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CAS No. : | 498-00-0 | MDL No. : | MFCD00004659 |
Formula : | C8H10O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ZENOXNGFMSCLLL-UHFFFAOYSA-N |
M.W : | 154.16 | Pubchem ID : | 62348 |
Synonyms : |
p-(Hydroxymethyl)guaiacol;Vanillin alcohol;4-Hydroxy-3-methoxybenzenemethanol;3-Methoxy-4-hydroxybenzyl alcohol;Vanillic alcohol;4-Hydroxy-3-methoxybenzyl alcohol
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 41.08 |
TPSA : | 49.69 Ų |
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) : | -7.25 cm/s |
Log Po/w (iLOGP) : | 1.79 |
Log Po/w (XLOGP3) : | -0.02 |
Log Po/w (WLOGP) : | 0.74 |
Log Po/w (MLOGP) : | 0.6 |
Log Po/w (SILICOS-IT) : | 1.18 |
Consensus Log Po/w : | 0.86 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.05 |
Solubility : | 13.6 mg/ml ; 0.0881 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.57 |
Solubility : | 41.1 mg/ml ; 0.267 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.76 |
Solubility : | 2.65 mg/ml ; 0.0172 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.26 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | at 80℃; for 3 h; Green chemistry | General procedure: Sulfated tungstate (10 wtpercent) was added to a mixture of p-methoxybenzyl alcohol (1 g, 7.25 mmol) and n-butanol (1.34 g, 18.11 mmol), and the reaction mixture was stirred at 80 °C for 1 h. The progress of the reaction was monitored by thin-layer chromatography (TLC). After completion of the reaction, the reaction mixture was diluted with EtOAc (15 ml) and filtered to recover the catalyst. The organic layer was concentrated under reduced pressure, and the residue obtained was purified by chromatography on silica gel (60–120) with n-hexane–EtOAc (90:10) as eluent to get pure p-methoxybenzyl ether as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.6% | With potassium thiosulfate; sodium acetate; acetic acid In water at 100℃; for 12h; | 1; 2; 3 Synthesis of Compound (I-1): In a three-necked flask equipped with a thermometer, a magnetic stirrer and a reflux condenser, 12 g of acetic acid, 8.2 g of sodium acetate, and 200 mL of deionized water were added, followed by stirring and dissolving; Then added 12.4 g of 3-methoxy-4-hydroxybenzyl alcohol (11-1) and 9.52 g of potassium thiosulfate, continued stirring, and heated to 100 ° C for 12 h. After cooling down, it was extracted twice with 200 mL of dichloromethane, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a bright yellow oil; Further, it was recrystallized by adding 200 mL of a 50% ethanol solution to obtain a pure product: 8.8 g of bis(3-methoxy-4-hydroxybenzyl) sulfide, and the yield was 71.6%. |
With sodium sulfide | ||
With hydrogen sulfide |
Multi-step reaction with 2 steps 1: BF3-Et2O 2: aq. NaOH / ethane-1,2-diol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium sulfide | ||
With hydrogen sulfide | ||
4.62 g | With hydrogenchloride; sodiumsulfide nonahydrate In water at 20 - 100℃; for 5h; | 2 Example 2: Preparation of 4,4'-[disulfide(methylene)]bis(2-methoxyphenol) Weigh sodium sulfide nonahydrate (19.2g) into water (200mL), stir to dissolve at room temperature 20-25, add 6N hydrochloric acid solution (25mL), add 4-hydroxy-3-methoxybenzyl alcohol (6.16g), The temperature was raised to 90-100°C and refluxed and stirred for 5 hours. The reaction solution was cooled to room temperature, extracted with ethyl acetate (200 mL×2), and dried over anhydrous sodium sulfate. Petroleum ether: ethyl acetate=2:1 silica gel column chromatography to obtain 4,4'-[disulfide(methylene)]bis(2-methoxyphenol) (4.62g) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dihydrogen peroxide In acetonitrile at 40℃; for 8h; | Also, for the vanillin alcohol oxidation reaction, 8 mL of acetonitrile was poured into a carouseltube and the temperature was increased to 40 C to provide suitable conditions for complete dissolutionof vanillyl alcohol. Then 0.77 g (5 mmol) of vanillyl alcohol was added to the solvent and after completedissolution of vanillyl alcohol in acetonitrile, 1.2 mL of hydrogen peroxide with 0.1 g catalyst wereadded to the reaction mixture. The carousel was adjusted to 90 C with a magnetic stirrer speed of800 rpm. To evaluate the progress of the reactions, the reaction mixture was sampled at dierent times.Sampling was done by a syringe with a filter. To study the reusability of the samples, catalysts wereseparated after reaction by a paper filter and washed by acetonitrile. Then, they were oven dried at110 C for 24 h and re-used in the vanillin production reaction. To obtain conversion and selectivity ofthe reaction, products were analyzed by the same gas chromatograph and also, results were confirmedby GC-MS. |
100% | With palladium; oxygen; Sodium hydrogenocarbonate In water monomer at 80℃; for 6h; | 2.7 Vanillic Alcohol, Veratryl AlcoholandHydrobenzoin Oxidations The reactions were performed in a 100mL round-bottomedflask. A colloidal suspension of PVP stabilized Pd NPs(20mL, 7.05 × 10-5mol of Pd), or a dispersion of Pd/TiO2(277mg, 7.05 × 10-5mol Pd) in 20mL of HPLC-gradewater, was introduced in the flask. NaHCO3(400mg) wasadded and the mixture heated at 80°C under vigorous stirring.The reactant (7.05 × 10-3mol for vanillic and veratrylalcohol, 100 equiv./Pd or 7.05 × 10-4mol for hydrobenzoin,10 equiv./Pd) was then added. The mixture was heated atthe desired temperature stirred under air or O2flow, for adetermined time with regular sampling for analysis. |
99% | With titanium(IV) dioxide; oxygen at 29.84℃; for 6h; Sealed tube; Irradiation; |
99% | With Pd0 immobilized on surface-functionalized SBA-15 In water monomer at 80℃; for 7h; Inert atmosphere; Green chemistry; | |
99% | With oxygen In 5,5-dimethyl-1,3-cyclohexadiene at 110℃; for 1h; | |
99% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; C21H22Cl2CuN2S In ethanol; water monomer at 70℃; for 24h; | |
96% | With NaClO adsorbed on montmorillonite K10 In dichloromethane at 20℃; for 0.416667h; | |
96% | With potassium carbonate In toluene at 20℃; for 10h; | |
93% | With mesoporous silica; 4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxoammonium perchlorate In dichloromethane | |
93% | With [Rh((5-H-dibenzo[a,d]cyclohepten-5-yl)2NH)(PPh3)]OTf; potassium carbonate; Nitrosobenzene In tetrahydrofuran at 20℃; | |
93% | With tert.-butylhydroperoxide In neat (no solvent) at 70℃; for 1h; | |
92% | With guanidinium chlorochromate; tetrabutylammonium bromide | |
92% | With MoO2Cl2(DMSO)2; dimethyl sulfoxide for 0.166667h; Microwave irradiation; | |
92% | With C30H56AgN4(1+)*C2F3O2(1-); potassium-t-butoxide In toluene at 20℃; for 4h; Darkness; | |
92% | With MoO2(2+)*C2H6OS*2Cl(1-) In dimethyl sulfoxide for 0.166667h; Microwave irradiation; | |
90% | With oxygen; 2,3-dicyano-5,6-dichloro-p-benzoquinone; NaNO2 In dichloromethane; acetic acid at 20℃; for 5h; | |
90% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; copper (II) acetate In water monomer; 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. |
90% | With potassium tetrakis-μ-pyrophosphitodiplatinate(II); tetra-n-butyl-ammonium chloride In dichloromethane; water monomer at 20℃; for 8h; Inert atmosphere; Irradiation; | |
89% | With |
|
89% | With dmap; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; copper (II) acetate In acetonitrile at 25℃; for 48h; Green chemistry; | |
88% | With K<SUB>2</SUB>OsO<SUB>4</SUB>.2H<SUB>2</SUB>O; potassium carbonate; potassium hexacyanoferrate(III) In water monomer; acetonitrile at 60℃; for 0.75h; chemoselective reaction; | |
88% | With tert.-butylnitrite; oxygen; 3,6-di(2'-pyridyl)-1,2,4,5-tetrazine; acetic acid In acetonitrile at 20℃; for 4.5h; Irradiation; | |
88.5% | With carbon supported Fe3O4; air In toluene at 80℃; for 4h; | |
88% | With pyridinium chlorochromate supported on montmorillonite KSF for 0.166667h; Milling; | Typical procedure for the oxidation and oxidative deprotection reactions General procedure: A mixture containing the PCC supported on KSF (1.7 g) and the substrate (0.5 mmol)was introduced into a clean and dry ball-milling vessel (grinding jar 12 mL) with twostainless steel grinding balls (d 15 mm). Next, the milling process was started at350 rpm for the time mentioned in Tables 2 and 3 and the progress of the reaction wasscreened by TLC (n-hexane, ethyl acetate 9:1). After completion, the resulting solid mixturewas washed with diethyl ether (2310 mL) and then the obtained filtrate was concentratedunder reduced pressure. Eventually, further purification was carried out bycolumn chromatography on silica gel (n-hexane/ethyl acetate, 9:1) if it was required. Allof the products were known compounds, identified on the basis of matching meltingpoints (for solids), Rf values (for liquids) and 1H-NMR and 13CNMR spectra with thosein the literature cited in Tables 2 and 3. Original spectra were submitted for review andare available in the Supplementary Materials or from the corresponding author uponrequest. For the sake of completeness, representative data are provided below. |
87% | With tert.-butylhydroperoxide; oxygen In decane; N,N-dimethyl-formamide; toluene at 80℃; Schlenk technique; | |
87% | With NiCl2/γ-Al2O3; potassium-t-butoxide In toluene at 80℃; for 7h; chemoselective reaction; | |
86% | With FeOx/MC-1; air In toluene at 80℃; for 8h; | |
86% | With triethylamine In o-dimethylbenzene at 140℃; for 36h; Inert atmosphere; Sealed tube; | |
85% | With 2,3-dicyano-5,6-dichloro-p-benzoquinone In 1,4-dioxane for 16h; Ambient temperature; | |
83% | With [Rh(1,3,4,5-tetramethylimidazole-2-ylidene)(trop2NH)][trifluoromethanesulfonate]; potassium-t-butoxide; Nitrous oxide In tetrahydrofuran; toluene at 50℃; Schlenk technique; | |
82% | With zinc(II) chlorosulphate In dichloromethane for 1h; Ambient temperature; | |
78% | With hydrogen bromide; dimethyl sulfoxide at 100℃; for 2h; | |
78% | With tert.-butylnitrite; oxygen; carbonic acid dimethyl ester; 2,3-dicyano-5,6-dichloro-p-benzoquinone at 18℃; for 15h; Irradiation; Sealed tube; | |
73.2% | With dihydrogen peroxide In neat (no solvent) at 80℃; for 2h; | General procedure: All reactions were carried out in a glass reactor (∼50 mL) withbenzyl alcohol (1 mmol) as model substrate. The optimized amountof nano catalyst (0.04 g), H2O2(30 wt% in water) was added tothe reaction mixture and vigorously stirred at optimized reactionconditions. The aliquots of the reaction mixture were analysedby GC. |
73.5% | With oxygen; C54H60N6O6Pd(2+)*2Br(1-); potassium carbonate In toluene at 80℃; for 8h; Autoclave; | |
70% | With [Mn(OAc){3-t-Bu-5-(CH2PPh3)salicylideneethylenediamine}]Cl2; dihydrogen peroxide; oxygen In methanol; water monomer | |
61.3% | With oxygen; La0.25CoO(x) In acetonitrile at 120℃; Autoclave; | 2.3. Catalytic performance General procedure: Benzyl alcohol (28.8 mmol, 3.0 mL) and catalyst (0.100 g) were added into an autoclave. The autoclave was sealed and purged three times with 0.1 MPa O2. At the room temperature, the autoclave was filled with 1.0 MPa O2. Then, the reaction was conducted at 120 °C for 10 h. Concentrations of benzaldehyde and benzyl alcohol were determined by a HPLC (YILITE LC 3000-2 series instrument) using an Ultimate MBC18 (250 mm x 4.60 mm) column by UV detector at 254 nm wavelength (Fig. S1). The mobile phase consisted of a methanol/water solution 25/75 (V/V) fed at a flow-rate of 1.0 mL/min. The yield and selectivity of the benzaldehyde were calculated according to the formula: |
60% | With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In tetrahydrofuran at 20℃; Darkness; | |
56% | With 1,4-diaza-bicyclo[2.2.2]octane; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; oxygen In toluene at 100℃; for 10h; | |
51.7% | With 2,2,6,6-tetramethyl-1-piperidinyloxy free radical; oxygen; potassium carbonate In water monomer at 50℃; for 24h; | 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. |
50% | With rose bengal disodium salt; oxygen; ammonium thiocyanate In acetonitrile at 20℃; for 20h; Irradiation; | (b) Millimolar scale reactions: General procedure: A glass vial fitted with magnetic stirrer and a magnetic bar containing a reaction mixture of alcohol (0.1 mmol), NH4SCN (3 eq.), catalyst (5 mol%) and 2 ml of solvent. The vial was closed with rubber septum and O2 was bubbling for 15 minutes using needles. The reaction mixture was irradiated under a 23W CFL lamp for a certain time period. Reaction progress was monitored by TLC. After, completion of the reaction, a yellow solid was formed. The reaction mixture of three vials with the same content were combined and filter it through whatman filter paper. The mixture was evaporated under reduced pressure and purified by column chromatography using hexane/ethyl acetate as eluent. Further, the reaction mixture was run on a GC-MS instrument for characterisation. Yield, conversion and selectivity were calculated using following equations. |
35% | With catalase from Micrococcus lysodeikticus; NAD; oxygen; magnesium(II) chloride In aq. phosphate buffer at 30℃; for 24h; Enzymatic reaction; | |
32% | With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In tetrahydrofuran at 20℃; for 6h; | |
19% | With tricobalt tetraoxide; dihydrogen peroxide In water monomer at 75℃; for 0.25h; Sonication; Green chemistry; | 2.2.2. Ultrasound-assisted oxidation of vanillyl alcohol 0.2 g (1.3 mmol) of vanillyl alcohol were dissolved in distilledwater at 75° C. The catalyst (4 mg, 2 wt%) was added, followedby the addition of 1-4 molar equivalents of 30 wt% aqueous hydrogenperoxide solution (135-540 μL) so that the total volume was4 mL. Ultrasound was generated by a Digital Sonifier S-250D fromBranson (power of standby P0 = 27.0 W, nominal electric power ofthe generator Pelec = 8.2 W). A 3.2 mm diameter tapered microtipprobe operating at a frequency of 19.95 kHz was used. The volumeacoustic power of this system was Pacous.vol = 0.25 W.mL-1 in water(determined by calorimetry measurements) [24] and an averageradical formation rate of v(I3) = 1.94 106 mol s-1 in 4 mL ofwater (determined by dosimetry method from 0.1 mol L-1 solution)[25]. The reaction medium (vanillyl alcohol, catalyst, H2O2and water) was inserted in a rounded cylindrical glass reactor(17 mm in interior diameter, 102 mm in height) and the temperaturewas not controlled. The ultrasonic probe was directlyimmersed in the reaction medium. Energy consumption was measuredwith a wattmeter (Perel). |
durch Oxydation; | ||
bei der Oxydation; | ||
With sodium hydroxide; nitrobenzene at 120℃; ΔH(excit.), ΔS(excit); | ||
With potassium cyanide; PMS; HCl buffer pH 7.5; 2,6-Dichlorophenolindophenol; ammonia hydrochloride; 2-amino-2-(hydroxymethyl)propane-1,3-diol at 30℃; for 4h; determination of Michaelis constant, vanillyl alcohol dehydrogenase from Rhodopseudomonas acidophila M402, further alcohols; | ||
With alcohol dehydrogenase in Nocardia cell-free extract; NADP In phosphate buffer; N,N-dimethyl-formamide at 20℃; Enzymatic reaction; | ||
With CoCl2·6H2O; oxygen; sodium hydroxide at 79.84℃; Ionic liquid; Autoclave; | ||
With lead (II) acetate; sodium hydroxide at 60 - 80℃; for 1h; | ||
65 %Chromat. | With potassium-t-butoxide; oxygen; copper chloride (II); 4-methyl-2-((pyridin-2-ylmethylene)amino)phenol In water monomer; acetonitrile at 20℃; for 8h; | |
With oxygen; sodium hydroxide In toluene at 149.84℃; for 4h; Autoclave; | ||
With oxygen In toluene at 80℃; for 1.5h; | ||
With cobalt oxide; oxygen; sodium hydroxide In water monomer; isopropanol at 80℃; for 6h; Autoclave; | ||
With oxygen In toluene at 70℃; for 3h; Sealed tube; | ||
With dihydrogen peroxide In water monomer; acetonitrile at 80℃; | ||
With dihydrogen peroxide In neat (no solvent) at 20℃; for 2.33333h; Green chemistry; | ||
With oxygen In toluene at 70℃; for 2h; Sealed tube; | 1 Procedure for synthesis of vanillylamine from vanillyl alcohol An oven dried Microwave vial was loaded with vanillyl alcohol (la) (46.3 mg, 0.3 mmol, 1.0 equiv.) and Pd(o)-Nanocatalyst (Pd(o)-AmP-MFC, 20.1 mg, 0.015 mmol, 8 wt%)27 or (Pd(o)-CPG, 500A, 90.0 mg, 0.015 mmol, 166 μηιο/g, 2 wt%) followed by addi- tion of toluene (0.6 mL). Next, the mixture was sealed and a balloon filled with 02 was connected to the vial and the reaction stirred at 70°C. After 3 h (when Pd(o)-AmP-MFC was used) or 2 h (when Pd(o)-CPG, 500A was used) conversion had reached >99% to vanillin (2a). Vanillin: IR (neat) λ 3335 (br), 3016 (w), 2838 (w), 1668 (m), 1583 (m), 1509 (m), 1461 (w), 1432 (w), 1400 (w), 1265 (s), 1207 (w), 1150 (s), 1118 (m), 1027 (m), 957 (w), 866 (w), 820 (w), 779 (w), 750 (m), 728 (s), 666 (w), 628 (w), 588 (w), 551 (w) cnr1; NMR (500 MHz, CDCI3): δ 9-82 (s, lH), 743-740 (m, 2H), 7.03 (d, J = 8.6 Hz, lH), 6.35 (br s, lH), 3-95 (s, 3H). C NMR (125MHz, CDCI3): δ 191.1, 151-9, 147-3, 130.0, 127.7, H4-5, 108.9, 56.2; HRMS (ESI+) [M+H]+ calcd for C8H903: 153.0546, found: 153.0544. | |
With eugenol oxidase from Rhodococcus jostii RHA1 In dimethyl sulfoxide at 20℃; for 4h; Enzymatic reaction; | ||
90 %Chromat. | With [η6-areneRuCl(N-(pyridin-2-ylmethylene)aniline)]PF6; potassium carbonate In para-xylene Inert atmosphere; Schlenk technique; Reflux; | Procedure for the oxidation of benzyl alcohol derivativescatalysed by complexes 1 and 3 General procedure: The benzyl alcohol derivatives (1 mmol), catalyst 1 or 3 (2 mol%),base (5 mol%) and toluene or p-xylene (20 mmol) were added to aSchlenk tube under argon or nitrogen atmosphere. The mixture wasstirred magnetically at reflux temperature. The yields of the prod-ucts were analyzed by GC chromatography using chlorobenzene asan internal standard. |
With Cu1.5Mn1.5O4; dihydrogen peroxide; sodium hydroxide In isopropanol at 85℃; for 2.5h; Autoclave; | ||
0.15 g | With Pd-modified SBA-15 catalyst In water monomer for 5h; Inert atmosphere; Reflux; | 2 In a 100 mL round bottom flask, 30 mg of cat-1, 0.2 g of 3-methoxy-4-hydroxybenzyl alcohol and 20 ml of water were added and the reaction temperature was 80 ° C. under a nitrogen atmosphere. Stirring and condensing under reflux conditions for 5h, until the end of the reaction, the catalyst was filtered, the organic extract was extracted with ethyl acetate, the solvent was distilled off under reduced pressure to give vanillin 0.15g, 3-methoxy-4-hydroxybenzyl alcohol conversion 76%. |
