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Chemical Structure| 121-33-5
Chemical Structure| 121-33-5
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Product Details of [ 121-33-5 ]

CAS No. :121-33-5 MDL No. :MFCD00006942
Formula : C8H8O3 Boiling Point : -
Linear Structure Formula :- InChI Key :MWOOGOJBHIARFG-UHFFFAOYSA-N
M.W : 152.15 Pubchem ID :1183
Synonyms :
p-Vanillin;m-Methoxy-p-hydroxybenzaldehyde;NSC 48383;NSC 403658;NSC 15351;3-methoxy-4-Hydroxybenzaldehyde;FEMA 3107;p-Hydroxy-m-methoxybenzaldehyde

Calculated chemistry of [ 121-33-5 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.12
Num. rotatable bonds : 2
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 40.34
TPSA : 46.53 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.37 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.57
Log Po/w (XLOGP3) : 1.21
Log Po/w (WLOGP) : 1.21
Log Po/w (MLOGP) : 0.51
Log Po/w (SILICOS-IT) : 1.49
Consensus Log Po/w : 1.2

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.82
Solubility : 2.32 mg/ml ; 0.0152 mol/l
Class : Very soluble
Log S (Ali) : -1.78
Solubility : 2.5 mg/ml ; 0.0164 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.88
Solubility : 2.0 mg/ml ; 0.0132 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.15

Safety of [ 121-33-5 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P273-P305+P351+P338 UN#:N/A
Hazard Statements:H319-H412 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 121-33-5 ]

* 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.

  • Upstream synthesis route of [ 121-33-5 ]
  • Downstream synthetic route of [ 121-33-5 ]

[ 121-33-5 ] Synthesis Path-Upstream   1~110

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Reference: [1] Molecules, 2012, vol. 17, # 5, p. 5013 - 5020
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  • [ 494-08-6 ]
Reference: [1] Carbohydrate Research, 2018, vol. 460, p. 41 - 46
[2] Carbohydrate Research, 2018, vol. 460, p. 41 - 46
[3] Carbohydrate Research, 2018, vol. 460, p. 41 - 46
  • 3
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Reference: [1] Tetrahedron Letters, 2006, vol. 47, # 5, p. 695 - 699
  • 4
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Reference: [1] European Journal of Medicinal Chemistry, 2006, vol. 41, # 9, p. 1059 - 1072
  • 5
  • [ 133-89-1 ]
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  • [ 494-08-6 ]
Reference: [1] Phytochemistry, 2009, vol. 70, # 4, p. 473 - 482
  • 6
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  • [ 57-50-1 ]
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Reference: [1] Chemical and Pharmaceutical Bulletin, 2005, vol. 53, # 4, p. 361 - 365
  • 7
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  • [ 137-07-5 ]
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YieldReaction ConditionsOperation in experiment
95% With cadmium sulphide In methanol at 20℃; for 0.416667 h; Irradiation General procedure: In the experimental procedure for catalytic reaction, amixture of aldehyde (3 mmol), 2-aminothiophenol (3 mmol) and CdSnanosphere (5 mg) was taken in a 100 ml double walled quartz beaker flaskhaving water inlet and outlet to maintain the temperature of the reactionvessel at room temperature in methanol (20 ml). The beaker was exposed tovisible light under stirring condition for the required time period (Table 3).After completion of the reaction (monitored by TLC and GC), methanol wasevaporated by rotary and the product was dissolved in dichloromethane. Thecatalyst was separated from the reaction mixture by centrifugation.Dichloromethane was then evaporated to dryness and the product waspurified by column chromatography using silica gel G60.
91% With lithium bromide In ethanol at 25 - 30℃; for 0.25 h; Sonication General procedure: Aromatic aldehydes (1.0 mmol), o-aminothiophenol (1.0 mmol), and lithiumbromide (20 mol percent) in ethanol (5 mL) were added into a 50-mL round-bottomedflask. The reaction flask was placed in the ultrasonic cleaner bath with the surface ofreactants slightly lower than the water level and irradiated at 25–30 C for theperiod of time indicated in Table 4. The progress of the reaction was monitored byTLC, using petroleum ether/ethyl acetate (8:2) as a solvent system. Aftercompletion of the reaction, the reaction mixture was poured into ice-cold water.The precipitate was filtered off and washed with water, dried, and purified bycrystallization from ethanol as solvent to afford pure product.
89.2% at 25 - 30℃; for 1.4 h; Sonication General procedure: Aromatic aldehydes (2, 1.0 mmol), o-aminothiophenol (1, 1.0 mmol), FeCl3/Montmorillonite K-10 (160 mg, 0.1 mmol, based on FeCl3) and absolute methanol (5 mL) were added into a 25 mL conical flask. The reaction flask was placed in the ultrasonic cleaner bath, where the surface of reactants was slightly lower than the water level and irradiated at 25–30 °C for the period of time (sonication was continued until aromatic aldehydes disappeared as indicated by TLC) as indicated in Tables 1–4 . After completion of the reaction, the reaction mixture was dissolved in ethyl acetate and FeCl3/Montmorillonite K-10 was filtered off. The filtrate was concentrated and purified by silica-gel column chromatography (200–300 mesh) using petroleum ether or the mixture of petroleum ether and ethyl acetate as eluent to give a light yellow crystalline solid. All of the products described herein were previously reported in the literatures [16–35]. The authenticity of the products was established by spectroscopic data and by comparing their melting points with literature values. brown crystals, IR (KBr, cm-1): 3099, 3004, 2934, 1616, 1604, 1584, 1559, 1529, 1478, 1462, 1427, 1387, 1364, 1315, 1279, 1256, 1194, 1124, 1033, 1011, 894, 872, 776, 756, 727; 1H NMR: δH 9.85 (s, 1H, OH), 8.06 (d, J = 8.2 Hz, 1H, ArH), 7.89 (d, J = 7.9 Hz, 1H, ArH), 7.75 (d, J = 1.8 Hz, 1H, ArH), 7.56 (dd, 1H, J1 = 8.2 Hz, J2 = 1.9 Hz, ArH), 7.48-7.51 (m, 1H, ArH), 7.37-7.39 (m, 1H, ArH), 7.03 (d, J = 8.2 Hz, 1H, ArH), 4.00 (s, 3H, CH3); 13C NMR: δC 168.2, 154.0, 148.6, 147.0, 134.8, 126.3, 126.2, 124.9, 122.7, 122.0, 121.5, 114.8, 109.3, 56.2; m/z (ESI): 258 [M+H]+.
85%
Stage #1: With sodium hydrogen sulfate In ethanol
Stage #2: Reflux
General procedure: Equimolar mixture of NaHSO3 (1.25 g, 0.012 mol) and corresponding aldehyde, viz. anisaldehyde (1.63 g, 0.012 mol) for mpb, vanillin (1.82 g, 0.012 mol) for mhpb, and salicylaldehyde (1.47 g, 0.012 mol) for hpbH, were refluxed in ethanol (15 mL) for 15–20 min. To the mixture o-aminothiophenol (1.25 g, 0.01 mol) was added and continued to reflux for 4–5 h. On slow cooling, colorless crystalline compound formed in each case was filtered, washed with water, recrystallized from ethanol, and dried over fused CaCl2. The solids were recrystallised from hot ethanol (scheme 1).
