* 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 tetrabutyl ammonium fluoride; sodium hydroxide In water at 25℃; for 4 h;
In a 3 L dry reaction flask, 157 g of sodium hydroxide was dissolved in 1500 ml of water, 500 g of isovanillin, 120 g of tetrabutylammonium fluoride, and 537 g of ethyl bromide were added, and the reaction was stirred at 25° C. for 4 hours. After filtration by suction, an off-white solid powder of 3-ethoxy-4-methoxybenzaldehyde was obtained with a purity of 99.9percent and a yield of 96.1percent.
Reference：
[1] Patent: CN107827722, 2018, A, . Location in patent: Paragraph 0034-0041
Reference：
[1] Gazzetta Chimica Italiana, 1934, vol. 64, p. 381,390, 393
[2] Justus Liebigs Annalen der Chemie, 1939, vol. 537, p. 143,153
[3] Canadian Journal of Research, Section B: Chemical Sciences, 1937, vol. 15, p. 164[4] Canadian Journal of Research, Section B: Chemical Sciences, 1940, vol. 18, p. 80,83
[5] Chemische Berichte, 1933, vol. 66, p. 450,459
Reference：
[1] Journal of the American Chemical Society, 2006, vol. 128, # 22, p. 7136 - 7137
[2] Journal of Organic Chemistry, 2004, vol. 69, # 9, p. 2920 - 2928
[3] Chemical and Pharmaceutical Bulletin, 1999, vol. 47, # 10, p. 1512 - 1513
[4] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1987, p. 931 - 936
[5] Journal of the American Chemical Society, 2014, vol. 136, # 6, p. 2583 - 2591
[6] Synthesis (Germany), 2018, vol. 50, # 17, p. 3408 - 3419
19
[ 621-59-0 ]
[ 54246-06-9 ]
Reference：
[1] Synthesis, 2002, # 17, p. 2503 - 2512
[2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 18, p. 4367 - 4371
20
[ 621-59-0 ]
[ 67-56-1 ]
[ 6702-50-7 ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: at 0 - 4℃; Stage #2: Reflux
3 - hydroxy -4 - methoxybenzaldehyde (10g, 65.7mmol) is dissolved in formic acid (9.1g, 197 . 1mmol) in, solution is cooled to 0 °C, the 35percent hydrogen peroxide (22.3g, 230mmol) slow instillment like in the above solution, keep the 4 °C reaction overnight. Filtering the solid material after completion of the reaction, ice water after washing, drying to obtain solid material. The solid is dissolved in methanol (50 ml) in, slowly adding concentrated sulfuric acid (98percent, 3.2 ml, 59 . 1mmol), heating to reflux, the solvent is removed to obtain the crude product, 10percent methanol aqueous solution by recrystallization to obtain 3 - hydroxy -4 - methoxybenzoic acid methyl ester (II) (9.6g), yield 80percent.
89 %Chromat.
at 70℃; for 24 h;
General procedure: The reaction of 3,4,5-trimethoxybenzaldehyde (0.01mol)withH2O2(0.04 mol) and methanolwas carried out in 100 mL round bottomflask.The reaction mixture was reflux for 24 h. After completion of the reaction,the reaction mixture pour in distilled water; the aqueous solutionwas the extracted with ethyl acetate (3 × 20 mL) and brine solution toget clear ethyl acetate layer. The organic layerwas driedwith anhydrous sodiumsulfate. It was filtered and vaporized to dryness at reduced pressureto obtained corresponding methyl etster.
Reference：
[1] Patent: CN105153065, 2017, B, . Location in patent: Paragraph 0157; 0158; 0159
[2] Organic and Biomolecular Chemistry, 2005, vol. 3, # 12, p. 2271 - 2281
[3] Journal of Molecular Liquids, 2017, vol. 242, p. 1085 - 1095
21
[ 621-59-0 ]
[ 6702-50-7 ]
Reference：
[1] Chemische Berichte, 1941, vol. 74, p. 79,94
[2] Monatshefte fuer Chemie, 1966, vol. 97, p. 570 - 578
[3] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2014, vol. 53B, # 10, p. 1269 - 1274
[4] Chemistry of Natural Compounds, 2015, vol. 51, # 4, p. 620 - 625[5] Khim. Prir. Soedin., 2015, vol. 51, # 4, p. 536 - 540,5
With sulfuryl dichloride In acetic acid at 0 - 2℃; for 2 h;
Neat sulfuryl chloride (14.85 g, 110mmol, 1.1 eq.) was added dropwise over 5 minutes to a solution of isovanillin (15.00 g, 100 mmol, 1 eq)in 120 mL of glacial acetic acid in an ice-water bath. After 2 hours of stirring with ice-water bath cooling,the reaction was filtered, washed with cold acetic acid, and dried under vacuum to afford 14.16 g ofwhite solid. HPLC and 1H-NMR indicate indicated the presence of unreacted isovanillin. This solid wasdissolved in boiling ethanol and recrystallized to yield 11.91 g (80percent) of fluffy white needles (mp = 200.0– 209.9 °C). 1H-NMR indicated <1percent isovanillin after one recrystallization. 1H NMR (300 MHz, CDCl3): 10.19 (s, 1H, CHO), 9.83 (d, J = 31.4 Hz, 1H, OH), 7.41 (d, J = 8.6 Hz, 1H, ArH), 7.12 (d, J = 8.6 Hz, 1H, ArH),3.93 (s, 3H, OCH3); 1H-NMR (300 MHz, DMSO-d6): 10.19 (s, 1H, CHO), 9.89 (s, 1H, OH), 7.42 (d, J = 8.6Hz, 1H, Ar-H), 7.12 (d, J = 8.6 Hz, 1H, Ar-H), 3.93 (s, 3H, OMe); EI-MS m/z: 187 (M+2), 185 (M+, 100percent),171, 157, 143, 129, 115, 107, 99, 79, 65, 51. UV-Vis: 215.3, 237.2, 283.8 nm.
69%
With tert-butylhypochlorite In acetic acid
Step 1 Synthesis of 2-chloro-3-hydroxy-4-methoxybenzaldehyde 41.2 g (0.271 mol) of isovanillin was dissolved in 160 ml of 90percent AcOH under heating. 29.41 g of t-BuOCl was added dropwise to the solution while it was kept at 35° to 40° C. The solution was stirred at room temperature for 3 hours and then 200 ml of ether was added thereto. The mixture was left to stand overnight and crystals thus formed were separated by filtration and washed with ether. 42.0 g of the crude crystals were recrystallized from acetonitrile to obtain 35 g of 2-chloro-3-hydroxy-4-methoxybenzaldehyde (69percent). mp 203°~205° C. NMR (90 MHz, DMSO-d6) δ:3.94 (3H, s), 7.10 (1H, d), 7.42 (1H, d), 9.84 (1H, s), 10.16 (1H, s)
Reference：
[1] Journal of Medicinal Chemistry, 1986, vol. 29, # 11, p. 2315 - 2325
[2] Organic Process Research and Development, 2001, vol. 5, # 1, p. 45 - 49
[3] Synlett, 2014, vol. 25, # 20, p. 2891 - 2894
[4] Journal of Organic Chemistry, 2012, vol. 77, # 2, p. 977 - 984
[5] Journal of Heterocyclic Chemistry, 1986, vol. 23, # 6, p. 1805 - 1814
[6] Turkish Journal of Chemistry, 2010, vol. 34, # 2, p. 181 - 186
[7] Patent: US5292521, 1994, A,
[8] Angewandte Chemie - International Edition, 1998, vol. 37, # 9, p. 1236 - 1239
[9] Yakugaku Zasshi, 1956, vol. 76, p. 1122,1125[10] Chem.Abstr., 1957, p. 3505
[11] Arzneimittel-Forschung/Drug Research, 1986, vol. 36, # 3, p. 457 - 460
[12] Patent: US5866513, 1999, A,
24
[ 621-59-0 ]
[ 2973-58-2 ]
Yield
Reaction Conditions
Operation in experiment
93%
With N-Bromosuccinimide In dichloromethane at 20℃; for 0.5 h; Inert atmosphere
3-Hydroxy-4-methoxybenzaldehyde (10.0 g, 65.7 mmol) in CH2Cl2(150 mL) was treated with NBS (11.7 g, 65.7 mmol) for 30 min at r.t. togive 2-bromo-3-hydroxy-4-methoxybenzaldehyde (14.1 g, 93percent).40
88.74%
With bromine; sodium acetate; iron In acetic acid at 23℃; for 8 h; Cooling with ice
Isovanillin 10.00g (65.73mmol) dissolved in 200ml glacial acetic acid was added to a 500ml round bottom flask. To this was added sodium acetate 0.78g (131.45mmol), iron powder 0.37g (6.57mmol). Liquid bromine 3.4ml (65.73mmol) containing 20ml of glacial acetic acid was then added to a constant pressure funnel. In an ice bath, it was slowly added dropwise to the round bottom flask with stirring. After dropping, it was reacted at 23°C for 8h. TLC detection. Completion of the reaction. The reaction system was added to 500ml of ice water. After stirring for a few minutes, it was left to stand for 10min then filtered. Ice water washed free of acetic acid. The filter cake was dried and weighed giving 13.40g of white solid 2-bromo-3-hydroxy-4-methoxybenzaldehyde (Compound 2), yield 88.74percent; m.p.206-207°C.
83%
With N-Bromosuccinimide In 1,4-dioxane; water at 0℃; for 2.5 h;
Example 33 N-(2-cyano- 1 -(1 -hydroxy-7-phenoxy-l .3-dihydrobenzo[c] [ 1.2]oxaborol-6-yloxy)propan- 2-yl)-4-(trifluoromethoxy)benzamide 3-Hydroxy-4-methoxybenzaldehyde (30.4g, 0.2mol), 1,4-dioxane (250ml) and water (100ml) are mixed, and N-bromosuccinimide (37.38g, 0.21mol) is added over 30 minutes at 0°C. After 2h, water (400ml) is added, and the precipitated crystals are collected by filtration. The crystals are washed with water (1000ml) to give the desired product (38.5g, yield 83percent) as a white solid.
