19676-64-3|2,3,4-Trimethoxyphenol| Ambeed

Structure of 19676-64-3

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Quality Control of [ 19676-64-3 ] Purity: 97% SDS Specification

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Product Details of [ 19676-64-3 ]

CAS No. :	19676-64-3
Formula :	C₉H₁₂O₄
M.W :	184.19
SMILES Code :	COC1=C(OC)C(OC)=C(O)C=C1
MDL No. :	MFCD00068804
InChI Key :	OLUNIGWWQYXBJA-UHFFFAOYSA-N
Pubchem ID :	603577

Safety of [ 19676-64-3 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 19676-64-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	6
Fraction Csp3	0.33
Num. rotatable bonds	3
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	47.94
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	47.92 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.24
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	0.94
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.42
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.6
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	1.36
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.31

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.72
Solubility	3.53 mg/ml ; 0.0192 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.53
Solubility	5.4 mg/ml ; 0.0293 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-2.21
Solubility	1.15 mg/ml ; 0.00622 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.76 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.66

Application In Synthesis of [ 19676-64-3 ]

* 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.

Downstream synthetic route of [ 19676-64-3 ]

[ 19676-64-3 ] Synthesis Path-Downstream 1~35

1
[ 2103-57-3 ]
[ 19676-64-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sulfuric acid; dihydrogen peroxide; In methanol; water; at 20℃; for 24h;	Synthesis of 2,3,4-trimethoxyphenolA solution of 2,3,4-trimethoxybenzaldehyde (5.0 g, 36.7 mmol) and 31% aqueous H202 (5.3 g,48 mmol) in methanol (50 mL) was stirred with sulfuric acid (0.5 mL) at room temperature for24 h, the reaction was quenched with water, and extracted with CH2C12. The organic layer waswashed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel with EtOAc/hexane (15:85) toyield a pure product of 2,3,4-trimethoxyphenol (6.3 g, 95% yield). C9H,204 ‘H NMR (400 MHz,CDC13) 6.57 (1 H, d, J= 8.0 Hz), 6.50 (1 H, d, J= 8.0 Hz), 3.87 (3 H, br s), 3.83 (3 H, br s),3.74 (3 H, br s). ‘3C NMR (100 MHz, CDC13) 146.7, 143.3, 142.2, 140.5, 108.7, 107.6, 61.0,60.7, 56.4. HRMS (negative mode) calcd for C9H,,04: 183.0657, found: mlz 183.0661 [M- Hf.
94%	With formic acid; dihydrogen peroxide; In dichloromethane; water; at 20℃;Reflux;	2,3,4-trimethoxybenzaldehyde (11.7 g, 59.7 mmol) was dissolved in 200 mL of DCM. H2O2 30% (15.4 mL, 2.5 equiv) and formic acid (9.2 mL, 4 equiv) were added and the solution was stirred and heated to reflux for 6 h. The reaction mixture was then allowed to cool to room temperature and stirred overnight at the same temperature. 1.5 N NaOH (200 mL) was added to the solution, and the mixture was further stirred for 15 min. The organic layer was concentrated under vacuum and the residue was gathered with the aqueous layer. 130 mL of methanol were added, and the mixture was stirred for 30 min at r.t. The methanol was evaporated, and the mixture was extracted with DCM. The crude was purified by column chromatography on silicagel (eluent: petroleum ether/ethyl acetate 7:3) to give 1b (10.3 g, 94%). 1H NMR (500MHz, CDCl3) d: 3.81 (3H, s, OCH3), 3.89 (3H, s, OCH3),3,95 (3H, s, OCH3), 5.40(1H, s, OH), 6.55 (1H, d, J = 10 Hz,CH-5), 6.61 (1H, d, J = 10 Hz, CH-6).13C NMR (500MHz, CDCl3) d:56.6 (OCH3-4), 60.9 (OCH3-3), 61.2 (OCH3-2), 107.6 (CH-5), 108.5 (CH-6), 140.1 (C-2) 142.9(C-1), 145.2 (C-3), 150.4 (C-4); EIMS m/z 184 [M]+ (100), 169 (80), 154 (20), 126 (40); anal. C,58.71; H, 6.62 %, calcd for C9H12 O4 C, 58.69;H, 6.57 %,
79%	With sulfuric acid; dihydrogen peroxide; In methanol; at 0 - 20℃; for 0.5h;	A solution of 2,3,4-trimethoxybenzaldehyde (20g, 100.9mmol) and sulfuric acid (2mL) in MeOH (200mL) was stirred at 0C. To the previous solution, 30% H2O2 (13.6mL, 131.2mmol) was added dropwise at 0C and then was stirred at room temperature for 30min. The solution was evaporated and extracted with EtOAc. The crude product was purified through chromatography to provide a transparent oil (14.8g, 79%; EtOAc/hexane, Rf=0.25). 1H NMR (300MHz, CDCl3): δ 3.79 (s, 3H), 3.88 (s, 3H), 3.94 (s, 3H), 5.54 (s, 1H), 6.54 (d, 1H, J=9.0Hz), 6.62 (d, 1H, J=9.0Hz).