73.4% With sodium metabisulfite In N,N-dimethyl-formamideReflux General procedure: Sodium metabisulfite (0.49 g, 2.5 mmol) was added to a DMF solution of 2-aminothiophenol (2.50 g, 20 mmol) and 4-hydroxybenzaldehyde (2.46 g, 20.2 mmol ). The reaction mixture was stirred and heated to reflux for 2–2.5 h. The progress of reaction was monitored periodically by TLC for completion. Then the mixture was poured into crushed ice, the formed precipitate was separated by filtration and washing to obtain 4-(benzothiazol-2-yl)phenol 4a. Other benzothiazole intermediates 4-(benzothiazol-2-yl)-2-methoxyphenol 4b and 3-(benzothiazol-2-yl)phenol 4c were prepared using a similar synthetic method.21 (see Supplementary file.)
55.6% at 20℃; for 22 h; Inert atmosphere General procedure: To a stirred solution or suspension of substituted benzaldehydes (1.33 mmol, 1a-1l) in MeOH (3-7 mL), 2-aminothiophenol (1.60 mmol) was added and the reaction mixture was stirred at room temperature for 5-96 h. Work-up was conducted by one of the following three methods (Methods A-C). Method A: After evaporation of methanol, the resulting solid was filtered and the filter cake was washed with hexane, methylene chloride, ethyl acetate, and/or cold methanol. Method B: After evaporation of methanol, the resultant residue was dissolved in a small amount of methylene chloride, ethyl acetate, and/or cold methanol, followed by the addition of hexane. After cooling, the resulting precipitate was filtered and washed with hexane, methylene chloride, ethyl acetate, and/or cold methanol. Method C: After evaporation of half the volume of methanol, the reaction mixture was kept in a refrigerator, or water (20 ml) was added to the reaction mixture before refrigerator storage. The resulting precipitate was filtered and the filter cake was washed with hexane, methylene chloride, ethyl acetate, and/or cold methanol. In the cases of compounds, 2b and 2k, flash column chromatography (hexane/methylene chloride = 4/1 to 2/1 for 2b; methylene chloride/MeOH = 90/1 and then methylene chloride only for 2k) was conducted for further purification. The title products (2a-2l) were generated in yields ranging from 15.2percent to 82.6percent.
47.1% With montmorillonite K-10; air In ethanol at 20℃; for 40 h; General procedure: Aldehyde (2, 1.0 mmol) and o-aminothiophenol (1, 1.0 mmol) were mixed inabsolute ethanol (10 mL) in a 50-mL three-necked flask equipped with a watercooledcondenser and a gas inlet, as reported elsewhere [45]. The solution wasstirred at room temperature, then montmorillonite K-10 (25 mg) was added. Air wasbubbled continuously through the reaction system, at a speed of 60 bubbles perminute on average, by means of a small air pump. After completion of the reaction(monitored by TLC) the catalyst was recovered by filtration and washed with EtOH.The filtrate was concentrated and purified by short column chromatography on silicagel, with petroleum ether or a mixture of petroleum ether and ethyl acetate aseluent, to give the pure product. The products (3a–r) are all known compounds andwere identified by 1H NMR spectroscopy, by comparison of their melting pointswith those reported in the literature, and by comparison of their TLC Rf values withthose of standards.
20.23% for 24 h; Reflux General procedure: A mixture of 2-aminothiophenol (0.32 ml, 3 mmol), 0.30 ml(3 mmol) of benzaldehyde and 5 ml of pyridine in a 50 mlround-bottomed flask was refluxed for 24 hrs. Workup includedcooling the reaction mixture and transferred into 50ml of HCl 0.5 N solution. Precipitates formed were filteredand washed with water and dried at 60-70°C to dryness togive brown needle.

Reference: [1] Chemistry Letters, 2004, vol. 33, # 3, p. 274 - 275
[2] Tetrahedron Letters, 2013, vol. 54, # 9, p. 1090 - 1096
[3] Heterocycles, 2007, vol. 71, # 8, p. 1837 - 1842
[4] Research on Chemical Intermediates, 2015, vol. 41, # 10, p. 7509 - 7516
[5] Journal of Heterocyclic Chemistry, 2009, vol. 46, # 1, p. 91 - 95
[6] Ultrasonics Sonochemistry, 2013, vol. 20, # 2, p. 627 - 632
[7] Journal of Coordination Chemistry, 2015, vol. 68, # 13, p. 2253 - 2270
[8] Chinese Chemical Letters, 2010, vol. 21, # 7, p. 790 - 793
[9] Research on Chemical Intermediates, 2013, vol. 39, # 5, p. 2077 - 2086
[10] RSC Advances, 2014, vol. 4, # 74, p. 39606 - 39611
[11] Arkivoc, 2018, vol. 2018, # 7, p. 86 - 99
[12] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 8, p. 2445 - 2449
[13] Research on Chemical Intermediates, 2015, vol. 41, # 8, p. 5159 - 5166
[14] Medicinal Chemistry, 2011, vol. 7, # 2, p. 127 - 134
[15] New Journal of Chemistry, 2015, vol. 39, # 7, p. 5116 - 5120
[16] Asian Journal of Chemistry, 2012, vol. 24, # 11, p. 5129 - 5132
[17] Journal of Molecular Structure, 2017, vol. 1148, p. 282 - 292
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YieldReaction ConditionsOperation in experiment
46% With silver(I) 4-methylbenzenesulfonate In water at 100℃; for 12 h; Sealed tube; Inert atmosphere; Green chemistry General procedure: A sealed pressure vessel was charged with benzothiazole (68 mg, 0.5 mmol), AgOTs (280 mg, 1 mmol),aldehyde (0.6 mmol) and 2.0 mL of H2O. The resulting solution was stirred at 100 C for 12 h under N2.Upon completion of the reaction, H2O (8.0 mL) was added, then extracted with EtOAc (5 mL × 3), driedover Na2SO4, and concentrated under reduced pressure. The residue was further purified with flashcolumn chromatography.
Reference: [1] Green Chemistry, 2012, vol. 14, # 6, p. 1577 - 1580
[2] Heterocycles, 2018, vol. 96, # 7, p. 1226 - 1237
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YieldReaction ConditionsOperation in experiment
56% at 190℃; for 0.333333 h; Microwave irradiation; Green chemistry General procedure: 2,2-Disulfanediyldianiline (1a) or 5,5-dichloro-2,2-dithiobisaniline (1b) (0.50 mmol), the corresponding aldehydes(2a-p) (1.1 mmol), NaSH (0.3 mmol) and PEG-300 (2 mL) wereput into a round-bottomed ask, and the reaction mixture wasirradiated for 20 min at 25 W. After completion of the reactionmonitored by TLC with a mixture of petroleum ether and ethylacetate as eluent, the mixture was allowed to cool to roomtemperature. Distilled water (25 mL) was added into the ask,and then the solid was precipitated from the aqueous phaseafter stirring by magnetic stirrers in 5 min. The solid precipitatewas isolated by fltration, washed twice by distilled water (5 mL)and dried for 3 h. The pure targetproducts3a-3o were obtaineddirectly. The pure products 3p and 3q were obtained by columnchromatography(PE/EtOAc as eluent).Complete characterization of the products (all known) is found in the SupplementalMaterials (Figures S 1–S 34).