82%
Stage #1: at 20℃; for 0.5 h; Stage #2: at 23 - 25℃; for 3 h;
20.0 g (132 mmol) of 3-hydroxy-4-methoxybenzaldehyde (4),21.59 g (263 mmol) of sodium acetateAnd 0.68 g (12 mmol) of iron powderPlaced in a 500 ml three-necked flask,120 ml of glacial acetic acid was added,Stirring for 30 min at room temperature;After completion of the stirring,Control temperature 23 ~ 25 ,(140 mmol) of liquid bromine was added dropwise in advanceAnd 30mL glacial acetic acid mixed with the preparation of the solution,After the temperature drops 23 ~ 25 to continue stirring 3h;Then 250 mL of ice water was added,Stirring 1h;filter,Solid evaporated,Ethanol recrystallization,To give 24.70 g of 2-bromo-3-hydroxy-4-methoxybenzaldehyde (5)Yield 82percent;
81%
Stage #1: at 20℃; for 0.5 h; Stage #2: at 23 - 26℃; for 3 h;
To a mixture of isovanillin (1) (20.0 g, 132 mmol), NaOAc(21.59 g, 263 mmol) and iron powder (0.68 g, 12 mmol) was added glacial acetic acid (120 mL). The mixture was stirred atroom temperature for 30 min. Br2 (7.0 mL, 140 mmol) in glacial acetic acid (30 mL) was added dropwise into the abovemixture at 23–26C. The mixture was stirred at the same temperature for 3 h. Ice water (250 mL) was added and the mixturestirred for another 1 h and filtered. The solid obtained was dried and recrystallized from EtOH to give 4 (24.59 g, 81percent) as agray solid.
79%
With bromine; sodium acetate In acetic acidInert atmosphere
2-Bromo-3-Hydroxy-4-Methoxy-Benzaldehyde (8)To a stirred suspension of isovanillin (10 g, 66 mmol), powdered anhydrous sodium acetate (10.82 g, 0.132 mol) and iron powder (0.3 g, 5.4 mmol) in glacial acetic acid (60 mL) under argon, was added drop-wise over 15 min a solution Of Br2 (3.7 mL, 0.0726 mol) in acetic acid (12.5 mL). The reaction temperature rose during the course of addition, and the mixture became viscous. After all the starting material was consumed, as determined by TLC, the mixture was poured onto ice cold water, and the resulting precipitate filtered under vacuum. The precipitate was washed several times with cold water and air-dried. Crystallization from boiling ethanol gave 8 (11.93 g, 79 percent yield) as a gray powder. Rf = 0.10 (1 :5 EtOAc/hexanes). M.p. 196- 200 °C. IR (thin film) 3215, 1662, 1588, 1561, 1491, 1273 cm"1. 1H NMR (300 MHz, CDCl3) δ 10.27 (IH, s), 7.59 (IH, d, J= 9 Hz), 6.96 (IH, d, J= 9 Hz), 6.02 (IH, bs), 4.00 (3H, s). 13C NMR (75MHz, CDCl3) δ 56.58, 109.24, 112.84, 113.84, 122.74, 143.25, 151.65, 190.87. HRMS calcd. for C8H8O3Br (MH+) 230.9657, found 230.9652.
77%
With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione In chloroform at 20℃; for 9 h;
To a solution of isovanillin (2) (5.0 g, 32.9 mmol) in CHCl3(1000 mL), DBDMH (5.2 g, 18.2 mmol) was portionwise added,and the mixture was stirred for 9 h at ambient temperature.After the addition of water (300 mL), the organic layer wasseparated, washed with brine, and dried over MgSO4. Theorganic solvent was removed in vacuo to give a crude material which was purified by recrystallization from AcOEt. Thetitle compound (3, 5.8 g, 25.1 mmol, 77percent) was obtained as apale orange powder, mp 200.2–201.0 °C (AcOEt) [lit.15) mp206–207 °C (EtOH)]. 1H-NMR (400 MHz, CDCl3) δ: 10.26 (d,1H, CHO), 7.58 (d, J=8.8 Hz, 1H, ArH), 6.93 (d, J=8.8 Hz,1H, ArH), 6.07 (s, 1H, OH), 4.01 (s, 3H, OMe).
74.8%
With N-Bromosuccinimide In 1,4-dioxane; water
PREPARATIVE EXAMPLE 88 3-Hydroxy-4-methoxybenzaldehyde (200 g, 1.31 mol), dioxane (1000 ml) and water (400 ml) were mixed, and N-bromosuccinimide (245.7 g, 1.38 mol) was added over 10 minutes. After 60 and 70 minutes, N-bromosuccinimide was further added in an amount of 16.4 g (92.1 mmol) and 7.02 g (39.4 mmol), respectively, and the mixture was further stirred for 30 minutes. Water (1600 ml) was added, and the precipitated crystals were collected by filtration. The crystals were washed with water (1000 ml) to give 2-bromo-3-hydroxy-4-methoxybenzaldehyde (227.1 g, 74.8percent) as pale-red crystals. 1 H-NMR (DMSO-d6, 300 MHz) δ: 10.1(1 H, s), 9.59(1 H, s), 7.40(1 H, d, J=8.4 Hz), 7.14(1 H, d, J=8.4 Hz), 3.92(3 H, s). FABMS (m/z): 232[M+ H+ ] (20), 185(100).
65%
Stage #1: With sodium acetate; iron In acetic acid at 20℃; for 0.5 h; Stage #2: With bromine In acetic acid at 20℃; for 3 h;
To a mixture of 1 (10.0 g, 0.066 mol), NaOAc (10.8 g, 0.132 mol), Fe powder (0.34 g, 0.006 mol) was added acetic acid (60 mL), and then the mixture was stirred for 30 min at room temperature. Next, Br2 (3.5 mL, 0.07 mol) in 15 mL of acetic acid was slowly added to the above mixture at room temperature. The mixture was stirred for another 3 h at the same temperature. Ice-water (125 mL) was then added into the mixture and stirred for another 1 h and filtered. The solid was dried and then recrystallized from EtOH to give 2 as a gray solid (9.9 g, 65percent). 1H NMR (400 MHz, Acetone-d6): δ 10.23(s, 1H, -CHO), 7.49 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 4.00 (s, 3H, -OCH3); 13C NMR (100 MHz, Acetone-d6): δ 192.1, 154.7, 146.0, 129.0, 123.5, 114.5, 111.7, 57.8. HRMS (ESI): m/z calcd for [M+Na]+ C8H7BrNaO3 252.9471, obsd 252.9454.
60%
With bromine In tetrachloromethane; chloroform at 20℃; for 16 h;
Liquid Br2 (36.85 g, 11.6 mL, 225mmol, 1.5 equiv.) was added dropwise at a rate of 0.1 mL/min over a period of 2 hours, using a syringepump or addition funnel, to a three-neck flask, equipped with septum and overhead stirring assembly,containing a solution of isovanillin, 3-hydroxy-4-methoxybenzaldehyde (22.8g, 150 mmol), in 75 mL ofCCl4 and 75 mL of CHCl3. The reaction mixture was allowed to stir overnight (approximately 12 hours) atroom temperature. The resulting reddish brown precipitate was vacuum filtered and rinsed with 50 mLof a 1:1 solution of CCl4 and CHCl3. After removing solvent under reduced pressure, the precipitate wasdissolved in 300 mL of ethyl acetate (EtOAc) to give a bright yellow solution. This extract was washedwith 150 mL of brine, 50 mL of 10percent w/v sodium thiosulfate, and twice more with brine (2 x 150 mLportions).The organic phase was dried with MgSO4, vacuum-filtered, and solvent was removed by underreduced pressure at room temperature. The recovered white solid was recrystallized in ethanol andvacuum filtered to afford 22.11 g (60percent) of a fine, grainy, white solid, 2-bromo-3-hydroxy-4-methoxybenzaldehyde (mp = 204.5–210.4°C). 1H-NMR (300 MHz, DMSO-d6): 10.11 (s, 1H, CHO), 9.94 (s, 1H, OH), 7.42 (d, J =8.6 Hz, 1H, Ar-H), 7.15 (d, J = 8.6 Hz, 1H, Ar-H), 3.93 (s, 3H, OMe); EI-MSm/z: 232 (M+2), 231(100percent), 230 (M+), 229, 214, 201,189, 187, 173, 161,159, 150, 143, 131, 122, 107,94, 79, 78, 77, 63, 51; UV-Vis: 215.3, 239.1, 297.4 nm.
2.1 g
at 20℃; for 1 h; Inert atmosphere
Compound 8 (iso-vanillin, 3 g, 19.7 mmol) was dissolved in 20 ml of glacial acetic acid under argon and sodium acetate was added.(3.2 g, 39.4 mmol), reduced iron powder (110 mg, 1.96 mmol).After bromine (1.1ml, 21.1mmol) of glacial acetic acidThe (5 ml) solution was gradually added to the above reaction solution, and stirred vigorously at room temperature for 1 hour.. The reaction was monitored by TLC until compound 8 was completely reacted.The reaction mixture was poured into 150 ml of ice water and washed, and then filtered to give a colorless crystals.After recrystallization from ethanol, 2.1 g of light brown needle-like crystalline solid compound 7 was obtained.The next reaction can also be carried out without further purification.
81.9 g
With N-Bromosuccinimide In 1,4-dioxane; water at 20℃; for 3 h;
Dissolving isocoumarin X (60.86 g, 400 mmol), NBS (74.76 g) in dioxane/water (500 ml/200 ml) in, then stirring the reaction mixture at room temperature for 3 hours, TLC shows the reaction is complete, the addition of water, filtered, the filter cake is dried under vacuum to obtain compound IXa (81.9 g).