With vanillyl alcohol oxidase; oxygen In aq. phosphate buffer at 19 - 20℃; Enzymatic reaction; | 4.5. Enzymatic Reactions for the Xylenol Orange Assay General procedure: Enzymatic reactions were performed in 96-wells plates. Substrate solution (180 L) was addedto 20 L enzyme solution to give a reaction mixture containing 20 nM enzyme and 2 mM substratein 50 mM potassium phosphate buffer, pH 7.5. For measurements where the oxidation of eugenolor vanillyl alcohol was followed in time, the reaction mixtures were incubated for the desired time(ranging from 1-20 min) at room temperature (19-20 C), after which 20 L of the reaction mixture wasremoved and the hydrogen peroxide concentration was determined using the xylenol orange assayas described below. Reaction rates were determined by fitting a curve to the linear range of the datausing IgorPRO. For substrate specificity screening, the reaction mixtures were incubated for 10 minat room temperature (19-20 C), after which a 20 L sample was taken and the hydrogen peroxideconcentration was determined using the xylenol orange assay as described below. Three of the testedcompounds, 4-n-nonylphenol, 4-hydroxybenzyl alcohol and 4-cyclohexylphenol, were poorly solublein water at the used concentration and therefore were added to the reaction mixtures as (partial)suspensions. Reaction rates were estimated by assuming that there is a linear increase in hydrogenperoxide concentration during the reaction time. | |
With vanillyl alcohol oxidase from Penicillium simplicissimum In aq. phosphate buffer at 25℃; Enzymatic reaction; | ||
With oxygen at 60℃; for 24h; | ||
With sodium hydroxide; m-nitrobenzene sulfonic acid sodium salt | ||
With 10percent of carbon nanofibers/Zinc oxide composite In water monomer at 20℃; for 8h; Inert atmosphere; Darkness; UV-irradiation; | 2.4. Photocatalytic experiments The reaction medium was continuously saturated with argon (200 mL min-1) and kept in dark conditions for 15 min. The irradiation was performed using a four UV-LED system emitting at 370 nm located symmetrically from the outside at 4 cm from the reactor wall. The average nominal irradiance of each UV-LED was 450W m-2, determined using a UV-vis spectroradiometer (OceanOptics USB2000+). The suspension was irradiated for 8 h and samples were periodically withdrawn to monitor alcohol and aldehyde concentration by HighPerformance Liquid Chromatography (HPLC), using a Shimadzu Corporation apparatus equipped with a Diode Array Detector (SPDM20 A). A KinetexTM F5 1.7 μm 100 Å column (100mm×2.1 mm)was used with a solvent delivery pump (LC-30AD) using a flow ratefixed at 0.15 mL min-1. The temperature of the column oven and autosamplerwere set at 35 °C and 4.0 °C, respectively. An equilibratedmixture of 0.1% v/v of formic acid (A) and methanol (B) with volumeratio of 30:70 (A:B) was isocratically eluted for 15 min. The concentrationof VA, VAD, PA and PAD were determined at 230 nm. TheBA concentration was determined at 207 nm, while BAD concentrationwas determined at 250 nm. The AA and AAD concentration were determined at 226 nm and 282 nm, respectively.The conversion (C) of alcohol, selectivity (S) and yield (Y) towardsthe aldehyde production were determined as described elsewhere [20]. | |
With air; Au-Pd alloy nanoparticles supported on phosphate-modified Mg-Al hydrotalcite In 1,4-dioxane at 20℃; for 24h; Irradiation; chemoselective reaction; | ||
With 2,2'-azinobis(3-ethylbenzthiazolinesulfonate); horse-radish peroxidase; choline oxidase from Arthrobacter cholorphenolicus, mutant S101A/D250G/F253R/V355T/F357R/M359R In aq. phosphate buffer at 30℃; for 24h; Enzymatic reaction; | ||
With nanoparticles of Au-Pd alloy with molar ratio 1:1.2 supported on γ-alumina; air In water monomer at 80℃; for 2h; | ||
With oxygen In ethanol at 100℃; for 4h; Green chemistry; | ||
With 4-ethylphenol oxidase from Gulosibacter chungangensis In aq. phosphate buffer; dimethyl sulfoxide at 25℃; for 24h; Enzymatic reaction; | ||
With oxygen In isopropanol at 120℃; for 4h; Autoclave; | ||
With oxygen at 99.84℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium tetrahydridoborate In methanol for 1h; | |
97% | With aluminum(III) oxide; zinc(II) tetrahydroborate In tetrahydrofuran at 20℃; for 0.08h; chemoselective reaction; | A typical procedure for reduction of aldehydes with the Zn(BH4)2/Al2O3 system in THF General procedure: Zn(BH4)2 was prepared from ZnCl2 and NaBH4 according to an established procedurefrom the literature.5 In a round-bottomed flask (10 mL) equipped with a magnetic stirrer, asolution of benzaldehyde (0.106 g, 1 mmol) in THF (3 mL) was prepared. To this solution,Zn(BH4)2 (0.048 g, 0.5 mmol) and then neutral Al2O3 (0.101 g, 1 mmol) were added and themixture was stirred at room temperature for 5 minutes. Completion of the reaction wasmonitored by TLC (eluent, CCl4/Et2O: 5/2). Then, distilled water (1 mL) was added to thereaction mixture and stirring was continued stirred for 5 min.. The mixture was extracted withCH2Cl2 (3×6 mL) and dried over anhydrous Na2SO4. Evaporation of the solvent and a shortcolumn chromatography of the resulting crude material over silica gel (0.015-0.040 mm, eluent,CCl4/Et2O: 5/3) afforded the pure liquid benzyl alcohol (0.102 g, 94 %, Table III, entry 1). |
95% | With lithium hydroxide monohydrate; nickel (II) chloride; zinc In N,N-dimethyl-formamide for 2h; Ambient temperature; |
95% | With cobalt(II) chloride; zinc In lithium hydroxide monohydrate; N,N-dimethyl-formamide for 2.5h; Ambient temperature; | |
95% | With sodium tetrahydridoborate; mesoporous silica at 40 - 45℃; for 2h; | |
95% | With sodium tetrahydridoborate; pyrographite In tetrahydrofuran; lithium hydroxide monohydrate at 20℃; for 0.1h; | |
95% | With sodium tetrahydridoborate; diammonium oxalate In acetonitrile at 20℃; for 0.666667h; | |
95% | With zinc(II) tetrahydroborate In tetrahydrofuran; lithium hydroxide monohydrate at 20℃; for 0.0166667h; | |
95% | With sodium cyanotrihydridoborate at 20℃; for 0.05h; | |
94% | With sodium tetrahydridoborate; nickel(II) phthalocyanine In PEG-400 at 20℃; for 0.416667h; chemoselective reaction; | |
93% | With mesoporous silica; sodium cyanotrihydridoborate for 0.0125h; Neat (no solvent); Microwave irradiation; regioselective reaction; | |
91% | With isopropanol at 120℃; for 4h; | 2.4. Catalytic reaction General procedure: The MPV reaction of the biomass-derived compounds with 2-propanol was carried out in an oil-heated condition in a 15 ml Ace pressure tube (Synthware, Beijing). Typically, aldehydes (1.0 mmol), catalysts (0.1 g), and 2-propanol (10 mL) were added into the reactor, and then placed into the oil bath at stated temperature of 80-140 °C, followed bythe magnetic stirring for specific time at 600 rpm. After completion, the reaction tube was cooled to room temperature with cold water in a beaker. The reaction mixture was centrifuged and collected for analysis. Quantitative analysis of reactants and products on a standard sample using toluene as an internal standard on a GC (Shimadzu Nexis GC-2030) equipped with an HP-5 capillary column (30.0m×250mm×0.25 mm) and a flame ionization detector. Identification of products were observed using GC-MS (GCMS-QP2010 Ultra) equipped with HP-5MS capillary column (30.0m×250mm×0.25 mm). |
89% | With sodium tetrahydridoborate In methanol at 0 - 20℃; for 24.5h; Inert atmosphere; | 4-(Hydroxymethyl)-2-methoxyphenol 16 To a suspension of NaBH4 (9.9 g, 0.26 mol) in MeOH (250 mL), under an atmosphere of nitrogen at 0°C, was added a solution of vanillin 15 (20 g, 0.13 mol) in MeOH (250 mL) dropwise over 30 min and the resultant mixture was warmed to room temperature and stirred for 24 h. The mixture was diluted with ethyl acetate (100 mL) and a saturated aqueous solution of NH4Cl (50 mL) was added. The volatile solvent was removed under reduced pressure and the aqueous mixture was extracted with ethyl acetate (5x50 mL). The combined organic extracts were washed with brine (40 mL), dried (MgSO4) and the solvent was removed under reduced pressure to yield the title compound (18 g, 89%) as a viscous yellow oil which required no further purification. RF (2:1 hexanes, ethyl acetate) 0.45; dH (400 MHz; CDCl3; Me4Si) 3.91 (3H, s,OCH3), 4.61 (2H, d, J 5.2 Hz, CH2Ar), 5.62 (1H, s, OH), 6.83-6.93 (3H, m, 3-, 5- and 6-H), 8.80 (1H, s, OH); Spectroscopic data were in accordance with literature values. |
88% | With cobalt(II) chloride; zinc In tetrahydrofuran at 25℃; for 2h; | |
85% | In tetrahydrofuran for 0.0833333h; Ambient temperature; | |
84% | With sodium tetrahydridoborate; Montmorillonite K10 In hexane at 20℃; for 1.25h; | |
83% | With sodium tetrahydridoborate; zinc(II) phthalocyanine In PEG-400 at 20℃; for 2h; | |
83% | With methanol; sodium tetrahydridoborate at 20℃; for 1h; | |
80% | With sulfurated borohydride exchange resin In methanol at 25℃; for 0.583333h; | |
78% | With borohydride exchange resin; anhydrous nickel acetate In methanol for 3h; Ambient temperature; | |
78% | With Cocos nucifera juice at 20℃; for 30h; Inert atmosphere; | |
77% | With C54H60N6O6Pd(2+)*2Br(1-); hydrogen; 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene at 100℃; for 6h; | General procedure for the hydrogenation of aldehyde and ketones General procedure: A mixture of aldehyde (2.0 g, 18.8 mmol), toluene (20 mL), DBU (12.5 mg, 0.082 mmol) and catalyst 5 were pressurised under a hydrogen atmosphere (10 bar) at 100 °C for 6 h. The reaction is monitored by GC for reaction completion. The reaction mass is then removed from the reactor filtered over hyflo bed and concentrated to remove the solvent. It was then purified using column chromatography using Silica gel 60-120 mesh (Hexane:Ethyl acetate) as eluent or by distillation using Kugelrohr instrument. The final product is then analysed by NMR and GC-MS to confirm the products |
75% | With magnesium; stannous chloride In tetrahydrofuran for 0.25h; | |
74% | With cucumber juice at 30 - 35℃; for 72h; Inert atmosphere; Green chemistry; | |
70% | With sodium tetrahydridoborate In methanol | |
70% | With sodium tetrahydridoborate In tetrahydrofuran at 20℃; Inert atmosphere; | |
63% | Stage #1: vanillin With chlorocyclopentadienylbis(triphenylphosphine)ruthenium(II); phenylsilane In toluene for 24h; Reflux; Stage #2: With N,N,N-tributylbutan-1-aminium fluoride In toluene at 20℃; for 0.5h; chemoselective reaction; | 4.3. General procedure for the reduction of solid aldehydes with the system PhSiH3/[CpRu(PPh3)2Cl] General procedure: To a solution of [CpRu(PPh3)2Cl] (1 mol%) and solid aldehyde (1.0 mmol) in toluene (3 ml) was added PhSiH3 (1.2 mmol). The reaction mixture was stirred at reflux temperature under an air atmosphere (the reaction times are indicated in Table 4). Then, TBAF (1.0 mmol) was added and the reaction mixture was stirred at room temperature during 30 min. After evaporation, the reaction mixture was purified by silica gel column chromatography with ethyl acetate:n-hexane (1:3) to afford the corresponding alcohols. |
57.3% | With 1% Pd/C; hydrogen In toluene at 160℃; for 0.25h; Flow reactor; | |
54% | With nickel In tetrahydrofuran at 20℃; | |
36% | With hydrogen In methanol at 100℃; for 4h; Sealed tube; Green chemistry; chemoselective reaction; | |
12% | With culture of Aspergillus niger GC-4 In dimethyl sulfoxide for 336h; Microbiological reaction; | |
7% | With whole seeds of Bauhinia variegata L. In lithium hydroxide monohydrate; dimethyl sulfoxide at 40℃; for 96h; | |
katalytische.Hydrogenation; | ||
With ammonium hydroxide | ||
With Adams’s catalyst; ethanol; iron(II) chloride Hydrogenation.weiteres Reagens: Natriumaethylat; | ||
With Pd-BaSO4; glacial acetic acid Hydrogenation; | ||
With mercury-cathode at 8 - 10℃; bei der elektrolytischen Reduktion; | ||
With methanol; platinum Hydrogenation; | ||
With ethanol; platinum Hydrogenation; | ||
With ethyl acetate; platinum Hydrogenation; | ||
With sodium hydroxide; sodium tetrahydridoborate | ||
With sodium tetrahydridoborate; glacial acetic acid Ambient temperature; | ||
With sodium tetrahydridoborate In methanol Yield given; | ||
90 % Chromat. | With aluminium; nickel (II) chloride In tetrahydrofuran for 0.166667h; | |
With dicyanodihydroborate; trifluoroacetic acid In tetrahydrofuran Heating; | ||
With sodium tetrahydridoborate In methanol | ||
With sodium tetrahydridoborate In ethanol Ambient temperature; | ||
With hydrogen; nickel In ethanol for 1h; | ||
With hydrogen In lithium hydroxide monohydrate at 90℃; | ||
With sodium tetrahydridoborate In methanol at 20℃; for 2h; | ||
With Ru/CNT; hydrogen In lithium hydroxide monohydrate; Bicyclo[4.4.0]decane at 50℃; for 3h; | 2.4 Hydrodeoxygenation of vanillin General procedure: The vanillin hydrodeoxygenation reactions were performed in a 100mL autoclave under stirring. Hydrodeoxygenation of vanillin was used to probe the catalytic hydrogenation activities of the Ru/CNT catalysts, as illustrated in Eq. (1). For a typical run, the reaction was carried out with 5.9mmol vanillin, 0.2mol% Ru/CNTs, 20mL decalin and 20mL water as bi-solvents, and 1MPaH2 at 100°C for 3h. After each reaction, the emulsion was broken by filtering out the catalyst particles. The two liquid phases were separated and analyzed individually by means of GC (2014C, SHIMADZU) and GC-MS (QP 2010 Plus, SHIMADZU). | |
90 %Chromat. | With methyl ammonia borane In lithium hydroxide monohydrate at 20℃; for 0.5h; Green chemistry; chemoselective reaction; | General Procedure for the Hydrogenation of Carbonyl Compounds to Alcohols General procedure: A mixture of carbonyl compound (1 mmol) and MeAB (1 mmol) in neat water (2 mL) was stirred at room temperature for an appropriate time. The reaction was monitored by TLC and gas chromatography (GC). After completion, the reaction mixture was extracted with ethyl acetate (310 mL). Then, the organic extracts were concentrated by rotary evaporation, and the residue was purified by silica-gelcolumn chromatography (elution by using petroleum ether=ethyl acetate 5:1) to obtain the alcohol product. |
With sodium tetrahydridoborate; lithium hydroxide monohydrate In acetonitrile | ||
With hydrogen In lithium hydroxide monohydrate; Bicyclo[4.4.0]decane at 50℃; for 6h; chemoselective reaction; | ||
With sodium tetrahydridoborate In methanol at 20℃; for 2h; | ||
Stage #1: vanillin In methanol; lithium hydroxide monohydrate for 0.25h; Stage #2: With hydrogenchloride In methanol; lithium hydroxide monohydrate | ||
Multi-step reaction with 2 steps 1.1: hydrogenchloride; lithium hydroxide monohydrate / methanol 1.2: 25 °C / Reflux 2.1: lithium hydroxide monohydrate / 3 h / 100 °C | ||
Multi-step reaction with 3 steps 1.1: hydrogenchloride; lithium hydroxide monohydrate / methanol 1.2: 25 °C / Reflux 2.1: hydrogenchloride / methanol / pH 2 - 3 3.1: lithium hydroxide monohydrate / 3 h / 100 °C | ||
With hydrogen In N,N-dimethyl-formamide at 150℃; for 4h; Autoclave; | ||
Ca. 97 %Chromat. | With Pd/Al2O3; hydrogen In ethanol at 50℃; for 1h; | 2.3. Catalytic reactions, yield, and rate calculations General procedure: Vanillin hydrogenation/hydrodeoxygenation (HDO) reactions were performed in a 100 mL liquid-phase semi-batch reactor at 50 °C in 200 psi H2 for one hour, with a stirring rate of 1200 rpm. The reaction solution included 32 mL ethanol (solvent), 267 mg (0.05 M) vanillin(reactant), 20 mg supported Pd catalysts (PdTotal:Vanillin=1:176 mol/mol), and 1 mL methanol (internal standard for gas chromatography analysis). For Pd black catalyst, 2 mg (PdTotal:Vanillin=1:88 mol/mol) was used to reach a similar conversion with the Pd/Al2O3 catalysts after the reaction course of 1 h. Styrene hydrogenation reactions were performed in the same reactor at room temperature, with a lower H2 pressure of 30 psi and a lower catalyst loading(Pdtotal:styrene=1:628 mol/mol) to obtain a moderate reaction rate.Seven 1 mL liquid samples were taken from the reactor during the 1 h reaction period for vanillin hydrogenation/HDO. For styrene hydrogenation, a total of six samples were taken at 30 s intervals in the first 2.5 min of the reaction to calculate initial rates. For recycling reactions, the catalyst was rinsed twice with 20 mL methanol in a sonication cleaner and subsequently centrifuged. The methanol supernatant was then poured out and the catalyst was dried in a vacuum desiccator before reuse. The activity of the catalyst was characterized by the rate of creosol production during the first 5 min of the reaction. With vigorous stirring, the solid catalyst was expected to be uniformly dispersed in the reaction mixture; the ratio of the catalyst to the reaction solution was thus held constant within the reactor by simultaneously sampling liquid and catalyst with continuous stirring, and subsequently filtering out the catalyst using a syringe filter (0.22 μm, nylon). The liquid samples were analyzed by an Agilent 7890 A gas chromatography witha flame ionization detector, using an Agilent HP-5 capillary column. |
93 %Chromat. | With isopropanol at 140℃; for 2h; | |
With ethanol; nickel at 40 - 50℃; Hydrogenation; | ||
With hydrogen In isopropanol at 179.84℃; for 2.5h; | ||
With sodium tetrahydridoborate | ||
With sodium tetrahydridoborate at 20℃; for 4h; Inert atmosphere; | In process 200-3, the benzyl alcohol diol derivative 230 of vanillin is produced in a reduction reaction with sodium borohydride. Sodium borohydride (NaBH4) is added to a solution of vanillin 205 in anhydrous ether or tetrahydrofuran (THF). The mixture is stirred at room temperature under an inert gas (e.g., argon or nitrogen) for approximately four hours. The mixture is then concentrated, and purified by column chromatography to give the benzyl alcohol diol derivative 230 as a colorless oil. | |
With hydrogen In lithium hydroxide monohydrate at 25℃; for 12h; | ||
With hydrogen In toluene at 100℃; for 5h; | ||
94 %Chromat. | With hydrogen In ethanol at 140℃; for 3h; Autoclave; | |
With 2,4,6-trimethyl-pyridine; hydrogen In isopropanol at 100℃; for 24h; | ||
With Potassium phosphate, dibasic; manganese sulphate monohydrate; magnesium sulphate heptahydrate; galactose; ammonium citrate dibasic; anhydrous Sodium acetate at 42℃; for 24h; | ||