Reference: [1] RSC Advances, 2015, vol. 5, # 89, p. 72745 - 72754
[2] European Journal of Organic Chemistry, 2010, # 15, p. 2849 - 2851
[3] Phosphorus, Sulfur and Silicon and the Related Elements, 2017, vol. 192, # 4, p. 464 - 468
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Reference: [1] Green Chemistry, 2017, vol. 19, # 18, p. 4289 - 4293
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Reference: [1] Journal of the American Chemical Society, 1925, vol. 47, p. 3078[2] Journal of the Chemical Society, 1926, vol. 48, p. 250
[3] Chemische Berichte, 1916, vol. 49, p. 1145
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Reference: [1] Journal of the American Chemical Society, 1925, vol. 47, p. 3078[2] Journal of the Chemical Society, 1926, vol. 48, p. 250
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Reference: [1] Monatshefte fur Chemie, 2018, vol. 149, # 12, p. 2265 - 2285
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Reference: [1] Journal of the Chemical Society, 1932, p. 1236,1238
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YieldReaction ConditionsOperation in experiment
10 %Chromat. With sodium hydroxide In water at 20℃; for 24 h; Inert atmosphere To an aqueous solution of NaOH (20 wtpercent, 20 mL) wereadded guaiacol (5 mmol, 0.62 g) and zeolite (5 g) under N2atmosphere at room temperature. Then chloroform(20 mL) was dropped to the mixture. Dodecane (1 mmol,0.224 mL) was added as GC internal standard. The reactionmixture was stirred at room temperature for 24 h. Thereaction was quenched with 3 N aqueous HCl. The mixturewas extracted with ethyl acetate. The yield and selectivityof products was detected by GC.
Reference: [1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 4, p. 1287
[2] Chemische Berichte, 1881, vol. 14, p. 2021
[3] Catalysis Letters, 2015, vol. 145, # 2, p. 712 - 714
[4] Catalysis Letters, 2015, vol. 145, # 2, p. 712 - 714
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YieldReaction ConditionsOperation in experiment
11.5%
Stage #1: With copper(I) oxide In trifluoroacetic acid for 5 h; Reflux
Stage #2: With hydrogenchloride In water at 20℃; for 1 h;
General procedure: To a solution of substrates (1a–1q, 0.15 mmol) in trifluoroacetic acid (5 ml), hexamethylenetetramine (0.3 mmol) and cuprous oxide (0.15 mmol) were added. The reaction mixture was refluxed for about 5 h, cooled to room temperature, followed by addition of hydrochloric acid (3 N, 5 ml). After stirring for another 1 h, the solution was concentrated under reduced pressure. The products were purified by silica gel column chromatography (200–300 mesh).
Reference: [1] Research on Chemical Intermediates, 2015, vol. 41, # 11, p. 8147 - 8158
  • 17
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  • [ 90-05-1 ]
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Reference: [1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1992, vol. 31, # 8, p. 543 - 546
[2] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1992, vol. 31, # 8, p. 543 - 546
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Reference: [1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 19, p. 764
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Reference: [1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 19, p. 764
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Reference: [1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 19, p. 764
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Reference: [1] Indian Journal of Chemistry - Section B Organic Chemistry Including Medicinal Chemistry, 1989, vol. 28, # 5, p. 431 - 434
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  • [ 7417-21-2 ]
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[2] Chemical Biology and Drug Design, 2011, vol. 78, # 1, p. 101 - 111
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  • [ 97-53-0 ]
Reference: [1] Journal of Organic Chemistry, 1982, vol. 47, # 10, p. 1983 - 1984
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  • [ 97-53-0 ]
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Reference: [1] Green Chemistry, 2017, vol. 19, # 18, p. 4423 - 4434
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  • [ 51020-86-1 ]
  • [ 458-35-5 ]
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  • [ 2316-26-9 ]
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[3] Journal of the Chemical Society, 1925, vol. 127, p. 1977
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Reference: [1] Patent: US2016/9706, 2016, A1,
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  • [ 67-64-1 ]
  • [ 1080-12-2 ]
YieldReaction ConditionsOperation in experiment
88% With sodium hydroxide In ethanol; water at 0 - 20℃; General procedure: To a solution of substituted benzaldehydes (6a1–d1, 6e, 6f) and acetone (10–25 equivalents, excess) in ethanol was added 20percent (w/v) aqueous NaOH at 0–5°C. The reaction mixture was stirred at ambient temperature and the progress of the reaction was monitored by TLC. When the substituted benzaldehyde was consumed, the excess acetone was removed in vacuo; cold water was then added and the resulting solution was acidified with 3M HCl. The product which appeared as a solid was collected by vacuum filtration, washed with water and dried in vacuo. The residue was purified by column chromatography or recrystallized from appropriate solvent system to yield the substituted 4-phenylbut-3-en-2-ones 7a1–d1, 7e and 7f.
87% With sodium hydroxide In ethanol; water at 20℃; for 15 h; 4-(4-Hydroxy-3-methoxy-phenyl)but-3-ene-2-one: To a solution of acetone (15.30 g, 263.76 mmol) in a mixture of ethanol (35 niL) and water (15 mL) were added sodium hydroxide (2.90 g,72.54 mmol) and 4-hydroxy-3-methoxybenzaldehyde (5.01 g, 32.97 mmol). The reaction mixture was stirred at room temperature for 15 h. The reaction was cooled to 0° C and quenched with 2.0 N hydrochloric acid until the solution became slightly acidic. The solution was extracted with ethyl acetate (4x 100 mL). The combined organic layers were washed with water (50 mL) and saturated aqueous sodium chloride (50 mL). EPO <DP n="65"/>The organic layer was dried over magnesium sulfate, filtered, and concentrated at reduced pressure to afford 4-(4-hydroxy-3-methoxy-phenyl)but-3-ene-2-one (5.52 g, 87percent yield) as a yellow solid: MS (EI) for CH12O3: 193 (MH+).
87% at 20℃; for 1 h; Green chemistry General procedure: A mixture of aromatic aldehyde (2 mmol) and ketone (2 mmol) was added in one portion to 11 mol percent of dry catalyst A-2XMP at RT and was stirred for 1 h. Progress of the reaction was monitored by TLC (hexane:ethylacetate :: 88:12,v/v). After completion of the reaction, excess of ethyl alcohol was added. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Crystallization was observed at RT. Pure products (15a-18a) were purified by recrystallization from ethyl alcohol giving 87-94percent yields.
85% at 20℃; for 3 h; 4.1.2. General procedure for the preparation of compounds (1f,g). Toa stirred solution of p-hydroxybenzaldehydes (10 mmol) in anhydrousacetone (15 mL) was added 10percent NaOH solution (25 mL), andthe mixture was stirred for 3 h at room temperature. Acidification using 10percent HCl until the color change of Congo red paper from red toblue. The resulting mixture was extracted with dichloromethane(30 mL3). The organic layers werewashed with brine (20 mL) and dried over MgSO4 were filtered, evaporated, and the residue waspurified by column chromatography (ethyl acetate/n-hexane1:10)to give pure 1f-g.
72% at 20℃; for 2 h; Vanillin (20 g) was dissolved in acetone (50 mL) in a round bottomflask and 40percent KOH (5 mL) was added to this reaction mixture.It was kept on stirring at room temperature. After the completionof reaction (monitored by TLC), reaction mixture was acidified withdilute hydrochloric acid until pH 7 was achieved. It was thenpoured in ice-cold water, filtered and dried to get the desired product,that is, vinyldenacetone (VDA). The physical data of vinyldenacetoneis given below:4.2.1. (E)-4-(4-Hydroxy-3-methoxyphenyl)but-en-2-one (VDA)Yield 72percent; mp 71–73 C. 1H NMR (CDCl3, 500 MHz, d, TMS = 0):2.36 (s, 3H), 3.91 (s, 3H), 6.58 (d, J = 16.5 Hz, 1H), 6.92 (d, J = 7.5 Hz,1H), 7.04–7.08 (m, 2H), 7.45 (d, J = 16.5 Hz, 1H). 13C NMR (CDCl3,125 MHz, d, TMS = 0): 27.22, 55.84, 109.56, 114.99, 123.52,124.82, 126.79, 144.03, 147.08, 148.51, 198.72.
