* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Organic Chemistry, 1995, vol. 60, # 17, p. 5494 - 5503
2
[ 121-33-5 ]
[ 6635-20-7 ]
Yield
Reaction Conditions
Operation in experiment
87%
With yttrium(lll) nitrate hexahydrate In acetic acid at 20℃; for 0.166667 h;
Phenol (94 mg, 1 mmol) dissolved in 3 mL glacial acetic acidin a 50 mL test tube was treated with solid Y(NO3)3.6H2O(383 mg, 1 mmol) with constant shaking at RT for 10 min.The reaction was monitored by TLC at 10percent EtOAc inPetroleum benzene. Ice-cold water (30 mL) was added to thereaction mixture after completion of reaction and left for 15min. Solid was collected by filtration and washed with water.Solid product isolated in this way was used for analysis withoutfurther purification. Experimental procedure for the synthesisof compounds 2a–2e is mentioned in the SupportingInformation.
83%
at 0 - 20℃;
To a solution of vanillin (5.0 g, 32.9 mmol) in acetic acid (50 ml) was added nitric acid (60percent, 2.6 ml) slowly at 0 °C. Afterwards the solution was warmed up to room temperature and allowed to stir for another 30 min. The precipitate was filtered off and washed with cold water, to give compound 94 as a yellow solid (5.40 g, 83percent). 1H NMR (300 MHz, DMSO-d6): δ = 3.95 (s, 3H), 7.61 (d, J = 1.8 Hz, 1H), 8.08 (d, J = 1.9 Hz, 1H), 9.85 (s, 1H) ppm; 13C NMR (75 MHz, DMSO-d6): δ = 56.8, 112.5, 120.8, 126.8, 137.0, 147.7, 150.0, 190.4 ppm; HRMS (ESI): m/z [M-H]- calcd for C8H6NO5: 196.0251, found: 196.0277.
78.8%
With oxygen; Nitrogen dioxide In chloroform at 10℃; for 12 h;
120 ml of chloroform, 15.2 g of vanillin and 2.8 g of SAPO-11 molecular sieve catalyst were uniformly stirred, 4.0 ml of nitrogen dioxide was added, and the mixture was stirred in an oxygen atmosphere and reacted at 10° C. for 12 h. After the reaction was completed, the mixture was filtered to separate SAPO-. 11 Catalyst, the organic phase was washed several times with distilled water to neutrality and distilled under reduced pressure to give 15.52 g of 5-nitro vanillin in a yield of 78.8percent.
74%
With nitric acid In acetic acid at 5℃; for 0.5 h; Inert atmosphere
To a solution of vanillin (7) (10 g, 65 mmol) in acetic acid stirred at 5 °C under nitrogen atmosphere, nitric acid (70 percent) was added carefully over a period of 30 minutes. The yellow coloured solid formed was filtered washed with water throughly to wash out acetic acid and allowed to dry under vaccum to afford 4-hydroxy-3-methoxy-5-nitrobenzaldehyde (9) as yellow solid (9.5 g, 74 percent); mp: 171oC; 1H NMR (300 MHz, CDCl3): = 9.89 (s, 1H), 8.16 (d, J = 1.8 Hz, 1H), 7.61 (d, J = 1.8 Hz, 1H), 3.98 ppm (s, 3H).
64%
With nitric acid In dichloromethane at 20℃; for 0.333333 h;
The 5-nitrovanillin compound was synthesized fromVanillin by Yadav method [10] with some modifications. Avanillin (0.07 mol) was dissolved in 55 mL of dichloromethane,squirted by 12 mL of HNO3, then stirred for 20 min at roomtemperature, added 25 mL of ice water then leave it for 2 h,the solid formed was recrystallized with ethanol. The meltingpoint of synthesized product was determined and characterizedby FTIR instrument. The synthesized 5-nitrovanillin is lightyellow powder, 64 percent yield, m.p 175-177 °C (reference, 176°C); FTIR (KBr, νmax, cm–1): 1560.77 due to NO2 group
Reference：
[1] Journal of Physical Organic Chemistry, 2000, vol. 13, # 9, p. 511 - 517
[2] Journal of Medicinal Chemistry, 2010, vol. 53, # 8, p. 3396 - 3411
[3] Tetrahedron Letters, 2006, vol. 47, # 15, p. 2507 - 2509
[4] Synthetic Communications, 2008, vol. 38, # 11, p. 1745 - 1752
[5] Tetrahedron, 1992, vol. 48, # 10, p. 1895 - 1910
[6] Tetrahedron, 1999, vol. 55, # 22, p. 6733 - 6738
[7] Journal of Chemical Sciences, 2017, vol. 129, # 1, p. 39 - 43
[8] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 24, p. 7318 - 7337
[9] Synthetic Communications, 2005, vol. 35, # 2, p. 263 - 270
[10] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 20, p. 5740 - 5749
[11] Patent: CN107652184, 2018, A, . Location in patent: Paragraph 0011-0014
[12] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 10, p. 2309 - 2314
[13] Tetrahedron Letters, 2006, vol. 47, # 28, p. 4933 - 4935
[14] Asian Journal of Chemistry, 2018, vol. 30, # 9, p. 1933 - 1936
[15] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 3, p. 641 - 647