96 %Chromat. | With trans-[Ru(6-(4-methoxyphenyl)-2-aminomethylpyridine)(CO)(PCy3)(PPh3)][BArf4]; potassium carbonate; isopropanol at 82℃; for 36h; Inert atmosphere; Schlenk technique; | |
With sodium tetrahydridoborate | ||
With hydrogen In methanol at 20℃; for 12h; | ||
With hydrogen In lithium hydroxide monohydrate at 110℃; for 1h; | ||
With hydrogen In ethanol at 120℃; for 4h; Autoclave; | 2.5. Catalytic hydrogenation reactions General procedure: Catalytic hydrogenation of carbonyl compounds was completed in a 50 mL stainless steel autoclave lined with polytetrafluoroethylene. Inthe typical process, 15.0 mg catalyst and 1.0 mmol substrate were dispersed in 5.0 mL ethanol and then sealed in the autoclave. The pressure reactor was purged 3 times with nitrogen in order to remove the internal air and then purged 3 times with hydrogen. Finally, the reaction device was stirred at a certain reaction temperature for several hours. The liquid mixture was separated by filtration and analyzed by gas chromatograph (GC). | |
1.763 g | With sodium tetrahydridoborate; pyrographite In tetrahydrofuran; lithium hydroxide monohydrate at 20℃; for 0.116667h; | 4.2.1. 4-(Hydroxymethyl)-2-methoxyphenol (5) Initially, a solution of vanillic aldehyde (2 g, 13.15 mmol, 1 eq.) in THF (10 mL) was placed in around bottomed flask under vigorous stirring, followed by the addition of activated carbon (158 mg,1 eq.) and NaBH4 (249 mg, 0.5 eq.). The resulting solution was stirred for 1 min and then 2 mL ofdistilled H2O were slowly added to the reaction. The reaction mixture was kept under stirring for afurther 2 min. Finally, an additional 5 mL of distilled H2O was added and the solution was stirred fora further 5 min until total consumption of starting material [22]. For isolation of the desired alcohol,10 mL of distilled H2O was added and the aqueous solution was filtered off the activated carbon andexhaustively extracted with CH2Cl2. The organic phase was concentrated and the pure product wasobtained as white crystals (1.763 g, 11.44 mmol). |
With methanol; titanium(IV) dioxide for 12h; Irradiation; Inert atmosphere; | Evaluation of Photocatalytic Performance General procedure: For the conversion of furfural, TiO2 (5 mg), furfural (100 mL, 1.2 mmol) and solvent(CH3OH, 5 mL) were added into a quartz reactor (10 mL). The reactor was evacuatedand purged with N2 for 5 min. The reaction mixture was stirred at 650 rpm and irradiatedunder 300WXe lamp (l = 320-780 nm). During the reaction, water was circulatedto cool the reactor, keeping the temperature of the reactor at 40C. To ensurethe complete conversion of furfural in Figure 6, 50 mg of catalyst and 4 h of reactiontime were adopted. For the conversions of 5-methlyfurfual and villain, the reaction conditions were the same as those for the conversion of furfural in Figure 6 except forusing reactant of 0.5 mmol and reaction time of 12 h. The light intensity was 600 mWcm2 and the illumination area was 3.7 cm2. After reaction, the solid catalyst wasfiltered and the products in the filtrate were identified by GC-MS and quantifiedby GC-FID and HPLC. | |
With sodium tetrahydridoborate In ethyl acetate at 20℃; for 1h; | 5.1. General preparation of compounds (1a-1i) General procedure: NaBH4 (4.76 μmol) was added to the ethyl alcohol (3 mL) and the reaction mixture was stirred at room temperature for 5 min. Respectively, aldehyde compound (4.76 μmol) was added to the reaction mixture and stirred continuously for 1 h. Reaction mixture completion was confirmed by the TLC. After completion of the reaction, the mixture was quenched with 10% HCl (3 mL) and ethanol was evaporated under reduced pressure. After the complete removal of ethanol, saturated sodium bisulfite (1 5 mL) was added. The organic compound was extracted with dichloromethane (20 mL) and water (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure; to give 1a-1i compounds. Yield, 1H NMR, ESI-MS (M+H) data of all compounds, and CHNS/O elemental analysis (Perkin-Elmer 2400, PerkinElmer Inc., Waltham, MA, USA) composition data of each product are given below. | |
91 %Spectr. | With methanol; borane-ammonia complex at 20℃; for 0.5h; Inert atmosphere; Schlenk technique; Glovebox; Green chemistry; | |
With naphthalene; MOF-808 In isopropanol at 82℃; for 2h; | Catalytic test and product analysis General procedure: The catalytic activity of Zr-MOFs in the transfer hydrogenation of flavoring compounds was evaluated at moderate reaction conditions. Before use, Zr and Hf-MOFs were dried in an oven at 100°C for 12 h. In a typical procedure, a known amount of dried catalyst (9.5 mol% on the metal basis) of the dried catalyst, 2.6 mmol of carbonyl substrate, 0.05 g of naphthalene as an internal slandered, and 20 ml of isopropanol were added into a two-neck round bottom flask of 50 mL capacity. The reaction mixture in RBF equipped with a rubber septum and reflux condenser was heated at the boiling point of isopropanol for the desired time. The catalyst was separated by centrifugation and washed thoroughly with methanol and dried at 100°C. The filtrate was subjected to quantitative analysis using gas chromatography (GC, FID detector, and DB-624 column). Substrate conversion and the yield of products were determined using a single point internal standard calibration method. | |
With alcohol dehydrogenase (NC_001145.3) from Saccharomyces cerevisiae S288C; phenylacetaldehyde reductase (EF613490.1) from Solanum lycopersicum | ||
78 %Spectr. | With formic acid; (RuCl<SUB>2</SUB>(p-cymene))<SUB>2</SUB>(dppf); tetrabutylammonium bromide; triethylamine at 60℃; for 15h; | 4.1 General procedure for the catalytic TH of carbonyl compounds and imines General procedure: The selected substrate (0.2-1.0mmol, 1 eq), [RuCl2(p-cymene)}2-μ-dppf] (6) (0.002-0.01mmol, 0,01-0,05 eq, 2.3-58.3mg), NEt3 (1.4-8.6mmol, 0.2-1.2mL) and CPME (0.5-1.5mL) were transferred into a 4mL vial. The mixture was heated at the selected temperature (40-80°C) under stirring for ca. 15min and finally the DES-5 (0.45-1.7mL) was added. After the addition of the DES, the vial was put into the oil bath and the Teflon cap pierced with a needle to help the emission of the CO2 produced. The reaction was then leaved to react at the selected temperature from 2 to 24h, depending on the substrate. The reaction mixture was worked taken up with water (1.5mL) and extracted with diethyl ether (4×1.5mL), then the combined organic layers washed with brine (1.5mL). The organic phase was then separated, dried over Na2SO4 and filtered. The solvent was removed and the crude was analysed by 1H and, when pure products were afforded, by 13C NMR spectroscopy. |
With sodium tetrahydridoborate In methanol | ||
With hydrogen In lithium hydroxide monohydrate at 79.84℃; for 5h; Autoclave; | ||
With hydrogen; C27H41IrN3P In 2-methyltetrahydrofuran at 25℃; for 24h; Inert atmosphere; Glovebox; chemoselective reaction; | ||
With hydrogen In lithium hydroxide monohydrate at 60℃; for 6h; Autoclave; | 2.4. Catalyst performance evaluation and product analysis General procedure: All catalyst performance evaluation experiments were conductedin a 25 mL stainless steel autoclave (Anhui Kemi MachineryTechnology Co., Ltd) with a pressure gauge, a mechanicalstirrer and an automatic temperature control apparatus. Ina typical experiment, a Teflon vessel loaded with a mixture ofreactants (0.5 mmol), catalyst (30 mg) and H2O (10 ml) was placed into the autoclave, purged three times with N2 to removethe air, pressurized with H2 to a desired level and heated to apre-determined temperature under a constant stirring rate of600 rpm. Once the desired reaction time was reached, the autoclavewas quickly cooled down to room temperature. Thecatalyst and products were then separated from the reactionsolution by centrifugation and ethyl acetate extraction, respectively.For catalyst reusability tests, the centrifugation recoveredcatalyst was washed with water and ethanol several timesand dried under vacuum oven at 60 °C. | |
95.7 %Chromat. | Stage #1: vanillin With 3-(trimethoxysilyl)propan-1-amine In lithium hydroxide monohydrate for 0.25h; Green chemistry; Stage #2: With hydrogen In lithium hydroxide monohydrate at 30℃; for 0.5h; Green chemistry; | Catalytic reaction General procedure: The hydrodeoxygenation (HDO) of vanillin using formic acid as hydrogen source was conducted in a 25-mL two-necked glass flask. Typically, 100-mg catalyst, 0.585-mmol substrate, and 5-mL water were added into the reactor, with one neck sealed by a rubber stopper and another connected with a reflux condenser. After stirring for 15min, 2.34-mL HCOOH (5 M) was injected and started the reaction time. The reaction temperature in this system was controlled by thermocouple. The reaction solution was taken at certain intervals, extracted with ethyl acetate and analyzed the products by GC-FID with a Rtx-1071 column and GC-MS. m-cresol was used as an internal standard for quantitative analysis. The HDO process of other substrates were the same as the process mentioned earlier, only the reaction conditions were slightly different. To test the stability of Pd/HPC-NH2 catalyst, the recovered catalyst was reused after filtering, washing, and drying overnight. A small amount of lost catalyst was replenished with the first used catalyst. |
With xanthine oxidase from bovine serum milk In aq. buffer at 30℃; | ||
With lithium hydroxide monohydrate; hydrogen for 11h; | ||
With lithium hydroxide monohydrate; hydrogen at 20℃; for 3h; | ||
With hydrogen In lithium hydroxide monohydrate at 20℃; for 12h; Autoclave; | ||
With Hf-MOF-808 catalyst In isopropanol at 82℃; for 5h; | Table 7 below shows an experiment for hydrogenation of the M-MOF-808 catalyst when the substrate is α,β-unsaturated carbonyl. The reaction condition of Table 7 below was the same as that of Table 6, except that the reaction temperature was 82° C. In the table below, the type of the central metal of MOF-808 was set to Zr or Hf. | |
With hydrogen In tetrahydrofuran at 90℃; for 8h; Autoclave; | 2.4 Hydrogenation Process In a typical run for selective hydrogenation reduction offurfural to furfuryl alcohol, 0.50mmol furfural, 50.0mgcatalyst, and 5.0mL THF were put into a 25mL stainlesssteel autoclave. After three purging of the reactor with pureH2,the reactor was then pressurized with H2and heatedto 100°C for 6.0h with stirring at 600rpm. Likewise, theone-pot reductive amination of furfural was carried out in a25mL stainless steel autoclave, followed by the introductionof 0.50mmol furfural, 1.0mmol aniline, 50.0mg catalyst,and 5.0mL THF. The reactor was further purged with H2three times and treated at 110°C with stirring of 600rpm.After the reaction, the autoclave reactor was cooled downto 30°C. The used catalyst was firstly separated from thereaction mixture through filtration. The recycled catalystwas washed with ethanol five times and reused after drying.The liquid products were qualitatively identified throughgas chromatography-mass spectrometry (GC-MS, ThermoTrace 1300 GC-ISQ) and quantitatively analyzed usinginternal standard dodecane by gas chromatography (ThermoTrace 1310) with flame ionization detector. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With toluene-4-sulfonic acid at 20℃; | |
100% | at 20℃; | 1.a Our synthesis commenced with commercially available vanillyl alcohol 3a. Compound 3a was treated with catalytic amounts of tosyl acid in methanol to afford 3b, presumably via a p-quinone methide intermediate (Scheme 2) . The aromatic methyl group was then installed regiospecifically at the more hindered site through directed lithiation followed by methylation to afford 6. A subsequent 2,3- Dichloro-5, 6-dicyano-l, 4-benzoquinone (DDQ) -mediated oxidation gave rise to 2 -methyl vanillin 7 in 44% overall yield from 3a. Crotylation of the phenolic hydroxyl group, followed by a Claisen rearrangement produced phenol 8. For greater flexibility in later transformations, the phenol was protected either as a benzyl ether 9a or as a MOM ether 9b. Baeyer-Villiger oxidation of these compounds followed by hydrolysis afforded phenols 10a and 10b in 54% and 95% overall yields, respectively, from 8. The resultant phenolic hydroxyl group in each compound was then tosylated to produce 11a and lib in the yields shown. These compounds were hydrof ormylated with acetyl acetonate dicarbonyl rhodium (1) (Rh (CO) 2 (acac) ) and the Billig bis- organophosphite ligand according to Buchwald's protocol, to give exclusively the desired linear aldehydes 12a and 12b in 90% and 82% yields, respectively (Cuny, et al . , J. Am. Chem. Soc. 1993, 115, 2066) . EPO Scheme 2. Synthesis of Aldehydes 12a and 12b [a]a R27 = B n 10a R27=Bn 11a R27=Bn 12a R27=Bn b R27=MOM 10b R27=MOM 11b R27=MOM 12b R27=MOM[a] Key: a) MeOH, p-TSA, rt, 100%; b) BuLi, THF, -15 °C to O 0C, then -100C, MeI; c) DDQ, CH2C12/H2O 19 : 1, rt, 44% for two steps ; d) Crotyl bromide, K2CO3, acetone, reflux; e) neat, 185 °C, 81% for two steps ; f) MOMCl, DIEA, CH2Cl2, rt, 98% or BnBr, K2CO3, acetone, reflux, 93%; g) m-CPBA, CH2Cl2, 0 °C; h) Et3N, CH2Cl2/Me0H 1 : 1, rt, 61% (10a) and 96% ( 10b) over two steps ; i ) TsCl , Et3N, CH2Cl2, rt, 88% (lla) and 91% (lib) ; j ) Rh (CO) 2 (acac) , Billig Ligand, CO/H2 1 : 1, toluene, 60 °C, 90% ( 12a) and 82% (12b) . |
99% | With toluene-4-sulfonic acid |
97% | With toluene-4-sulfonic acid at 23℃; for 6h; Inert atmosphere; | |
95% | at 80℃; for 2h; Neat (no solvent); | |
88% | With toluene-4-sulfonic acid for 6h; Ambient temperature; | |
84% | With 1,3,5-trichloro-2,4,6-triazine; dimethyl sulfoxide at 20℃; for 0.75h; chemoselective reaction; | |
77% | With L-valine hydrochloride Ambient temperature; | |
27.3 g | With toluene-4-sulfonic acid In methanol at 20℃; for 6h; | |
Ca.60 %Chromat. | With hydrogen; zinc(II) chloride at 150℃; for 8h; Sealed tube; | |
With toluene-4-sulfonic acid at 20℃; for 5h; | ||
With toluene-4-sulfonic acid at 20℃; for 6h; | ||
97.6 %Chromat. | With hydrogen at 160℃; for 4h; Autoclave; Green chemistry; | |
With trifluorormethanesulfonic acid; hydrogen at 100℃; for 1h; | ||
99.95 %Chromat. | With trifluorormethanesulfonic acid; hydrogen at 100℃; for 1h; | 2; 4.1.7 Example 2 Vanillyl alcohol (VA) was used as a surrogate for lignin-derived monomers, and catalytic conversion of VA was carried out as shown in Scheme 3. For all catalysts and conditions studied, the catalytic reaction yielded two major products labeled as A and B in Scheme 3 and ring hydrogenation products were not observed. Product A (creosol) reduces the oxygen content of VA through the desired hydrodeoxygenation reaction. Product B (methyl vanillyl ether) is the alkylation product (Williamson ether synthesis) in methanol solvent and is considered an undesired product as it does not reduce the oxygen content of VA. In fact, control experiments in which the transition metal catalyst was omitted (Table 1, entries 16-17) illustrate that product B can be obtained as the major product readily by treating VA with methanol under hydrogen (290 psi) in the presence of a base (44% yield) or acid (>99% yield). However, no significant yield of product A is obtained without a transition metal catalyst (Table 1, entry 15). (“Cat.” Refers to the catalyst structures shown in Scheme 3) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium nitrososulfonate | |
83% | With potassiuim nitrosodisulfonate In chloroform for 1h; | |
83% | With potassium nitrososulfonate |
83% | With C44H60CoN4O2(2+); oxygen In methanol at 0℃; for 16h; Inert atmosphere; | |
68% | With C45H72CoN4O2; oxygen In methanol at 20℃; for 16h; | |
58% | With oxygen; copper dichloride In dichloromethane Ambient temperature; | |
55% | With {bis(salicylidene-γ-iminopropyl)methylamine}cobalt(II); oxygen; N-ethyl-N,N-diisopropylamine In methanol at 20℃; for 24h; | Formation of 2-methoxybenzoquinone in the presence of a sterically hindered base. General procedure: 5 mL of MeOH or CH2Cl2 were mixed in a Fisher-Potter bottle with 1 mmol of substrate, 0.1 mmol of catalyst and 1 mmol of hindered base. The vessel was pressurized to 60 psi with oxygen after flushing with the same gas, and the mixture was stirred for 24 hrs. The filtrate was evaporated under pressure and the residue was redisolved in a small amount of CH2Cl2 and passed through a silica column with 3:2 EtOAc:hexanes as the eluting solvent. 2-methoxy quinone elutes as a yellow fraction. The 1H and 13C NMR data were identical to those reported in the literature.1 2-methoxybenzoquinone, 1H NMR: 3.80, 5.90, 6.69; 13C NMR: 56.4, 107.9, 134.6, 137.4, 159.0, 182.0 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.9% | With hydrogen In lithium hydroxide monohydrate at 70℃; | |
1: 90.9% 2: 9.1% | With hydrogen In lithium hydroxide monohydrate at 20 - 100℃; for 1h; Autoclave; | |
1: 78.3% 2: 21.8% | With 2 wt% Pd/C; hydrogen In lithium hydroxide monohydrate at 20 - 100℃; for 1h; Autoclave; |
1: 12.9% 2: 17.1% | With hydrogen In lithium hydroxide monohydrate at 150℃; for 6h; Autoclave; | |
1: 91 % Spectr. 2: 9 % Spectr. | With hydrogenchloride; sodium cyanotrihydridoborate In tetrahydrofuran for 24h; | |
With palladium on activated charcoal; hydrogen In lithium hydroxide monohydrate at 90℃; for 0.5h; | ||
With Pd/TiO2; hydrogen In lithium hydroxide monohydrate at 110℃; for 2h; | ||
With hydrogen In lithium hydroxide monohydrate at 90℃; for 6h; | ||
With Ru/CNT; hydrogen In Bicyclo[4.4.0]decane at 100℃; for 3h; Autoclave; | 2.4 Hydrodeoxygenation of vanillin General procedure: The vanillin hydrodeoxygenation reactions were performed in a 100mL autoclave under stirring. Hydrodeoxygenation of vanillin was used to probe the catalytic hydrogenation activities of the Ru/CNT catalysts, as illustrated in Eq. (1). For a typical run, the reaction was carried out with 5.9mmol vanillin, 0.2mol% Ru/CNTs, 20mL decalin and 20mL water as bi-solvents, and 1MPaH2 at 100°C for 3h. After each reaction, the emulsion was broken by filtering out the catalyst particles. The two liquid phases were separated and analyzed individually by means of GC (2014C, SHIMADZU) and GC-MS (QP 2010 Plus, SHIMADZU). | |
With hydrogen In lithium hydroxide monohydrate; Bicyclo[4.4.0]decane at 100℃; for 6h; chemoselective reaction; | ||
With hydrogen In lithium hydroxide monohydrate; Bicyclo[4.4.0]decane at 200℃; for 4h; Autoclave; | ||