72% With potassium hydroxide In water at 20℃; for 2 h; Vanillin (20g) was dissolved in acetone (50ml) in a round bottom flask and 40percent KOH (5ml) was added to this reaction mixture. It was kept on stirring at room temperature. After the completion of reaction (monitored by TLC), reaction mixture was acidified with dilute hydrochloric acid until pH 7 was achieved. It was then poured in ice-cold water, filtered and dried to get the desired product i.e. vinyldenacetone (VDA). The physical data of vinyldenacetone is given below. Yield 72percent; mp 71–73°C. 1H NMR (CDCl3, 500MHz, δ, TMS=0): 2.36 (s, 3H), 3.91 (s, 3H), 6.58 (d, J=16.5Hz, 1H), 6.92 (d, J=7.5Hz, 1H), 7.04–7.08 (m, 2H), 7.45 (d, J=16.5Hz, 1H). 13C NMR (CDCl3, 125MHz, δ, TMS=0): 27.22, 55.84, 109.56, 114.99, 123.52, 124.82, 126.79, 144.03, 147.08, 148.51, 198.72

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YieldReaction ConditionsOperation in experiment
98% at 90℃; for 0.5 h; Green chemistry General procedure: A suspension of an appropriate aromatic aldehyde (1 eq.), and ylide I or II (1.3–1.5 eq.) inwater (4–10 mL) was stirred at 90 °C for 0.5–24 h. Next, the heterogeneous reaction mixturewas cooled to room temperature, and the aqueous phase was extracted with DCM (3 10 mL).The solvent was evaporated under diminished pressure. Column chromatography (hexane–ethylacetate, or chloroform–methanol) of the residue gave the E-alkene as the major product.
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YieldReaction ConditionsOperation 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

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YieldReaction ConditionsOperation in experiment
97% With dipotassium peroxodisulfate; iron(II) sulfate In water at 80 - 120℃; for 1 h; 5 g of vanillin, (33 mmol, manufactured by Wako Pure Chemical Industries, Ltd.) was dissolved in 200 ml of ion-exchanged water heated to 80 ° C. To this solution, 200 mg (0 72 mmol) of iron sulfate (manufactured by Wako Pure Chemical Industries, Ltd.) and 5 g (19 mmol, potassium peroxodisulfate manufactured by Wako Pure Chemical Industries, Ltd.) were added and heated at 120 ° C. for 1 hour And refluxed. After completion of the reaction, unreacted vanillin was removed by hot filtration to obtain an intermediate (a1) (yield 97percent).
96% With laccase from Trametes versicolor; oxygen In acetone at 20℃; for 24 h; Green chemistry; Enzymatic reaction General procedure: A solution of phenol substrate (1–7) (1.5g) in acetone (20mL) was added to NaOAc buffer (180mL, 0.1M, pH 5.0). O2 was bubbled into the solution for 5 min. Laccase from Trametes versicolor (20U, 12.4mg) was added and the reaction was stirred at room temperature for 24 h. The precipitate was filtered off the solution and the product dried overnight at 80°C under vacuum.
71% With sodium persulfate; ferrous ammonium sulphate hexahydrate In water for 0.5 h; Heating Divanillin was prepared as previously described for the preparation of diapocynin with modifications[30]. Vanillin (0.912 g, 6 mmol) was dissolved in 200 mL of hot water. Then, the heating wasturned off and ammonium iron(II) sulfate hexahydrate (118 mg, 0.3 mmol) and potassium persulfate(811 mg, 3.0 mmol) were added and stirred for 30 min. The precipitated product was filteredand washed with cold water. The product was re-dissolved by adding sodium hydroxide (50 mL,4 mol L-1) and filtered. The solution was acidified by adding hydrochloric acid (50 mL, 4 mol L-1).The precipitate was filtered and washed with cold water. The product was dried in vacuum overphosphorus pentoxide, yielding 0.64 g (71percent) of a yellow pale solid. The purity was confirmed byHPLC analysis in line with a diode array detector set at 254 nm (Jasco, Tokyo, Japan). The analyseswere carried on a Luna C18 reversed-phase column (250 x 4.6 mm, 5 m) using solvent A(aqueous formic acid 0.1percent) as a mobile phase and solvent B (formic acid 0.1percent in acetonitrile).The gradient was solvent A 90percent to 10percent in 22 min. The flow rate was 1 mL min-1. NMR spectrawere obtained using DMSO- D6 as solvent and internal reference for 1H and 13C (Bruker DRX400 spectrometer, MA, USA): 1H NMR (400 MHz) δ (ppm): 9.80±9.88 (m, 2OH), 9.82 (s,2CHO), 7.43±7.45 (m, 4 CH-Ar), 3.94 (s, 2 OCH3). 13C NMR (100 MHz) δ(ppm): 191.2(2CHO), 150.4 (2C), 148.1 (2C), 128.1 (2CH), 127.8 (2C), 124.6 (2C), 109.2 (2CH), 56.0(2OCH3) (S1 and S2 Figs). These results are consistent with those previously reported [31].
50% With iron(III) chloride hexahydrate In water at 20 - 50℃; for 29 h; To the mixture of 10 vanillin (32.9mmol) and 76 FeCl3.6H2O (36.2mmol) taken in a round bottom flask, 150mL of 12 water was added. The reaction mixture was shaken for few minutes and then heated at 50°C for 5h. Thereafter, the reaction mixture was kept on stirring for 24hat room temperature. The mixture was cooled on ice-bath for 30 min and vacuum filtered. The obtained precipitates were washed initially with water, then with methanol and finally dried in hot air oven to provide bisvanillin (9 1a) whose 77 structure was confirmed through NMR [44] and mass spectrometry. 5.2.1.1 77 Bisvanillin or 3-(5-formyl-2-hydroxy-3-methoxyphenyl)-4-hydroxy-5-methoxybenzaldehyde (1a) (0019) Grey powder (Yield 50percent) m. p. 310–315°C, 1H NMR (DMSO‑d6, 300MHz): δ 9.85 (2H, s), 9.70 (2H, s), 7.36 (4H, s), 3.82 (6H, s); 13C NMR (DMSO‑d6, 75.4MHz): δ 191.5, 150.9, 148.6, 128.6, 128.1, 125.0, 109.8 and 56.8. HRMS-ESI: m/z [M+H]+ for C16H14O6, calculated 303.1073; observed 303.1068.

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YieldReaction ConditionsOperation in experiment
96.2% at 130℃; for 1 h; Autoclave; Inert atmosphere 3.04 g (20.0 mmol) of vanillin, 5.93 g (40.0 mmol) of ethyl orthoformate, 15.0 mg of p-toluenesulfonic acidmonohydrate, and 15.0 mg of 5percent palladium carbon were added into a 100 ml autoclave (using an inner tube). After theinside of the system was substituted with nitrogen, substitution with hydrogen was performed and 3.0 MPa of a hydrogengas was enclosed. The temperature in the autoclave was controlled to 130°C and stirring was continued for 1 hour. Afterthe stirring, the reaction solution was cooled and then the hydrogen gas was purged. Thereafter, the palladium catalystwas removed by filtration operation and ethyl orthoformate was collected under reduced pressure to thereby obtain 3.60g (value at internal standard quantitative determination: 97.4 wtpercent, yield: 96.2percent) of vanillyl ethyl ether.1H-NMR (CDCl3): σ = 1.37 (3H, t), 3.42 (1H, q), 3.86 (3H, s), 4.44 (2H, s), 5.92 (1H, s), 6.88 (3H, m)
Reference: [1] Patent: EP2813482, 2014, A1, . Location in patent: Paragraph 0139; 0140
  • 63
  • [ 64-17-5 ]
  • [ 121-33-5 ]
  • [ 13184-86-6 ]
YieldReaction ConditionsOperation in experiment
98% at 30℃; for 24 h; Autoclave; Industrial scale Add 1 kg of vanillin in the autoclave, 6. 6 liters of ethanol (vanillin concentration of lmol / L), 0.3 kg of catalyst B and 0.15 kg of catalyst F, and charged with 1. 5 MPa of hydrogen, heated to 30 ° C reaction 24h, the detection of vanillin reaction is complete, stop heating, after the reactor cooling filter catalyst, the catalyst directly after drying. The filtrate was subjected to rotary evaporation to remove excess ethanol, To give vanillin ether 1. 36 kg, yield 98percent, purity> 98percent.