Reference：
[1] Synthesis (Germany), 2018, vol. 50, # 5, p. 1053 - 1089
[2] Organic and Biomolecular Chemistry, 2018, vol. 16, # 42, p. 7851 - 7860
[3] Organic and Biomolecular Chemistry, 2007, vol. 5, # 9, p. 1466 - 1471
[4] Angewandte Chemie - International Edition, 2011, vol. 50, # 17, p. 3892 - 3894
[5] Synlett, 2000, # 8, p. 1163 - 1165
[6] Patent: CN105001107, 2016, B, . Location in patent: Paragraph 0039; 0040
[7] Medicinal Chemistry, 2011, vol. 7, # 4, p. 286 - 294
[8] Patent: WO2014/149793, 2014, A1, . Location in patent: Page/Page column 102; 132-133
[9] Patent: CN103980153, 2016, B, . Location in patent: Paragraph 0048; 0054; 0055
[10] European Journal of Medicinal Chemistry, 2010, vol. 45, # 7, p. 2798 - 2805
[11] Chemistry of Natural Compounds, 2015, vol. 51, # 4, p. 620 - 625[12] Khim. Prir. Soedin., 2015, vol. 51, # 4, p. 536 - 540,5
[13] Synthesis, 2009, # 15, p. 2501 - 2504
[14] Journal of the American Chemical Society, 2009, vol. 131, # 44, p. 16045 - 16047
[15] Patent: WO2010/132570, 2010, A1, . Location in patent: Page/Page column 67-68
[16] European Journal of Organic Chemistry, 2018, vol. 2018, # 40, p. 5605 - 5614
[17] Chemical and Pharmaceutical Bulletin, 2017, vol. 65, # 11, p. 1078 - 1080
[18] Journal of the American Chemical Society, 2005, vol. 127, # 42, p. 14785 - 14803
[19] Patent: US6017919, 2000, A,
[20] European Journal of Organic Chemistry, 2017, vol. 2017, # 20, p. 2883 - 2915
[21] Journal of Organic Chemistry, 1983, vol. 48, # 14, p. 2356 - 2360
[22] Journal of Organic Chemistry, 1987, vol. 52, # 3, p. 473 - 475
[23] Organic Letters, 2010, vol. 12, # 23, p. 5546 - 5549
[24] Journal of Organic Chemistry, 1988, vol. 53, # 20, p. 4694 - 4708
[25] Organic and Biomolecular Chemistry, 2013, vol. 11, # 16, p. 2724 - 2727
[26] Canadian Journal of Chemistry, 2011, vol. 89, # 6, p. 709 - 728
[27] Tetrahedron Letters, 2008, vol. 49, # 36, p. 5309 - 5311
[28] Advanced Synthesis and Catalysis, 2014, vol. 356, # 2-3, p. 333 - 339
[29] Tetrahedron Letters, 2009, vol. 50, # 7, p. 831 - 833
[30] Tetrahedron Asymmetry, 2015, vol. 26, # 20, p. 1145 - 1149
[31] Journal of Heterocyclic Chemistry, 2008, vol. 45, # 3, p. 797 - 801
[32] Synlett, 2014, vol. 25, # 20, p. 2891 - 2894
[33] Synlett, 2006, # 18, p. 2977 - 2980
[34] Tetrahedron, 1995, vol. 51, # 18, p. 5341 - 5350
[35] Journal of Medicinal Chemistry, 1986, vol. 29, # 11, p. 2315 - 2325
[36] Chemische Berichte, 1915, vol. 48, p. 2013
[37] Journal of the Chemical Society, 1965, p. 6914 - 6922
[38] Russian Journal of Organic Chemistry, 1993, vol. 29, # 11.2, p. 1868 - 1870[39] Zhurnal Organicheskoi Khimii, 1993, vol. 29, # 11, p. 2251 - 2254
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[41] Tetrahedron Letters, 1998, vol. 39, # 47, p. 8725 - 8728
[42] Patent: US4265889, 1981, A,
[43] Patent: US4165372, 1979, A,
[44] Patent: EP2070913, 2009, A1, . Location in patent: Page/Page column 16
[45] Patent: WO2004/37805, 2004, A1, . Location in patent: Page 54
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[48] Journal of Organic Chemistry, 2014, vol. 79, # 8, p. 3348 - 3357
[49] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 5, p. 1044 - 1054
[50] European Journal of Organic Chemistry, 2017, vol. 2017, # 17, p. 2512 - 2539
[51] Patent: CN108191878, 2018, A, . Location in patent: Paragraph 0025; 0026
[52] Patent: US4171359, 1979, A,
[53] Patent: CN108727190, 2018, A, . Location in patent: Paragraph 0016; 0118-0119
25
[ 621-59-0 ]
[ 2973-59-3 ]
[ 2973-58-2 ]
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[1] Journal of the Chemical Society, 1930, p. 2279,2287
[2] Journal of Organic Chemistry, 1940, vol. 5, p. 204,208
26
[ 621-59-0 ]
[ 7726-95-6 ]
[ 64-19-7 ]
[ 2973-59-3 ]
[ 2973-58-2 ]
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[1] Journal of the Chemical Society, 1930, p. 2279,2287
[2] Journal of Organic Chemistry, 1940, vol. 5, p. 204,208
27
[ 621-59-0 ]
[ 141-82-2 ]
[ 537-73-5 ]
Yield
Reaction Conditions
Operation in experiment
85%
With N,N-dimethyl acetamide; triethylamine; N,N-dimethyl-formamide In toluene for 4 h; Reflux
To a suspension of isovanillin (1) (152 mg, 1.00 mmol) and malonic acid (416 mg, 4.00 mmol) in toluene (5 mL) were added Et3N (0.70 mL, 5.00 mmol) and DMF-DMA (0.20 mL, 1.50 mmol). The resulting mixture was heated at reflux for 4 h, then allowed to cool to room temperature, and concentrated on a rotary evaporator. The residue was dissolved in 1 M NaOH solution (20 mL), and the resulting solution washed with CH2Cl2 (3 .x. 20 mL). The aqueous phase was then acidified to pH 1 by addition of 3 M HCl. The creamy precipitate was collected in a Hirsch funnel, washed with dilute HCl and allowed to air dry. The precipitate was then recrystallised (MeOH-H2O) and dried in a vacuum desiccator over P2O5 to afford trans-isoferulic acid (164 mg, 85percent) as a cream-coloured crystalline solid. The 1H NMR data were consistent with the literature (McCorkindale, N. J.; McCulloch, A. W.; Magrill, D. S.; Caddy, B.; Martin-Smith, M.; Smith, S. J.; Stenlake, J. B. Tetrahedron1969, 25, 5475).
77.2%
for 4 h; Reflux; Inert atmosphere
To a solution of isovanillin (1) (22.81g, 150mmol) and malonic acid (62.44g, 600mmol) in pyridine (150mL) was added 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU, 34.26g). The stirred reaction solution was heated at reflux for 4h, then cooled to room temperature. The cooled reaction mixture was poured into a solution (500mL) of concentrated HCl and ice (v/v=1:1) and the resulting precipitate was filtered and washed with acidified water to give a crude product. The crude product was dissolved in aqueous NaOH (1M, 200mL) and extracted with CH2Cl2) (3×50mL). The aqueous solution was acidified to pH=1 and the resultant precipitate washed with acidified water to afford 22.56g (77.2percent) of isoferulic acid as white solid. Mp: 228–230°C.
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[1] Synthetic Communications, 1995, vol. 25, # 20, p. 3187 - 3197
[2] Chemical Communications, 1998, # 21, p. 2335 - 2336
[3] Tetrahedron, 2007, vol. 63, # 4, p. 960 - 965
[4] Tetrahedron Letters, 2012, vol. 53, # 20, p. 2537 - 2539
[5] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 9, p. 2707 - 2713
[6] Journal of Agricultural and Food Chemistry, 2005, vol. 53, # 5, p. 1782 - 1790
[7] Journal of the Chemical Society, 1931, p. 3163,3168[8] Journal of the Chemical Society, 1933, p. 280
[9] Justus Liebigs Annalen der Chemie, 1932, vol. 497, p. 47,52
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[13] Patent: WO2007/71348, 2007, A1, . Location in patent: Page/Page column 246
[14] MedChemComm, 2014, vol. 5, # 6, p. 711 - 718
[15] European Journal of Medicinal Chemistry, 2018, vol. 143, p. 361 - 375
Step 114.2 g Isovanillin , 1 5 g sodium formate in 75 mL formic acid was stirred at 85°C. 9 gHydroxylamine hydrochloride was added in portions and the mixture stirred for 4 h at 85°C.The mixture was poured on to an almost saturated sodium chloride solution and the precipitate was isolated, washed with water and petroleum ether and dried.Yield: 14.2 g (93percent of theory)Analysis: HPLC-MS (method D): Rt: 1 .18 min
93%
at 85℃; for 4 h;
14.2 g Isovanillin, 15 g sodium formate in 75 mL formic acid was stirred at 85° C. 9 g Hydroxylamine hydrochloride was added in portions and the mixture stirred for 4 h at 85° C. The mixture was poured on to an almost saturated sodium chloride solution and the precipitate was isolated, washed with water and petroleum ether and dried.Yield: 14.2 g (93percent of theory)Analysis: HPLC-MS (method D): Rt: 1.18 min
92%
With hydroxylamine hydrochloride; sodium formate In formic acid at 85℃; for 5 h;
In a 100 ml flask in three, sequentially adding a 3-hydroxy-4-methoxybenzaldehyde 10.04g (65.99mmol), formic acid 45 ml, sodium formate 13.75g (132.16mmol), heating and stirring to 85 °C, have all been soluble in formic acid in the reactant. In 85 °C lower, adding 6.12g (88.07mmol) of hydroxylamine hydrochloride, TLC monitoring reaction, 5h end of after-reaction. Stop heating, cooling to room temperature, the reaction solution by adding 200 ml saturated salt water, stirring 30 min; filtered, washing the solid with water to neutral, drying to obtain white solid 9.04g, the yield is 92percent
92%
at 85℃; for 5 h; Industrial scale
In a 100 mL three-necked flask, 10.04 g (65.9 mmol) of 3-hydroxy-4-methoxybenzaldehyde, 45 mL of formic acid and 13.75 g (132.1 mmol) of sodium formate were successively added, and the mixture was heated to 85 ° C with stirring. Formic acid. At 85 ° C, 6.12 g (88.1 mmol) of hydroxylamine hydrochloride was added and the reaction was monitored by TLC and the reaction was complete after 5 h. The reaction mixture was cooled to room temperature, and the reaction solution was poured into 200 mL of saturated brine and stirred for 30 minutes. The solid was suction filtered, washed with water until neutral, and dried to obtain 9.04 g of a white solid in a yield of 92percent
92%
at 85℃; for 5 h;
A mixture of 3-hydroxy-4-methoxybenzaldehyde (2.0 g,13.4 mmol), sodium formate (1.8 g, 26.3 mmol), and formic acid (9.6 mL) was heated to 85 °C.Hydroxylamine sulfate (1.3 g, 7.9 mmol) was added to the above mixture in six equal portionsat 30 min intervals, and the mixture was stirred for 5 h. The reaction was cooled to room temperatureand poured to a solution of sodium chloride (8.0 g) in water (40 mL). The resultant solid was collectedby filtration, washed with water, and dried to give an off-white solid 2 (1.8 g, 92percent). IR νmax (KBr)cm-1: 3311, 3071, 2938, 2231, 1611, 1578, 1511, 1451, 1337, 1284, 1252, 1128, 1020, 952, 860, 810, 610.
89.7%
at 85℃; for 7 h;
10.0g (65.8 mmol) of 3-hydroxy-4-methoxybenzaldehyde(Compound 1),15 mL (362 mmol) of formic acid, 4.5 g (65.8 mmol)sodium formate was placed in a 100 mL three-necked flask. The temperature is raised to 85°C with stirring. Slowly hydroxylamine sulfate 22.9g (329mmol)The reaction system was added to the reaction system within two hours. After the addition, the reaction was continued at this temperature for 5 hours.Then stop heating, cool to room temperature, add 25mL of distilled water to the reaction flask, stir for 1 hour,It is filtered with suction, washed with 20 mL of ice water and dried.8.8 g (89.7percent) of a powdery solid was obtained.