79%	With sulfuric acid; dihydrogen peroxide; In methanol; at 20℃; for 0.5h;Inert atmosphere;	4.1.7 2,3,4-Trimethoxyphenol (15) H2O2 (30%, 13.6 mL, 131.2 mmol) was added dropwise at 0 C to a solution of 2,3,4-trimethoxybenzaldehyde (20 g, 100.9 mmol), and sulfuric acid (2 mL) in MeOH (200 mL) and the resulting mixture was stirred at room temperature for 30 min. The reaction was evaporated and extracted with EtOAc. The organic layer was collected and purified by column chromatography to afford 15 (14.8 g, 79%) as a transparent oil. 1H NMR (300 MHz, CDCl3): δ 3.79 (s, 3H), 3.88 (s, 3H), 3.94 (s, 3H), 5.54 (s, 1H), 6.54 (d, J = 9.0 Hz, 1H), 6.62 (d, J = 9.0 Hz, 1H).
	With sulfuric acid; dihydrogen peroxide; In methanol; at 25℃;Inert atmosphere;	INTERMEDIATE 12,3,4-Trimethoxyphenol; A solution of 2,3,4-trimethoxybenzaldehyde (1,00 g, 5.10 mmol) and 30 wt/v % hydrogen peroxide (0.672 mL, 6.52 mmol) in cone. H2SO4 (0.102 mL) and MeOH (10.19 niL) was stirred overnight at 25 0C under N2. After this time the mixture was diluted with water (20 mL) and extracted with CH2Cl2 (3 x 30 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Biotage Horizon, 4OM, Si9 -30 niL/min, 100% hexanes for 360 mL, gradient to 50% EtOAc in hexanes over 2088 mL) to afford 2,3,4-trimethoxyphenol, as a colorless oil. R/ = 0.93 (50% EtOAc/hexanes). LCMS calc. = 185.1; found = 185.2 (M+H)+. 1H NMR (600 MHz, CDCl3): δ 6.62 (d, J- 9.0 Hz5 1 H); 6.55 (d, J= 8.9 Hz, 1 H); 5.49 (s, 1 H); 3.94 (s, 3 H); 3.89 (s, 3 H); 3.80 (s, 3 H).
	With sulfuric acid; dihydrogen peroxide; In methanol; at 20℃; for 12h;	To a solution of 2,3,4-trimethoxybenzaldehyde (1.0 g, 5.1mmol) in MeOH (7.3 mL), 31% H2O2 (0.75 mg, 6.6 mmol)and H2SO4 (0.07 mL) were added at room temperature.After stirring for 12 h at the same temperature, the volatilesolvent was removed in vacuo to leave a residue. Theresidue was treated with H2O (30 mL) and extracted twicewith CHCl3. The extract was washed with H2O, saturatedNaHCO3 aqueous solution, and brine. The organic layerwas dried over Na2SO4 and concentrated in vacuo to givecrude 2,3,4-trimethoxyphenol (1.1 g), which was used forthe next step without further purification.1H NMR (CDCl3; 400 MHz) δ 6.63 (1H, d, J = 9.0 Hz),6.56 (1H, d, J = 9.0 Hz), 5.39 (1H, s), 3.96 (3H, s), 3.90(3H, s), 3.81 (3H, s).
79 g		To a solution containing 150.0 g ( 0.77 mol) of 2,3,4-trimethoxybenzaldehyde in 1000 mL of DCM was added 300.0 g (1.74 mol) of m- CPBA in five portions (30 g each) at 0C - 10C (ice-water bath). After the addition the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was filtered to remove the solid and the filtrate was washed with aqueous NaHC03 (400 mL c 3), water (300 mL) and brine (300 mL). The organic layer was separated and dried over anhydrous Na2S04 and the mixture was filtered. The filtrate was concentrated to provide a dark yellow colored oil which was dissolved in EtOH (600 mL) and treated with a 10% aqueous KOH solution (500 mL) in one portion. The mixture was stirred at 50C for 4 h. The mixture was then cooled and acidified to pH=1 with 1 M HCI and extracted with DCM (500 mL x 3). The combined organic extracts were washed with water (500 mL) and brine (500 mL), dried over anhydrous Na2S04 and then filtered. The filtrate was concentrated and purified by silica gel chromatography (column height: 50 cm, diameter: 20 cm, 100-200 mesh silica gel, petroleum ether / EtOAc = 30/1 , 20/1 , 15/1 , 10/1) to give Int V-1 (79.0 g) as yellow oil. 1H NMR: (CDCIs, 400 MHz): d 6.63 (d, J = 8 Hz, 1 H), 6.55 (d, J = 8 Hz, 1 H), 5.38 (brs, 1 H), 3.96 (s, 3H), 3.90 (s, 3H), 3.81 (s, 3H).
79.0 g		Int V-1 To a solution containing 150.0 g (0.77 mol) of 2,3,4-trimethoxybenzaldehyde in 1000 mL of DCM was added 300.0 g (1.74 mol) of m- CPBA in five portions (30 g each) at 0C - 10C (ice-water bath). After the addition the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was filtered to remove the solid and the filtrate was washed with aqueous NaHC03 (400 mL c 3), water (300 mL) and brine (300 mL). The organic layer was separated and dried over anhydrous Na2S04 and the mixture was filtered. The filtrate was concentrated to provide a dark yellow colored oil which was dissolved in EtOH (600 mL) and treated with a 10% aqueous KOH solution (500 mL) in one portion. The mixture was stirred at 50C for 4 h. The mixture was then cooled and acidified to pH=1 with 1 M HCI and extracted with DCM (500 mL x 3). The combined organic extracts were washed with water (500 mL) and brine (500 mL), dried over anhydrous Na2S04 and then filtered. The filtrate was concentrated and purified by silica gel chromatography (column height: 50 cm, diameter: 20 cm, 100-200 mesh silica gel, petroleum ether / EtOAc = 30/1, 20/1, 15/1, 10/1) to give Int V-1 (79.0 g) as yellow oil. 1H NMR: (CDCIs, 400 MHz): d 6.63 (d, J = 8 Hz, 1H), 6.55 (d, J = 8 Hz, 1H), 5.38 (brs, 1H), 3.96 (s, 3H), 3.90 (s, 3H), 3.81 (s, 3H).