Reference: [1] Patent: CN105622363, 2016, A, . Location in patent: Paragraph 0027; 0028
  • 64
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  • [ 79411-60-2 ]
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  • 66
  • [ 121-33-5 ]
  • [ 123-54-6 ]
  • [ 458-37-7 ]
YieldReaction ConditionsOperation in experiment
85%
Stage #1: With boron trioxide; boric acid tributyl ester In ethyl acetate at 50℃; for 0.166667 h;
Stage #2: With N-butylamine In ethyl acetate at 50 - 80℃; for 4.25 h;
General procedure: Acetylacetone (10 mmol) was added to a solution of boric anhydride (5.0 mmol) in ethyl acetate (30 mL), followed by the addition of vanillin (20 mmol) or 4-hydroxybenzaldehyde (20 mmol) and tributyl borate (40 mmol). The reaction mixture was stirred at 50 °C for 10 min. Subsequently, n-butylamine (5.0 mmol) in ethyl acetate (5 mL) was added dropwise over 15 min at 50 °C and additionally stirred for 4 hours at 80 °C. Hydrochloric acid (1 N, 30 mL) was added, and the mixture was stirred for another 40 min. The organic layers were washed with water, dried with Na2SO4. The solvent was evaporated, and the residue was recrystallized from methanol to give the corresponding curcuminoids (1a and 1b) as yellow solids.
77%
Stage #1: at 120℃; for 0.0833333 h;
Stage #2: With Trimethyl borate; n-butylammonium acetate; N-butylamine In ethyl acetate; N,N-dimethyl-formamide at 20℃; for 48 h;
Step B. Curcumin AnaloguesAcetylacetone or a 3-substituted acetylacetone (lOmmol) and boron oxide (0.49 g, 7 mmol, 0.7 eq) were placed in a 50 mL flask and heated to 120°C for 5 min to form a pale-yellow suspension. The appropriate aldehyde (20 mmol, 2.0 eq) and trimethyl borate (4.16 g, 40 mmol, 4.0 eq) were dissolved in ethyl acetate (10 mL) and gradually added to reaction mixture. Thereafter, with stirring, 0.05mL of butylamine and 0.2 mL of butylammonium acetate in dimethylformamide solution (0.136 g/mL) were added. After 1 hour, a red-colored precipitate started to form. The whole reaction mixture was stirred at room temperature for 48 hours. The precipitate was filtered and dried, then dissolved in methanol (50 mL) and boiled for 30 min at 60°C. Methanol was removed by rotary evaporation and the crystalline crude product was purified by recrystallization from dichloromethane (20 mL) and methanol (20 mL) .1. Curcumin (Compound 1 ) : 1 , 7-Bis ( 4-hydroxy-3- methoxyphenyl) hepta-??, 6E-dien-3, 5-dione derived from vanillin and acetylacetone: orange crystals, 77.0percent yield, mp 175-176 °C. ESI (-ve) MS m/z 367.2 [M-H]". 1R NMR (DMSO- d6, 300 MHz) : ? 3.335(s, 6H) , 5.556(s, 1H) , 6.256(d, J=15.6Hz, 2H) , 6.320(d, J=7.8Hz, 2H) , 6.647(d, J=8.4Hz, 1H) , 6.653(d, J=8.1Hz, 1H) , 6.822(d, J=2.1Hz, 2H) , 7.044 (d, J=15.9 Hz, 2H) , 9.162(s. 2H) , 15.889 (s, 1H) ;2. 4-Methoxycarbonylcurcumin : 1 , 7-Bis ( 4-hydroxy-3- methoxyphenyl ) -4-methoxycarbonylhepta-lE, 6E-dien-3, 5-dione (Compound 2) : derived from vanillin and 3-methoxycarbonyl- 2 , 4-pentandione : yellow crystals, 72.0percent yield, mp 175-176 °C. ESI (-ve) MS m/z 425.2 [M-H]". 1R NMR (DMSO-d6, 300MHz) : ? 3.819 (s, 3H) , 3.903(s. 6H) , 6.834(d, J=7.2Hz, 2H) , 7.019 (d, J= 15.6, 2H) , 7.189 (d, J=8.1Hz, 1H) , 7.195 (d, J=8.4Hz, 1H) , 7.272 (d, J=1.5 Hz, 2H) , 7.722 (d, J=15.6 Hz, 2H) , 9.840 (s. 2H) , 18.294 (s, 1H) ;3. 4-Ethoxycarbonylcurcumin . (Compound 5) : 1, 7-Bis (4- hydroxyphenyl ) -4-methoxycarbonylhepta-lE, 6E-dien-3, 5-dione derived from 4-hydroxybenzaldehyde and 3-methoxycarbonyl- 2 , 4-pentandione : yellow crystals, 49.2percent yield, mp 214-216 °C. ESI (-ve) MS m/z 365.0 [M-H]". 1H NMR (DMSO-d6, 300 MHz) : ? 3.900 (s. 3H) , 6.831 (d, J=8.4Hz, 4H) , 6.986 (d, J=15.6 Hz, 2H) , 7. 576 (d, J=8.7 Hz, 4H) , 7.729 (d, J=15.6 Hz, 2H) , 10.172 (s. 2H) ,18.267 (s, 1H) ;4. (Compound 3) : 1 , 7-Bis ( 4-hydroxy-3-methoxyphenyl ) -4-2V- phenylaminocarbonylhepta-lE, 6E-dien-3, 5-dione derived from vanillin and 3-phenylaminocarbonyl-2 , 4-pentandione : orange crystals, 46.6percent yield, mp 193-194 °C . ESI (-ve) MS m/z 486.0 [M-H]". 1R NMR (DMSO-d6, 300 MHz) : ? 3.701 (s. 6H) , 6.730 (d, J=15.6 Hz), 6.790 (d, J=8.1 Hz), 7.082-7.152 (m, 5H) , 7.371 (t, 2H) , 7.685 (d, J=3.9 Hz, 2H) , 7.723 (d, J=3.9 Hz, 2H) , 9.788 (s. 2H) , 10.586 (s. 1H) , 17.556 (s, 1H) ;5. Compound 4: 1 , 7-Bis ( 4-hydroxyphenyl ) -4-2V- phenylaminocarbonylhepta-lE, 6E-dien-3, 5-dione derived from 4-hydroxybenzaldehyde and 3-phenylaminocarbonyl-2 , 4- pentandione: yellow crystals, 46.2percent yield, mp 220-221 °C . ESI (-ve) MS m/z 426.0 [M-H]". 1H NMR (DMSO-d6, 300 MHz) : ? 6.681 (d, J=15.6 Hz, 4H) , 6.787 (d, J=8.7 Hz, 4H) , 7.133 (t, 1H) , 7.375 (t, 2H) , 7.453 (d, J=9.0 Hz, 2H) , 7.695 (d, J=6.3Hz, 2H) , 7.723 (d, J=9.0 Hz, 2H) , 10.144 (s. 2H) , 10.605 (s. 1H) , 17.559 (s, 1H) ;
72%
Stage #1: With boric acid In N,N-dimethyl-formamide for 0.0333333 h; Microwave irradiation
Stage #2: With 1,2,3,4-tetrahydroisoquinoline; acetic acid In N,N-dimethyl-formamide for 0.333333 h; Microwave irradiation
2.1.2
Microwave assisted rapid synthesis of curcumin I (1)
Vanillin (0.304 g, 2 mmol), boric acid (0.2 g) and acetylacetone (0.1 mL, 1 mmol) in DMF (1.0 mL) were mixed in a conical flask and were subjected to 300 W microwave irradiation in a Samsung 800 W multimode domestic microwave oven for 2 min in such a way that after each irradiation for 15 s, 15 s cooling time was given to prevent boil offs.