[16] Journal of the American Chemical Society, 1898, vol. 20, p. 316
[17] American Chemical Journal, 1900, vol. 24, p. 176
[18] Chemische Berichte, 1903, vol. 36, p. 2935
[19] Monatshefte fuer Chemie, 1899, vol. 20, p. 398
[20] Journal fuer Praktische Chemie (Leipzig), 1927, vol. <2> 115, p. 287
[21] Patent: WO2007/10085, 2007, A2, . Location in patent: Page/Page column 41-42
[22] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 24, p. 6553 - 6557
[23] Journal of Medicinal Chemistry, 2010, vol. 53, # 18, p. 6595 - 6602
3
[ 121-33-5 ]
[ 2454-72-0 ]
[ 6635-20-7 ]
[ 2450-26-2 ]
Reference：
[1] Journal of Organic Chemistry, 1995, vol. 60, # 17, p. 5494 - 5503
4
[ 51673-97-3 ]
[ 6635-20-7 ]
Reference：
[1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2010, vol. 49, # 8, p. 1140 - 1143
Reference：
[1] Journal of the American Chemical Society, 1898, vol. 20, p. 316
[2] American Chemical Journal, 1900, vol. 24, p. 176
16
[ 121-33-5 ]
[ 2454-72-0 ]
[ 6635-20-7 ]
[ 2450-26-2 ]
Reference：
[1] Journal of Organic Chemistry, 1995, vol. 60, # 17, p. 5494 - 5503
17
[ 6635-20-7 ]
[ 15785-54-3 ]
Reference：
[1] Journal of the American Chemical Society, 1898, vol. 20, p. 316
[2] American Chemical Journal, 1900, vol. 24, p. 176
18
[ 6635-20-7 ]
[ 116313-85-0 ]
Yield
Reaction Conditions
Operation in experiment
86%
With pyridine; aluminum (III) chloride In chloroform at 0℃; for 16 h; Reflux
Compound 104 (10 g, 50.76 mmol) was added to a stirred suspension of AICI3 (7.44 g, 55.83 mmol) in dry chloroform (150 mL) at 0°C. Pyridine (18.0 mL, 223.35 mmol) was dropwise added to the resulting mixture, and the mixture was refluxed for 16h. The mixture was cooled to room temperature and poured into ice water. The solid was filtered, and the residue was purified by silica gel column chromatography to give the title compound 105 (8.0 g, 86percent) . 1HNMR (400 MHz, DMSO-d6) : δ 10.91 (br s, 2H) , 9.81 (s, 1H) , 7.98 (d, J= 2.0 Hz, 1H) , 7.46 (d, J = 2.0Hz, 1H) .
73%
With 1-N-ferrocenylmethyl benzimidazole tagged polymer In N,N-dimethyl-formamideReflux
General procedure: A mixture of aryl methyl ether (1 mmol) and [FemMerBenz]Al2Cl7 (200 mg, 0.96 mol percent) in DMF (5 mL) was refluxed in an oil bath. After completion of the reaction as monitored by the TLC, the reaction mixture was cooled and filtered. The filtrate was poured into water (20 mL) and extracted with ethyl acetate (3 20 mL). The combined organic layers were dried over Na2SO4. Evaporation of the solvent followed by column chromatography over silica gel using ethyl acetate/ petroleum ether (1:4 v/v) afforded pure O-demethylated product, which was characterized by spectral methods.
71%
With pyridine; aluminium(III) iodide In acetonitrile at 80℃; for 18 h;
General procedure: To a solution of AlI3 (36.6 mmol, 1.1 equiv) in MeCN (100 mL)was added dropwise a solution of pyridine (12.2 g, 154.2 mmol,4.6 equiv) and eugenol (5.4 g, 33.0 mmol). The mixture wasstirred at 80 °C for 18 h. After cooling to room temperature, themixture was quenched with aq HCl (2 mol/L, 50 mL), and wasextracted with EtOAc (4 × 50 mL). The combined organic phaseswere washed with brine and dried by MgSO4. After evaporationof solvents by a rotary evaporator, the residue was purifiedthrough flash column chromatography to afford 5 as a whitesolid (4.9 g, 99percent).
71%
Stage #1: With pyridine; iodine; aluminium In acetonitrile for 18 h; Reflux Stage #2: With hydrogenchloride In water; acetonitrile at 20℃;
To a 100 ml eggplant flask were added iodine (2.095 g), aluminum powder (0.368 g) and acetonitrile (40 ml), heated toReflux, stir for 2 hours to the purple red of iodine disappears. Pyridine (1.597 g) and 5-nitro vanillin (0.986 g) were added and the reaction was continuedThe reaction was carried out for 18 hours. After stirring, the mixture was cooled to room temperature and then 2 mol / L dilute hydrochloric acid (10 ml) was added to the reaction solution,Ester (50 ml x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was evaporated to dryness with a rotary evaporator and the residue was removedPurification by flash column chromatography (mobile phase ethyl acetate: petroleum ether = 1: 3, volume ratio) gave 3,4-dihydroxy-5-nitroBenzaldehyde (yellow solid, 0.650 g, 71percent yield).