References: [1]Journal of Medicinal Chemistry,2022,vol. 65,p. 460 - 484.
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Angew. Chem.,2015,vol. 127,p. 3863 - 3867,5.
[6]Organic and Biomolecular Chemistry,2017,vol. 15,p. 9903 - 9909.
[7]Chemical and pharmaceutical bulletin,1980,vol. 28,p. 1648 - 1650.
[8]Journal of Chemical Research,2009,p. 186 - 187.
[9]Organic and Biomolecular Chemistry,2015,vol. 13,p. 5510 - 5519.
[10]Patent: WO2016/11130,2016,A1 .Location in patent: Paragraph 00228.
[11]Tetrahedron Letters,2016,vol. 57,p. 4053 - 4055.
[12]Synlett,2016,vol. 27,p. 1725 - 1727.
[13]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1994,vol. 33,p. 1103 - 1104.
[14]Journal of Natural Products,2019,vol. 82,p. 3074 - 3082.
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[20]Tetrahedron Letters,2009,vol. 50,p. 3084 - 3087.
[21]Chemische Berichte,1940,vol. 73,p. 795,802.
[22]Bulletin de la Societe Chimique de France,1968,p. 1026 - 1035.
[23]Acta Chimica Hungarica,1985,vol. 120,p. 163 - 166.
[24]Journal of the Chemical Society. Perkin transactions I,1987,p. 2017 - 2022.
[25]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1986,vol. 25,p. 1163 - 1164.
[26]Tetrahedron Letters,2005,vol. 46,p. 559 - 562.
[27]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2637 - 2640.
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[34]Chemical Communications,2011,vol. 47,p. 2868 - 2870.
[35]Patent: US2015/18566,2015,A1 .
[36]Organic Letters,2018,vol. 20,p. 1597 - 1599.
[37]Organic Process Research and Development,2019,vol. 23,p. 595 - 602.
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[39]Journal of Antibiotics,2019,vol. 72,p. 71 - 78.
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[43]Tetrahedron,2022.