With hydrogen In lithium hydroxide monohydrate at 90℃; for 2 - 3h; Autoclave; | ||
With hydrogen In lithium hydroxide monohydrate; Bicyclo[4.4.0]decane at 100℃; for 0.5h; Autoclave; | ||
With formic acid; Pd/C In lithium hydroxide monohydrate at 150℃; for 2h; | ||
With hydrogen In tetrahydrofuran at 25℃; for 3h; | ||
With formic acid In lithium hydroxide monohydrate at 20 - 150℃; Autoclave; | ||
With hydrogen In isopropanol at 150℃; for 4h; Autoclave; | ||
With hydrogen In lithium hydroxide monohydrate at 100℃; Schlenk technique; | ||
With hydrogen In lithium hydroxide monohydrate at 120℃; for 5h; | ||
With hydrogen In lithium hydroxide monohydrate at 100℃; | ||
With hydrogen In lithium hydroxide monohydrate at 90℃; for 2h; Sealed tube; | ||
1: 27.5 %Chromat. 2: 64.9 %Chromat. | With hydrogen In tetrahydrofuran at 160℃; for 4h; Autoclave; Green chemistry; | |
With hydrogen In methanol at 20℃; for 12h; | ||
With Ni-Co-P (hydroxyapatite) amorphous alloy at 190℃; for 3h; Autoclave; Inert atmosphere; | ||
With formic acid; potassium hydroxide at 25℃; for 1h; | ||
1: 29 %Chromat. 2: 71 %Chromat. | Stage #1: vanillin With 3-(trimethoxysilyl)propan-1-amine In lithium hydroxide monohydrate for 0.25h; Green chemistry; Stage #2: With formic acid In lithium hydroxide monohydrate at 30℃; for 0.5h; Green chemistry; | Catalytic reaction General procedure: The hydrodeoxygenation (HDO) of vanillin using formic acid as hydrogen source was conducted in a 25-mL two-necked glass flask. Typically, 100-mg catalyst, 0.585-mmol substrate, and 5-mL water were added into the reactor, with one neck sealed by a rubber stopper and another connected with a reflux condenser. After stirring for 15min, 2.34-mL HCOOH (5 M) was injected and started the reaction time. The reaction temperature in this system was controlled by thermocouple. The reaction solution was taken at certain intervals, extracted with ethyl acetate and analyzed the products by GC-FID with a Rtx-1071 column and GC-MS. m-cresol was used as an internal standard for quantitative analysis. The HDO process of other substrates were the same as the process mentioned earlier, only the reaction conditions were slightly different. To test the stability of Pd/HPC-NH2 catalyst, the recovered catalyst was reused after filtering, washing, and drying overnight. A small amount of lost catalyst was replenished with the first used catalyst. |
1: 67 %Chromat. 2: 10 %Chromat. | With formic acid In lithium hydroxide monohydrate; ethyl acetate at 20℃; for 1h; Green chemistry; | |
With lithium hydroxide monohydrate; hydrogen at 80℃; for 2h; | ||
With hydrogen In lithium hydroxide monohydrate at 20℃; for 8h; Autoclave; | ||
With hydrogen In ethanol at 200℃; for 5h; | 2.4 Catalytic Activity Test The catalytic activity of Ni2P-based catalysts loaded on differentzeolites for vanillin HDO was tested in a 100ml batchreactor. During the reaction process, 200mg of vanillin and100mg of catalyst were put into the reactor, followed byadding 20ml of ethanol as solvent and n-decane as internalstandard. Prior to the experiment, the reactor was washedthree times using H2and pressurized with H2.The catalyticreaction proceeded at the desired temperature, and then thereactor was rapidly cooled to ambient temperature. After thereaction, the liquid phase was gathered and analyzed by gaschromatography spectrometry (SDPTOP, GC1120) equippedwith a SE-30 capillary column (30m × 0.32mm × 0.5m)and a flame ionization detector (FID) with detector conditionsof 240°C for the front sample, 250°C for the backsample and 120°C for the column chamber. The productcomponents in the gas phase were analyzed using gas chromatography.In addition, the conversion of vanillin (X) andthe product selectivity (S product-i) was calculated by thefollowing formulas:Among them, molar product-i represents the moles ofproduct-i of the final mixture. | |
With hydrogen In ethanol at 180℃; for 5h; | 2.4 Catalytic Activity Test The catalytic activity of Ni2P-based catalysts loaded on differentzeolites for vanillin HDO was tested in a 100ml batchreactor. During the reaction process, 200mg of vanillin and100mg of catalyst were put into the reactor, followed byadding 20ml of ethanol as solvent and n-decane as internalstandard. Prior to the experiment, the reactor was washedthree times using H2and pressurized with H2.The catalyticreaction proceeded at the desired temperature, and then thereactor was rapidly cooled to ambient temperature. After thereaction, the liquid phase was gathered and analyzed by gaschromatography spectrometry (SDPTOP, GC1120) equippedwith a SE-30 capillary column (30m × 0.32mm × 0.5m)and a flame ionization detector (FID) with detector conditionsof 240°C for the front sample, 250°C for the backsample and 120°C for the column chamber. The productcomponents in the gas phase were analyzed using gas chromatography.In addition, the conversion of vanillin (X) andthe product selectivity (S product-i) was calculated by thefollowing formulas:Among them, molar product-i represents the moles ofproduct-i of the final mixture. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate In acetone Reflux; | |
93% | With potassium carbonate In acetone at 60℃; | |
93% | With potassium carbonate In acetone at 60℃; | Acetone (107.5 mL), vanillyl alcohol(25 g, 0.163 mol), and allyl bromide (15.8 mL, 0.183 mol) were added to a 250 mL, round-bottomed flask and stirred until homogeneous. Potassium carbonate (22.5 g, 0.163 mol) was then added slowly, which briefly gave a light pink color that indicated deprotonation of the phenol. The mixture was heated at 60 0C overnight. The reaction was monitored by TLC using 10% acetone in CH2CI2 as eluent. Upon completion, the reaction mixture was allowed to cool to rt with stirring. The acetone was removed under vacuum, yielding a white residue. CH2CI2 (200 mL) and H2O (200 mL) were added to redissolve the residue and transferred to a separatory funnel. The aqueous layer was removed and the organic layer was washed with 1 M NaOH (3 x 100 mL) and saturated NaCl (1 x 100 mL). The organic layer was then collected, dried over MgSO4. After filtration, the solvent was removed under vacuum to afford a yellow powder. The yellow powder was redissolved in EtOAc (250 mL), which was subsequently removed under vacuum (in order to remove excess allyl bromide) to afford the product as a fine, white powder (30.0 g, 93% yield). 1H NMR δ = 6.94 (s, I H), 6.86 (s, 2H), 6.09 (multi, IH), 5.42 (dd, J] = 20, J2 = 1.5, IH), 5.30 (dd, JJ = 20, J2 = 1.5, I H), 4.63 (d, / = 3.6, 2H), 4.62 (d, 7 = 5, 2H), 3.89 (s, 3H), 1.57 (t, J = 6, 1 H). |
93% | With potassium carbonate In acetone at 60℃; | |
87% | With potassium carbonate In acetone at 65℃; for 4.5h; | Scaffold synthesis and derivatization 1-O-allyl-vanillyl alcohol (4) Compound 4 was prepared according to a modified literature procedure.21 To the solution of vanillyl alcohol 3 (55.0g, 356.8mmol) in acetone (82mL), K2CO3 (49.8g, 360.3mmol) and allyl bromide (34.0mL, 392.5mmol) were added. The resulting mixture was stirred under reflux for 4.5h. Afterwards, acetone was removed under reduced pressure and the residue was partioned between CH2Cl2 (500mL) and water (400 mL). The organic phase was then dried over MgSO4, and filtered. Crude 4 (65.1g, 94.0%) was obtained upon removal of CH2Cl2 under reduced pressure. The crude product was crystallized from MTBE/n-hexane affording 4 (60.3g, 87.0%) as white crystals. Rf=0.32 (n-hexane/EtOAc 6/4). 1H NMR (400MHz, CDCl3): δ=1.94 (s, 1H), 3.89 (s, 3H), 4.61-4.63 (m, 4H), 5.29 (dd, J=1.4Hz, 10.5Hz, 1H), 5.41 (dd, J=1.5Hz, 17.3Hz, 1H), 6.04-6.14 (m, 1H), 6.86 (s, 2H), 6.94 (s, 1H). 13C NMR (100MHz, CDCl3): δ=55.9, 65.2, 70.0, 110.9, 113.5, 117.9, 119.3, 133.3, 134.1, 147.5, 149.6. HRMS-ESI: m/z calcd for C11H14NaO3 [M+Na]+, 217.0835; found, 217.0834. This compound has been also previously reported.21 |
80% | With potassium carbonate In acetone for 4h; Heating; | |
80% | With potassium carbonate In acetone for 4h; Reflux; | |
65% | With potassium carbonate In acetone Reflux; Inert atmosphere; | (4-(Allyloxy)-3-methoxyphenyl)methanol Vanillyl alcohol (100 g, 649 mmol) in 1 L flaskwas totally dissolved in refluxing acetone (150 mL), then allyl bromide (61.8 mL, 714 mmol) and K2CO3 (89.7 g, 649 mmol) were added. After 1 h, additional allyl bromide (22.5mL, 260 mmol) was poured into the flask, and the mixture was further stirred for overnight.Filtration of the resultant reaction mixture through a pad of celite (eluent; CH2Cl2) and thefollowing evaporation of the filtrate gave the solid materials. These were dissolved inCH2Cl2 and washed with water (20 mL), and dried over Na2SO4, and filtered, andconcentrated in vacuo to afford 125 g of crude as yellow solid stuff. Recrystallization fromfreshly distilled benzene (1.0 mL/crude 1 g) afforded 81.3 g (65%) of the desiredcompound as white solid crystals. The physical data were ensured according to theliterature. 1H NMR (400 MHz, CDCl3) 6.94 (s, 1H), 6.86 (s, 1H), 6.85 1 (s, 1H), 6.08 (ddt, J= 17.2, 10.4, 5.5 Hz, 1H), 5.40 (dd, J = 17.2, 1.4 Hz, 1H), 5.28 (dd, J = 10.4, 1.4 Hz, 1H),4.63-4.60 (m, 4H), 3.89 (s, 3H), 1.63 (t, J = 6.0 Hz, 1H) ppm. |
With potassium carbonate In acetone Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; hydroquinone In diethyl ether | ||
With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | 36 Synthesis of Vanillyl Alcohol Dimethacrylate Using Methacryloyl Chloride A 3-neck round bottom flask is equipped with a magnetic stir bar, addition funnel, and a thermometer. The below 0° C. chilled flask is charged with vanillyl alcohol (1 eq), triethylamine (4 eq), and dichloromethane. The flask is sparged with dry argon gas for 40 minutes then placed in an ice bath and kept below 0° C. as methacryloyl chloride (4 eq) dissolved in dichloromethane is added dropwise through the addition funnel. The reaction mixture is allowed to warm to room temperature overnight after the full addition of methacryloyl chloride. The organic phase is extracted three times each with concentrated sodium bicarbonate solution, 1.0 M sodium hydroxide, 1.0 N hydrochloric acid, and deionized water sequentially, dried with anhydrous sodium sulfate, then concentrated under vacuum. The product is obtained through silica gel chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With sodium iodide; sodium hydroxide In ethanol; water for 5h; Reflux; | Compound 2 Compound 1 was synthesized according to the previously reported procedure. In a stirred solutionof chloroacetic acid (22.8 g, 241 mmol) in EtOH (170 mL) and a 35% NaOH aqueous solution (25 mL)was added vanillyl alcohol (35.0 g, 227 mmol), NaI (0.38 g, 2.5 mmol) and a 35% NaOH aqueoussolution (25 mL). The mixture was refluxed for 5 hours and stored at 4 °C during a night. Theprecipitate was filtered off on a frit and was recrystallized in water (100 mL). Compound 2 wasobtained as a white solid (38.1 g, 73%). 1H NMR spectrum was consistent with literature.1H NMR (D2O, 300 MHz, 298 K) δ 7.16 (s, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 4.66 (s,2H), 4.58 (s, 2H), 3.98 (s, 3H) |
66% | With sodium hydroxide; sodium iodide for 5h; Heating; | |
With sodium hydroxide; sodium iodide In ethanol; water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 59% 2: 22% | With C38H58CoN4O2; oxygen In methanol at 20℃; for 16h; | |
1: 12 % Spectr. 2: 3 % Spectr. | With oxygen In methanol for 17h; Ambient temperature; | |
With peracetic acid at 50℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium tetrahydroborate; Trimethyl borate; dimethyl sulfate In tetrahydrofuran at 20℃; for 1.5h; | |
73% | With diisopropoxytitanium(III) tetrahydroborate In dichloromethane for 4h; Ambient temperature; | |
69% | With D-glucose In aq. phosphate buffer at 30℃; for 29h; Enzymatic reaction; | 2.10. Reduction with whole cell biocatalyst General procedure: Glucose (22.2 mM), E. coli BL21(DE3)/pETDuet-1-PPTase-CAR (wet cells, 10 g), and the substrate (20a, 5.0 mM) were mixed in the sodium phosphate buffer (100 mL, 100 mM, pH 8). The resulting mixture was incubated at 200 rpm in a rotary shaker at 30°C, and the reaction was monitored by GC. After 29 h, the pH of the reaction mixture was adjusted to 2-3 with 2 M HCl and the mixture was filtered through a Celite pad to remove the biomass. The resulting aqueous solution was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was puriedby a silica gel column to give the product. |
With hydrogen In aq. phosphate buffer at 50℃; for 24h; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With 18-crown-6 ether; potassium carbonate In toluene Heating; | |
70.3% | With potassium carbonate In methanol Inert atmosphere; Reflux; | 2-2.1 (1) Synthesis of (4- (benzyloxy) -3-methoxyphenyl) methanol 19.5 g (126.4 mmol) of vanillyl alcohol and 41.5 g of potassium carbonate in a 500 ml flask under a nitrogen atmosphere(300 mmol), 200 ml of methanol as a solvent,While stirring, 44.5 g (260 mmol) of benzyl bromide was slowly dropped at the reflux temperature. The resulting solution is concentrated to ethyl acetate,The solution was separated with water, the organic layer was concentrated and isolated by recrystallization,(4- (benzyloxy) -3-methox in 70.3% yieldyphenyl) methanol (compound 13) was obtained. |
With 18-crown-6 ether; potassium carbonate for 9h; Reflux; |
In methanol at 60℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With porcine pancreatic lipase (PPL, Type II) In tetrahydrofuran at 42 - 45℃; for 24h; | |
With Pseudomonas cepacia PS lipase In di-isopropyl ether at 25℃; for 0.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With hydrogen In ethanol at 120℃; for 8h; chemoselective reaction; | |
99% | With hydrogen In ethanol at 120℃; for 8h; chemoselective reaction; | |
95% | Stage #1: 4-hydroxymethyl-2-methoxyphenol With ammsnium formate In ethanol; lithium hydroxide monohydrate at 22℃; for 0.166667h; Stage #2: With formic acid In ethanol; lithium hydroxide monohydrate at 22℃; for 1h; chemoselective reaction; | Heterogeneous Palladium-Catalyzed Transfer Hydrogenolysis of Benzylic Alcohols; General Procedure General procedure: A microwave-vial was charged with a solution of 1 (0.4 mmol, 1.0 equiv), HCO2NH4 (6.0 mg, 0.095 mmol, 25 mol%), and Pd(0)-nanocatalyst [Pd(0)-AmP-MFC, 26.8 mg, 0.02 mmol, 8 wt%, 5 mol%]22-24,29 or [Pd(0)-CPG, 569Å, 148.0 mg, 0.02 mmol, 135 mol/g] in EtOH (2.4 mL), and H2O (0.6 mL), and the contents were stirred for 10 min at r.t. Afterwards, formic acid (0.09 mL, 2.4 mmol, 6 equiv) was added and the resulting mixture was stirred at r.t. for the time shown in Table 2. NMR samples for NMR yield were prepared by removing 0.05 mL aliquots from the reaction mixture and filtered through Celite using CDCl3 (1.5 mL) as eluent, and mesitylene was used as an internal standard. Before the purification of the products, the crude reaction mixture was filtered through Celite using CHCl3 (10 mL) as eluent and evaporated. The crude material was purified by silica gel flash column chromatography. |
87% | With lithium aluminium hydride In tetrahydrofuran; chlorobenzene for 3h; Heating; | |
96 %Chromat. | With triethylsilane; palladium (II) chloride In ethanol at 20℃; for 0.166667h; Inert atmosphere; | |
96 %Chromat. | With triethylsilane; palladium (II) chloride In ethanol at 20℃; for 0.166667h; Inert atmosphere; | |
With hydrogen In lithium hydroxide monohydrate at 90℃; chemoselective reaction; | ||
80 %Chromat. | With hydrogen In methanol at 150℃; for 8h; Sealed tube; | |
92 %Chromat. | With triethylsilane In ethanol at 20℃; for 0.166667h; Inert atmosphere; | 2.4. General procedure for benzyl alcohol hydrogenolysis General procedure: To a solution of benzyl alcohol (1mmol) and triethylsilane (amountindicated in Table 2) in ethanol (5mL)was added 10 mg of Pd NPs/rGO under an argon atmosphere. The resulting mixture was stirred for thetime indicated in Table 2 prior to GC-MS analysis. The resultingmixturewas filtered and washed by ethyl acetate for catalyst separation. Thepure product in entry 1 was isolated by distillation; for entries 2-10the products were isolated by column chromatography using hexane/ethyl acetate (9/1) as eluent. |
With pyridine; hydrogen In lithium hydroxide monohydrate at 100℃; for 1h; Autoclave; | ||
With hydrogen In methanol at 180℃; for 18h; Sealed tube; Green chemistry; chemoselective reaction; | ||
With formic acid; palladium and silver nanoparticles over graphitic carbon nitride surface In lithium hydroxide monohydrate at 20℃; for 4h; Sealed tube; Irradiation; | ||
With formic acid In lithium hydroxide monohydrate at 160℃; for 2.5h; Sealed tube; Inert atmosphere; Green chemistry; | ||
90.2 %Chromat. | With hydrogen In tetrahydrofuran at 200℃; for 4h; Autoclave; Green chemistry; | |
Multi-step reaction with 2 steps 1: hydrogen / 4 h / 160 °C / 15001.5 Torr / Autoclave; Green chemistry 2: hydrogen / methanol / 4 h / 160 °C / 15001.5 Torr / Autoclave; Green chemistry | ||
Multi-step reaction with 2 steps 1: hydrogen / 4 h / 160 °C / 15001.5 Torr / Autoclave; Green chemistry 2: hydrogen / methanol / 4 h / 160 °C / 15001.5 Torr / Autoclave; Green chemistry | ||
With Ru-[{Im(Me)-py(4-OH)-Im(Me)}(CH3CN)2Cl]triflate; hydrogen; anhydrous sodium carbonate In methanol at 100℃; for 1h; Sealed tube; | ||
Multi-step reaction with 2 steps 1: Ru-[{Im(Me)-py(4-OH)-Im(Me)}(CH3CN)2Cl]triflate; hydrogen; anhydrous sodium carbonate / 4 h / 100 °C / 14997.7 Torr 2: Ru-[{Im(Me)-py(4-OH)-Im(Me)}(CH3CN)2Cl]triflate; hydrogen; anhydrous sodium carbonate / methanol / 1 h / 100 °C / 14997.7 Torr | ||
Multi-step reaction with 2 steps 1: hydrogen; trifluorormethanesulfonic acid / 1 h / 100 °C / 14997.7 Torr 2: Ru-[{Im(Me)-py(4-OH)-Im(Me)}(CH3CN)2Cl]triflate; hydrogen; anhydrous sodium carbonate / methanol / 1 h / 100 °C / 14997.7 Torr | ||
With hydrogen In methanol at 20℃; for 12h; | ||
With hydrogen at 150℃; | ||
With hydrogen In methanol; lithium hydroxide monohydrate at 140℃; for 1h; Autoclave; | ||
