With glacial acetic acid In ethyl acetate; propan-2-one at 20℃; for 16h; UV-irradiation; Green chemistry;
2-Aminobenzamides 4-6; General Procedure
General procedure: A mixture of 2-nitrobenzaldehyde 1 (0.2 mmol, 1.0 equiv), primary amine 2 or 3 (0.8 mmol, 4.0 equiv), acetic acid (19.2 L, 0.4 mmol, 2.0 equiv), and EtOAc/acetone (6:1, 3.0 mL) in a 5-mL glass bottle (equipped with a magnetic stirring bar) at r.t. was irradiated with UV light (24-W, 365-375 nm) for 16 h. Purification was by column chromatography (silica gel).
90%
With glacial acetic acid In ethyl acetate; propan-2-one at 20℃; for 16h; UV-irradiation;
27 preparation example 27
In a 10mL reaction tube, 4,5-dimethoxy-2-nitrobenzaldehyde 0.2mmol, benzylamine 0.8mmol, acetic acid 0.4mmol, 3.0mL of ethyl acetate mixed with acetone in a 6:1 ratio of solution as a solvent, at room temperature by 365-375nm ultraviolet light irradiation, the reaction for 16h. 2-amino-N-benzyl-4,5-dimethoxybenzylbenzamide was obtained by column chromatography to obtain a brown solid with a yield of 90%.
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