50%
With hydrogen bromide In water for 4 h; Reflux
A solution of 94 (3.5 g, 17.8 mmol) in hydrobromic acid (48percent, 32 ml) was refluxed for 4 h. After cooling to room temperature and addition of water and ice, the precipitate was filtered off and washed with cold water, to give compound 95 as a brown solid (1.62 g, 50percent). 1H NMR (300 MHz, DMSO-d6): δ = 7.46 (d, J = 1.9 Hz, 1H), 7.95 (d, J = 1.9 Hz, 1H), 9.79 (s, 1H), 10.52 (br m, 2H) ppm; 13C NMR (75 MHz, DMSO-d6): δ = 115.8, 119.6, 127.0, 137.2, 147.2, 148.3, 190.5 ppm; HRMS (ESI): m/z [M-H]- calcd for C7H4NO5: 182.0059, found: 182.0088.
43%
With aluminium(III) iodide; diisopropyl-carbodiimide In acetonitrile at 80℃; for 18 h;
General procedure: To a suspension of AlI3 (5.5 mmol, 1.1 equiv) in hot CH3CN (40 mL) were added sequentially DIC (0.379 g, 3 mmol, 0.6 equiv) and eugenol (1, 0.821 g, 5.0 mmol). The mixture was stirred for 18 h at 80 °C, and then it was cooled to r.t., acidified with HCl (2 mol/L, 10 mL), and extracted with EtOAc (3 × 50 mL). The organic phases were combined, washed with sat. aq Na2S2O3 (10 mL) and brine (10 mL), and was dried (MgSO4). The solvent was removed on a rotary evaporator and the residue was purified by flash column chromatography (PE/EtOAc, 4:1) to afford 2 (0.750 g, 99percent) as a white solid
43%
With aluminium(III) iodide; diisopropyl-carbodiimide In acetonitrile at 80℃; for 18 h;
To a 100 ml eggplant flask were added aluminum triiodide (2.248 g), acetonitrile (40 ml) Heated to reflux, followed by the addition of DIC (0.378 g) and 5-nitro vanillin (0.986 g), heated to 80 ° C, After stirring for 18 hours, the mixture was stirred, cooled to room temperature and then acidified with 2 mol / L dilute hydrochloric acid (10 ml) And extracted with ethyl acetate (50 ml X). The combined organic phases were washed first with a saturated aqueous solution of sodium thiosulfate (10 ml), washed with saturated brine (10 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated Instrument evaporated, The residue was purified by flash column chromatography (eluent: ethyl acetate / petroleum ether = 2: 3, volume ratio) To give 0.395 g of 3,4-dihydroxy-5-nitrobenzaldehyde (yellow solid in 43percent yield)
39.5%
at 90℃; for 17 h;
00455] Intermediate 45 : Synthesis of 8-nitro-2,3-dihydrobenzo[b][l,4]dioxine-6- carbaldehyde:[00456] Step 1: Synthesis of 3,4-dihydroxy-5-nitrobenzaldehyde: To a solution of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde (3 g, 15.2 mmol) in acetic acid (3.1 mL) was added 40percent hydrobromic acid (9.24 mL). The mixture was heated at 90°C for 17 h. Reaction mixture was cooled and poured into ice water (100 mL), followed by a standardaqueous/EtOAc workup and purified by column chromatography on silica gel (petroleum ether/ethyl acetate =5: 1) to give 3,4-dihydroxy-5-nitrobenzaldehyde (1.1 g, yield 39.5percent).
14%
With aluminium(III) iodide; calcium oxide In acetonitrile at 80℃; for 18 h;
To a 100 ml eggplant flask was added aluminum triiodide (2.242 g, 5.5 mmol), acetonitrile (40 ml),CaO (0.421 g, 7.5 mmol) and 5-nitro vanillin (0.985 g, 5.0 mmol) were heated to 80 °C,After 18 hours of reaction, stirring was stopped. After cooling to room temperature, 2 mol/L dilute hydrochloric acid (10 ml) was acidified in an eggplant-shaped flask.Extract with ethyl acetate (50ml x 3) and combine the organic phases and wash first with saturated aqueous sodium thiosulfate (10ml).It was washed with saturated brine (10 ml), dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness on a rotary evaporator.The residue was purified by flash column chromatography (eluent: ethyl acetate/petroleum ether=1:3, volume ratio).0.131 g of 3,4-dihydroxy-5-nitrobenzaldehyde (yellow solid, yield 14percent) was obtained.