88%
at 85℃;
3-Hydroxy-4-methoxybenzaldehyde (10.00 g, 65.72 mmol), sodium formate (8.94 g, 131.44 mmol), and formic acid (50 mL) was heated to 85 °C. To this mixture hydroxylamine sulfate (6.47 g, 39.42 mmol) was added in six equal portions at 30 min intervals, and the mixture was heated at 85 C for 5 h. The reaction was cooled to room temperature and poured to a solution of sodium chloride (40 g) in water (200 mL). The resultant solid was collected by filtration, washed with water, and dried to give an off-white solid 2 (8.60 g, 88percent). 1H NMR (300 MHz, DMSO-d6, δ): 9.77 (s, 1H), 7.24 (dd, J = 2.2, 8.1 Hz, 1H), 7.00–7.13 (m, 2H), 3.83 (s, 3H).
85%
at 85℃;
Isovanillin 9 (12.4 g, 81.5 mmol), sodium formate (13.3 g, 195.6 mmol), and formic acid(65.0 mL) was heated to 85 °C. To this mixture hydroxylamine hydrochloride (7.9 g, 114.1mmol) was added portion wise for 30 min, and the mixture was heated at 85 °C for overnight.The reaction was cooled to room temperature and poured to saturated aq. NaCl solution (300mL). The resultant solid was collected by filtration, washed with water. The residue was thendissolved in ether, dried over MgSO4, concentrated in rotavapor and dried in high vacuum togive desired product 10 as an off-white solid. Yield: 10.3 g, 85percent.
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33
[ 621-59-0 ]
[ 141-53-7 ]
[ 52805-46-6 ]
Yield
Reaction Conditions
Operation in experiment
94%
Stage #1: at 85℃; Stage #2: With hydroxyammonium sulfate In formic acid at 85℃; for 5 h;
The 3-hydroxy-4-methoxybenzonitrile solution used as a starting material was obtained as follows:- 3-Hydroxy-4-methoxybenzaldehyde (36.7 kg) and sodium formate (30.6 kg) were added to formic acid (96percent, 204 kg) and the resultant mixture was heated to approximately [85°C.] Hydroxylamine sulphate (21.6 kg) was added in eight equal portions at 30 minute intervals and the mixture was heated to [85°C] for 5 hours. The resultant mixture was cooled to approximately [25°C] and added to a solution of sodium chloride (140 kg) in water (700 litres). The resultant solid was collected by filtration, washed with water and dried to give 3-hydroxy- 4-methoxybenzonitrile (34 kg, 94percent; Chemical Abstracts Registry Number 52805-46-6).
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39
[ 621-59-0 ]
[ 138490-96-7 ]
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[2] Journal of Medicinal Chemistry, 1992, vol. 35, # 3, p. 466 - 479
40
[ 621-59-0 ]
[ 85416-73-5 ]
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[2] Tetrahedron Letters, 2017, vol. 58, # 46, p. 4333 - 4335
41
[ 621-59-0 ]
[ 5911-08-0 ]
[ 153200-64-7 ]
Reference：
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42
[ 621-59-0 ]
[ 2516-33-8 ]
[ 1972-28-7 ]
[ 153200-64-7 ]
Reference：
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43
[ 621-59-0 ]
[ 172900-69-5 ]
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[3] Organic Process Research and Development, 2013, vol. 17, # 11, p. 1458 - 1462
44
[ 621-59-0 ]
[ 286371-64-0 ]
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45
[ 621-59-0 ]
[ 675126-27-9 ]
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[ 621-59-0 ]
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[ 621-59-0 ]
[ 912556-91-3 ]
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48
[ 621-59-0 ]
[ 164161-49-3 ]
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With N,N-dimethyl acetamide; triethylamine; N,N-dimethyl-formamide; In toluene; for 4h;Reflux;
To a suspension of isovanillin (1) (152 mg, 1.00 mmol) and malonic acid (416 mg, 4.00 mmol) in toluene (5 mL) were added Et3N (0.70 mL, 5.00 mmol) and DMF-DMA (0.20 mL, 1.50 mmol). The resulting mixture was heated at reflux for 4 h, then allowed to cool to room temperature, and concentrated on a rotary evaporator. The residue was dissolved in 1 M NaOH solution (20 mL), and the resulting solution washed with CH2Cl2 (3 × 20 mL). The aqueous phase was then acidified to pH 1 by addition of 3 M HCl. The creamy precipitate was collected in a Hirsch funnel, washed with dilute HCl and allowed to air dry. The precipitate was then recrystallised (MeOH-H2O) and dried in a vacuum desiccator over P2O5 to afford trans-isoferulic acid (164 mg, 85%) as a cream-coloured crystalline solid. The 1H NMR data were consistent with the literature (McCorkindale, N. J.; McCulloch, A. W.; Magrill, D. S.; Caddy, B.; Martin-Smith, M.; Smith, S. J.; Stenlake, J. B. Tetrahedron1969, 25, 5475).
77.2%
With pyridine; 1,8-diazabicyclo[5.4.0]undec-7-ene; for 4h;Reflux; Inert atmosphere;
To a solution of isovanillin (1) (22.81g, 150mmol) and malonic acid (62.44g, 600mmol) in pyridine (150mL) was added 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU, 34.26g). The stirred reaction solution was heated at reflux for 4h, then cooled to room temperature. The cooled reaction mixture was poured into a solution (500mL) of concentrated HCl and ice (v/v=1:1) and the resulting precipitate was filtered and washed with acidified water to give a crude product. The crude product was dissolved in aqueous NaOH (1M, 200mL) and extracted with CH2Cl2) (3×50mL). The aqueous solution was acidified to pH=1 and the resultant precipitate washed with acidified water to afford 22.56g (77.2%) of isoferulic acid as white solid. Mp: 228-230C.
58%
With piperidine; pyridine; at 120℃; for 4h;
General procedure: To a solution of the substituted benzaldehyde (1 eq.) and malonate(1.2 eq.) in pyridine (2.5 mL/mmol) at 120 C piperidine (0.04 eq.) wasadded, and the reaction mixture was heated under reflux for 4 h [31].The solvents were removed in vacuo as an azeotrope with toluene(3×70 mL). Water (100 mL) was added, and the aqueous phase wasextracted with ethyl acetate (3×100 mL), brine (1×100 mL), dried(MgSO4) and concentrated. Compounds 1a and 1c-1m were preparedfollowing procedure A.
The mixture of 3-hydroxy-4-methoxy-benzaldehyde(30g) and malonic acid(42g ) in pyridine(80ml) and piperidine (4ml) was heated at 120 0C for 6 hours. The solution was cooled to room temperature and concentrated to 20ml. The residue was dissolved in 500ml of water and the solution was acidified with concentrated HCl until PH =3. The solid was collected to give 3-(3-Hydroxy-4- methoxy-phenyl) -acrylic acid (4Og). LC-MS: m/e 195 (MH+)
With pyridine; at 90℃;
General procedure: 7a-u were prepared by Knoevenagel condensation [45]. Briefly, 5mmol of different aldehydes (6a-u) and 10mmol malonic acid (1.04g) were stirred at 90C in 2mL pyridine solvent overnight. When the reaction was finished as monitored by TLC, 3M HCl was slowly dropped into the mixture until precipitation was complete. The formed precipitate was collected by filtration, washed with cold water and dried in vacuum, yielding compounds 7a-u. Intermediates 7c and 7d (1mmol) was further reacted with different substituted benzyl bromides (2.5mmol) in CH3CN with the presence of K2CO3 (2.0 equiv), followed by hydrolysis in 1M NaOH for 1h to give intermediates 7v-z, which were used in the next step without further purification.
With sodium tetrahydroborate; ethanol; at 20℃; for 0.5h;
In a round-bottom flask equipped with magnetic stirrer was added 15 sodium borohydride (0.2mmol; 0.01g) to the solution of 9 1 (0.2mmol; 0.03g) prepared in ethanol (1mL). The mixture was stirred at room temperature for 30min. The consumption of all starting material was detected by thin layer chromatography (TLC); the solvent was evaporated under reduced pressure. Subsequently, 10mL of saturated NaCl solution was added and then extracted with ethyl acetate (3×10mL). The organic phase was dried over anhydrous MgSO4, filtered and evaporated, providing 0.03g of colorless oil, 90% yield of 2
With sulfuryl dichloride; In acetic acid; at 0 - 2℃; for 2.0h;
Neat sulfuryl chloride (14.85 g, 110mmol, 1.1 eq.) was added dropwise over 5 minutes to a solution of isovanillin (15.00 g, 100 mmol, 1 eq)in 120 mL of glacial acetic acid in an ice-water bath. After 2 hours of stirring with ice-water bath cooling,the reaction was filtered, washed with cold acetic acid, and dried under vacuum to afford 14.16 g ofwhite solid. HPLC and 1H-NMR indicate indicated the presence of unreacted isovanillin. This solid wasdissolved in boiling ethanol and recrystallized to yield 11.91 g (80%) of fluffy white needles (mp = 200.0- 209.9 C). 1H-NMR indicated <1% isovanillin after one recrystallization. 1H NMR (300 MHz, CDCl3): 10.19 (s, 1H, CHO), 9.83 (d, J = 31.4 Hz, 1H, OH), 7.41 (d, J = 8.6 Hz, 1H, ArH), 7.12 (d, J = 8.6 Hz, 1H, ArH),3.93 (s, 3H, OCH3); 1H-NMR (300 MHz, DMSO-d6): 10.19 (s, 1H, CHO), 9.89 (s, 1H, OH), 7.42 (d, J = 8.6Hz, 1H, Ar-H), 7.12 (d, J = 8.6 Hz, 1H, Ar-H), 3.93 (s, 3H, OMe); EI-MS m/z: 187 (M+2), 185 (M+, 100%),171, 157, 143, 129, 115, 107, 99, 79, 65, 51. UV-Vis: 215.3, 237.2, 283.8 nm.