2
[ 50-00-0 ]
[ 19676-64-3 ]
[ 39068-88-7 ]

References: [1]Journal of Chemical Research,2009,p. 186 - 187.
[2]Chemical and pharmaceutical bulletin,1980,vol. 28,p. 1648 - 1650.

3
[ 634-36-6 ]
[ 19676-64-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium peroxymonosulfate; In d(4)-methanol; water-d2; at 20℃; for 5h;	General procedure: To an NMR tube, 8.4 mg (50 µmoles) of 1 and 2.2 mg (30 µmoles) of tBuOH (used as an internal standard) in a 750 µL solution of 10% (v/v) d3-ACN in D2O were added. A 1H-NMR spectrum was recorded as a zero point (time = 0). A stock solution of 400 mM Oxone in 10% (v/v) d3-ACN in D2O was prepared and a 250 µL aliquot of the Oxone solution was added to the NMR tube to initiate the reaction. The reaction was followed by 1H-NMR spectroscopy over the course of 5 hrs at room temperature. The yields reported were based on the integration of aromatic peaks against the internal standard. This procedure was repeated for each of the different mol equivalents of Oxone, for the different cosolvents, and substrates.

References: [1]Journal of Organic Chemistry,1985,vol. 50,p. 1766 - 1768.
[2]Chemical Communications,2011,vol. 47,p. 2868 - 2870.
[3]Tetrahedron Letters,2013,vol. 54,p. 2344 - 2347.
[4]Organic Process Research and Development,2019,vol. 23,p. 595 - 602.

4
[ 13909-73-4 ]
[ 19676-64-3 ]

References: [1]Tetrahedron,1980,vol. 36,p. 123 - 129.
[2]Synthesis,1989,p. 167 - 172.
[3]Bulletin de la Societe Chimique de France,1970,p. 3617 - 3624.