Reference：
[1] Journal of Medicinal Chemistry, 2018, vol. 61, # 5, p. 1969 - 1989
[2] Journal of Organic Chemistry, 2000, vol. 65, # 23, p. 8001 - 8010
[3] Journal of the American Chemical Society, 2000, vol. 122, # 44, p. 10781 - 10787
[4] Organic Letters, 2008, vol. 10, # 7, p. 1369 - 1372
[5] Patent: WO2016/199943, 2016, A1, . Location in patent: Paragraph 0402
[6] Synthetic Communications, 2002, vol. 32, # 4, p. 641 - 649
[7] Tetrahedron Letters, 2012, vol. 53, # 47, p. 6361 - 6366,6
[8] Synlett, 2017, vol. 28, # 1, p. 138 - 142
[9] Patent: CN106278825, 2017, A, . Location in patent: Paragraph 0080; 0081; 0082; 0083
[10] Journal of Medicinal Chemistry, 1992, vol. 35, # 24, p. 4584 - 4588
[11] Journal of Medicinal Chemistry, 2010, vol. 53, # 8, p. 3396 - 3411
[12] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 24, p. 7318 - 7337
[13] Synthesis (Germany), 2017, vol. 49, # 12, p. 2721 - 2726
[14] Patent: CN106866377, 2017, A, . Location in patent: Paragraph 0179-0181
[15] Patent: WO2011/38204, 2011, A1, . Location in patent: Page/Page column 149
[16] Patent: CN107473916, 2017, A, . Location in patent: Paragraph 0105-0107
[17] Chemische Berichte, 1903, vol. 36, p. 2935
[18] Patent: WO2005/63695, 2005, A1, . Location in patent: Page/Page column 10
[19] Patent: US5236952, 1993, A,
[20] Synthetic Communications, 2008, vol. 38, # 15, p. 2507 - 2520
[21] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 24, p. 6553 - 6557
[22] Patent: US2010/234632, 2010, A1, . Location in patent: Page/Page column 3-4
[23] Patent: WO2015/69110, 2015, A1, . Location in patent: Page/Page column 70; 71
19
[ 6635-20-7 ]
[ 7440-44-0 ]
[ 116313-85-0 ]
Yield
Reaction Conditions
Operation in experiment
80%
With acetic acid In conc. hydrobromic acid; water
EXAMPLE 111 3,4-Dihydroxy-5-nitrobenzaldehyde A solution containing 8.0 kg of 5-nitrovanillin and 8.7 kg of acetic acid in 35 kg of conc. hydrobromic acid was refluxed for 20 h. 0.6 kg of charcoal was added and the mixture was filtered. 32 kg of water was added with stirring and the solution was cooled to -10° C. and stirring was continued for 2 h more. The crystalline product was filtered and washed with water. Yield 5.66 kg (80percent), m.p. 135°-137° C.
Reference：
[1] Patent: US4963590, 1990, A,
20
[ 6635-20-7 ]
[ 130929-57-6 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 24, p. 7318 - 7337
[2] Patent: CN108440340, 2018, A,
[3] Patent: CN108440340, 2018, A,
With pyridine; aluminum (III) chloride; In chloroform; at 0℃; for 16h;Reflux;
Compound 104 (10 g, 50.76 mmol) was added to a stirred suspension of AICI3 (7.44 g, 55.83 mmol) in dry chloroform (150 mL) at 0C. Pyridine (18.0 mL, 223.35 mmol) was dropwise added to the resulting mixture, and the mixture was refluxed for 16h. The mixture was cooled to room temperature and poured into ice water. The solid was filtered, and the residue was purified by silica gel column chromatography to give the title compound 105 (8.0 g, 86%) . 1HNMR (400 MHz, DMSO-d6) : delta 10.91 (br s, 2H) , 9.81 (s, 1H) , 7.98 (d, J= 2.0 Hz, 1H) , 7.46 (d, J = 2.0Hz, 1H) .
73%
With 1-N-ferrocenylmethyl benzimidazole tagged polymer; In N,N-dimethyl-formamide;Reflux;
General procedure: A mixture of aryl methyl ether (1 mmol) and [FemMerBenz]Al2Cl7 (200 mg, 0.96 mol %) in DMF (5 mL) was refluxed in an oil bath. After completion of the reaction as monitored by the TLC, the reaction mixture was cooled and filtered. The filtrate was poured into water (20 mL) and extracted with ethyl acetate (3 20 mL). The combined organic layers were dried over Na2SO4. Evaporation of the solvent followed by column chromatography over silica gel using ethyl acetate/ petroleum ether (1:4 v/v) afforded pure O-demethylated product, which was characterized by spectral methods.
71%
With pyridine; aluminium(III) iodide; In acetonitrile; at 80℃; for 18h;
General procedure: To a solution of AlI3 (36.6 mmol, 1.1 equiv) in MeCN (100 mL)was added dropwise a solution of pyridine (12.2 g, 154.2 mmol,4.6 equiv) and eugenol (5.4 g, 33.0 mmol). The mixture wasstirred at 80 C for 18 h. After cooling to room temperature, themixture was quenched with aq HCl (2 mol/L, 50 mL), and wasextracted with EtOAc (4 × 50 mL). The combined organic phaseswere washed with brine and dried by MgSO4. After evaporationof solvents by a rotary evaporator, the residue was purifiedthrough flash column chromatography to afford 5 as a whitesolid (4.9 g, 99%).