During all microwave irradiation, a beaker containing water (50 mL) was used to absorb excess microwave energy.
After microwave irradiation for 2 min, tetrahydroquinoline (0.02 mL) and glacial acetic acid (0.06 mL) were added to the above mixture and it was subjected to 300 W microwave irradiation as above.
After 20 min, which involved 10 min of total heating, the reaction mixture thus obtained was worked up by adding to acetic acid (20percent, 10 mL) under rapid stirring and the mixture was further stirred for 1 h.
The precipitate so obtained was filtered and air dried.
It was purified by dry column flash chromatography using TLC grade silica gel-G eluted with dichloromethane - chloroform (1:1) (
Scheme 1
) to obtain curcumin I (1); yield 72percent; mp 182-184 °C. Lit. mp 182 °C.
39
Anal. Calcd for C21H20O6: C, 68.28; H, 5.47. Found: C, 68.32; H, 5.31; UV λmax (methanol): 268 and 430 nm; IR (KBr): 3350, 2900, 2950, 1620, 1580, 1505, 1460, 1420, 1280, 1260, 1200, 1160, 1120, 1030, 964, 940, 910 cm-1; 1H NMR (300 MHz, CDCl3): δ 3.91 (s, 6H, OMe), 5.82 (s, 1H, 4H), 6.56 (d, J = 16 Hz, 2H, 2,6H), 6.9-7.2 (m, 6H), 7.58 (d, J = 16 Hz, 2H, 1,7H); FAB MS spectrum, m/z: 369.78 [M+H]+. Calcd. For [C21H20O6+H]: m/z 369.14.
71% With boric acid; 2-methoxyethylamine In N,N-dimethyl-formamide; m-xylene at 59 - 62℃; for 3 h; Example 6 In a 4 neck round bottom flask equipped with thermometer, mechanical stirrer, a short distillation column and a water separator (6 ml hold up) with a reflux cooler (cooling media 100C) were provided 12.Og (194 mmole) of boric acid, 30.4g (200 mmole) of vanillin, 6.6g of m-xylene, 10.4g (104 mmole) of acetylacetone, 15 ml of dimethylformamide and 20 ml (20 mmole) of 2-methoxyethylamine In in DMF.The mixture was refluxed at 32 mmHg over the water separator for 2 hours at 59°-62°C. The level of the phase boundaries in the water separator was held constant by approx. 5 ml water phase and 1 ml organic phase, by occasional removal of water. To the red solution were added 5 ml (5 mmole) of 2-methoxyethylamine In in DMF. The reaction mixture was <n="8"/>refluxed for approx. 1 hour until complete conversion of the intermediate. Curcumin was isolated from the reaction mixture according to Example 2. 29.4g of curcumin were obtained (content = 89percent [wpercent], yield = 71percent).
68% With boric acid; N-butylamine In N,N-dimethyl-formamide; m-xylene at 79 - 82℃; for 2.5 h; Example 5.In a 4 neck round bottom flask equipped with thermometer, mechanical stirrer, a short distillation column and a water separator (6 ml hold up) with a reflux cooler (cooling media 100C) were provided 12.Og (194 mmole) of boric acid, 30.4g (200 mmole) of vanillin, 6.6g of m-xylene, 10.4g (104 mmole) of acetylacetone, 35 ml of dimethylformamide and 2.0 ml (20 mmole) of 1-butylamine.The mixture was refluxed at 75 mmHg over the water separator for 1.5 hours at 79 -82°C. The level of the phase boundaries in the water separator was held constant by approx. 5 ml water phase and 1 ml organic phase, by occasional removal of water. To the red solution were added 0.5 ml (5 mmole) of 1-butylamine and approx. 10ml DMF. The reaction mixture was refluxed for approx. 1 hour until conversion of the intermediate. Curcumin was isolated from the reaction mixture according to Example 2. 32.8g of curcumin were obtained (content = 76percent [wpercent], yield = 68percent)
62%
Stage #1: With boron trioxide; boric acid tributyl ester In ethyl acetate at 20℃; for 0.166667 h;
Stage #2: With N-butylamine In water; ethyl acetate at 20 - 60℃; for 1 h;
Take 60g vanillin and 210 mL of tributyl borate, Add 200mL dry ethyl acetate, stirring and mixing; Then, 20 g of acetylacetone and 10 g of boric anhydride were added, Room temperature stirring lOmin, Followed by the addition of 1-n-butylamine to the catalytic reaction, Stir at room temperature to complete reaction, Add dilute hydrochloric acid aqueous solution 300mL, 60 ° C stirring 60min, The ethyl acetate layer was separated and concentrated, and the appropriate amount of methanol precipitated product was added. The mixture was allowed to stand at -4 ° C, filtered and dried in vacuo to give 43.5 g of yellow curcumin in a yield of 62percent (Synthetic route shown in Figure 1, characterization map shown in Figure 2-4).
54% With boric acid; benzylamine In N,N-dimethyl-formamide; m-xylene at 50 - 53℃; for 2 - 3.5 h; Example 1In a 4 neck round bottom flask equipped with thermometer, mechanical stirrer, a short distillation column and a water separator (6 ml hold up) with a reflux cooler (cooling media -1°C) were provided 12.Og (194 mmole) of boric acid, 30.4g (200 mmole) of vanillin, 6.6g of m-xylene, 10.4g (104 mmole) of acetylacetone, 15 ml of dimethylformamide and 20 ml of Im benzylamine in DMF (20 mmole) .The mixture was refluxed at 18 mmHg over the water separator for 2 hours at 50 - 53°C. The level of the phase boundaries in the water separator was held constant by approx. 5 ml water phase and 1 ml organic phase, by occasional removal of water. To the red solution were added 10 ml of 0.5m benzylamine in DMF (5 mmole). The reaction <n="6"/>mixture was refluxed for approx. 1-3 hours (see table below) until complete conversion of the intermediates.If the reaction mixture got too viscous then the mixture was diluted with addition of dimethylformamide.The reaction mixture was analysed by HPLC after different reaction times with the following results [wpercent] :
25 g
Stage #1: With pyrrolidine; acetic acid In isopropyl alcohol for 0.5 h; Reflux
Stage #2: for 2.66667 h;
In a dry three-neck reaction flask, 30.4 g of vanillin and 40 g of isopropanol were added and dissolved by stirring. Then, 1.0 g of tetrahydropyrrole and 0.8 g of glacial acetic acid were added, and nitrogen gas was introduced to displace the air inside the bottle, and the temperature was brought to reflux. After refluxing for 0.5 hour, 10 g of acetylacetone was slowly added dropwise into the reaction flask and the addition was completed within about 2 hours. After the completion of the dropwise addition, the incubation reaction was performed and the incubation reaction was monitored by HPLC. After 40 minutes, the heat-retaining reaction was stopped, and the solvent was recovered by rotary evaporation. Then, 40 g of a saturated ammonium chloride solution was added to the reaction flask, and the mixture was cooled to room temperature under stirring to precipitate a large amount of an orange solid. The filter cake was collected by filtration. The filter cake was purified with ethanol to obtain 25 g of curcumin. The content is greater than 98percent (HPLC external standard).