100 %Chromat. | With Ru-[{Im(Me)-py(4-OH)-Im(Me)}(CH3CN)2Cl]triflate; hydrogen; anhydrous sodium carbonate In methanol at 150℃; for 1h; | 2; 4.1.4; 4.1.5; 4.1.6; 4.1.7; 4.1.8 1.5 Optimizing the Reaction Temperature As shown in Table 4, the substantially quantitative conversion was observed for reaction temperature above 150° C. However, the unusual color change of the reaction solution was observed for temperature above 160° C. Without wishing to be bound by any theory, it is believed that such change can be caused by catalyst decomposition. To avoid the changes in color, the temperature of 150° C. was chosen for further testing. |
Multi-step reaction with 2 steps 1: Ru-[{Im(Me)-py(4-OH)-Im(Me)}(CH3CN)2Cl]triflate; hydrogen / 4 h / 100 °C / 14997.7 Torr / Sealed tube 2: Ru-[{Im(Me)-py(4-OH)-Im(Me)}(CH3CN)2Cl]triflate; hydrogen; anhydrous sodium carbonate / methanol / 1 h / 100 °C / 14997.7 Torr | ||
Multi-step reaction with 2 steps 1: hydrogen; trifluorormethanesulfonic acid / 1 h / 100 °C / 14997.7 Torr 2: Ru-[{Im(Me)-py(4-OH)-Im(Me)}(CH3CN)2Cl]triflate; hydrogen; anhydrous sodium carbonate / methanol / 1 h / 100 °C / 14997.7 Torr | ||
With hydrogen In lithium hydroxide monohydrate at 60℃; for 8h; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With potassium carbonate In ethanol at 110℃; for 6h; | |
60% | With potassium carbonate In N,N-dimethyl-formamide at 55℃; | |
58% | With potassium carbonate In N,N-dimethyl-formamide |
58% | Stage #1: 4-hydroxymethyl-2-methoxyphenol With potassium carbonate In acetone at 20℃; for 0.5h; Inert atmosphere; Stage #2: ethylene dibromide In acetone at 57℃; Inert atmosphere; | |
50% | With potassium carbonate In ethanol | |
50% | With potassium carbonate In ethanol | |
50% | With potassium carbonate In ethanol Inert atmosphere; Schlenk technique; | |
50% | With potassium carbonate In ethanol | |
48% | With potassium carbonate In ethanol at 50℃; for 6h; Inert atmosphere; Schlenk technique; | |
48% | With potassium carbonate In ethanol at 50℃; for 6h; Inert atmosphere; Schlenk technique; | |
48% | With potassium carbonate In ethanol at 50℃; for 6h; Inert atmosphere; Schlenk technique; | |
48% | With potassium carbonate In ethanol at 50℃; for 6h; | |
45% | With potassium carbonate In ethanol for 6h; Reflux; Inert atmosphere; Schlenk technique; | |
44% | With potassium carbonate In ethanol for 6h; Reflux; | |
34% | With potassium carbonate In ethanol at 80℃; for 21h; Inert atmosphere; | |
20% | With potassium carbonate In acetone at 80℃; | |
With potassium carbonate In ethanol at 50℃; for 6h; Inert atmosphere; Schlenk technique; | ||
36 g | With potassium carbonate for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With Novozym 435; 4 Angstroem MS In 1,4-dioxane at 25℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.6% | at 50℃; for 16h; | 6 [Example 6] Synthesis of capsiate; trans-8-Methyl-6-nonenoic acid (1.00 g, 5.87 mmol) , vanillyl alcohol (1.085 g, 7.04 mmol) and Novozym 435 (100 mg) were measured and placed in a flask (25 ml) . The mixture in the flask free of a plug was heated with stirring in an oil bath at 50°C for 16 hrs. After 2 to 3 hrs of stirring with heating, attachment of water on the wall of the upper part of the flask was observed. The reaction mixture was returned to room temperature, hexane (25 ml) was added, and Novozym 435 and precipitated vanillyl alcohol were filtered off. Hexane (25 ml) was added to the filtrate, and the mixture was washed with 5% agueous citric acid solution (25 ml) and saturated brine (25 ml) , and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. Since production of polar impurity other than vanillyl alcohol was confirmed by TLC, the residue was dissolved in 50 ml of hexane and passed through a short column packed with 1.5 g of silica gel, and the silica gel was sufficiently washed away with a mixed solvent of hexane and ethyl acetate (volume ratio 10:1) . The above-mentioned impurity was not detected in the eluent by TLC. The eluent was concentrated under reduced pressure to give capsiate (1.56 g, yield 86.6%) as a colorless oil. This capsiate contained a trace amount of trans-8-methyl-6-nonenoic acid. EPO 1H-NMR (CDCl3, δ) : 0.95 (d, 6H, J=6.74Hz), 1.33-1.40 (m, 2H), 1.59-1.67 (m, 2H), 1.94-1.99 (m, 2H), 2.18-2.23 (m, IH), 2.33 (t, 2H, J=7.52Hz), 3.89 (s, 3H), 5.02 (s, 2H), 5.26-5.39 (m, 2H), 5.63 (br, IH), 6.83-6.90 (m, 3H) |
51% | With di-isopropyl azodicarboxylate; thiamine diphosphate In tetrahydrofuran at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
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88% | With sodium hydrogen sulfate; silica gel In dichloromethane at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
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79% | With potassium carbonate In acetone at 20℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
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86% | Stage #1: 4-hydroxymethyl-2-methoxyphenol With TentaGel-N(R)C(O)CH2C2F4OC2F4SO2F; potassium carbonate In N,N-dimethyl-formamide at 20℃; Stage #2: With formic acid; 1,3-bis-(diphenylphosphino)propane; triethylamine In N,N-dimethyl-formamide at 85℃; for 2h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 1h; | 1.1c Preparation of (4-(5-methyl-2-phenyloxazole-4-yl)methoxy)-3-methoxyphenyl)methanol 311g of 4-(chloromethyl)-5-methyl-2-phenyloxazole, 277g of vanillyl alcohol, and 415g of powdered potassium carbonate were added to 1L of N,N-dimethylformamide and stirred at 90 °C for 1 hour. The reaction mixture was cooled to room temperature, and 2.5L of ice water was added to the reaction mixture under stirring. The precipitate crystal was filtered off, and washed with 1L of water and 0.5L of IPE. The obtained crystal was dissolved by heating into 2L of isopropyl alcohol. A part of the insoluble matter was filtered and the filtrate was stirred overnight. The precipitate crystal was isolated by filtration and washed with 0.5L of isopropyl alcohol. The obtained crystal was dried under reduced pressure and 325g of the subject compound was prepared. 1H-NMR(400MHz, CDCl3)δ ppm: 1.77(1H, d) 2.41(3H, s) 3.88(3H, s) 4.63(2H, d) 5.05(2H, s) 6.87(1H, dd) 6.95(1H, d) 7.02(1H, d) 7.40-7.47(3H, m) 7.98-8.03(2H, m) |
Yield | Reaction Conditions | Operation in experiment |
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94% | With potassium carbonate; potassium iodide In acetone for 48h; Heating; | |
94% | With potassium carbonate; potassium iodide In acetone for 48h; Heating / reflux; | 1 Example 1 Synthesis of 3-methoxy-4-propargyloxybenzylalcohol (I) Finely powdered K2CO3, 10.4 grams (0.075 moles), and KI, 9.1 grams (0.060 moles), were placed in a 300 mL round-bottomed flask equipped with a magnetic stir bar, and 150 mL acetone was added. 3-methoxy-4-hydroxybenzyl alcohol, 7.71 grams (0.050 moles), and propargyl chloride, 4.10 grams (0.055 moles), were then added, and the mixture stirred and refluxed for approximately 48 hours. The results from thin layer chromatography showed no starting material (3-methoxy-4-hydroxybenzyl alcohol) as well as the presence of a new compound. The solution was then filtered. The acetone of the resulting filtrate was removed by rotary evaporation, leaving an oily residue. The oily residue was dissolved in 50 mL dichloromethane and washed with water (30 mL*2) and then dried over anhydrous potassium carbonate. After filtering the organic phase, the solvents were removed by rotary evaporation, leaving a liquid product. 9 grams of product was obtained, which corresponds to a 94% yield. The product gave the following proton nuclear magnetic resonance (1H NMR) spectrum in ppm (in CDCl3 solvent): 2.49 (triplet, 1H, alkynyl); 2.57 (singlet, 1H, hydroxyl); 3.81 (singlet, 3H, methyl); 4.55 (doublet, 2H, methylene); 6.83 (multiplet, 1H, aryl); 6.89 (multiplet, 1H, aryl); 6.94 (multiplet, 1H, aryl). The product gave the following proton-decoupled carbon-13 nuclear magnetic resonance (13C NMR) spectrum in ppm (in CDCl3 solvent): 55.8 (methylene); 56.8 (methyl); 64.8 (methylene); 75.8 (alkynyl); 78.5 (alkynyl); 110.2 (aryl); 114.3 (aryl); 119.0 (aryl); 135.2 (aryl); 146.0 (aryl); 149.7 (aryl). The mass spectrum (FAB) showed a parent ion peak of 192.1 that matched the molecular weight of the compound. |
Yield | Reaction Conditions | Operation in experiment |
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83% | With sulfated tungstate; at 80℃; for 3h;Green chemistry; | General procedure: Sulfated tungstate (10 wt%) was added to a mixture of p-methoxybenzyl alcohol (1 g, 7.25 mmol) and n-butanol (1.34 g, 18.11 mmol), and the reaction mixture was stirred at 80 C for 1 h. The progress of the reaction was monitored by thin-layer chromatography (TLC). After completion of the reaction, the reaction mixture was diluted with EtOAc (15 ml) and filtered to recover the catalyst. The organic layer was concentrated under reduced pressure, and the residue obtained was purified by chromatography on silica gel (60-120) with n-hexane-EtOAc (90:10) as eluent to get pure p-methoxybenzyl ether as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
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Multi-step reaction with 2 steps 1: 52.6 percent / 0.1 N KOH, 0.05 N LiClO4 / acetonitrile; H2O / 0 °C / anodic oxidation at Pt electrode 2: 37.6 percent / 0.1 N KOH, 0.05 N LiClO4 / acetonitrile; H2O / 0 °C / cathodic reduction at Pt electrode | ||
With 3,4-Dihydroxybenzoic acid; holo-corrinoid protein reconstructed from recombinant apo-protein and methyl cobalamin; methyl transferase I from Desulfitobacterium hafniense; potassium chloride; potassium hydroxide In dimethyl sulfoxide at 30℃; for 24h; Enzymatic reaction; | ||
With 3-mercaptopropionic acid ethyl ester In aq. buffer at 30℃; for 24h; Inert atmosphere; Glovebox; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
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98% | In toluene at 40℃; for 22h; | 18 [Example 18] Synthesis of vanillyl decanoate - 4; Decanoic acid (10.0 g, 58.1 mmol) , vanillyl alcohol (8.05 g, 52.2 mmol) and lipase PS-C "Amano" I (enzyme immobilized on ceramic: 1.44 g) were measured and placed in a flask (500 ml) , and toluene (200 ml) was added. Under an argon atmosphere, the mixture was heated with stirring in an EPO oil bath at 400C for 2 hrs . This reaction mixture was concentrated under reduced pressure, and dehydration was promoted by azeotropic effect. Toluene (150 ml) was further added to the concentrate and the mixture was heated with stirring in an oil bath at 400C for 20 hrs. The reaction mixture was again concentrated under reduced pressure and heptane (200 ml) was added. The mixture was stirred at room temperature for 2.5 hrs. and immobilized enzyme and precipitated vanillyl alcohol were filtered off. The filtrate was concentrated under reduced pressure to give a mixture(15.8 g) of vanillyl decanoate and decanoic acid. As a result of the analysis, the yield of vanillyl decanoate was 98% and the purity was 97.9 area% by HPLC. The mixture contained 8.6 wt% of decanoic acid relative to vanillyl decanoate. |
94.1% | at 50℃; for 20 - 48h; | 8; 14 [Example 8] Synthesis of vanillyl decanoate - 2 (repeated use of enzyme); Decanoic acid (2.00 g, 11.61 mmol), vanillyl alcohol (1.74 g, 11.27 mmol) and Novozym 435 (100 mg) were measured and placed in a flask (25 ml) . The mixture in the flask free of a plug was heated with stirring in an oil bath at 500C for 20 hrs. After 2 to 3 hrs of stirring with heating, attachment EPO of water on the wall of the upper part of the flask was observed. The reaction mixture was returned to room temperature, hexane (50 ml) was added, and Novozym 435 and a small amount of precipitated vanillyl alcohol were filtered off. The filtrate was washed with 5% aqueous citric acid solution (25 ml) and saturated brine (25 ml) , and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give a mixture (3.41 g) of vanillyl decanoate and decanoic acid as a colorless oil. As a result of the analysis, the yield of vanillyl decanoate was 94.1%. The mixture contained 6.0 wt% of decanoic acid relative to vanillyl decanoate.The above-mentioned operation was repeated using, as a catalyst, a mixture recovered by the above-mentioned operation, which contained Novozym 435 and a small amount of vanillyl alcohol. A mixture (3.42 g) of vanillyl decanoate and decanoic acid was obtained as a colorless oil. As a result of the analysis, the yield of vanillyl decanoate was 95.5%. The mixture contained 3.2 wt% of decanoic acid relative to vanillyl decanoate.The above-mentioned operation was repeated using, as a catalyst, a mixture recovered by the above-mentioned operation, which contained Novozym 435 and a small amount of vanillyl alcohol. A mixture (3.47 g) of vanillyl decanoate and decanoic acid was obtained as a colorless oil. As a result of the analysis, the yield of vanillyl decanoate was 94.8%. The mixture contained 5.1 wt% of decanoic acid relative to vanillyl decanoate.The above-mentioned operation was repeated using, as a catalyst, a mixture recovered by the above-mentioned operation, which contained Novozym 435 and a small amount of vanillyl alcohol. A mixture (3.46 g) of vanillyl decanoate and decanoic acid was obtained as a colorless oil. As a result of the analysis, the yield of vanillyl decanoate was 95.4%. The EPO mixture contained 4.1 wt% of decanoic acid relative to vanillyl decanoate.; [Example 14] Synthesis of vanillyl decanoate - 3; Decanoic acid (25.0 g, 145 mmol), vanillyl alcohol (21.7 g, 141 mmol) and Novozym 435 (723 mg) were measured and placed in a flask (25 ml) . The mixture in the flask free of a plug was heated with stirring in an oil bath at 50°C for 48 hrs. EPO After 2 to 3 hrs of stirring with heating, attachment of water on the wall of the upper part of the flask was observed. The flask was returned to room temperature, hexane (100 ml) was added to the reaction mixture, and the mixture was stirred for 1 hr. The immobilized enzyme and a small amount of precipitated vanillyl alcohol were filtered off. Hexane (100 ml) and 10% aqueous citric acid solution (200 ml) was added to the filtrate to allow partitioning. The aqueous layer was further extracted with hexane (150 ml) and the combined hexane layer was washed with 10% aqueous citric acid solution (100 ml) , water (100 ml) and saturated brine (100 ml) . The hexane layer was dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give the mixture (43.7 g) of vanillyl decanoate and decanoic acid. As a result of the analysis, the yield of vanillyl decanoate was 97.0% and the purity was 98.6 area% by HPLC. The mixture contained 3.94 wt% of decanoic acid relative to vanillyl decanoate. |
93.1% | In hexane at 50℃; for 48h; | 7 [Example 7] Synthesis of vanillyl decanoate - 1; Decanoic acid (1.00 g, 5.80 mmol) , vanillyl alcohol (880 mg, 5.71 mmol) and Novozym 435 (25 mg) were measured and placed in a flask (25 ml) and hexane (0.5 ml) was added. The mixture in the flask free of a plug was heated with stirring in an oil bath at 50°C for 48 hrs. After 2 to 3 hrs of stirring with heating, attachment of water on the wall of the upper part of the flask was observed. The flask was returned to room temperature, hexane (25 ml) was added to the reaction mixture, and Novozym 435 and a small amount of precipitated vanillyl alcohol were filtered off. Hexane (25 ml) was added to the filtrate, and the mixture was washed with 5% aqueous citric acid solution (25 ml) and saturated brine (25 ml) , and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give a mixture (1.69 g) of vanillyl decanoate and decanoic acid as a colorless oil. As a result of the analysis, the yield of vanillyl decanoate was 93.1%. The mixture contained 2.9 wt% of decanoic acid relative to vanillyl decanoate. 1H-NMR (CDCl3, δ) : 0.87 (t, 3H, J=7.1Hz), 1.18-1.30 (m, 12H), 1.55-1.65 (m, 2H), 2.33 (t, 2H, J=7.7Hz), 3.90 (s, 3H), 5.03 (s, 2H), 5.64 (br, IH), 6.80-6.90 (m, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.7% | at 50 - 55℃; for 16 - 45h; | 5; 15; 16; 17 [Example 5] Synthesis of dihydrocapsiate - 1; 8-Methylnonanoic acid (1.00 g, 5.80 mmol) , vanillyl alcohol (851 mg, 5.52 mmol) and Novozym 435 (50 mg) were measured and placed in a flask (25 ml) . The mixture in the flask free of a plug was heated with stirring in an oil bath at 50°C for 20 hrs. After 2 to 3 hrs of stirring with heating, attachment of water on the wall of the upper part of the flask was observed. The reaction mixture was returned to room temperature, hexane (25 ml) was added, and Novozym 435 and a small amount of precipitated vanillyl alcohol were filtered off. Hexane (25 ml) was added to the filtrate, and the mixture was washed with 5% aqueous citric acid solution (25 ml) and saturated brine (25 ml) , and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and EPO the filtrate was concentrated under reduced pressure to give a mixture (1.66 g) of dihydrocapsiate and 8-methylnonanoic acid as a colorless oil. As a result of the analysis, the yield of dihydrocapsiate was 89.7%, and the purity was 99.5 area% by HPLC. The mixture contained 8.0 wt% of 8-methylnonanoic acid relative to dihydrocapsiate.1H-NMR (CDCl3, δ) : 0.86 (d, 6H, J=6.60Hz), 1.12-1.37 (m, 8H), 1.46-1.64 (m, 3H), 2.32 (t, 2H, J=7.56Hz), 3.89 (s, 3H), 5.02 (s, 2H), 5.63 (br, IH), 6.83-6.90 (m, 3H); [Example 15] Synthesis of dihydrocapsiate - 7; 8-Methylnonanoic acid (1.54 g, 8.95 mmol) , vanillyl alcohol (1.34 g, 8.70 mmol) and Novozym 435 (67.0 mg) were measured and placed in a flask (25 ml) . The mixture in the flask free of a plug was heated with stirring in an oil bath at 55°C for 16 hrs. After 2 to 3 hrs of stirring with heating, attachment of water on the wall of the upper part of the flask was observed. The flask was returned to room temperature, heptane (5 ml) was added to the reaction mixture, and the mixture was stirred for 10 min. Novozym 435 and a small amount of precipitated vanillyl alcohol were filtered off. The filtrate was concentrated under reduced pressure and the obtained colorless oil (2.74 g) was analyzed by HPLC to find that dihydrocapsiate was contained in 96.0 area%. The mixture was partitioned with heptane (15 ml) and 10% aqueous citric acid solution (15 ml) and the aqueous layer was further EPO extracted with heptane (15 ml) . The combined heptane layer was washed with water (10 ml) and saturated brine (10 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give a mixture (2.65 g) of dihydrocapsiate and 8- methylnonanoic acid as a colorless oil. As a result of the analysis, the yield of dihydrocapsiate was 97.6%, and the purity was 99.8 area% by HPLC. The mixture contained 1.12 wt% of 8-methylnonanoic acid relative to dihydrocapsiate.; [Example 16] Synthesis of dihydrocapsiate - 8; 8-Methylnonanoic acid (1.54 g, 8.95 mmol) , vanillyl alcohol (1.34 g, 8.70 mmol) and Novozym 435 (8.90 mg) were measured and placed in a flask (25 ml) . The mixture in the flask free of a plug was heated with stirring in an oil bath at 550C for 45 hrs . After 2 to 3 hrs of stirring with heating, attachment of water on the wall of the upper part of the flask was observed. The flask was returned to room temperature, heptane (10 ml) was added to the reaction mixture, and the mixture was stirred for 30 min. Novozym 435 and a small amount of precipitated vanillyl alcohol were filtered off. The filtrate was concentrated under reduced pressure and the obtained colorless oil (2.67 g) was analyzed by HPLC to find that dihydrocapsiate was contained in 97.2 area%. The mixture was partitioned with heptane (15 ml) and 10% aqueous citric acid solution (15 ml) and the aqueous layer was further extracted with heptane (15 ml) . The combined heptane layer was washed with water (15 ml) and saturated brine (15 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give a mixture (2.67 g) of dihydrocapsiate and 8- methylnonanoic acid as a colorless oil. As a result of the analysis, the yield of dihydrocapsiate was 95.9%, and the purity was 99.4 area% by HPLC. The mixture contained 3.86 wt% of 8-methylnonanoic acid relative to dihydrocapsiate.; [Example 17] Synthesis of dihydrocapsiate - 9; 8-Methylnonanoic acid (310 g, 1.80 mol) and Novozym 435 (9.0 g) were placed in a IL four-neck flask. The mixture was heated with stirring in an oil bath at 500C. Then vanillyl alcohol (90 g, 0.58 mol) was added, and the mixture was stirred with heating at the same temperature under reduced pressure (74 mmHg) with a pump upon cramping the trap. Vanillyl alcohol (90 g, 0.58 mol) was added 1 hr later and 2 hr later each time, and the mixture was reacted with heating reduced pressure reaction. The reduced pressure was stopped after 45 hrs from the start of the reaction and the stirring with heating was stopped. At this time, the trap contained water. After confirmation that the reaction mixture returned to room temperature, n-hexane (465 ml) was added dropwise over 1 hr, and the mixture was stirred at atmospheric pressure and room temperature.The stirring was stopped 20 hrs later, and the mixture was filtrated while washing with n-hexane (155 ml) . 