5
[ 19676-64-3 ]
[ 3117-02-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium peroxymonosulfate; In [D3]acetonitrile; water-d2; at 20℃; for 5h;	General procedure: To an NMR tube, 8.4 mg (50 µmoles) of 1 and 2.2 mg (30 µmoles) of tBuOH (used as an internal standard) in a 750 µL solution of 10% (v/v) d3-ACN in D2O were added. A 1H-NMR spectrum was recorded as a zero point (time = 0). A stock solution of 400 mM Oxone in 10% (v/v) d3-ACN in D2O was prepared and a 250 µL aliquot of the Oxone solution was added to the NMR tube to initiate the reaction. The reaction was followed by 1H-NMR spectroscopy over the course of 5 hrs at room temperature. The yields reported were based on the integration of aromatic peaks against the internal standard. This procedure was repeated for each of the different mol equivalents of Oxone, for the different cosolvents, and substrates.
4.7 g	With ammonium cerium (IV) nitrate; In water; at 20℃; for 1.5h;	A solution of 2,3,4-trimethoybenzaldehyde 12 (9.78 g, 49.8 mmol) in CH2Cl2 (22 mL) was added slowly to a solution of m-CPBA (77 wt%, 12.1 g, 54.0 mmol) in CH2Cl2 (88 mL) at 0 C and the mixture allowed to warm to rt and stirred for 3 h. Saturated aqueous NaHCO3 (100 mL) was then added and the layers separated. The organic phase was washed with 10% (w/v) aqueous Na2S2O3, dried over Na2SO4 and evaporated to provide crude formate ester 13 as a yellow oil. This residue was re-dissolved in MeOH (50 mL), 10% (w/v) aqueous NaOH (50 mL) was added and the mixture stirred at rt for 16 h. The reaction was then acidified to PH 1 using 6.0 M aqueous HCl and diluted with CH2Cl2. The layers were separated and the aqueous phase extracted with CH2Cl2 (4x). The combined organic fraction were dried over MgSO4 and evaporated to provide the crude phenol 14 as orange oil. The material was carried forward without further purification. A solution of ceric ammonium nitrate (71.3 g, 13 mmol) in H2O (65 mL) was added to a flask charged with silica gel (150 g). CH2Cl2 (600 mL) was added, followed by a solution of the above crude product 14 in CH2Cl2 (50 mL) and the mixture stirred at rt for 1.5 h. The silica was then removed by suction filtration, rinsing with CH2Cl2. The layers of the filtrate were separated and the aqueous phase extracted with CH2Cl2 (2x). The combined organic fractions were evaporated. The residue was purified by flash column chromatography (EtOAc / petroleum ether = 1 / 20) to provide 15 as an orange solid (4.70 g, 28.0 mmol, 56 % over three steps from 12). 1H NMR (400 MHz, CDCl3) δ 7.12 (s, 1H), 4.07 (s, 3H), 4.01 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 181.5, 176.5, 145.6, 144.6, 135.7, 135.3, 61.6, 61.3. MS (ESI): m/z 169.2 [M+H]+

References: [1]Synthetic Communications,1985,vol. 15,p. 515 - 520.
[2]Angewandte Chemie - International Edition,2015,vol. 54,p. 3792 - 3796.
Angew. Chem.,2015,vol. 127,p. 3863 - 3867,5.
[3]Organic and Biomolecular Chemistry,2017,vol. 15,p. 9903 - 9909.
[4]Acta Chimica Hungarica,1985,vol. 120,p. 163 - 166.
[5]Journal fur praktische Chemie (Leipzig 1954),1985,vol. 327,p. 808 - 822.
[6]Tetrahedron Letters,2013,vol. 54,p. 2344 - 2347.
[7]Organic Letters,2018,vol. 20,p. 1597 - 1599.
[8]Bioorganic Chemistry,2019,vol. 89.

6
[ 30225-80-0 ]
[ 19676-64-3 ]

References: [1]Bulletin de la Societe Chimique de France,1970,p. 3617 - 3624.
[2]Synthesis,1989,p. 167 - 172.

7
[ 19676-64-3 ]
[ 107-30-2 ]
[ 104202-37-1 ]

References: [1]Journal fur praktische Chemie (Leipzig 1954),1985,vol. 327,p. 808 - 822.

8
[ 19676-64-3 ]
[ 77-78-1 ]
[ 21450-56-6 ]

Yield	Reaction Conditions	Operation in experiment
42 g	With potassium carbonate; In acetone; for 20h;Reflux;	To a solution of <strong>[19676-64-3]2,3,4-trimethoxyphenol</strong> (71g, 0.38mol), K2CO3 (50g, 0.36mol) in acetone (400mL) at room temperature was added dimethvl sulfate (53g, 0.42mol) in 15min. The reaction mixture was stirred and refluxed for 20h, and the solvent was evaporated followed by the addition of water (400mL). The mixture was simply stirred for 15min and allowed to stand at room temperature for 4h. The crude crystalline product formed and was collected, washed with water and purified by recrystallization from MeOH to afford 1,2,3,4-tetramethoxybenzene 45 (42g) as white solid. Total yield (from step 1 to 3): 70.6%. Mp 85.8-86.1C (lit [70]. mp 87-87.5C). TLC: Rf=0.75 (1:5 EtOAc/hexanes). 1H NMR (600MHz, Chloroform-d) δ 6.58 (s, 2H), 3.90 (s, 6H), 3.82 (s, 6H). 13C NMR (151MHz, Chloroform-d) δ 147.91, 143.52, 106.53, 61.33, 56.52. HRMS (+ESI) 199.0968 [M+ H]+, 221.0788 [M+ Na]+ (calcd. for C10H15O4+ 199.0965 and C10H14O4Na+ 221.0784).