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YieldReaction ConditionsOperation in experiment
75% at 20℃; Reflux To a stirred solution of aqueous formaldehyde (37percent mlv, 37.5 mmol, 2.8 mL) and aqueous dimethylamine (40percent mlv, 37.5 mmol, 4.8 mL) in ethanol (25 mL) was added 4-hydroxy-3-methoxybenzaldehyde (25 mmol, 3.883 g), the reaction mixture being stirred and heated at reflux for 45 minutes and then stirred at room temperature overnight. The cream-colored solid that precipitated was filtered under reduced pressure, washed with ice-cold acetone and dried at room temperature under vacuum, yielding 3- ((dimethylamino)methyl)-4-hydroxy-5-methoxybenzaldehyde as an off-white solid. See, e.g., (Scheme 2, Figure 2). Yield: 75percent, 3.910 g; mp (°C): 140-142 (Lit. 139-141; see reference [43j); ‘H NMR (400 MHz,CDC13): , ppm = 10.6 (1H, bs, OH), 9.77 (1H, s, CH), 7.34 (1H, s, ArH), 7.15 (1H, s,ArH), 3.94 (3H, s, OCH3), 3.76 (2H, s, CH2), 2.38 (6H, s, 2xCH3); ‘3C NMR (100 MHz,CDC13): , ppm = 190.7, 154.5, 148.6, 128.1, 125.3, 121.4, 109.8, 62.2, 56, 44.3.
70.3%
Stage #1: at 20℃; for 0.25 h;
Stage #2: at 20℃; for 24.5 h; Reflux
25 ml round bottom flask is added in aqueous solution of dimethylamine (2.25 ml, 15mmol), 37percent formaldehyde aqueous solution (1.11 ml, 15mmol), stir at room temperature 15 min, then adding ethanol (9 ml) of dissolved 4-hydroxy-3-methoxybenzaldehyde (1.52g, 10mmol), reflux reaction 30 min, stirring at room temperature to 24h, a white solid precipitated, the stirring under ice bath to 15 min, filtered, the filter cake are sequentially water, cold ethanol washing, collecting filter cake, drying to obtain the kind of white solid (1.47g, yield 70.3percent).
39.1 g for 0.75 h; Reflux Aqueous formalin (37percent m/v, 28 mL, 375 mmol), dimethylamine in water (40percent m/v, 48 mL, 375 mmol) and absolute ethanol (250 mL) were added to the three-necked flask.4-Hydroxy-3-methoxybenzaldehyde (38.9 g, 250 mmol) was added while stirring, and the mixture was warmed to reflux and stirred for 45 minutes. The mixture was then cooled to room temperature and stirred overnight. Filter, filter cake with ice cold acetoneAfter washing, it was dried under reduced pressure at room temperature to obtain 39.1 g of 3a product.
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[3] Patent: WO2016/80853, 2016, A1, . Location in patent: Paragraph 00310; 00311
[4] Patent: CN105418601, 2016, A, . Location in patent: Paragraph 0271; 0272, 0273
[5] Bulletin of the Chemical Society of Japan, 1956, vol. 29, p. 265,269
[6] Patent: CN107789628, 2018, A, . Location in patent: Paragraph 0196; 0197; 0198
  • 91
  • [ 121-33-5 ]
  • [ 87743-10-0 ]
Reference: [1] Patent: US2010/64450, 2010, A1,
  • 92
  • [ 121-33-5 ]
  • [ 1477-68-5 ]
Reference: [1] Patent: CN105481849, 2016, A,
[2] Organic Letters, 2016, vol. 18, # 15, p. 3542 - 3545
  • 93
  • [ 121-33-5 ]
  • [ 7149-10-2 ]
YieldReaction ConditionsOperation in experiment
112 g
Stage #1: With ammonia In methanol at 20℃; for 3 h;
Stage #2: at 45℃;
Stage #3: With hydrogenchloride In water at 0℃; for 3 h;
100 g of vanillin was added to 800 g of a methanol solution containing 20 wtpercent of ammonia in a reactor equipped with a heating, stirring, and a thermometer, and after stirring for 3 hours at room temperature, 270 g of sodium borohydride was added, and the temperature was raised to 45 after the reaction was detected by TLC. °C, 600 ml of methanol was distilled off under reduced pressure. After the reaction solution was cooled to room temperature, it was poured into 300 ml of distilled water at a temperature of 10° C., 800 ml of ethyl acetate was added, and the mixture was stirred uniformly and placed in a separatory funnel to obtain an organic phase. The ethyl acetate layer was successively washed with 5 wtpercent sodium bicarbonate solution and saturated brine three times with an amount of 800 ml/time, and then 100 g of anhydrous sodium sulfate was added to the ethyl acetate layer of the organic phase and dried for 3 hours to remove sodium sulfate by filtration. The filtrate was placed in a reactor, and the temperature was lowered to 0° C. with an ice-water bath while stirring. 120 g of dry hydrogen chloride gas was introduced and the temperature was maintained for 3 hours while stirring. The resulting solid was washed with 200 ml of ethyl acetate and then dried at 40-. Drying at 45°C for 10 hours yielded 112 g of the intermediate vanillin amine hydrochloride.
Reference: [1] Patent: EP2511283, 2012, A1,
[2] Patent: US2013/45942, 2013, A1,
[3] Patent: CN103288665, 2017, B, . Location in patent: Paragraph 0029; 0030; 0032; 0033
[4] Journal of Medicinal Chemistry, 2018, vol. 61, # 18, p. 8255 - 8281
  • 94
  • [ 121-33-5 ]
  • [ 80407-64-3 ]
Reference: [1] Patent: CN105566233, 2016, A,
  • 95
  • [ 121-33-5 ]
  • [ 130929-57-6 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 24, p. 7318 - 7337
[2] Synthetic Communications, 2012, vol. 42, # 9, p. 1359 - 1366
[3] Patent: WO2013/149566, 2013, A1,
  • 96
  • [ 121-33-5 ]
  • [ 162364-72-9 ]
Reference: [1] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 245 - 254
[2] Patent: CN105884699, 2016, A,
  • 97
  • [ 121-33-5 ]
  • [ 151103-08-1 ]
Reference: [1] Chinese Chemical Letters, 2013, vol. 24, # 8, p. 727 - 730
[2] Patent: CN106883118, 2017, A,
  • 98
  • [ 121-33-5 ]
  • [ 151103-09-2 ]
Reference: [1] Patent: CN106883118, 2017, A,
  • 99
  • [ 121-33-5 ]
  • [ 71-36-3 ]
  • [ 82654-98-6 ]
YieldReaction ConditionsOperation in experiment
96% at 20℃; for 18 h; Industrial scale 1 kg of vanillin, 13.1 liters of n-butanol (vanillin concentration of 0.5 mol / L), 0.2 kg of catalyst A and 0. 05 kg of catalyst E were added to the reactor and charged with IMPa hydrogen, Heated to 20 ° C reaction 18h, the detection of vanillin reaction is complete, stop heating, until the reaction tank after cooling the catalyst, the catalyst directly dry and then use. The filtrate was subjected to rotary evaporation to excess excess butanol, To give vanillin butyl ether 1. 33 kg, yield 96percent, purity> 98percent.
Reference: [1] Patent: CN105622363, 2016, A, . Location in patent: Paragraph 0025; 0026
  • 100
  • [ 121-33-5 ]
  • [ 179688-29-0 ]
Reference: [1] Patent: CN105566233, 2016, A,
  • 101
  • [ 121-33-5 ]
  • [ 79-07-2 ]
  • [ 186685-89-2 ]
YieldReaction ConditionsOperation in experiment
86% With potassium carbonate In N,N-dimethyl-formamide; acetonitrileReflux General procedure: A mixture of the corresponding halide (0.010 mol), hydroxybenzaldehyde (0.011 mol), and potassium carbonate (2.00 g, 0.0145 mol) in a mixture of acetonitrile-DMF (20 mL, 8 : 2, v/v) was refluxed for 5-7 h with stirring (TLC monitoring). After evaporation of the solvents, the residue was treated with water, a precipitate formed was filtered off, washed with 30percent aqueous methanol, and dried in air. Yields and physicochemical characteristics of aldehydes 9-12 are given in Table 4.