10% Aqueous citric acid solution (775 ml) was added to the filtrate to allow partitioning. The n-hexane layer was washed with water (775 ml) , water (310 ml) and 15% brine (310 ml) , and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give a mixture (532 g) of dihydrocapsiate and 8-methylnonanoic acid as a colorless oil. As a result of the analysis, the yield of dihydrocapsiate was 96% and the purity was 99.2 area% by HPLC. The mixture contained 3.1 wt% of 8-methylnonanoic acid relative to dihydrocapsiate. |
80.9% | at 55℃; for 45h; | 9 [Example 9] Synthesis of dihydrocapsiate - 2; 8-Methylnonanoic acid (1.50 g, 8.70 mmol) , vanillyl alcohol (1.34 g, 8.70 mmol) and lipase PS "Amano" (375 mg) were measured and placed in a flask (25 ml) . The mixture in the flask free of a plug was heated with stirring in an oil bath at 55°C for 45 hrs. After 2 to 3 hrs of stirring with heating, attachment of water on the wall of the upper part of the flask was observed. The flask was returned to room temperature, heptane (10 ml) was added to the reaction mixture, and the mixture was stirred for 10 min. Lipase PS "Amano" and a small amount of precipitated vanillyl alcohol were filtered off. The filtrate was concentrated under reduced pressure and the obtained oil (2.48 g) was analyzed by HPLC to find that dihydrocapsiate was contained in 94.0 area%. The mixture was partitioned with heptane (15 ml) and 10% aqueous citric acid solution (15 ml) and the aqueous layer was further extracted with heptane (15 ml) . The combined heptane layer was washed with saturated brine (15 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give a mixture (2.45 g) of dihydrocapsiate and 8-methylnonanoic acid as a colorless oil. As a result of the analysis, the yield of dihydrocapsiate was 80.9%, and the purity was 97.4 area% by HPLC. The mixture contained 12.6 wt% of 8-methylnonanoic acid relative to dihydrocapsiate. |
73.1% | at 45 - 55℃; for 13.5 - 45h; | 10; 11; 13 [Example 10] Synthesis of dihydrocapsiate - 3; 8-Methylnonanoic acid (1.50 g, 8.70 mmol), vanillyl alcohol (1.34 g, 8.70 mmol) and lipase PS-C "Amano" I (enzyme immobilized on ceramic: 375 mg) were measured and placed in a flask (25 ml) . The mixture in the flask free of a plug was heated with stirring in an oil bath at 55°C for 45 hrs. After 2 to 3 hrs of stirring with heating, attachment of water on EPO the wall of the upper part of the flask was observed. The flask was returned to room temperature, heptane (10 ml) was added to the reaction mixture, and the mixture was stirred for 10 min. The immobilized enzyme and a small amount of precipitated vanillyl alcohol were filtered off. The filtrate was concentrated under reduced pressure and the obtained oil (2.68 g) was analyzed by HPLC to find that dihydrocapsiate was contained in 92.9 area%. The mixture was partitioned with heptane (15 ml) and 10% aqueous citric acid solution (15 ml) and the aqueous layer was further extracted with heptane (15 ml) . The combined heptane layer was washed with saturated brine (15 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give a mixture (2.61 g) of dihydrocapsiate and 8-methylnonanoic acid as a colorless oil. As a result of the analysis, the yield of dihydrocapsiate was 95.5%, and the purity was 97.1 area% by HPLC. The mixture contained 1.97 wt% of 8-methylnonanoic acid relative to dihydrocapsiate.; [Example 11] Synthesis of dihydrocapsiate - 4; 8-Methylnonanoic acid (1.65 g, 9.59 mmol) , vanillyl alcohol (1.34 g, 8.70 mmol) and lipase PS-C "Amano" I (enzyme immobilized on ceramic: 335 mg) were measured and placed in a flask (25 ml) . The mixture in the flask free of a plug was heated with stirring in an oil bath at 45°C for 37.5 hrs.After 2 to 3 hrs of stirring with heating, attachment of water on the wall of the upper part of the flask was observed. The flask was returned to room temperature, heptane (10 ml) was added to the reaction mixture, and the mixture was stirred for 10 min. The immobilized enzyme and a small amount of precipitated vanillyl alcohol were filtered off. The filtrate was concentrated under reduced pressure and the obtained oil was analyzed by HPLC to find that dihydrocapsiate was contained in 95.7 area%. The mixture was partitioned with EPO heptane (20 ml) and 10% aqueous citric acid solution (20 ml) and the aqueous layer was further extracted with heptane (20 ml) . The combined heptane layer was washed with saturated brine (15 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give a mixture (2.50 g) of dihydrocapsiate and 8-methylnonanoic acid as a colorless oil. As a result of the analysis, the yield of dihydrocapsiate was 73.1%, and the purity was 99.3 area% by HPLC. The mixture contained 27.4 wt% of 8-methylnonanoic acid relative to dihydrocapsiate.; [Example 13] Synthesis of dihydrocapsiate - 6; 8-Methylnonanoic acid (1.54 g, 8.95 mmol) , vanillyl alcohol (1.34 g, 8.70 mmol) and lipase PS-C "Amano" I (enzyme immobilized on ceramic: 335 mg) were measured and placed in a flask (25 ml) . The mixture in the flask free of a plug was heated with stirring in an oil bath at 55°C for 13.5 hrs. After 2 to 3 hrs of stirring with heating, attachment of water on the wall of the upper part of the flask was observed. The flask was returned to room temperature, heptane (5 ml) was added to the reaction mixture, and the mixture was stirred for 15 min. The immobilized enzyme and a small amount of precipitated vanillyl alcohol were filtered off. The filtrate was concentrated under reduced pressure and the obtained oil (2.73 g) was analyzed by HPLC to find that dihydrocapsiate was contained in 96.3 area% . The mixture was partitioned with heptane (15 ml) and 10% aqueous citric acid solution (15 ml) and the aqueous layer was further extracted with heptane (15 ml) . The combined heptane layer was washed with water (10 ml) and saturated brine (10 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give a mixture (2.67 g) of dihydrocapsiate and 8-methylnonanoic acid as a colorless oil. As a result of the analysis, the yield of dihydrocapsiate was 95.5%, and the purity was 99.3 area% by HPLC. The mixture contained 4.18 wt% of 8-methylnonanoic acid relative to dihydrocapsiate. |
72.3% | In n-heptane at 55℃; for 13.5h; | 12 [Example 12] Synthesis of dihydrocapsiate - 5; 8-Methylnonanoic acid (1.54 g, 8.95 mmol) and vanillyl alcohol (1.34 g, 8.70 mmol) were measured and placed in a flask (25 ml) and dissolved in heptane (0.5 ml) . Lipase PS-C "Amano" I (enzyme immobilized on ceramic: 335 mg) was added and the mixture was heated with stirring in an oil bath at 55°C for 13.5 hrs. After 2 to 3 hrs of stirring with heating, attachment of water on the wall of the upper part of the flask was observed. The flask was returned to room temperature, heptane (5 ml) was added to the reaction mixture, and the mixture was stirred for 10 min. The immobilized enzyme and a small amount of precipitated vanillyl alcohol were filtered off. The filtrate was> concentrated under reduced pressure and the obtained oil (2.42 g) was analyzed by HPLC to find that dihydrocapsiate was contained in 97.2 area%. The mixture was partitioned with heptane (15 ml) and 10% aqueous citric acid solution (15 ml) and the aqueous layer was further extracted with heptane (15 ml) . The combined heptane layer was washed with water (10 ml) and saturated brine (10 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give a mixture (2.42 g) of dihydrocapsiate and 8- methylnonanoic acid as a colorless oil. As a result of the EPO analysis, the yield of dihydrocapsiate was 72.3%, and the purity was 99.6 area% by HPLC. The mixture contained 24.8 wt% of 8-methylnonanoic acid relative to dihydrocapsiate. |
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In toluene at 70℃; for 10h; Inert atmosphere; | 2; 4-5; 7 Mix 8-methylnonanoic acid, vanillyl alcohol, DMAP, EDC and toluene evenly,Stir the temperature to 70°C in a nitrogen atmosphere, keep it warm for 10 hours, and cool to room temperature.Wash with deionized water, extract with chloroform, dry the extract and spin dry.The obtained dihydrocapsaicin ester was measured by high-purity liquid chromatography (HPLC),Its purity is 92%. |
Yield | Reaction Conditions | Operation in experiment |
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In N-methyl-acetamide; water; | Example B1.1 {4-[2-(4-Fluoro-phenoxy)-ethoxy]-3-methoxy-phenyl}-acetonitrile A mixture of 4-hydroxy-3-methoxy-benzyl alcohol (14.7 g) and sodium cyanide (5 g) in dimethylformamide (200 ml) is stirred under an atmosphere of nitrogen for 3 hours at +1 20 C. The mixture is then cooled to +100 C. and 1-(2-bromo-ethoxy)-4-fluoro-benzene (25 g) is added in one portion. The mixture is stirred at +100 C. for another 4 hours. Upon cooling water (800 ml) is added. The mixture is extracted with ethyl acetate (2*500 ml). The organic phases are washed with brine (2*500 ml), dried (MgSO4) and evaporated. The residue is recrystallized from ethyl acetate/hexane. {4-[2-(4-Fluoro-phenoxy)-ethoxy]-3-methoxy-phenyl}-acetonitrile is obtained, m.p. 126-128 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With acetic anhydride In potassium hydroxide; cyclohexane | Synthesis of 4-acetoxy-3-methoxy-benzylalcohol Synthesis of 4-acetoxy-3-methoxy-benzylalcohol 2 g (3-methoxy-4-hydroxy) benzyl-alcohol (MW 154.17, 0.013 mol), are dissolved in 4 ml of 5.45 M KOH aqueous solution, while cooling the reaction mixture with ice. As soon as this reactant results completely dissolved 1,3 g acetic anhydride (0.013 mol) are then added dropwise. The reaction is left under stirring for about three hoursuntil completion for about three hours (TLC eluant: ethyl acetate/ cyclohexane 6:4). The reaction mixture is extracted with diethyl ether and the organic phase is washed carefully with water. The organic phase is then dried on anhydrous sodium sulfate, filtered and evaporated to dryness. The oily raw product thus obtained results to be sufficiently pure from 1H-NMR analysis and it can be therefore used for the successive reaction (yield 78%). 1H-NMR (CDCl3) (CDCl3) δ: 2.3 (s,3H, OCOCH3); 3.8 (s, 3H, OCH3); 4.6 (d, J =4.3 Hz, 2H, CH2); 4.8 (broad. s, exchanges with D2O, 1H, OH); 6.9 (dd) Jortho=8 Hz, Jmeta=1 Hz, 1H, H6); 7.0-7.1 (m, 2H arom, H2 + H5.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | novozyme 435; In acetone; at 20℃; for 2h;Molecular sieve; | This compound was synthesized by the method described in Kobata et al. (Biosci. Biotechnol. Biochem., 66(2), 319-327, 2002). Decanoic acid methyl ester (2.13 mL, 10.5 mmol), vanillyl alcohol (1.62 g, 10.5 mmol), molecular sheaves 4 A (10 g), and Novozyme 435 (2.5 g) were added to acetone (50 mL) and stirred for 2 hours at room temperature. The reaction solution was filtered through cellite and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by silica gel chromatography, yielding 2.25 g (7.30 mmol, 73.0 percent) of vanillyl decanoate in the form of a colorless oily substance. 1H-NMR (CDCl3,delta): 0.87 (t,3H, J=7.Hz), 1.18-1.30(m,12H), 1.55-1.65 (m,2H), 2.33 (t,2H, J=7.7 Hz), 3.90 (s, 3H), 5.03 (s, 2H), 5.64 (br, 1H), 6.80-6.90 (m, 3H). |
73.0% | novozyme 435; In acetone; at 20℃; for 48h;Molecular sieve 4A; | <strong>[110-42-9]Methyl decanoate</strong> (2.13 ml, 10.5 mmol), vanillyl alcohol (1.62 g, 10.5 mmol), molecular sieves 4 angstrom (10 g) and Novozyme 435 (2.5 g) were added to acetone (50 ml), and the mixture was stirred at room temperature for 2 days. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by chromatography on silica gel to yield 2.25 g of vanillyl decanoate (7.30 mmol; 73.0%) as a colorless oily material. 1H-NMR (CDCl3, delta) : 0.87 (t, 3H, J=7.1Hz), 1.18-1.30 (m, 12H), 1.55-1.65 (m, 2H), 2.33 (t, 2H, J=7.7Hz), 3.90 (s, 3H), 5.03 (s, 2H), 5.64 (br, 1H), 6.80-6.90 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With sodium tetrahydroborate; 1% Pd/C; water; potassium hydroxide In methanol at 20℃; for 72h; In air; | |
79% | With potassium phosphate; carbon dioxide; CrH6Mo6O24(3-)*3H3N*3H(1+) In dimethyl sulfoxide at 80℃; for 24h; Green chemistry; | |
With oxygen; sodium hydroxide In 2-methoxy-ethanol at 80.04℃; for 8h; Inert atmosphere; | The substrates were activated by NaOH General procedure: The importance of NaOH to activate the substrate was confirmedby control experiments. No reaction occurred when no alkali wasadded (Entries 1-4 in Table 1). However, when equivalent molarof NaOH was added, the reaction proceeded smoothly. The phe-nomenon was reinforced when the 4-methyl guaiacol sodium saltwas used as the substrate. We concluded that the p-cresol sodiumsalt was much easier to be oxidized than 4-methyl guaiacol, whichcould be explained by the higher electron-donating ability of thephenolate anion than that of hydroxyl group. Namely, the abstrac-tion of proton from the hydroxyl group by alkali was a key stepduring the oxidation of p-cresols. |
Multi-step reaction with 4 steps 1: silver(l) oxide 2: 2,3-dicyano-5,6-dichloro-p-benzoquinone 3: silver(l) oxide; sodium hydroxide / 0.5 h / 20 °C 4: sodium hydroxide; nitrobenzene / 2 h / 170 °C | ||
Multi-step reaction with 4 steps 1: silver(l) oxide 2: 2,3-dicyano-5,6-dichloro-p-benzoquinone 3: sodium hydroxide; nitrobenzene / 2 h / 170 °C 4: sodium hydroxide; nitrobenzene / 2 h / 170 °C | ||
Multi-step reaction with 7 steps 1: silver(l) oxide 2: 2,3-dicyano-5,6-dichloro-p-benzoquinone 3: pyridinium p-toluenesulfonate 4: sodium hydride 5: diisobutylaluminium hydride / toluene / 0.5 h / 0 °C / Sealed tube 6: sodium hydroxide; nitrobenzene / 2 h / 170 °C 7: sodium hydroxide; nitrobenzene / 2 h / 170 °C | ||
Multi-step reaction with 8 steps 1.1: silver(l) oxide 2.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone 3.1: potassium carbonate / N,N-dimethyl-formamide / 1.5 h / 20 °C 4.1: lithium diisopropyl amide / tetrahydrofuran; n-heptane; ethylbenzene / 1.5 h / -78 °C / Sealed tube; Inert atmosphere 4.2: 3 h / -78 °C 5.1: sodium tetrahydroborate / tetrahydrofuran / 24 h / 0 - 20 °C 6.1: palladium on activated charcoal; hydrogen / tetrahydrofuran / 20 °C 7.1: sodium hydroxide; nitrobenzene / 2 h / 170 °C 8.1: sodium hydroxide; nitrobenzene / 2 h / 170 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | In N,N-dimethyl-formamide at 120℃; for 24h; Inert atmosphere; | 2'-(4-Hydroxy-3-methoxyphenyl)acetonitrile 17 To a solution of alcohol 16 (18 g, 0.12 mol) in DMF (300 mL), under an atmosphere of nitrogen was added NaCN (6.9 g, 0.14 mol), and the mixture was heated at 120°C and stirred for 24 h. The solution was cooled to room temperature and water (100 mL) was added cautiously. The reaction mixturewas basified (solid NaOH) to pH 10 and the DMF was removed by distillation. Water (250 mL) and acetic acid (20 mL) were added until a neutral pH (~7) was achieved. The aqueous mixture was extracted with chloroform (5x100 mL) and the combined organic extracts were washed with water (5x50 mL), dried (MgSO4), and the solvent was removed under reduced pressure to give the title compound (13 g, 68%, quantitative brsm.) as a brown oil which was used without purification in the subsequent reaction. RF (2:1 hexanes, ethyl acetate) 0.33; dH (400 MHz; CDCl3; Me4Si) 3.68 (2H, s, CH2Ar), 3.90 (3H, s, OCH3), 5.73 (1H, br s, OH), 6.81-6.90 (3H, m, 2-, 5- and 6-H); Spectroscopic data were in accordance with literature values. |
315 mg | In N,N-dimethyl-formamide at 120℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With novozyme 435 In <i>tert</i>-butyl alcohol at 55℃; for 4h; Enzymatic reaction; regioselective reaction; | |