References: [1]Tetrahedron,1980,vol. 36,p. 123 - 129.
[2]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2637 - 2640.
[3]Australian Journal of Chemistry,2000,vol. 53,p. 749 - 754.
[4]Heterocycles,1982,vol. 19,p. 691 - 695.
[5]Bulletin de la Societe Chimique de France,1970,p. 3617 - 3624.
[6]Journal of the Chemical Society. Perkin transactions I,1987,p. 2017 - 2022.
[7]European Journal of Medicinal Chemistry,2019,vol. 183.

9
[ 41038-42-0 ]
[ 19676-64-3 ]

References: [1]Journal of Organic Chemistry,1986,vol. 51,p. 5436 - 5439.

10
[ 30225-82-2 ]
[ 19676-64-3 ]

Yield	Reaction Conditions	Operation in experiment
2.22 g	With sodium hydroxide; In methanol; at 0℃; for 1.5h;	To a stirred solution of 2,3,4-trimethoxybenzaldehyde (3.0 g, 15.3 mmol) in DCM (60 mL) was added a solution of mCPBA (3.26 g, 18.9 mmol) dissolved in DCM (60 mL). After 5 h, the solvent was concentrated to half its volume and filtered to remove the precipitated m-chlorobenzoic acid. The filtrate was then washed with 5% aq. NaHCO3, water and sat. NaCl. The solvent was subsequently removed under reduced pressure to afford an oily residue. This was re-dissolved in methanol (30 mL) and 2.5M aq. NaOH (25 mL) was added to the solution at 0 C. After 1.5 h, the reaction was acidified with 2M aq. HCl and the product was isolated by extraction with ether (320 mL). The combined organic layers were dried under sodium sulphate, filtered and concentrated to an oil. This was purified by flash column chromatography (stationary phase: silica gel; mobile phase: hexane/ethyl acetate 2:1). All homogenous fractions were collected and the solvent was removed in vacuo to afford 13.1 as a yellow solid (2.22 g, 79%). The phenol 13.1 (1.5 g, 8.15 mmol) was re-dissolved in acetone (40 mL) and K2CO3 (5.0 g, 36.2 mmol) was subsequently added followed by ethyl bromoacetate (2 mL, 17.3 mmol). The reaction was refluxed for 12 h. On completion, the solvent was concentrated in vacuo and a solution of sat. NaCl (40 mL) was added. The product was extracted using diethyl ether (330 mL), dried under sodium sulphate, filtered and concentrated to an oil. It was purified by flash column chromatography (stationary phase: silica gel; mobile phase: hexane/ethyl acetate 5:1). All homogenous fractions were collected and the solvent was removed in vacuo to afford 13.2 as a yellow oil (1.67 g, 76%).
	With sodium hydroxide; In methanol; water; at 0 - 20℃; for 16h;	A solution of 2,3,4-trimethoybenzaldehyde 12 (9.78 g, 49.8 mmol) in CH2Cl2 (22 mL) was added slowly to a solution of m-CPBA (77 wt%, 12.1 g, 54.0 mmol) in CH2Cl2 (88 mL) at 0 C and the mixture allowed to warm to rt and stirred for 3 h. Saturated aqueous NaHCO3 (100 mL) was then added and the layers separated. The organic phase was washed with 10% (w/v) aqueous Na2S2O3, dried over Na2SO4 and evaporated to provide crude formate ester 13 as a yellow oil. This residue was re-dissolved in MeOH (50 mL), 10% (w/v) aqueous NaOH (50 mL) was added and the mixture stirred at rt for 16 h. The reaction was then acidified to PH 1 using 6.0 M aqueous HCl and diluted with CH2Cl2. The layers were separated and the aqueous phase extracted with CH2Cl2 (4x). The combined organic fraction were dried over MgSO4 and evaporated to provide the crude phenol 14 as orange oil. The material was carried forward without further purification. A solution of ceric ammonium nitrate (71.3 g, 13 mmol) in H2O (65 mL) was added to a flask charged with silica gel (150 g). CH2Cl2 (600 mL) was added, followed by a solution of the above crude product 14 in CH2Cl2 (50 mL) and the mixture stirred at rt for 1.5 h. The silica was then removed by suction filtration, rinsing with CH2Cl2. The layers of the filtrate were separated and the aqueous phase extracted with CH2Cl2 (2x). The combined organic fractions were evaporated. The residue was purified by flash column chromatography (EtOAc / petroleum ether = 1 / 20) to provide 15 as an orange solid (4.70 g, 28.0 mmol, 56 % over three steps from 12
71 g	With sodium hydroxide; In water; at 0 - 40℃; for 2h;	Crude 2,3,4-trimethoxyphenyl formate (73g) was added to methanol (120mL) and treated with aq. 10% NaOH (300mL) at 0C. The resulting homogeneous solution was stirred and allowed to warm to 40C for 2h and determined to be complete by TLC. Methanol was distilled out completely from the reaction mixture under reduced pressure. The residue was added to H2O (200mL), acidified with 3N HCI and extracted with DCM (3×150mL). The organic layer was washed with H2O (2×200mL), dried over Na2SO4, filtered and concentrated completely under reduced pressure to yield 2,3,4-trimethoxyphenol (71g) as a white solid (wet). TLC: Rf=0.50 (1:5 EtOAc/hexanes). This material was used for the subsequent reaction without further purification.