71%
To a 100 ml eggplant flask were added iodine (2.095 g), aluminum powder (0.368 g) and acetonitrile (40 ml), heated toReflux, stir for 2 hours to the purple red of iodine disappears. Pyridine (1.597 g) and 5-nitro vanillin (0.986 g) were added and the reaction was continuedThe reaction was carried out for 18 hours. After stirring, the mixture was cooled to room temperature and then 2 mol / L dilute hydrochloric acid (10 ml) was added to the reaction solution,Ester (50 ml x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was evaporated to dryness with a rotary evaporator and the residue was removedPurification by flash column chromatography (mobile phase ethyl acetate: petroleum ether = 1: 3, volume ratio) gave 3,4-dihydroxy-5-nitroBenzaldehyde (yellow solid, 0.650 g, 71% yield).
50%
With hydrogen bromide; In water; for 4h;Reflux;
A solution of 94 (3.5 g, 17.8 mmol) in hydrobromic acid (48%, 32 ml) was refluxed for 4 h. After cooling to room temperature and addition of water and ice, the precipitate was filtered off and washed with cold water, to give compound 95 as a brown solid (1.62 g, 50%). 1H NMR (300 MHz, DMSO-d6): delta = 7.46 (d, J = 1.9 Hz, 1H), 7.95 (d, J = 1.9 Hz, 1H), 9.79 (s, 1H), 10.52 (br m, 2H) ppm; 13C NMR (75 MHz, DMSO-d6): delta = 115.8, 119.6, 127.0, 137.2, 147.2, 148.3, 190.5 ppm; HRMS (ESI): m/z [M-H]- calcd for C7H4NO5: 182.0059, found: 182.0088.
43%
With aluminium(III) iodide; diisopropyl-carbodiimide; In acetonitrile; at 80℃; for 18h;
General procedure: To a suspension of AlI3 (5.5 mmol, 1.1 equiv) in hot CH3CN (40 mL) were added sequentially DIC (0.379 g, 3 mmol, 0.6 equiv) and eugenol (1, 0.821 g, 5.0 mmol). The mixture was stirred for 18 h at 80 C, and then it was cooled to r.t., acidified with HCl (2 mol/L, 10 mL), and extracted with EtOAc (3 × 50 mL). The organic phases were combined, washed with sat. aq Na2S2O3 (10 mL) and brine (10 mL), and was dried (MgSO4). The solvent was removed on a rotary evaporator and the residue was purified by flash column chromatography (PE/EtOAc, 4:1) to afford 2 (0.750 g, 99%) as a white solid
43%
With aluminium(III) iodide; diisopropyl-carbodiimide; In acetonitrile; at 80℃; for 18h;
To a 100 ml eggplant flask were added aluminum triiodide (2.248 g), acetonitrile (40 ml) Heated to reflux, followed by the addition of DIC (0.378 g) and 5-nitro vanillin (0.986 g), heated to 80 C, After stirring for 18 hours, the mixture was stirred, cooled to room temperature and then acidified with 2 mol / L dilute hydrochloric acid (10 ml) And extracted with ethyl acetate (50 ml X). The combined organic phases were washed first with a saturated aqueous solution of sodium thiosulfate (10 ml), washed with saturated brine (10 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated Instrument evaporated, The residue was purified by flash column chromatography (eluent: ethyl acetate / petroleum ether = 2: 3, volume ratio) To give 0.395 g of 3,4-dihydroxy-5-nitrobenzaldehyde (yellow solid in 43% yield)
39.5%
With hydrogen bromide; acetic acid; at 90℃; for 17h;Product distribution / selectivity;
00455] Intermediate 45 : Synthesis of 8-nitro-2,3-dihydrobenzo[b][l,4]dioxine-6- carbaldehyde:[00456] Step 1: Synthesis of 3,4-dihydroxy-5-nitrobenzaldehyde: To a solution of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde (3 g, 15.2 mmol) in acetic acid (3.1 mL) was added 40% hydrobromic acid (9.24 mL). The mixture was heated at 90C for 17 h. Reaction mixture was cooled and poured into ice water (100 mL), followed by a standardaqueous/EtOAc workup and purified by column chromatography on silica gel (petroleum ether/ethyl acetate =5: 1) to give 3,4-dihydroxy-5-nitrobenzaldehyde (1.1 g, yield 39.5%).
14%
With aluminium(III) iodide; calcium oxide; In acetonitrile; at 80℃; for 18h;
To a 100 ml eggplant flask was added aluminum triiodide (2.242 g, 5.5 mmol), acetonitrile (40 ml),CaO (0.421 g, 7.5 mmol) and 5-nitro vanillin (0.985 g, 5.0 mmol) were heated to 80 C,After 18 hours of reaction, stirring was stopped. After cooling to room temperature, 2 mol/L dilute hydrochloric acid (10 ml) was acidified in an eggplant-shaped flask.Extract with ethyl acetate (50ml x 3) and combine the organic phases and wash first with saturated aqueous sodium thiosulfate (10ml).It was washed with saturated brine (10 ml), dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness on a rotary evaporator.The residue was purified by flash column chromatography (eluent: ethyl acetate/petroleum ether=1:3, volume ratio).0.131 g of 3,4-dihydroxy-5-nitrobenzaldehyde (yellow solid, yield 14%) was obtained.