61% | With immobilized Candida antarctica Lipase B at 60℃; for 0.25h; Molecular sieve; Flow reactor; Enzymatic reaction; | 2.1. General procedure for the flow esterification and in-line work up General procedure: A glass column (i.d.: 6.6 mm) was packed with a previously preparedmixture of Novozyme 435 (692 mg) and powder molecular sieves 4 Å(692 mg) to obtain a packed bed reactor (PBR) with a final volume of3.0 mL. A 0.1 M solution of the phenolic alcohol in CPME (20 mL) and a0.3 M solution of the fatty acid in CPME (20 mL) were mixed in a T-piece and the resulting flow stream was directed into the reactor column keptat 60 C. The total flow rate was 0.2 mL/min (residence time: 15 min).The exiting flow stream was flowed through a column (i.d.: 10 mm)packed with Amberlite IRA67 (2.8 g, total exchange capacity ≥ 1.60 eq/L FB form, PBR volume: 5.5 mL) at a total flow rate of 0.4 mL/min thanksto an inlet of CPME delivered through a third peristaltic pump. Theorganic solvent was collected and evaporated under pressure and, ifnecessary, the crude was purified by flash chromatography. |
61% | With immobilized Candida antarctica Lipase B at 60℃; for 0.25h; Molecular sieve; Flow reactor; Enzymatic reaction; | 2.1. General procedure for the flow esterification and in-line work up General procedure: A glass column (i.d.: 6.6 mm) was packed with a previously preparedmixture of Novozyme 435 (692 mg) and powder molecular sieves 4 Å(692 mg) to obtain a packed bed reactor (PBR) with a final volume of3.0 mL. A 0.1 M solution of the phenolic alcohol in CPME (20 mL) and a0.3 M solution of the fatty acid in CPME (20 mL) were mixed in a T-piece and the resulting flow stream was directed into the reactor column keptat 60 C. The total flow rate was 0.2 mL/min (residence time: 15 min).The exiting flow stream was flowed through a column (i.d.: 10 mm)packed with Amberlite IRA67 (2.8 g, total exchange capacity ≥ 1.60 eq/L FB form, PBR volume: 5.5 mL) at a total flow rate of 0.4 mL/min thanksto an inlet of CPME delivered through a third peristaltic pump. Theorganic solvent was collected and evaporated under pressure and, ifnecessary, the crude was purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen In decalin at 250℃; for 20h; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate In acetone; toluene Reflux; | |
With tetrabutylammomium bromide; potassium carbonate In acetone Reflux; | ||
With potassium carbonate; potassium iodide In acetone at 75℃; for 8h; | 1 Step 1. Preparation of (3-methoxy-4- (prop-2-yn-1-yloxy) phenyl) methanol (130-01) : To a solution of 4- (hydroxymethyl) -2-methoxyphenol (770mg, 4.6mmol) in acetone was added K2CO3 (1.04g, 5.5mmol) and KI (910mg, 5.5mmol) , followed by addition of 3-bromoprop-1-yne (650mg, 5mmol) . The reaction mixture was refluxed at 75 for 8hrs. The reaction mixture was cooled to room temperature, and solvents were removed in vacuo. The residue was extracted by EtOAc and H2O 3 times. The organic layer was combined, washed with brine, dried over Na2SO4, concentrated and further purified by silica gel column chromatography (PE/EA4/1) , to give 725mg of (3-methoxy-4- (prop-2-yn-1-yloxy) phenyl) methanol as a yellow oil (182) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With cobalt(II,III) oxide; oxygen In isopropyl alcohol at 80℃; for 6h; Autoclave; | ||
With air; manganese-doped cobalt mixed oxide In acetonitrile at 140℃; for 2h; Autoclave; | ||
With oxygen In para-xylene at 120℃; for 6h; |
With dihydrogen peroxide In acetonitrile at 80℃; for 3h; | Catalytic reactions General procedure: Oxidation of lignin model compound wase undertaken in a150 mL semi-batch reactor equipped with a stirrer. In a typical procedure, 10 mmol of model compound, 50 ml of acetonitrileand 15 mmol of H2O2 were added, followed by 50 mg ofcatalyst (based the active species). After reaction at 80 °C for3 h, the catalyst was filtered off and the solvent wasevaporated under reduced pressure. The residues weredissolved in 25 μL of pyridine in the presence of 3,4-dimethoxytoluene as an internal standard for GC-MS analysis.For the lignin oxidation, the oxidized lignin were recovered byfiltration, and the obtained lignin sample was then dried at40 °C in vacuum for next analyses. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With Novozym 435 In propan-2-one for 62h; Reflux; Enzymatic reaction; | 21 n-Propionic acid (37) (1.73 g, 23.4 mmol) and vanillyl alcohol (5) (3.50 g, 22.7 mmol) were mixed at room temperature, Novozym 435 (350 mg) and acetone (7 ml) were added, and the mixture was heated under reflux for 14 hours. Since the remainder of the starting material was confirmed by TLC, acetone (7 ml) and Novozym 435 (349 mg) were added again, and the mixture was further stirred for 48 hours with heating. Since acetone evaporated during the reaction, supplemental acetone was added appropriately. The reaction mixture was cooled to room temperature, hexane (20 ml) was added, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by ODS column chromatography (gradient; ethyl acetate:n-hexane=1:99→17:3) to give compound 38-1 (3.94 mg, 17.6 mmol, yield 78%) as a colorless liquid. 1H-NMR (400 MHz, CDCl3) δ: 1.45 (t, 3H, J=7.6 Hz), 2.36 (q, 2H, J=7.6 Hz), 3.90 (s, 3H), 5.03 (t, 2H), 5.63 (s, 1H), 6.87-6.91 (m, 3H) |
75% | With immobilized Candida antarctica Lipase B at 60℃; for 0.25h; Molecular sieve; Flow reactor; Enzymatic reaction; | 2.1. General procedure for the flow esterification and in-line work up General procedure: A glass column (i.d.: 6.6 mm) was packed with a previously preparedmixture of Novozyme 435 (692 mg) and powder molecular sieves 4 Å(692 mg) to obtain a packed bed reactor (PBR) with a final volume of3.0 mL. A 0.1 M solution of the phenolic alcohol in CPME (20 mL) and a0.3 M solution of the fatty acid in CPME (20 mL) were mixed in a T-piece and the resulting flow stream was directed into the reactor column keptat 60 C. The total flow rate was 0.2 mL/min (residence time: 15 min).The exiting flow stream was flowed through a column (i.d.: 10 mm)packed with Amberlite IRA67 (2.8 g, total exchange capacity ≥ 1.60 eq/L FB form, PBR volume: 5.5 mL) at a total flow rate of 0.4 mL/min thanksto an inlet of CPME delivered through a third peristaltic pump. Theorganic solvent was collected and evaporated under pressure and, ifnecessary, the crude was purified by flash chromatography. |
75% | With immobilized Candida antarctica Lipase B at 60℃; for 0.25h; Molecular sieve; Flow reactor; Enzymatic reaction; | 2.1. General procedure for the flow esterification and in-line work up General procedure: A glass column (i.d.: 6.6 mm) was packed with a previously preparedmixture of Novozyme 435 (692 mg) and powder molecular sieves 4 Å(692 mg) to obtain a packed bed reactor (PBR) with a final volume of3.0 mL. A 0.1 M solution of the phenolic alcohol in CPME (20 mL) and a0.3 M solution of the fatty acid in CPME (20 mL) were mixed in a T-piece and the resulting flow stream was directed into the reactor column keptat 60 C. The total flow rate was 0.2 mL/min (residence time: 15 min).The exiting flow stream was flowed through a column (i.d.: 10 mm)packed with Amberlite IRA67 (2.8 g, total exchange capacity ≥ 1.60 eq/L FB form, PBR volume: 5.5 mL) at a total flow rate of 0.4 mL/min thanksto an inlet of CPME delivered through a third peristaltic pump. Theorganic solvent was collected and evaporated under pressure and, ifnecessary, the crude was purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With Novozym 435 at 65℃; for 69h; Enzymatic reaction; | 2 4-acetoxymethyl-2-methoxyphenol (6) Vanillyl alcohol (5) (10.3 g, 66.8 mmol) was dissolved in ethyl acetate (160 ml) at room temperature, Novozym 435 (2.00 g) was added, and the mixture was stirred at 65° C. for 69 hours. Then, the reaction mixture was cooled to room temperature, the enzyme was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient; ethyl acetate:n-hexane=19:81→40:60) to give 4-acetoxymethyl-2-methoxyphenol (6) (11.8 g, 59.8 mmol, yield 89%) as a colorless solid. 1H-NMR (400 MHz, CDCl3) δ: 2.10 (s, 3H), 3.91 (s, 3H), 5.04 (s, 2H), 5.79 (brs, 1H), 6.88-6.94 (m, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13.51% | Stage #1: 4-hydroxymethyl-2-methoxyphenol With potassium fluoride In acetic acid at 80℃; for 1h; Stage #2: With sodium azide; boron trifluoride diethyl etherate In N,N-dimethyl-formamide at 20℃; for 3h; Inert atmosphere; Darkness; | 4.2.6. 4-(Azidomethyl)-2-methoxyphenol; b 4-Hydroxy-3-methoxybenzyl alcohol (3.0000 g, 19.46 mmol) and potassium fluoride(1.3547 g, 23.35 mmol) were dissolved in acetic acid (5 mL). The reaction mixture was stirredat 80 C for 1 h. After reaction was completed, water (30 mL) was added to the reactionmixture and extracted with ethyl acetate (3 30 mL). The organic phase was washed withsaturated NaHCO3, brine, dried over Na2SO4, and concentrated under reduced pressure.The product was purified by column chromatography using dichloromethane to give a73.10% yield of the intermediate. This intermediate and NaN3 (4 eq) were dissolved indried DMF under nitrogen. Boron triuoride etherate (6 eq) was added to the reaction andstirred at room temperature with light protection for 3 h. After reaction was completed,dichloromethane (30 mL) was added to the reaction and washed with saturated NaHCO3,brine, dried over Na2SO4, and concentrated under reduced pressure, and the obtainedresidue was purified by column chromatography using hexane: ethyl acetate (9:1) to yieldof yellow liquid (0.4709 g, 13.51%); FTIR (ATR, cm1): 3511, 3423 (O-H, st), 3011 (aromaticC-H, st), 2936, 2844 (aliphatic C-H, st), 2096 (N=N=N, st), 1514 (C=C, st), 1272, 1237 (C-O,st), 1154 (C-N, st); 1H-NMR (300 MHz, DMSO-d6): 3.77 (3H, s), 4.30 (2H, s), 6.78 (2H, d,J = 1.07 Hz), 6.94 (1H, s), 9.12 (1H, s). HRMS (ESI) m/z calcd for [M]+ 179.06948, Found137.06065 [M-42]+. |
Multi-step reaction with 2 steps 1: phosphorus tribromide / diethyl ether / 0.5 h / 0 °C 2: sodium azide / dimethyl sulfoxide / 12 h / 20 °C | ||
Multi-step reaction with 2 steps 1: phosphorus tribromide / diethyl ether / 0.5 h / 0 °C 2: sodium azide / dimethyl sulfoxide / 12 h / 20 °C |
Multi-step reaction with 2 steps 1: thionyl chloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C 2: sodium azide / dimethyl sulfoxide / 0.16 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With sodium carbonate In water at 40℃; | 2 In the examples, the percentages mentioned areexpressed by weight.The reagents used, namely vanillin, vanillyl alcoholsodium carbonate Na2CO3, are introduced simultaneously.The reactions are carried out in the presence ofThe tables below indicate the operating conditionsimplemented and also the amounts of the various reagents VA: vanillinVOH: vanillyl alcohol1: 3-(4-hydroxy-3-methoxybenzyl)-4-hydroxy-5-methoxybenzaldehyde10051] CR: conversion rate (represents the amount of reagent converted relative to the amount of reagent introduced)10052] YLD: yield (ratio between the number of moles of compound 1 obtained and the number of moles of vanillin converted)10053] Thus, the process of the invention makes it possible to obtain the compound 3-(4-hydroxy-3-methoxybenzyl)-4- hydroxy-5-methoxybenzaldehyde with a very satisfactory yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; boron trifluoride diethyl etherate; iodosylbenzene In dichloromethane at 20℃; for 0.5h; | General procedure: General procedure: To the stirred mixture of methoxybenzene (2.0 mmol) and benzylalcohol (1.0 mmol) in DCM (5 mL) were added PhIO (1.2 equiv), TEMPO (0.13 equiv) with BF3.OEt2 (2.0 equiv). The reaction mixture was stirred 30 min at room temperature. The progress of the reaction was monitored by TLC. After completion of the reaction as indicated by TLC, NaHCO3 (3 equiv) was added to the reaction mixture and concentrated in vacuo. The crude product was directly poured into silica gel column chromatography (100-200 mesh) using ethyl acetate: hexane (03:97 to 10:90) as eluent to afford corresponding triarylmethane products. The all obtained products were characterized by 1H NMR, 13C NMR, Mass, HRMS and IR spectral data. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: tert-butyldimethylsilyl chloride With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 0.166667h; Inert atmosphere; Stage #2: 4-hydroxymethyl-2-methoxyphenol In N,N-dimethyl-formamide at 20℃; for 1.5h; Inert atmosphere; | 8.B11 Example 8: Synthesis procedures B11: NO-OMe-BA In an inert 25.0 mL three-necked flask 899 mg (13.2 mmol, 2.20 eq) imidazole and 995 mg (6.60 mmol, 1.10 eq) tert-butyl(chloro)dimethylsilane were provided. After evacuating and flooding with Argon twice, 7.00 mL dry DMF were added and stirred for 10 minutes at room temperature. Afterwards 925 mg (6.00 mmol, 1.00 eq) 4-(hydroxymethyl)-2-methoxyphenol were added. The stirring was continued for 1.5 h. The suspension was mixed with 20.0 mL brine and extracted twice with 20.0 mL ethyl acetate. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate = 10: 1) to obtain the title compound as a colourless oil in 1.40 g (5.23 mmol, 87 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 90.8 %Chromat. 2: 9.2 %Chromat. | Stage #1: vanillin With 5wt.% Rh on activated alumina; ammonia In water for 1h; Green chemistry; Stage #2: With hydrogen In water at 80℃; for 2h; Green chemistry; | |
With ammonium hydroxide; 5% rhodium on activated aluminium oxide; hydrogen at 80℃; for 3h; Autoclave; | 8 General procedure: For the synthesis reaction, a 50 mL stainless steel autoclave was used. Into the autoclave, the raw material furfural (0.2 g, 2 mM), the catalyst 5 wt% Rh / Al 2 O 3 (0.002 g, Rh average particle diameter 40 nm), 28 wt% ammonia water (4.0 mL, 66 mM), finally a magnetic stir bar were put and covered, then the temperature was raised while stirring. After about 1 hour, when the vessel reached the reaction temperature of 80 ° C, hydrogen gas (2 MPa) was introduced to start the reaction. After a reaction time of 2 hours, cooled to 5 ° C or less with ice water, then the remaining hydrogen gas was released by opening the valve slowly, and then after filtering with filter paper (No. 1), Qualitative and quantification were carried out using GC-MS (CP-3800 + 1200 L made by Bruker Daltonics Co) or GC (HP6890 manufactured by Agilent Technologies). As a result, the conversion rate of raw material furfural was 100% and disappeared and the target product methyl amino furan was obtained in a yield of 91.7% (based on mol%, same in the following examples also). Other by-products are 8.3% of N,N-bis(furanyl methyl)amine and no other by-products were detected.The reaction was carried out under the same conditions as in Example 1 except that various kinds of raw materials were used instead of furfural as the aromatic compound or furan derivative having an aldehyde group. The results are summarized in Table 2. In all the raw materials, the structure of the aromatic or furan ring was maintained even after the reaction. In the case of having a nitro group as a substituent, it was found that the nitro group was reduced to be converted to an amino group, but otherwise the aldehyde group was converted to a methyl amino group. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With oxalyl dichloride In dichloromethane at 20℃; for 6h; chemoselective reaction; | General procedure of O-formylation reaction General procedure: To a solution of phenolic substrate (5 mmol.) in DCM, oxalyl chloride (15 mmol) was added at 0 °C and after that DMF (7.5 mmol) was added in a dropwise manner. The reaction was allowed to reach room temperature slowly and stirring was continued as mentioned in Table 2. A saturated solution of sodium bicarbonate (15 mL) was added to the reaction mixture to quench of excess oxalyl chloride. The reaction mixture was extracted with ethyl acetate (3 x 10 mL), dried over anhydrous Na2SO4, and evaporated to dryness under vacuum. The crude product was purified by column chromatography over silica gel, mesh 60-120, using ethyl acetate/petroleum ether as an eluent to afford the desired O-formylated products, and their purity was routinely checked by thin-layer chromatography (TLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium formate; palladium diacetate In toluene at 80℃; for 20h; Inert atmosphere; Overall yield = > 99 %Spectr.; | 1 example 1 To a microwave-vial containing the Pd°-catalyst (5 mol%) and ammonium formate (37.8 mg, 0.6 mmol, 3.0 equiv.) was added the solid vanillin 1a (0.2 mmol, 1.0 equiv.) under ISb atmosphere. Next, toluene (1 mL) was added at room temperature. The temperature was then set to the one shown in Table 1 and the reaction mixture was stirred under N2 atmosphere. After the time shown in Table 1 , the crude reaction mixture was filtrated through Celite using CHCI3 (10 mL) as eluent and evaporated. The crude material was purified by silica gel flash column chromatography. NMR samples for NMR-yield were prepared by removing 0.05 mL aliquots from the reaction mixtures, filtration through Celite using CDCI3 ( .5 mL) as eluent and mesitylene as the internal standard. | |
With palladium on activated charcoal; ammonium formate In toluene at 80℃; for 2.5h; Inert atmosphere; chemoselective reaction; | ||
With ammonium formate In toluene at 80℃; for 2.5h; Inert atmosphere; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In dichloromethane at 20℃; for 0.25h; Green chemistry; | 2.2. Typical procedure for tosylation using 1 General procedure: To a stirred solution of compound (1 mmol) in DCM (3 ml) was added [DMAPTs]+Cl-, 1 (1.1 mmol) at rt and the reaction mixture was stirred until TLC indicates completion. The reaction mixture was quenched with brine and the aqueous layer was extracted in to DCM. Combined organic layers were dried over anhydrous sodium sulphate and evaporated under vacuum. The solids thus obtained were purified by recrystalization from ethanol to produce the pure tosyl derivatives. |
90% | In dichloromethane at 20℃; Green chemistry; chemoselective reaction; | 2.2. Typical procedure for tosylation using 1 General procedure: To a stirred solution of compound (1 mmol) in DCM (3 ml) was added [DMAPTs]+Cl-, 1 (1.1 mmol) at rt and the reaction mixture was stirred until TLC indicates completion. The reaction mixture was quenched with brine and the aqueous layer was extracted in to DCM. Combined organic layers were dried over anhydrous sodium sulphate and evaporated under vacuum. The solids thus obtained were purified by recrystalization from ethanol to produce the pure tosyl derivatives. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With CeO2 nanorods anchored on mesoporous carbon; air In toluene at 80℃; for 2h; | |