69%
With tert-butylhypochlorite; In acetic acid;
Step 1 Synthesis of 2-chloro-3-hydroxy-4-methoxybenzaldehyde 41.2 g (0.271 mol) of isovanillin was dissolved in 160 ml of 90% AcOH under heating. 29.41 g of t-BuOCl was added dropwise to the solution while it was kept at 35 to 40 C. The solution was stirred at room temperature for 3 hours and then 200 ml of ether was added thereto. The mixture was left to stand overnight and crystals thus formed were separated by filtration and washed with ether. 42.0 g of the crude crystals were recrystallized from acetonitrile to obtain 35 g of 2-chloro-3-hydroxy-4-methoxybenzaldehyde (69%). mp 203~205 C. NMR (90 MHz, DMSO-d6) delta:3.94 (3H, s), 7.10 (1H, d), 7.42 (1H, d), 9.84 (1H, s), 10.16 (1H, s)
15.9 g (85 mmol, 26%)
With chlorine;
Step 1--Formation of 2-Chloro-3-hydroxy-4-methoxybenzaldehyde Chlorine gas was bubbled through a solution of 50 g (0.33 mol) of isovanillin until a thick yellow precipitate formed. This precipitate was collected by vacuum filtration and the solids recrystallized from methanol to give 15.9 g (85 mmol, 26%) of a white solid shown to be desired product by 1 H NMR.
General procedure: 3-Hydroxy-4-methoxybenzaldehyde 1 (0.01 mol) was refluxedwith acetic anhydride (20 mL) for 0.5 h. After pure EtOH (100 mL),themixturewas refluxed for 0.5 h. After evaporation of the resulting solutionat 40-45 C, several recrystallizations of the residue from EtOHgave pure compound 2 (3-acetoxy-4-methoxybenzaldehyde) [20]. 2-Aminothiophenol (0.01 mol) was dissolved in acetic acid (20 mL) andtreated with compound 2 (0.01 mol). The mixture was refluxed for2 h and then evaporated at 50-55 C. After recrystallization, the compound4 (AMT) was obtained (Scheme 1).
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; copper diacetate; In water; acetonitrile; at 20℃; for 3h;Green chemistry;
General procedure: A mixture of alcohol (5.0 mmol), Cu(OAc)2 (9.1 mg, 0.05 mmol), and TEMPO (7.8 mg, 0.05 mmol) in CH3CN/H2O (5/10 mL) was stirred at room temperature for specified time. After completion of the reaction (monitored by TLC, eluents: petroleum ether/ethyl acetate = 4/1), dichloromethane (10 mL) was added to the resulting mixture. The dichloromethane phase was separated, and the aqueous phase was further extracted with dichloromethane (10 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give a residue, which was purified by column chromatography (eluents: petroleum ether/ethyl acetate = 10/1) to provide the desired product.
84.2%
With 2,2,6,6-tetramethyl-piperidine-N-oxyl; oxygen; potassium carbonate; In water; at 50℃; for 24h;Catalytic behavior;
General procedure: In a typical experiment, 2.0 mL of solvent, 31 mg of CuO-REC, 0.1 mmol of TEMPO, 0.1 mmol of K2CO3and 2.0 mmol of alcohol were mixed in a flask with a magnetic stirrer. The mixture was stirred at 50 C for 24 h in oxygen atmosphere and then extracted with ethyl acetate three times (10 mL × 3). The combined organic layer was concentrated and applied to a silica gel (200-300 mesh) column to separate the product.
With potassium carbonate; In N,N-dimethyl-formamide; at 85 - 90℃; for 20h;
MOECl 16 (4.1 mL, 44.7 mmol) was added to a slurry of compound 9 (4.0 g, 26.3 mmol)and potassium carbonate (6.5 g, 47.3 mmol) in DMF (30 mL). The reaction mixture was stirredat 85-90 C for 20 h, cooled to room temperature, filtered via Buechner funnel and the residuewashed with EtOAc. The EtOAc filtrate washed with 2N NaOH, water, brine, and dried(MgSO4), concentrated to get desired product as yellow oil. Yield: 5.3 g, 97%.
97%
With potassium carbonate; In N,N-dimethyl-formamide; at 85 - 90℃; for 20h;
Compound 5 (4.1 mL, 44.7 mmol) was added to and mixed with a first mixture including isovanillin (4.0 g, 26.3 mmol), potassium carbonate (6.5 g, 47.3 mmol), and dimethylformamide (DMF, 30 mL) to obtain a second mixture. The second mixture was then stirred at a temperature ranging from 85 C. to 90 C. for 20 hours, cooled to room temperature, and filtered via Buechner funnel, and the residue was washed with EtOAc. The EtOAc filtrate was washed with a sodium hydroxide aqueous solution (2N), water, and brine, and then dried over MgSO4, and concentrated to obtain a yellow oil (5.3 g, 97% yield). The spectrum analysis for the yellow oil obtained by the above procedures is: 1H NMR (400 MHz, CDCl3), delta (ppm): 9.83 (s, 1H), 7.47-7.42 (m, 2H), 6.97-6.95 (d, J=8.2 Hz, 1H), 4.23-4.21 (m, 2H), 3.93 (s, 3H), 3.81-3.79 (m, 2H), 3.44 (s, 3H); 13C NMR (100.6 MHz, CDCl3), delta (ppm): 190.7, 154.9, 148.8, 129.9, 126.8, 110.8, 110.7, 70.6, 68.2, 59.0, 56.0; LRMS-EI+ (m/z): 211 ([M+H]+, 13), 210 ([M]+, 100), 152(67), 123(4), 95(3), 77 (5), 59 (67); HRMS-TOF-ES+ (m/z): [M+H]+ calculated for C11H15O4, 211.0970, found: 211.0971. The yellow oil obtained was confirmed to be Compound 6 (4-methoxy-3-(2-methoxyethoxy)benzaldehyde).
With potassium carbonate;potassium iodide; In N,N-dimethyl-formamide; at 85℃;
To a solution of 3-hydroxy-4-methoxy-benzaldehyde (10 g, 65.73 mmol) (Aldrich) in DMF (100 mL), 1-chloro-2-methoxy-ethane (6.83 g, 6.6 mL, 72.30 mmol) (Aldrich) was added, followed by K2CO3 (31.80 g, 230 mmol), potassium iodide (1 g) (Aldrich), and heated at 85 C. overnight. The reaction was diluted with EtOAc (600 mL), washed with water (2*500 mL), brine, and dried with anhydrous sodium sulfate. Concentration gave 4-methoxy-3-(2-methoxy-ethoxy)-benzaldehyde as an oil which was used in next step without purification. (Yield 14.5 g). 1H NMR (CDCl3): delta 9.84 (s, 1H), 7.46 (m, 1H), 7.42 (s, 1H), 6.97 (m, 1H), 4.23 (m, 2H), 3.94 (s, 3H), 3.82 (m, 2H), 3.45 (s, 3H).
11 g
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃;
Preparation of 4-methoxy-3-(2-methoxyethoxy)benzaldehyde To a solution of 3-hydroxy-4-methoxybenzaldehyde (8.0 g) in DMF (60 mL) was added K2CO3 (8.0 g) and 1-chloro-2-methoxyethane (5.1 g). The resulting mixture was stirred at 80 C. overnight. After reaction finished, ethyl acetate (200 ml) was added, and washed with 2 N aqueous HCl solution, brine, dried over Na2SO4, filtered, concentrated. The residue was washed with petrol ether to give 4-methoxy-3-(2-methoxyethoxy)benzaldehyde (11 g) as a yellow solid. 1H-NMR (400 MHz, CDCl3): delta: 9.84 (s, 1H); 7.49-7.43 (m, 2H); 6.98 (d, J=8.0, 1 H); 4.25-4.22 (m, 2H); 3.95 (s, 3H); 3.83-3.81 (m, 2H); 3.46 (s, 3H).
Step 1. Preparation of 2-chloro-3-hydroxy-4-methoxybenzaldehyde Chlorine gas is introduced into a solution of 3-hydroxy-4-methoxybenzaldehyde in N,N-dimethylformamide at -10° to -30° C. When the addition of chlorine is complete, the reaction mixture is stirred at -25° C. for 30 minutes and, then, poured into water. The product is separated by filtration and washed with water. The wet product may be dried or used directly in the next step. Average yield, 73percent. Step 2. Preparation of 2-chloro-3,4-dimethoxybenzaldehyde (1)
With chlorine; potassium carbonate; dimethyl sulfate; In N-methyl-acetamide; chloroform; water;
EXAMPLE 2 Isovanillin (200 g, 1.32 mole) was suspended in 1200 cc chloroform. Chlorine (103 g, 1.45 mole) was added by means of 3 500 cc portions of carbon tetrachloride, in which it was dissolved. The suspension was stirred vigorously during the addition and the reaction was kept around 25° by a water bath. The suspension was stirred for 22 minutes after the completion of the addition of chlorine. The precipitate was filtered and crystallized from methanol, then recrystallized from isopropanol/ethyl acetate. Yield 98.7 g (40percent, m.p. 204°-206°) of 2-chloro-3-hydroxy-4-methoxybenzaldehyde. The aldehyde product (189.3 g, 1.02 mole) was suspended in 1 l. of dry dimethylformamide, 350 g of potassium carbonate was added. 145 cc (124 g, 1.54 mole) of dimethyl sulfate was added dropwise over a 20 minute period. After the addition the reaction was heated on the steam bath for 5 minutes. 70 cc of water were added and the reaction was again heated for 5 minutes on the steam bath. The mixture was then poured into ice water and the precipitate was collected. It was crystallized from acetic acid/water (800 cc-50 cc). A second crop was obtained from the mother liquor. Yield 180 g (90percent) of 2-chloro-3,4-dimethoxybenzaldehyde after drying, m.p. 69°-70°.
With chlorine; potassium carbonate; dimethyl sulfate; In N-methyl-acetamide; chloroform; water;
EXAMPLE 1 Isovanillin (200 g, 1.32 mole) was suspended in 1200 cc chloroform. Chlorine (103 g, 1.45 mole) was added by means of 3 500 cc portions of carbon tetrachloride, in which it was dissolved. The suspension was stirred vigorously during the addition and the reaction was kept around 25° by a water bath. The suspension was stirred for 22 minutes after the completion of the addition of chlorine. The precipitate was filtered and crystallized from methanol, then recrystallized from isopropanol/ethyl acetate. Yield 98.7 g (40percent, m.p. 204-206°) of 2-chloro-3-hydroxy-4-methoxybenzaldehyde. The aldehyde product (189.3 g, 1.02 mole) was suspended in 1 l. of dry dimethylformamide, 350 g of potassium carbonate was added. 145 cc (124 g, 1.54 mole) of dimethyl sulfate was added dropwise over a 20 minute period. After the addition the reaction was heated on the steam bath for 5 minutes. 70 cc of water were added and the reaction was again heated for 5 minutes on the steam bath. The mixture was then poured into ice water and the precipitate was collected. It was crystallized from acetic acid/water (800 cc-50 cc). A second crop was obtained from the mother liquor. Yield 180 g (90percent) of 2-chloro-3,4-dimethoxybenzaldehyde after drying, m.p. 69°-70°.