With sodium chloride; In dichloromethane; ethyl acetate;
a) 17.1 g of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde are treated with 170 ml of constant-boiling hydrobromic acid and heated under reflux for 3.5 hours. After cooling the separated precipitate is filtered under suction, washed twice with ice-water and taken up in ethyl acetate. The organic phase is washed twice with 50 ml of sodium chloride solution each time, dried over magnesium sulfate and evaporated in a water-jet vacuum. The crystals obtained are taken up in methylene chloride, whereupon the solution is filtered over a ten-fold amount of silica gel. The material obtained is crystallized from ethyl acetate/isopropyl ether. There is obtained 3,4-dihydroxy-5-nitrobenzaldehyde in the form of yellow crystals of m.p. 142-143.
Example 1; Preparation of 3,4-dihydroxy 5-nitrobenzaldehyde; A mixture of anhydrous aluminum chloride (40.5 gm) under nitrogen atmosphere, pyridine (130 ml) and 5-nitro vanillin (50 gm) was charged at 5-10 C. and followed by heating at 50-55 C. After completion of reaction water (500 ml) and concentrated hydrochloric acid (150 ml) was added at 5-10 C. The reaction temperature was raised to 25-30 C. followed by addition of ethylacetate (500 ml). The layers were separated and organic layer was washed with saturated brine solution. Ethyl acetate was distilled out under reduced pressure and material was crystallized with cyclohexane (200 ml) and ethyl acetate (50 ml) to get 3,4-dihydroxy 5-nitrobenzaldehyde (41 gm).
With boron tribromide; In dichloromethane; at 0 - 20℃;
To a suspension of 5-nitrovanilline (5.00 g, 25 mmol) in DCM (50 mL) at 0C was added drop-wise pure BBr3 (25.0 g, 100 mmol). The mixture was allowed to warm up to RT overnight. It was re-cooled in ice and H20 (60 mL) was added, initially drop-wise. NH4C1 sat. (60 mL) was added and the whole mixture was filtered over Celite. The pad was washed with EtOAc (100 mL). The filtrate separated into two layers and the pad was washed with EtOAc (2 x 100 mL). The filtrates were used to extract the water layer. The combined organic layers were washed with H20 (2 x 20 mL), 15% Na2S2O3 (50 mL), brine, dried (Na2SO4) and concentrated to a brown oil/solid (6.2 g,>100%). The product was used in the next step without any further purification.
With piperidine; acetic acid; In toluene; at 105 - 110℃; for 15h;Heating / reflux;
Charged 3-methoxy4-hydroxy-5-nitrobenzaldehyde 25g (0.126 mole) of the formula 2, where R= methyl) and N, N-diethylamino cyanoacetamide of the formula (3)) 22.2g, ( 0. 158 mole) acetic acid 4.18g and piperidine 5.94g along with toluene 250ml and heated to reflux temperature of about 105-110 and remove the water azeotrophically for 15 hours. The reaction mixture is concentrated and quenched in to dilute hydrochloric acid and chilled water 375ml and stirred for 3 hours. The precipitated solid was filtered and dried to get 36g (88.95%) with HPLC purity is 94.2% (including isomer) and the N, N-DIETHYL-2-CYANO-3- (-3- METHOXY - 4-HYDROXY-5-NITROPHENYL) ACRYLAMIDE which is used as such for the next stage. Small sample was purified to get the pure single isomer (HPLC) by crystallising form methanol. The pure product is having the following properties. HPLC PURITY: 99.63% MR; 130-132 C IR: (Cm'') : 2204 (-CN), 1637 (-C=O), PMR (200MHz), 6 value; 1.28 (m,. 6H), 3.49 (q, 4H), 4.02 (s, 3H), 7.608 (s, 1H,), 8.02 (d, 1H, J=0.01), 7.98 ( s, 1H, J=0.01), MS= M/Z= 320.2 (M+')
With acetic acid; In conc. hydrobromic acid; water;
EXAMPLE 111 3,4-Dihydroxy-5-nitrobenzaldehyde A solution containing 8.0 kg of 5-nitrovanillin and 8.7 kg of acetic acid in 35 kg of conc. hydrobromic acid was refluxed for 20 h. 0.6 kg of charcoal was added and the mixture was filtered. 32 kg of water was added with stirring and the solution was cooled to -10 C. and stirring was continued for 2 h more. The crystalline product was filtered and washed with water. Yield 5.66 kg (80%), m.p. 135-137 C.