References: [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 3759 - 3763.
[2]Tetrahedron,2005,vol. 61,p. 10061 - 10072.
[3]Bulletin de la Societe Chimique de France,1970,p. 3617 - 3624.
[4]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2637 - 2640.
[5]Chemical Communications,2011,vol. 47,p. 2868 - 2870.
[6]Patent: US2015/18566,2015,A1 .Location in patent: Paragraph 0413; 0414; 0415.
[7]Organic Letters,2018,vol. 20,p. 1597 - 1599.
[8]Organic Process Research and Development,2019,vol. 23,p. 595 - 602.
[9]Bioorganic Chemistry,2019,vol. 89.
[10]European Journal of Medicinal Chemistry,2019,vol. 183.
[11]Tetrahedron,2022.

11
[ 100-97-0 ]
[ 19676-64-3 ]
[ 59481-63-9 ]

Yield	Reaction Conditions	Operation in experiment
36 g		A mixture of Int V-1 (74 g, 400 mmol), HMTA (67.6 g, 480 mmol) and TFA (500 mL) was refluxed under N2for 20 h. The solution was cooled to room temperature and concentrated under vacuum. Toluene (200 mL) was added to the residue and the solution was further concentrated to remove trace amount of TFA. The residual oil was treated with THF (300 mL) and 2 M HCI (300 mL) and then heated to reflux for 2 h. The solution was cooled to room temperature and extracted with DCM (300 mL c 3). The combined organic layers were washed with water (300 mL) and brine (300 mL), dried over anhydrous Na2S0 and then filtered. The filtrate was concentrated and purified by silica gel chromatography (column height: 50 cm, diameter: 20 cm, 100-200 mesh silica gel, petroleum ether / EtOAc = 30/1 , 20/1 , 15/1 , 10/1) to give Int V-2 (36.0 g) as yellow solid. 1H NMR: (CDCIs, 400 MHz): d 10.96 (s, 1 H), 9.75 (s, 1 H), 6.75 (s, 1 H), 4.03 (s, 3H), 3.92 (s, 3H), 3.84 (s, 3H).
36.0 g	With trifluoroacetic acid; for 20h;Reflux; Inert atmosphere;	Int V-1 Int V-2 A mixture of Int V-1 (74 g, 400 mmol), HMTA (67.6 g, 480 mmol) and TFA (500 mL) was refluxed under N2for 20 h. The solution was cooled to room temperature and concentrated under vacuum. Toluene (200 mL) was added to the residue and the solution was further concentrated to remove trace amount of TFA. The residual oil was treated with THF (300 mL) and 2 M HCI (300 mL) and then heated to reflux for 2 h. The solution was cooled to room temperature and extracted with DCM (300 mL c 3). The combined organic layers were washed with water (300 mL) and brine (300 mL), dried over anhydrous Na2S04 and then filtered. The filtrate was concentrated and purified by silica gel chromatography (column height: 50 cm, diameter: 20 cm, 100-200 mesh silica gel, petroleum ether / EtOAc = 30/1, 20/1, 15/1, 10/1) to give Int V-2 (36.0 g) as yellow solid. 1H NMR: (CDCI3, 400 MHz): d 10.96 (s, 1H), 9.75 (s, 1H), 6.75 (s, 1H), 4.03 (s, 3H), 3.92 (s, 3H), 3.84 (s, 3H).