With potassium fluoride; In dimethyl sulfoxide; at 120℃; for 12h;
Step 2: Methyl-3-Bromo-4-(5-formyl-2-methoxyphenoxy) benzoate; Isovaniline (10 g, 65.78 mmoles) was dissolved in 50 ml DMSO. To this solution was added Methyl-(4-fluoro-3-Bromo) benzoate (22.98 g, 98.68 mmoles) followed by potassium fluoride (5.73 g, 98.68 mmoles) and heated at 12O0C for 12h. Reaction mass was poured in water (500 ml) and extracted with dichloromethane (100 x 3 ml) , dried and concentrated to get brown solid which was purified by silica gel column chromatography ( solvent -10 % ethyl acetate and petroleum ether) to yield white solid ( 16.5 g) . mp: 960C 1H nmr (300 MHz, DMSO-d6): delta 3.84 (s, 3H), 3.87(s, 3H), 6.79 (d, IH, J= 8.4 Hz), 7.46 (d, IH, J= 8.7Hz), 7.62 (s, IH), 7.85-7.90 (m, 2H), 8.20 (s, IH), 9.88 (s, IH). IR (KBr) cm-1: 3006, 2951, 2845, 2606, 1707, 1682, 1605, 1507, 1429, 1283, 1255, 1116, 1019, 975, 766.
4-Methoxy-3-[2-[4-(trifluoromethyl)phenyl]ethoxy]benzaldehyde Under an argon atmosphere, stirring and cooling with ice, diethyl azodicarboxylate (40% toluene solution, 3.80 mL, 8.38 mmol) was added dropwise to a solution of 2-[4-(trifluoromethyl)phenyl]ethanol (1.59 g, 8.36 mmol), isovanillin (1.28 g, 8.41 mmol) and triphenylphosphine (2.20 g, 8.39 mmol) in anhydrous tetrahydrofuran (50 mL). After completion of the dropwise addition, the mixture was stirred for 1 hour under cooling with ice, and then allowed to stand overnight at room temperature. The reaction mixture was concentrated and the residue was purified by silica gel column chro-matography (eluent: n-hexane:ethyl acetate=6:1 v/v) to afford 1.96 g (72%) of the title compound as colorless crystals. Mass analysis m/z 324 (M+).
With triphenylphosphine; In tetrahydrofuran; isopropyl alcohol;
a) A mixture of <strong>[41598-71-4]6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol</strong> (0.03544 mol), 3-hydroxy-4-methoxybenzaldehyde (0.0322 mol) and triphenylphosphine (0.0322 mol) in THF (100 ml) was stirred at 5 C. under N2 atmosphere. Bis(1-methylethyl) diazenedicarboxylate (0.0322 mol) was added dropwise and the resulting reaction mixture was stirred for 12 hours at RT. The solvent was evaporated. CH2 Cl2 was added to the residue. The mixture was washed with water, dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2 Cl2 /CH3 OH from 100/0 to 98.5/1.5). The desired fractions were collected and the solvent was evaporated. The residue was dissolved in 2-propanol and converted into the hydrochloric acid salt (1:1) with HCl/2-propanol. The solvent was evaporated. The residue was stirred in DIPE, filtered off and dried, yielding 8.2 g (83%) of 3-[(5,6-dihydro-7H-pyrindin-7-yl)oxy]-4-methoxybenzaldehyde hydrochloride (intermediate 34).
3-(bicyclo-[2.2.2]oct-2-yloxy)-4-Methoxybenzaldehyde Bicyclo[2.2.2]-2-octanol (5.00 g, 40 mmol), isovanillin (6.09 g, 40 mmol) and triphenylphosphine (13.1 g, 50 mmol) are dissolved in dry tetrahydrofuran. To this reaction mixture is added dropwise diethylazodicarboxylate (8.71 g, 50 mmol). The reaction is stirred for 1 hour at room temperature and is refluxed for 80 hours. The reaction mixture was cooled and concentrated in vacuo and the residue is mashed 3*150 ml of ether to remove the desired material from the triphenylphosphine oxide. The combined ethereal layers are washed with 2*100 ml H2 O, 2*100 ml 2N NaOH solution, 2*100 ml H2 O and 2*100 ml brine. The organics are dried, filtered and concentrated in vacuo. The compound is purified by flash silica gel (32-80 mesh) chromatography with 20% ethyl acetate/hexane. The appropriate fractions are concentrated in vacuo to yield 3.32 g (32%) of product as a viscous oil. 1 H NMR (250 MHz, CDCl3): delta 7.4 (dd, 1H, J=8.5 Hz, J=1.5 Hz), 7.35 (d, 1H, J=1.5 Hz), 6.95 (d, 1H, J=8.5 Hz), 4.52 (m, 1H), 3.91 (s, 3H), 2.2-1.3 (m, 12H). 13 C NMR (63 MHz, CDCl3): delta 190.9, 155.7, 147.9, 129.97, 126.2, 112.6, 110.9, 77.5, 56.1, 34.74, 28.18, 25.25, 24.55, 23.29, 22.78, 19.09 (16 lines).
In N-methyl-acetamide; tetrachloromethane; ethanol; acetonitrile;
EXAMPLE 1 Chlorine (25.6 g, 0.362 mole) was bubbled into a slurry of isovanillin (50.0 g, 0.328 mole) in 500 ml of carbon tetrachloride over a period of 25 minutes while maintaining an internal temperature of 15°-20°. Upon completion of the chlorine addition the slurry was stirred for 1 hour at room temperature; the precipitate filtered, washed with carbon tetrachloride and dried to 57.8 g (94.5percent crude yield), mp: 181°-196°. Recrystallization of 34.5 g of the crude produce from 600 ml of ethanol gave 17.3 g of white fibrous crystals, mp: 199°-203°; concentrating the mother liquors yielded a second crop of 6.3 g, mp: 196-202.5 (68percent recovery for two crops). Recrystallization of 11.4 g of crude <strong>[37687-57-3]2-chloroisovanillin</strong> from 170 ml of acetonitrile afforded 7.4 g, mp: 200°-204.5° (65percent recovery for one crop). This compound (189.3 g) was methylated using dimethylformamide solution with potassium carbonate and dimethylsulfate to give 2-chloro-3,4-dimethoxybenzaldehyde, m.p. 69°-70°.
With hydrogenchloride; In 2-methoxy-ethanol; water; at 80℃; for 96h;
Example 2: 3-[l-(3-Hydroxy-4-methoxy-phenyl)-meth-(E)-ylidene]-6-methyl- chroman-4-oneA 20 X 200 mm test tube was loaded with <strong>[39513-75-2]6-methylchroman-4-one</strong>, 4.7 g, then 2-methoxyethanol, 6 ml, then 3-hydroxy-4-methoxybenzaldehyde. The mixture was treated with concentrated hydrochloric acid, 0.1 ml, and warmed to 80 C. After 4 days the solid orange mass was washed into a 500 ml Erlenmeyer flask and suspended in 95% ethanol, 200 ml. The mix was warmed to reflux for 2 hours, dissolving all the solids. The hot solution was treated slowly with water, and at 60 ml a precipitate <n="35"/>began to form. The suspension was vigorously stirred and allowed to cool to room temperature for two hours. The yellow solids were collected by filtration, washed with 2 X 25 ml of 1 : 1 95% ethano I/water. The solids were air dried to provide 3-[l- (3-Hydroxy-4-methoxy-phenyl)-meth-(E)-ylidene]-<strong>[39513-75-2]6-methyl-chroman-4-one</strong>, 6.73 g, mp 160.3-161.3 0C.1H NMR (CDCl3, 500 MHz): 7.796(1H, d, J=2.1), 7.77(1H t, J=I.8), 7.28,(lH,dd, Jl=I.9, J2=8.4) , 6.92-6.90(2H ,m), 6.87-6.85(2H, m), 5.34(2H,d, J=I.9) 3.94(3H,s) , 2.33(3H, s)
With hydrogenchloride; In water; butan-1-ol; at 100℃; for 24h;Product distribution / selectivity;
Method A:A 20 X 200 mm test tube was loaded with <strong>[37674-72-9]6-chlorochroman-4-one</strong>, 1.00 g, and 3-hydroxy-4-methoxybenzaldehyde, 0.9 g, and a magnetic stirring bar. Then 4 ml of butanol was added, followed by 4 drops of concentrated hydrochloric acid. The mixture was warmed to 1000C for 24 hours, the tube full of solids was cooled to 220C. After standing three days at RT, 12 ml of ethano 1 was added, and the tube was warmed to 850C to dissolve the solids. The mix was then treated slowly with 4 ml of water, and cooled to 3O0C with stirring. The resulting solids were collected by filtration, washed with 4 ml of 1 :1 ethanol/water, and air dried to give 3-[l-(3- Hydroxy-4-methoxy-phenyl)-meth-(E)-ylidene]-<strong>[37674-72-9]6-chloro-chroman-4-one</strong>, 1.126 g, mp 155-156 C, elemental analysis C17H13C11O4 calc C 64.46%, H 4.14%, Found C 64.33%, H 4.32%.
With hydrogenchloride; In 2-methoxy-ethanol; water; at 100℃; for 18h;Product distribution / selectivity;
Method B:A 20 X 200 mm test tube was loaded with <strong>[37674-72-9]6-chlorochroman-4-one</strong>, 3.64 g, and 3-hydroxy-4-methoxybenzaldehyde, 3.04 g, and a magnetic stirring bar. Then 4 ml of methoxyethanol, followed by 0.1 ml of concentrated hydrochloric acid. The tube was then placed in a 1000C heat block, and heated with stirring for 18 hours. The mix was then cooled, and the resulting solids transferred to a 500 ml Erlenmeyer flask. The <n="36"/>solids were suspended wit 150 ml of ethanol, and warmed to reflux. Once all the solids had dissolved, 50 ml of water was slowly added, at which point solids began to separate from the hot solution. The mixture was stirred and allowed to cool. After 2 hours stirring at room temperature, the solids were collected by filtration, washed with 1 :1 ethanano I/water, 20 ml, and air dried to give of 3-[l-(3-Hydroxy-4-methoxy- phenyl)-meth-(E)-ylidene]-<strong>[37674-72-9]6-chloro-chroman-4-one</strong>, 4.6 grams, a red/orange solid, mp 156-157 0C.