acetic acid; glycine; In toluene; for 12 - 15h;Heating / reflux;
EXAMPLE-.Preparation of N,N-DIETHYL-2-CYANO-3-(3-lambdalambdaETHOXY-4-HYDROXY-S-NITROPHENYL)ACRYL AMIDE. ; STEP-I; 3-Methoxy-4-hydroxy-5-nitrobenzaldehyde of the formula (6) 150.0 gm (0.761 mole), N,N-diethyl cyanoacetamide of the formula (4) 135.3 gm <n="16"/>(0.96 mole), glycine 10.5 gm (0.13 mole) and acetic acid 25.12 gm (0.41 mole) were charged sequentially to 1500.0 ml toluene. The resulting reaction mixture was heated to reflux and maintained with removal of water by azeotropically for 12-15 hrs. After the completion of reaction the solvent is concentrated and quenched into a cooled solution of isopropy. alcohol, aqueous HBr and water (2400.0 ml) and stirred for 3 hrs. The precipitated solid is filtered and dried to get 229.0 gm (94.2%) of title product of trhe formula (7) as crystalline solid. This product is used for next stage with out purification.
With sodium hydroxide; In methanol; at 20℃; for 16h;
A suspension of 3-methoxy-4-hydroxy-5-nitro-benzaldehyde (100 g, 0.507 mol) in methanol (0.5 1) under nitrogen atmosphere at room temperature, is added with N,N-diethylamino-cyano-acetamide (142 g, 1.01 mol) and a sodium hydroxide solution (30.4 g, 0.761 mol) in methanol (0.5 l). The resulting mixture is reacted under mechanical stirring for 16 hours. After completion of the reaction, a 20% hydrochloric acid solution (0.5 l) is dropped in the mixture which is left to spontaneously cool to room temperature. The resulting product is filtered, washing with water (0.1 l for three times), then dried in the air. 155 g of product are obtained. Yield: 95%.1H-NMR (300 MHz), delta (DMS0): 8.10 (d, 1H); 7.85 (d, 1H); 7.70 (s, 1H); 3.40 (m, 4H); 1.15 (m, 6H).
95%
With sodium hydroxide; In methanol; for 16h;
Example 1 Preparation of N,N-diethyl-2-cyano-3-(-3-methoxy-4-hydroxy-5-nitrophenyl-)-acrylamide; (V) A suspension of 3-methoxy-4-hydroxy-5-nitro-benzaldehyde (100 g, 0.507 mol) in methanol (0.5 I) under nitrogen atmosphere at room temperature, is added with N,N-diethylamino-cyano-acetamide (142 g, 1.01 mol) and a sodium hydroxide solution (30.4 g, 0.761 mol) in methanol (0.5 1). The resulting mixture is reacted under mechanical stirring for 16 hours. After completion of the reaction, a 20% hydrochloric acid solution (0.5 I) is dropped in the mixture which is left to spontaneously cool to room temperature. The resulting product is filtered, washing with water (0.1 I for three times), then dried in the air. 155 g of product are obtained. Yield: 95%. 1H-NMR (300 MHz), delta (DMSO): 8.10 (d, 1 H); 7.85 (d, 1 H); 7.70 (s, 1 H); 3.40 (m, 4H); 1.15 (m, 6H).
70%
ammonium acetate; In ethanol;Heating / reflux;
(ii) Preparation of N1,N1-diethyl-(E)-2-cyano-3-(4-hydroxy-3-methoxy-5-nitrophenyl)-2-propenamide; The total quantity of N1,N1-diethyl-2-cyanoacetamide isolated in step (i), dissolved in dry ethanol (5 L) is charged to a reactor vessel under a nitrogen atmosphere. A further amount of dry ethanol (25 L) is added to the reactor. After the addition of 5-nitrovanillin (965.6 g, 4.898 mol) and ammonium acetate (830.6 g, 10.775 mol), the suspension is agitated and heated to reflux until an in process control indicated the disappearance of 5-nitrovanillin. The dark solution is allowed to cool to ambient temperature, whereas a yellow solid precipitates. The mixture is cooled to -5 C. and agitated for 1 hour at -5 C. and the solid isolated by collection on a 20 L Buchner funnel under reduced pressure. The filter cake is washed with -10 C. ethanol (2 L). The solid is transferred to trays and dried at 30 C. in a vacuum oven, to afford a yellow solid (1.093 kg, 70%).1H-NMR, 200 MHz, DMSO-d6: delta t 6H 1 ppm J 7 Hz, q 4H 3.45 ppm J 7 Hz, s 3H 3.65 ppm, bs 1H 5.7-6.1 ppm, s 1H 6.95, s 1H 7.5 ppm, s 1H 8.02 ppm.
With hydrogenchloride In ethanol; water for 1h; Reflux;
4.5. General procedure for the synthesis of NAH derivatives (3-30)
General procedure: To a solution of the corresponding hydrazide derivative (33a-33h) (0.829 mmol) in absolute ethanol (90 mL) containing a catalytic amount of 37% aq. hydrochloric acid was added 0.87 mmol of desired aromatic aldehyde derivative. The mixture was stirred at reflux for 60 min, when extensive precipitation was observed. The reaction mixture was then poured into cold water, neutralized with 10% aqueous sodium bicarbonate solution. The precipitate formed was filtered out and dried, furnishing the target compounds in the yields as described next.