References: [1]Journal of Medicinal Chemistry,2022,vol. 65,p. 460 - 484.
[2]Journal of Medicinal Chemistry,1999,vol. 42,p. 1448 - 1458.
[3]Tetrahedron Letters,2009,vol. 50,p. 3084 - 3087.
[4]Journal of Fluorine Chemistry,2009,vol. 130,p. 216 - 224.
[5]European Journal of Medicinal Chemistry,2014,vol. 86,p. 562 - 569.
[6]Patent: WO2019/152911,2019,A1 .Location in patent: Page/Page column 70.
[7]Patent: WO2019/152955,2019,A1 .Location in patent: Page/Page column 66.

12
[ 19676-64-3 ]
[ 79-11-8 ]
[ 79984-86-4 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 3759 - 3763.

13
[ 19676-64-3 ]
[ 3926-62-3 ]
[ 79984-86-4 ]

References: [1]Tetrahedron,2005,vol. 61,p. 10061 - 10072.
[2]Tetrahedron Letters,2004,vol. 45,p. 2377 - 2380.

14
[ 106-24-1 ]
[ 19676-64-3 ]
[ 845533-26-8 ]
[ 845533-25-7 ]

References: [1]Tetrahedron Letters,2005,vol. 46,p. 559 - 562.

15
[ 19676-64-3 ]
[ 74-88-4 ]
[ 21450-56-6 ]

References: [1]Journal of Natural Products,2019,vol. 82,p. 3074 - 3082.
[2]Organic Letters,2005,vol. 7,p. 2417 - 2420.
[3]Journal of Natural Products,2014,vol. 77,p. 1817 - 1824.
[4]Journal of Medicinal Chemistry,2010,vol. 53,p. 1200 - 1210.
[5]Chemical Communications,2011,vol. 47,p. 2868 - 2870.
[6]Organic Process Research and Development,2019,vol. 23,p. 595 - 602.
[7]Tetrahedron,2022.

16
[ 19676-64-3 ]
Q₄FA₁₂ [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2637 - 2640.

17
[ 19676-64-3 ]
Q₄FA₁₄ [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2637 - 2640.

18
[ 19676-64-3 ]
Q₄FA₁₅ [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2637 - 2640.

19
[ 19676-64-3 ]
Q₄FA₁₆ [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2637 - 2640.

20
[ 19676-64-3 ]
Q₄FA₁₈ [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2637 - 2640.

21
[ 19676-64-3 ]
[ 25245-39-0 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2637 - 2640.
[2]Tetrahedron,1980,vol. 36,p. 123 - 129.

22
[ 19676-64-3 ]
[ 857674-57-8 ]

References: [1]Organic Letters,2005,vol. 7,p. 2417 - 2420.
[2]Journal of Natural Products,2014,vol. 77,p. 1817 - 1824.
[3]Tetrahedron,2022.

23
[ 19676-64-3 ]
2-(4,5-dimethoxy-3,6-dioxo-cyclohexa-1,4-dienyl)-benzoic acid [ No CAS ]