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 140℃; for 5.25h;Inert atmosphere;
Intermediate 8: Preparation of 5-Cyano-5-(4-methoxy-8-trifluoromethyl- dibenzofuran-l-yl)-2-oxo-cyclohexanecarboxylic acid methyl esterStep-1: Preparation of 3-(2-Bromo-4-trifluoromethyl-phenoxy)-4-methoxy- benzaldehydeTo a stirred solution of Isovanillin (5 gm, 0.0328 moles) and Potassium carbonate (13.6 gm, 0.0985 moles) in dry DMF (20 ml) was added 3-Bromo-4- Fluorobenzotrifluoride (8.065 gm, 0.0331 moles) over a period of 15 min at room temperature under nitrogen atmosphere, and then above reaction mixture was stirred at 14O0C for 5 hrs. After completion of reaction, the reaction mixture was cooled to room temperature and the contents were poured in to water (100 ml) and extracted with ethyl acetate (3XlOOmI). The organic extracts were combined and washed with <n="41"/>IN sodium hydroxide, water and brine, dried with sodium sulfate, filtered and solvent evaporated under vacuum to obtain the title compound (11.58 gm, yield-94%) a pale yellow solid.1H NMR (300 MHz, CDCl3) delta 3.92 (s, 3H), 6.75 (d, J= 8.6 Hz, IH), 7.15 (d, J= 8.5 Hz, IH), 7.45 (d, J= 8.6 Hz, IH), 7.54 (d, J = 1.9 Hz, IH), 7.77 (dd, J=8.4 Hz, J=I.9Hz, IH,), 7.90 (s, IH), 9.87 (s, IH)MS (M++.): 376
With potassium carbonate; N,N-dimethyl-formamide; at 20 - 60℃;Inert atmosphere;
A mixture of A (5.0 g, 32.9 mmol) and <strong>[383-62-0]ethyl 2-chloro-2,2-difluoroacetate</strong> (5.7 g, 36.0 mmol), potassium carbonate (4.5 g. 32.9 mmol) in dry DMF (90 mL) were stirred at 600C for 6 hours under an N2 atmosphere. Then the reaction was stirred at rt. for another 60 hours. Ether (200 mL) was added to the mixture and the layers separated. The organic phase was washed with water (100 mL* 3), dried over Na2SO^, evaporated and purified on silica chromatography with eluent (EtOAc: PE = 1: 12) to afford B 2.3 g.
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 60℃; for 66h;Inert atmosphere;
35. Preparation of Compound 117; A to B; A mixture of A (5.0 g, 32.9 mmol) and <strong>[383-62-0]ethyl 2-chloro-2,2-difluoroacetate</strong> (5.7 g, 36.0 mmol), potassium carbonate (4.5 g, 32.9 mmol) in dry DMF (90 mL) were stirred at 60 C. for 6 hours under an N2 atmosphere. Then the reaction was stirred at rt. for another 60 hours. Ether (200 mL) was added to the mixture and the layers separated. The organic phase was washed with water (100 mL*3), dried over Na2SO4, evaporated and purified on silica chromatography with eluent (EtOAc: PE=1:12) to afford B 2.3 g.
With potassium carbonate; In acetonitrile; for 6h;Reflux;
Potassium carbonate (0.35 g, 2.6 mmol) was added to a solution (E)-methyl 2-(2-(bromomethyl)phenyl)-3-methoxyacrylate (0.5 g, 1.7 mmol) and 3-hydroxy-4-methoxybenzaldehyde (0.32 g, 2.1 mmol) in 20 mL of acetonitrile (CH3CN) which was then stirred for 6 hours under reflux. The reaction solvent was removed by vacuum concentration. The residue was stirred in water (20 mL), and the aqueous layer was extracted twice with 20 mL of dichloromethane. The organic was dried over anhydrous magnesium sulfate, filtered and concentrated in a vacuum to remove the solvent. Purification through silica gel chromatography afforded the title compound as a white oil (0.3 g, yield 49%). m/s [M+1]=357.10 1H NMR (300 MHz, CDCl3): delta 9.79 (s, 1H), 7.65 (s, 1H), 7.59-7.56 (m, 1H), 7.48-7.44 (dd, 1H), 7.35-7.30 (m, 3H). 7.21-7.18 (m, 1H), 7.01-6.98 (d, 1H), 5.27 (s, 2H), 3.99 (s, 3H), 3.88 (s, 3H), 3.74 (s, 3H)
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 65℃; for 19h;
General procedure: A suspension of isovanillin (8 g, 52.6 mmol, 1 equiv), anhydrous K2CO3 (10.9 g, 78.9 mmol, 1.5 equiv), and KI (1.75 g, 0.1 equiv) in dry DMF (50 mL) was stirred and heated to 65C. Compounds 6a-d (68.4 mmol, 1.3 equiv) was added portionwise over 1 h and the stirred mixture heated at 65 C for a further 18 h. After cooling to room temperature, the reaction mixture was treated with 1M aqueous HCl (100 ml), and extracted with CCl3H (2 × 100 ml), The combined organic extracts were separated, dried, filtered, and concentrated. The residue was purified by flash chromatography to provide 7a-d as a white solid. Isovanillin was treated with compound 6c according to general procedure to give the desired product 7c as a white solid, yield 81%.
General procedure: solutionof acid hydrazide (0.01 mol) and appropriate benzaldehyde/acetophenone (0.01 mol) in ethanol was refluxed for 5-6 h. The precipitated title compounds were then filtered off, washed with water and recrystallized from ethanol.
2-cyano-N,N-diethyl-3-(3-hydroxy-4-methoxyphenyl)prop-2-enamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With IRA 96 resin; In toluene;Reflux;
General procedure: To a solution of N, N-diethylcyanoacetamide(14.1 g, 0.1 mol) in toluene was added 0.2 g IRA 96 resin and isonitrovanillin (19.7g, 0.1 mol). The mixture was heated to reflux with azeotropic distillation of water. The reaction was continued until a TLC test showed completion of reaction.The mass was filtered hot. The filtrate was concentrated under vacuum to give the crude product, which wasre crystallized from absolute alcohol to afford 13. 61% isolated yield as light yellow solid.
6-fluoro-2-(2-(3-hydroxy-4-methoxybenzylidene)hydrazino)benzothiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With acetic acid; In ethanol; at 80℃; for 0.166667h;Microwave irradiation;
General procedure: A mixture of compound 2 (0.0549 g, 0.0003 mol), the appropriate aromatic aldehyde (0.00033 mol) and glacial acetic acid (0.1 mL) in ethanol (5 mL) was heated under microwave (20 W) at 80 °C for 10 min. On cooling, the precipitated solid was collected by filtration, washed with water, dried and crystallized to give compounds 3-29.
methyl 4-(5-formyl-2-methoxyphenoxy)-2-methoxy benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With pyridine; potassium carbonate; copper(II) oxide; for 12h;Reflux;
General procedure: A mixture of 2-(1,3-dioxan-2-yl)phenol (14, 10g, 0.05mol) [38], 3-bromo-benzaldehyde (16, 8.8g, 0.05mmol), potassium carbonate (13.5g, 0.09mol) and cupric oxide (0.95g, 5.9mmol) in pyridine (50mL) was stirred under reflux for 12h. The pyridine was distilled off in vacuo and the residue was extracted with ethyl acetate (200mL). The solution was concentrated and the residue was purified by flash column chromatograph (Al2O3), eluting with a 2:1 solution of petroleum ether-DCM to afford 19 (12.6g, 81%) as a yellow solid.
With potassium carbonate; In acetonitrile; for 15.0h;Reflux;
General procedure: Vanilline (3a, 6.85 g, 45 mmol) and <strong>[55943-72-1]1-(2-bromoethyl)pyrrolidine-2,5-dione</strong>1(4a, 10.2 g, 49.5 mmol) were heated with K2CO3 (8.28 g, 60 mmol) in 200 ml of acetonitrileunder reflux for 15 h. The precipitated KBr was filtered off, the filtrate was evaporated, theresidue was dissolved in 200 ml of dichloromethane, washed with water and 2N NaOHsolution, dried with Na2SO4 and evaporated. The remaining oil was triturated with n-hexaneto result in the desired 4-[2-(2,5-dioxopyrrolidin-1-yl)ethoxy]-3-methoxybenzaldehyde (5a)as white crystals.
KOH (250 mg, 4.47 mmol) ethanol solution (10 mL) was added to a solution of 26 (300 mg, 1.49 mmol) in EtOH (10 mL). Then, 3'-hydroxy-4'-methoxy benzaldehyde (226 mg, 1.49 mmol) was added to the reaction mixture and stirred at room temperaturefor 3 h. Five milliliters of aqueous HCl (10 M) was added and stirred at 55 C for 1 h. EtOH was removed under a vacuum. Distilled water was added to the residue, and the mixture was extracted with EtOAc three times. The organic layer was combined and dried over Na2SO4. The filtered EtOAc layer was evaporated to give a red-yellow oil that was purified by silica gel column chromatography eluting with MeOH and CHCl3 to give 28 as a yellow powder (65 mg, 14.6% yield).
Weigh 98% of the content of <strong>[520-33-2]hesperetin</strong> 0.302g,3-hydroxy-4-methoxybenzaldehyde, 0.150 g, 5.0 mL of n-propanol was added, Tetrahydropyrrole 100 muL, 50 deg C nitrogen nitrogen protection reaction 48h, Low temperature spinning dry propanol, Dissolved in acetone, Silica gel, Eluting with petroleum ether-ethyl acetate (1: 2) Low temperature recovery solvent, That was white powder 186mg, Is 8-[(1-pyrrolyl-1-(3-hydroxy-4-methoxyphenyl)methyne]<strong>[520-33-2]hesperetin</strong> (cpd13).
(E)-7-hydroxy-2-(3-hydroxy-4-methoxybenzylidene)-2,3-dihydro-1H-inden-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With thionyl chloride; In ethanol; at 25℃;
General procedure: Compounds 34, 35, 37, 38, 40, 41, 43-52, and 54-58 were prepared using method B [50]. For example, 5-hydroxy-1-indanone (IVb, 0.074g, 0.5mmol) was added to ethanol (5mL) followed by the addition of an equivalent amount of 3-hydroxybenzaldehyde (IIf, 0.061g, 0.5mmol). Thionyl chloride (0.054mL, 0.75mmol) was then added dropwise at room temperature and the mixture was stirred for 2h until precipitation occurred. The solvent (EtOH) was evaporated using a rotary evaporator. The residue was washed with water followed by cold methanol to obtain compound 34 as a dark orange solid.