With hydrogenchloride; In ethanol; water; for 1h;Reflux;
General procedure: To a solution of the corresponding hydrazide derivative (33a-33h) (0.829 mmol) in absolute ethanol (90 mL) containing a catalytic amount of 37% aq. hydrochloric acid was added 0.87 mmol of desired aromatic aldehyde derivative. The mixture was stirred at reflux for 60 min, when extensive precipitation was observed. The reaction mixture was then poured into cold water, neutralized with 10% aqueous sodium bicarbonate solution. The precipitate formed was filtered out and dried, furnishing the target compounds in the yields as described next.
2-cyano-3-(3-hydroxy-4-methoxy-5-nitrophenyl)prop-2-eneamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With IRA 96 resin; In toluene;Reflux;
To a solution of N,N-diethylcyanoacetamide (14.1g, 0.1mol) in toluene was added 0.2g IRA 96resin and isonitrovanillin(19.7g, 0.1mol). The mixture was heated to reflux withazeotropic distillation of water. The reaction was continued until a TLC test showed completion ofreaction. The mass was filtered hot. The filtrate was concentrated under vacuumto give the crude product, which was recrystallized from absolute alcohol toafford 6. Light yellow solid, yield:(61%),m.p. 172-173 C;1H NMR (400MHz, DMSO): deltaH1.13 (br s, 6H), 3.39 (br s, 4H), 3.92 (s, 3H), 7.67(s, 1H), 7.76 (d, J = 2.1Hz, Ar-H),7.78 (d, J = 2.1Hz, Ar-H), 10.98 (brs,-OH); HRMS (ES) calcd for C15H18N3O5,[M+H+] m/z 320.1241 found m/z 320.1242; IR (NEAT) 3039 (ArC-H), 2934 (C-H), 2211(-CN),1628 (C=O), 1601 (C=C), 1303, 1501 (N=O).
2-amino-3,4,5,8-tetrahydro-5-(4-hydroxy-3-methoxy-5-nitrophenyl)-7-(1H-indol-3-yl)-4-oxopyrido[2,3-d]pyrimidine-6-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With acetic acid; for 11h;Reflux;
General procedure: All the reagents and solvents used were reagent grade purchasedfrom Merck, Mallinckrodt, Honeywell, and J.T. Baker. Theywere used as purchased. The compounds were synthesized accordingto Scheme 1. A solution containing equimolar amounts of2,6-diaminopyrimidin-4(3H)-one 1, aromatic aldehyde (2a-f) and3-(2-cyanoacetyl)indole 3, and acetic acid as solvent was stirred atreflux temperature (see Table 1). In all cases, the reaction wasmonitored employing thin-layer chromatography (TLC, in chloroform/methanol, 8:2) and visualization by a conventional UV lamp(254 or 365 nm). After completion of the reaction and formation ofthe product precipitate, the solvent was removed under reducedpressure. The products were filtered and washed with ethanol toafford the desired purity of the products for characterization. Reactiontime varied in between 1 and 11 h and depended on therespective aldehyde employed.
(2Z)-7-chloro-2-[(4-hydroxy-3-methoxy-5-nitrophenyl)methylidene]benzofuran-3-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
With hydrogenchloride In water; isopropyl alcohol at 80℃;
4.1.4. General procedure of synthesis of aurones 9-15
General procedure: 100 mg of 1-benzofuran-3(2H)-ones, equimolar amount of corresponding substituted benzaldehyde and 1 drop of conc. hydrochloric acid were mixed with 1-3 ml of isopropanol. Mixture was heated on the water bath at 80 °C during 2-8 h. In the case of 1-benzofuran-3(2H)-ones 28 and 29 mixtures were kept at 80 °C for 16 h. Yellow, red or brown precipitates were filtered and washed with ethyl acetate. If obtained products contained impurities (in the most cases of starting aldehyde)- they were recrystallized from 0.2 to 1 ml DMF and washed with ethyl acetate.
(2Z)-7-bromo-2-[(4-hydroxy-3-methoxy-5-nitrophenyl)methylene]benzofuran-3-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
29%
With hydrogenchloride In water; isopropyl alcohol at 80℃;
4.1.4. General procedure of synthesis of aurones 9-15
General procedure: 100 mg of 1-benzofuran-3(2H)-ones, equimolar amount of corresponding substituted benzaldehyde and 1 drop of conc. hydrochloric acid were mixed with 1-3 ml of isopropanol. Mixture was heated on the water bath at 80 °C during 2-8 h. In the case of 1-benzofuran-3(2H)-ones 28 and 29 mixtures were kept at 80 °C for 16 h. Yellow, red or brown precipitates were filtered and washed with ethyl acetate. If obtained products contained impurities (in the most cases of starting aldehyde)- they were recrystallized from 0.2 to 1 ml DMF and washed with ethyl acetate.
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