Reference: [1] Russian Chemical Bulletin, 2015, vol. 64, # 2, p. 395 - 404[2] Izv. Akad. Nauk, Ser. Khim., 2015, # 2, p. 395 - 404,10
[3] Russian Journal of General Chemistry, 2005, vol. 75, # 7, p. 1113 - 1124
[4] European Journal of Medicinal Chemistry, 2014, vol. 81, p. 1 - 14
  • 102
  • [ 97-72-3 ]
  • [ 121-33-5 ]
  • [ 188417-26-7 ]
Reference: [1] Russian Journal of Applied Chemistry, 2005, vol. 78, # 1, p. 120 - 124
  • 103
  • [ 121-33-5 ]
  • [ 236750-65-5 ]
Reference: [1] Patent: CN106957274, 2017, A,
  • 104
  • [ 121-33-5 ]
  • [ 162401-62-9 ]
Reference: [1] Patent: CN106883118, 2017, A,
  • 105
  • [ 75-45-6 ]
  • [ 121-33-5 ]
  • [ 162401-70-9 ]
YieldReaction ConditionsOperation in experiment
80%
Stage #1: With sodium hydroxide In N,N-dimethyl-formamide at 90℃; for 2 h;
DMF (450 mL) was added to the reaction flask, vanillin (30.0 g, 0.2 mol) and sodium hydroxide (13.0 g, 0.325 mol) the temperature was raised to 90 ° C and stirred for 2 hours. And then the addition of difluorochloromethane gas, TLC detects the vanillin raw material disappears and stops heating. After the reaction system was cooled to room temperature, the reaction was quenched by addition of water (450 mL) and extracted with dichloromethane. The organic phase was washed successively with saturated sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated to give a pale yellow oil 3-methoxy-4-difluoromethoxybenzaldehyde (31.9 g, yield 80percent, purity 99.2percent, HPLC chromatogram shown in Figure 1), without purification can be directly used in the next step
Reference: [1] Chinese Chemical Letters, 2013, vol. 24, # 8, p. 727 - 730
[2] Patent: CN106883118, 2017, A, . Location in patent: Paragraph 0038-0042
  • 106
  • [ 1895-39-2 ]
  • [ 121-33-5 ]
  • [ 162401-70-9 ]
YieldReaction ConditionsOperation in experiment
91% With caesium carbonate In DMF (N,N-dimethyl-formamide); water at 100℃; for 3.5 h; A solution of 4-hydroxy-3-methoxybenzaldehyde (2.0 g, 0.013 mol), sodium 2-chloro- 2, 2-difluoroacetate (4.8 g, 0.031 mol) and cesium carbonate (72 mg, 0.018 mol) in DMF (14 mL) and water (14 mL) was heated at 100°C for 3.5 hours. The mixture was acidified with concentrated hydrochloric acid and extracted with ethyl acetate (2x 25 mL). The organic layer was washed with water (2x25 mL), dried (MgSO4) and the solvent removed under reduced pressure. Purification by column chromatography with silica gel and ethyl acetate/n-hexane (1: 4) as eluent gave 4-(difluoromethoxy)-3-methoxybenzaldehyde (2.41 g, 91percent) as an oil. 8 (250 MHz, CDCI3) : 3.76 (s, 3H); 6.49 (t, JF-H=74. 0 Hz, 1H) ; 7.11 (d, J=8.0 Hz, 1H) ; 7.27 (dd, Je=1. 7 Hz, J2=8.0 Hz, 1 H) ; 7.31 (d, J=1.7 Hz, 1 H) ; 9.74 (s, 1 H).
Reference: [1] Patent: WO2005/58883, 2005, A1, . Location in patent: Page/Page column 131
  • 107
  • [ 1514-87-0 ]
  • [ 121-33-5 ]
  • [ 162401-70-9 ]
YieldReaction ConditionsOperation in experiment
41% With potassium carbonate In N,N-dimethyl-formamide at 65 - 70℃; for 16 h; Methyl chlorodifluoroacetate (1.4 ml_, 13 mmol) was added to a suspension of vanillin (1.0 g, 6.6 mmol) and potassium carbonate (2.0 g, 14 mol) in DMF (10 ml_). The suspension was heated to 65-70 0C for 16 h and the suspension was diluted with water. The aqueous phase was extracted with EtOAc and the combined organic fractions were washed with saturated aqueous NaHCO3, water, brine, dried and concentrated. The residue was purified by column chromatography, eluting with 10percent EtOAc/petrol to give 4-(difluoromethoxy)-3-methoxybenzaldehyde (0.54 g, 41 percent) as a colourless oil; δH (400 MHz, CDCI3) 3.95 (s, 3H, OCH3), 6.60 (t, J = 74 Hz, 1 H, OCHF2), <n="39"/>7.30 (d, J5,6 = 8.0 Hz, 1 H, H5), 7.45 (dd, J5,6 = 8.0, J = 2.0 Hz, 1 H, H6), 7.50 (d, J = 2.0 Hz, 1 H, HZ), 9.93 (s, 1 H, CHO); δc (100 MHz, CDCI3) 56.2, 110.9, 115.5 (t, J = 256 Hz), 121.5, 125.0, 134.5, 144.9, 151.5, 190.8.
41% With potassium carbonate In N,N-dimethyl-formamide at 65 - 70℃; for 16 h; Methyl chlorodifluoroacetate (1.4 mL, 13mmol) was added to a suspension of vanillin (15) (1.0 g, 6.6 mmol) and potassium carbonate (2.0 g, 14 mol) inDMF (10 mL). The suspension was heated to 65–70 °C for 16 h and the suspension was diluted with water. The aqueousphase was extracted with EtOAc and the combined organic fractions were washedwith saturated aqueous NaHCO3, water, brine, dried and concentrated.The residue was purified by column chromatography, eluting with 10percentEtOAc/petrol to give 4-(difluoromethoxy)-3-methoxybenzaldehyde (0.54 g, 41percent) asa colourless oil; δH (400 MHz, CDCl3) 3.95 (s, 3H, OCH3), 6.60 (t, J = 74 Hz, 1H, OCHF2), 7.30 (d, J5,6= 8.0 Hz, 1H, H5), 7.45 (dd, J5,6 = 8.0, J2,6 = 2.0 Hz, 1H, H6), 7.50 (d, J2,6 = 2.0 Hz, 1H, H2),9.93 (s, 1H, CHO); δC (100MHz, CDCl3) 56.2, 110.9, 115.5 (t, J = 256 Hz), 121.5, 125.0,134.5, 144.9, 151.5, 190.8. 
Reference: [1] Patent: WO2009/79692, 2009, A1, . Location in patent: Page/Page column 37-38
[2] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 24, p. 6868 - 6873
[3] Patent: WO2009/98283, 2009, A1, . Location in patent: Page/Page column 131
  • 108
  • [ 56-93-9 ]
  • [ 121-33-5 ]
  • [ 162401-70-9 ]
Reference: [1] Patent: US5712298, 1998, A,
  • 109
  • [ 121-33-5 ]
  • [ 828911-76-8 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 20, p. 6040 - 6047,8
  • 110
  • [ 67515-59-7 ]
  • [ 121-33-5 ]
  • [ 1055361-35-7 ]
Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 3, p. 788 - 808
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