(Z)-5-(3-hydroxy-4-methoxybenzylidene)-2-iminothiazolidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78.9%
With sodium acetate; acetic acid; for 7h;Reflux;
General procedure: The desired compounds, (Z)-5-(substituted benzylidene)-2-iminothiazolidin-4-one analogues (1a- 1l) (Figure 1), were prepared by Knoevenagel condensation.With one exception, refluxing a solution of appropriate benzaldehydes and <strong>[556-90-1]pseudothiohydantoin</strong>in acetic acid in the presence of NaOAc produced (Z)-5-benzylidene-2-iminothiazolidin-4-ones as a single stereoisomer in yields of 41.4-94.1%. A Knoevenagel condensation between 2,4-dimethoxy benzaldehyde and <strong>[556-90-1]pseudothiohydantoin</strong> under the same conditions gave amixture of (E)- and (Z)-5-(2,4-dimethoxybenzylidene)-2-iminothiazolidin-4-ones. These compounds could not be easily separated by conventional silica gel column chromatography. Milder reaction conditions capable of accomplishing the Knoevenagel condensation were needed to synthesize only (Z)-stereoisomer. Interestingly,heating a solution of 2,4-dimethoxy benzaldehyde and <strong>[556-90-1]pseudothiohydantoin</strong> in ethanol:H2O (1:1) in the presence of 1.0 equiv. of piperidine as a base catalyst at 80 C afforded the corresponding (Z)-stereoisomer(1l) as a sole product. A suspension of an appropriate benzaldehyde (300 mg, 1.53-2.46 mmol), <strong>[556-90-1]pseudothiohydantoin</strong>(1.1 eq.), and sodium acetate (3.0 eq.) in acetic acid (1 mL/1 mmol of benzaldehyde) was refluxed for 3-7 h. The reaction mixture was cooled and water was added. The resulting precipitates were filtered, and washed with water and, if necessary, a small amountof methylene chloride or ethyl acetate, to produce (Z)-5-(substituted benzylidene)-2-iminothiazolidin-4-oneproducts (1a - 1k) in 41.4-94.1% yields. The resulting precipitates were filtered, and washed with water,ethyl acetate and methylene chloride to give (Z)-5-(2,4-dimethoxybenzylidene)-2-iminothiazolidin-4-one (1l) all final products were confirmed by 1H and 13C NMR spectroscopy and mass spectroscopy.
(E)-3-(3'-hydroxy-4'-methoxybenzylidene)-5,7-dimethoxychroman-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With toluene-4-sulfonic acid; In benzene; for 12h;Reflux;
The <strong>[54107-66-3]5,7-dimethoxychroman-4-one</strong> prepared in the above step 2(71 mg, 0.34 mmol), 3-hydroxy-4-methoxybenzaldehyde (62 mg, 0.041 mmol) and para-toluenesulfonic acid (7 mg, 0.03 mmol) were dissolved in benzene (2 ml) And reacted for 12 hours. After the reaction mixture was cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate: n-hexane = 1: 2)To give the title compound (72 mg, 62%).
(2E)-1,3-bis(3-Hydroxy-4-methoxyphenyl)prop-2-en-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With thionyl chloride; In ethanol; at 23℃; for 4h;Inert atmosphere;
Compound 17 was synthesized using a previously reported method, except that it required purification [23]. To a stirred solution of <strong>[6100-74-9]3-hydroxy-4-methoxyacetophenone</strong> 15 (1.20 g, 7.89 mmol)and 3-hydroxy-4-methoxybenzaldehyde 16 (1.31 g, 7.89 mmol) in absolute EtOH (5 mL), was added thionyl chloride (0.58 mL, 7.89 mmol) dropwise and the reaction mixture was stirred at 23°C for 4 h.The reaction mixture was precipitated by the addition of H2O (~5 mL), and the resulting precipitate was filtered, washed with ice-cold H2O, and ice-cold EtOH. After the crude product was allowed to air dry, purification by recrystallization from EtOH afforded 17 (1.97 g, 83percent) as a yellow solid. Analytical data were in accordance with literature data [27]. 1H-NMR (400 MHz, CDCl3):delta 7.72 (d, J = 16.2 Hz,1H), 7.63-7.60 (m, 2H), 7.40 (d, J = 16.2 Hz, 1H), 7.28-7.27 (m, 1H), 7.12 (dd, J = 10.4, 2.0 Hz, 1H), 6.93(d, J = 8.2 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 3H); 13C NMR (100 MHz, DMSO-d6):delta 188.5, 152.7, 150.7, 147.0, 146.9, 144.3, 131.3, 128.1, 122.8, 122.4, 119.8, 115.2, 114.8, 112.5, 111.8, 56.3,56.2; HRMS calcd. for C17H17O5 [M + H]+ 301.1076, found 301.1065. Anal. calcd. for C17H16O5: C,67.99; H, 5.37. Found: C, 67.80; H, 5.41.
4-methoxy-3-((1-methyl-1H-pyrazol-4-yl)methoxy)benzaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;
A stirred solution of (1 -methyl- lH-pyrazol-4-yl)methanol (0.74 g, 6.58 mmol, 1 equiv.) in tetrahydrofuran (30 mL) was treated with isovanillin (1.00 g, 6.58 mmol, 1 equiv.) and triphenylphosphine (2.10 g, 7.89 mmol, 1.2 equiv. ). The mixture was cooled to 0°C and diisopropyl azodicarboxylate (1.55 mL, 7.89 mmol, 1.2 equiv.) was added drop-wise. The mixture was then allowed to warm to room temperature and was stirred overnight. The mixture was concentrated to dryness under vacuum and the residue purified by chromatography on silica gel (Interchim 80 g column, eluting with 50 - 80percent ethyl acetate/isohexane) to afford the title compound as a pale yellow oil (1.37 g, 85percent) which was used without further purification; NMR (400 MHz, CDC13): delta 9.85 (s, IH), 7.70 - 7.64 (m, 2H), 7.58 - 7.44 (m, 3H), 5.08 (s, 2H), 3.94 (s, 3H), 3.89 (s, 3H)
With potassium carbonate; potassium iodide; In acetone;Reflux;
General procedure: Various substituted anilines were dissolved in glacial acetic acidat 0 C, to this was added over 30 min choloroacetylchloride (2equivalents). The reaction mixture was brought to room temperatureand stirred overnight. Saturated sodium bicarbonate solutionwas added till complete neutralization. The resulting precipitatewas filtered off and washed with n-hexane and dried. The resultantproduct was used further without any purification. Either of 3-hydroxy benzaldehyde, 4-hydroxy benzaldehyde, vanillin or isovanillin(1 equivalent) was dissolved in acetone and potassiumcarbonate (2 equivalents) was added. Then correspondingsubstituted acetamide was mixed to the stirring solution. Finally,potassium iodide (1.5 equivalent) was added. The reaction mixturewas refluxed for 8-10 h. After completion of reaction, the resultantmixture was concentrated and treated with water and extractedwith ethyl acetate (3 x 20 mL). The organic layers were combinedand treated with brine and dried over sodium sulfate andconcentrated. The crude mixture was purified over silica gel(60-120) using petroleum ether: ethyl acetate (9:1).
With potassium carbonate; potassium iodide; In acetone;Reflux;
General procedure: Various substituted anilines were dissolved in glacial acetic acid at0 C, to this was added over 30 min choloroacetyl chloride (2 equivalents).The reaction mixture was brought to room temperature andstirred overnight. Saturated sodium bicarbonate solution was added tillcomplete neutralization. The resulting precipitate was filtered off andwashed with n-hexane and dried. The resultant product (1) was usedfurther without any purification. Either of 4-hydroxy benzaldehyde(2a), vanillin (2b) or isovanillin (2c) (1 equivalent) was dissolved inacetone and potassium carbonate (2 equivalents) was added. Thencorresponding substituted acetamide (1) was mixed to the stirring solution.Finally, potassium iodide (1.5 equivalent) was added. The reactionmixture was refluxed for 8-10 h. After completion of reaction,the resultant mixture was concentrated and treated with water andextracted with ethyl acetate (3×20 mL). The organic layers werecombined and treated with brine and dried over sodium sulfate andconcentrated. The crude mixture was purified over silica gel (60-120)using petroleum ether: ethyl acetate (9:1).
With potassium carbonate; potassium iodide; In acetone;Reflux;
General procedure: Various substituted anilines were dissolved in glacial acetic acid at0 C, to this was added over 30 min choloroacetyl chloride (2 equivalents).The reaction mixture was brought to room temperature andstirred overnight. Saturated sodium bicarbonate solution was added tillcomplete neutralization. The resulting precipitate was filtered off andwashed with n-hexane and dried. The resultant product (1) was usedfurther without any purification. Either of 4-hydroxy benzaldehyde(2a), vanillin (2b) or isovanillin (2c) (1 equivalent) was dissolved inacetone and potassium carbonate (2 equivalents) was added. Thencorresponding substituted acetamide (1) was mixed to the stirring solution.Finally, potassium iodide (1.5 equivalent) was added. The reactionmixture was refluxed for 8-10 h. After completion of reaction,the resultant mixture was concentrated and treated with water andextracted with ethyl acetate (3×20 mL). The organic layers werecombined and treated with brine and dried over sodium sulfate andconcentrated. The crude mixture was purified over silica gel (60-120)using petroleum ether: ethyl acetate (9:1).
(E)-3-((3-hydroxy-4-methoxybenzylidene)amino)-2-thioxothiazolidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
In ethanol; at 20℃;
General procedure: General procedure for synthesis of N-substituted-rhodanine derivatives RhAs: To a solution of aldehydes (3a-3h, 1.0 equiv.) in ethanol (10 mL) was added slowly to the solution of <strong>[1438-16-0]3-amino-2-thioxothiazolidin-4-one</strong> (2, 1.0 equiv.) in EtOH. The reaction mixture was stirred at room temperature without a catalyst for between 4 h and 12 h, and was monitored by TLC. After, the mixture product was recrystallized from EtOH. After recrystallization, N-substituted-rhodanine derivatives (RhAs) were obtained as follows.
2-(3-hydroxy-4-methoxyphenyl)-1H-benzo[d]imidazole-5-sulfonic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With sodium metabisulfite; In ethanol; water; for 24h;Reflux;
General procedure: To a solution of the appropriate 3,4-diaminobenzene derivative (1ad)(2 mmol) in ethanol (15 mL) 2.85 N aqueous solution of sodium metabisulphite (1.6 mL) and the appropriate substituted arylaldehyde(2 mmol) were added. The reaction mixture was heated at reflux for 24 h. The solvent was then evaporated under reduced pressure. The residue was added with HCl 1 N (10 mL), the formed precipitate was filtered off, washed with water (3×10 mL) and purified by crystallization from the adequate solvent to give the title compounds.Following the general procedure benzimidazoles 3 [19], 4 [20], 5 [21],7 [24], 6, 32 and 33 [15] were prepared and their analytical and spectral data are in agreement with those reported in literature.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
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120K+ Compounds
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