72 %Chromat. | With TiO2 supported on MIL-101 framework, modified with CdS nanocrystals and decorated with co-catalytic Ni nanoparticles (Ni/CdS/TiO2-MIL-101) In acetonitrile at 27℃; for 48h; Inert atmosphere; Irradiation; | |
81.2 %Chromat. | With γ-iron(III) oxide In toluene at 80℃; for 8h; | 2.3. Catalytic test General procedure: A mixture of benzyl alcohol (1 mmol), aniline (2 mmol), catalyst(0.3 g), and toluene (10 mL) was added into a 50-mL two-neckflask. The flask was connected to an air balloon and the mixturewas vigorously stirred at 80 C for 8 h. Aliquots of the productswere taken with a sampling pipe and analyzed with a gas chromatographequipped with a HP-5 column and FID detector. Theproduct mixtures were further identified by GC-MS.A hot filtration test was carried out as follows: After 2 h of reaction,the solid catalysts were separated with a Buchner funnel.Then the mixture of the filtrate was put into the reactor and continuouslyreacted under the same conditions (80 C, air 1 atm)without any solid catalyst. In the recycling experiment, the usedcatalyst was separated from the reactant by an external magnetand treated at 350 C for 1 h in air before the next test cycle. |
With 3.3 wt% niobium oxide supported on cubic spinel cobalt oxide In neat (no solvent) at 140℃; for 20h; Sealed tube; | 2.3 Catalytic Reactions General procedure: A dehydrogenative coupling reaction was carried out in a35 mL screw-cap Borosil glass test tube. Typically, 1 mmolof alcohol, 3 mmol of aniline, and 25 mg freshly preparedcatalyst were added and tightly screw-capped. The reactiontube was heated to the desired reaction temperaturethrough the oil bath. The reaction mixture was stirredby using a magnetic stirrer. The progress of the reactionwas monitored periodically by withdrawing samples and quantified by Gas Chromatography (Agilent-7890B) andGC-MS (Shimadzu QP-2010, Japan) with HP-5 column,which consists of 5% diphenyl and 95% dimethyl polysiloxanecapillary column and FID as a detector). After thereaction, the solid catalyst was collected by centrifuge,washed with methanol and dried in an oven at 70 °C overnightand reuse for the further cycle. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sulfuric acid In ethanol; water Heating; | |
72% | Stage #1: 4-hydroxymethyl-2-methoxyphenol; 2-methoxy-phenol at 60℃; for 2h; Inert atmosphere; Stage #2: With DOWEX DR-2030 hydrogen at 60℃; for 15h; Inert atmosphere; | 1 Synthesis of Bisguaiacol F (BGF) with Vanillyl Alcohol and Guaiacol A 500 mL 3-neck round bottom flask equipped with overhead mechanical mixer, reflux condenser, inlet for dry argon gas, and thermometer. The flask was charged with 93.10 g guaiacol (0.75 mol) and 46.25 g vanillyl alcohol (0.30 mol). The mixture was allowed to reflux for 2 hours at 60° C. Next, 13.94 g DOWEX DR2030 hydrogen catalyst was slowly added with continuous mixing. The reaction was allowed to continue overnight at 60° C. for a total of 15 hours. The product was removed from heat and stirring and allowed to cool to room temperature. The resulting oil was dissolved in dichloromethane. The catalyst was removed via vacuum filtration and the filtrate was washed with deionized water. The organic phase was extracted three times, dried with anhydrous sodium sulfate, and concentrated under vacuum. Excess guaiacol was removed from the mixture via vacuum distillation leaving behind a solid BGF product with a yield of 72%. Further purification was carried out on a hexanes/ethyl acetate column. The product was characterized by 1H-NMR, 13C-NMR, and HRMS |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere; | General procedure for synthesis of 2-methoxy-1-(prop-2-ynyloxy)-4-((prop-2-ynyloxy)methyl)benzene (4) To a solution of vanillyl alcohol 3 (3.2 g, 20.75 mmol) in DMF (30 mL), caesium carbonate (2.4 equiv., 16.23 g, 49.82 mmol) and propargyl bromide (2.6 equiv., 4.8 mL, 53.95 mmol) were added under inert condition. The reaction mixture was stirred for 12 h at room temperature. After completion of reaction (monitored by TLC), reaction mixture wasin vacuo concentrated, extracted with CH2Cl2, and washed twice with 10% Na2CO3, water, and brine solution. The organic layer was dried over anhydrous Na2SO4. The residue obtained after removal of the solvent was purified by flash column chromatography using gradient mixtures of n-hexane-ethyl acetate as eluent to afford compound 4. 2-methoxy-1-(prop-2-ynyloxy)-4-((prop-2-ynyloxy)methyl)benzene) (4) Yellow liquid; 1H NMR (300 MHz, CDCl3): δ 7.01-6.87 (m, 3H), 4.75, (s, 2H), 4.55 (s, 2H), 4.16 (s, 2H), 3.88 (s, 3H), 2.49 (s, 1H), 2.47 (s, 1H); 13C NMR (75 MHz, CDCl3): δ 155.0, 149.6, 147.0, 129.0, 121.1, 113.9, 112.1, 78.3, 75.9, 69.7, 56.6, 55.9; MS: m/z 231 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45.3% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 12h; | 18 Example 18 4-(hydroxymethyl)-2-methoxyphenyl 3,5,6-trimethylpyrazine-2-carboxylate(6c).308 mg (2.0 mmol) of vanillyl alcohol were added to the round bottom bottle in turn.166mg (1.0mmol) TMP acid,229 mg (1.2 mmol) of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride,24 mg (0.2 mmol) of 4-dimethylaminopyridine;Add 20 mL of N,N-dimethylformamide,The reaction was stirred at room temperature for 12 h.TLC [V (petroleum ether): V (acetone) = 2:1] The reaction was found to be substantially complete. The mixture was extracted with EtOAc (EtOAc)EtOAc.The residue silica gel column separates white solid106.25 mg.M.P.: 142.3-143.4 °C,The yield was 45.3%. |
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39.5% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h; | |
39.5% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h; | 21 Example 21 2-methoxy-4-(((3,5,6-trimethylpyrazine-2-carbonyl)oxy)methyl)phenyl 3,5,6-trimethylpyrazine-2-carboxylate(7c).154 mg (1.0 mmol) of vanillyl alcohol were added to the round bottom bottle in turn.332mg (2.0mmol) TMP acid,420 mg (2.2 mmol) of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride,24 mg (0.2 mmol) of 4-dimethylaminopyridine; further 20 mL of anhydrous dichloromethane was added.The reaction was stirred at room temperature for 12 h.TLC [V (petroleum ether): V (acetone) = 2:1] The reaction was found to be substantially complete. The mixture was extracted with EtOAc (EtOAc)EtOAc.The residue silica gel column separates white solid186.54 mg.M.P.: 101.9-102.8 ° C,The yield was 39.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.2% | With potassium carbonate In N,N-dimethyl-formamide at 85℃; Inert atmosphere; | |
56.2% | With potassium carbonate In N,N-dimethyl-formamide at 85℃; for 4h; Inert atmosphere; | 3 Example 3 (3-methoxy-4-((3,5,6-trimethylpyrazin-2-yl)methoxy)phenyl)methanol (1c). Add in round bottom bottles308 mg (2.0 mmol) of vanillyl alcohol,341 mg (2.0 mmol) of TMP-Cl, 276 mg (2.0 mmol) of potassium carbonate;Further, 20 mL of N,N-dimethylformamide was added, and the reaction was carried out at 85 ° C for 4 h under a nitrogen atmosphere.TLC [V (petroleum ether): V (acetone) = 2:1] After the reaction was substantially complete, it was cooled and filtered.The filtrate was added with 5-10 times the amount of saturated aqueous sodium carbonate solution, and extracted with 3-4 times of the same amount of ethyl acetate. The ethyl acetate layer was combined and washed with a saturated aqueous solution of sodium chloride to neutral (small times). Dry over sodium sulfate, filter, and dryness under reduced pressure. The residue silica gel column separates white solid323.65mg.M.P.: 112.7-113.2 ° C, yield 56.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With sodium hydride In N,N-dimethyl-formamide Inert atmosphere; | |
65% | Stage #1: 4-hydroxymethyl-2-methoxyphenol With sodium hydride In N,N-dimethyl-formamide for 0.5h; Stage #2: 2-(chloromethyl)-3,5,6-trimethylpyrazine at 20 - 80℃; for 4.5h; | 6 Example 6 2-((2-methoxy-4-(((3,5,6-trimethylpyrazin-2-yl)methoxy)methyl)phenoxy)methyl)-3,5,6-trimethylpyrazine(2c).Take 308 mg (2.0 mmol) of vanillyl alcohol in a reaction flask.After adding 20 mL of N,N-dimethylformamide to the reaction flask, the mixture was stirred and dissolved.96 mg (4.0 mmol) of NaH was added and stirred for 0.5 h.After dropwise addition of 682 mg (4.0 mmol) of TMP-Cl at room temperature for 0.5 h, the reaction was heated in an oil bath at 80 ° C for 4 h.TLC [V (petroleum ether): V (acetone) = 2:1] The reaction was found to be substantially complete, the reaction was stopped, cooled and filtered. The filtrate was added with a 5-fold amount of a saturated aqueous solution of sodium chloride, and extracted with EtOAc (3 mL).The residue silica gel column separated 548.68 mg of white solid.M.P.: 108.8-109.0 ° C, yield 65.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With beta-galactosidase from Bacillus megaterium YZ08; magnesium chloride; In aq. phosphate buffer; dimethyl sulfoxide; at 35℃; for 12h;pH 7.4;Enzymatic reaction;Catalytic behavior; Kinetics; | General procedure: The reaction mixture (70 mL Na2PO4/KH2PO4 buffer (50 mM, pH 7.4) + 30 mL DMSO) containing MgCl2 (5 mM), <strong>[63-42-3]lactose</strong> (50 mmol), aromatic alcohols (30-40 mmol), crude enzyme solution (100 U) was prepared in a 250 mL Erlenmeyer flask. The reaction was conducted at 35 C with shaking at 200 rpm for 12 h. AB-8 macroporous resin column and flash column chromatography were used to purify the products. The procedure is detailed in supplementary material. The product structure was determined by NMR (Bruker AV-400 spectrometer, Switzerland). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With C44H60CoN4O2; oxygen In dichloromethane at 20℃; for 17h; Sealed tube; | 4.2. General procedure for the oxidation of lignin models General procedure: CAUTION: The oxidation reactions were performed in thick-walled, glass Fisher-Porter tubes under pressurized oxygen. Though no difficulties were experienced, adequate precautions should be considered when using organic compounds and oxygen above atmospheric pressure. Lignin models were oxidized according to a previously published procedure [19,30]. Briefly, to a Fisher-Porter tube was added 1 equivalent of the lignin model, 0.05 equivalents of Co-Schiff base catalyst, and the appropriate amount of methanol or dichloromethane to make a 0.2 M solution relative to the lignin model substrate. The tube was flushed three times and then pressurized to 50 psi using oxygen. Once pressurized, the reaction was stirred at room temperature for times denoted in Tables 1-3. If significant quantities of yellow solid (quinone) precipitated upon completion of the reaction, the mixture was filtered, and the mother liquor was concentrated under reduced pressure. This residue was analyzed by NMR to determine the amount of any additional quinone. If minimal or no yellow solid was present upon completion of the reaction, the mixture was concentrated under reduced pressure. Purification (silica gel; 0-2-5-10-100%EtOAc:DCM) gave the respective para-benzoquinones in yields reported in Tables 1-3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 13 %Spectr. 2: 9 %Spectr. | With C64H76CoN6O2; oxygen In dichloromethane at 20℃; for 18h; Sealed tube; | 4.2. General procedure for the oxidation of lignin models General procedure: CAUTION: The oxidation reactions were performed in thick-walled, glass Fisher-Porter tubes under pressurized oxygen. Though no difficulties were experienced, adequate precautions should be considered when using organic compounds and oxygen above atmospheric pressure. Lignin models were oxidized according to a previously published procedure [19,30]. Briefly, to a Fisher-Porter tube was added 1 equivalent of the lignin model, 0.05 equivalents of Co-Schiff base catalyst, and the appropriate amount of methanol or dichloromethane to make a 0.2 M solution relative to the lignin model substrate. The tube was flushed three times and then pressurized to 50 psi using oxygen. Once pressurized, the reaction was stirred at room temperature for times denoted in Tables 1-3. If significant quantities of yellow solid (quinone) precipitated upon completion of the reaction, the mixture was filtered, and the mother liquor was concentrated under reduced pressure. This residue was analyzed by NMR to determine the amount of any additional quinone. If minimal or no yellow solid was present upon completion of the reaction, the mixture was concentrated under reduced pressure. Purification (silica gel; 0-2-5-10-100%EtOAc:DCM) gave the respective para-benzoquinones in yields reported in Tables 1-3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | General experimental procedure for the synthesis of TMCA ester derivatives (1-28): General procedure: a mixture containing trans- 3,4,5- trimethoxycinnamic acid (trans-TMCA, 4.0mmol), 4-(dimethylamino)-pyridin (DMAP, 1.0mmol), 1-(3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (EDCI, 4.0mmol) and alcohol (3.0mmol) in the presence of anhydrous dichloromethane (30mL) was thoroughly stirred at room temperature for 6-10h till the completion of reaction as indicated by TLC analysis. The obtained product was washed with sodium bicarbonate water solution and diluted hydrochloric acid. The organic layer was dried over anhydrous sodium sulphate and evaporated to dryness to give the crude product. The obtained residue was purified by silica gel chromatography using petroleum ether: ethyl acetate (6:1, v:v) as original eluent to give compounds 2-28 (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; at 100℃; for 6h;Microwave irradiation; | 3 mmol ascorbic acid and 3 mmol vanillyl alcohol were dissolved in 10 ml water/ethanol (1/1; v/v). The solution was heated to 100 C. with constant stirring in the microwave (Mars Synthesis, CEM) for 7 minutes. The reaction mixture was subsequently heated in the microwave with constant stirring for further 6 h at 100 C. The LC-MS/QTOF chromatogram illustrated below shows the substances that are listed in Table 1 and form after 6 h as well as ethyl homovanillate (EHV, 17). Ethyl homovanillate (17) is contained in the primary reaction mixture at a quantity of 1.2%. (0188) Carrying out the above reaction with the indicated ratios of ascorbic acid and vanillyl alcohol with a boiling time of 4 h also leads to the formation of EHV. (0189) In this regard, refer to FIG. 1 (LC-MS/QTOF chromatogram of the primary reaction mixture after 6 h at 100 C.; upper chromatogram mass trace ESI positive, lower chromatogram UV-VIS totalled; the numbers represent the compounds according to Table 1 and EHV stands for ethyl homovanillate (17)). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane | 4.1.1. Synthesis of compounds 1-8 and 19-26 General procedure: General experimental procedure for the synthesis of vanillyl cinnamate derivatives (1-8 and 19-26): a mixture containing substituted cinnamic acids (4.0mmol, 1.0 equiv.), 1-(3-Dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (EDCI, 4.0mmol, 1.0equiv.), 4-(dimethylamino)-pyridin (DMAP, 1.0mmol, 0.25 equiv.) and vanillyl alcohol or 4-hydroxybenzyl alcohol (1.5mmol, 0.375 equiv.) in the presence of anhydrous dichloromethane (30mL) was thoroughly stirred at room temperature for 6-10h till the completion of reaction. The obtained product was extracted with sodium bicarbonate water solution and diluted hydrochloric acid. The organic layer was dried over anhydrous sodium sulphate and evaporated to dryness to give the crude product. The obtained residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (6:1, v:v) as original eluent to give the pure compounds 1-8 and 21-26 (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane | 4.1.1. Synthesis of compounds 1-8 and 19-26 General procedure: General experimental procedure for the synthesis of vanillyl cinnamate derivatives (1-8 and 19-26): a mixture containing substituted cinnamic acids (4.0mmol, 1.0 equiv.), 1-(3-Dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (EDCI, 4.0mmol, 1.0equiv.), 4-(dimethylamino)-pyridin (DMAP, 1.0mmol, 0.25 equiv.) and vanillyl alcohol or 4-hydroxybenzyl alcohol (1.5mmol, 0.375 equiv.) in the presence of anhydrous dichloromethane (30mL) was thoroughly stirred at room temperature for 6-10h till the completion of reaction. The obtained product was extracted with sodium bicarbonate water solution and diluted hydrochloric acid. The organic layer was dried over anhydrous sodium sulphate and evaporated to dryness to give the crude product. The obtained residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (6:1, v:v) as original eluent to give the pure compounds 1-8 and 21-26 (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane | 4.1.1. Synthesis of compounds 1-8 and 19-26 General procedure: General experimental procedure for the synthesis of vanillyl cinnamate derivatives (1-8 and 19-26): a mixture containing substituted cinnamic acids (4.0mmol, 1.0 equiv.), 1-(3-Dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (EDCI, 4.0mmol, 1.0equiv.), 4-(dimethylamino)-pyridin (DMAP, 1.0mmol, 0.25 equiv.) and vanillyl alcohol or 4-hydroxybenzyl alcohol (1.5mmol, 0.375 equiv.) in the presence of anhydrous dichloromethane (30mL) was thoroughly stirred at room temperature for 6-10h till the completion of reaction. The obtained product was extracted with sodium bicarbonate water solution and diluted hydrochloric acid. The organic layer was dried over anhydrous sodium sulphate and evaporated to dryness to give the crude product. The obtained residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (6:1, v:v) as original eluent to give the pure compounds 1-8 and 21-26 (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; | General procedure: General experimental procedure for the synthesis of vanillyl cinnamate derivatives (1-8 and 19-26): a mixture containing substituted cinnamic acids (4.0mmol, 1.0 equiv.), 1-(3-Dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (EDCI, 4.0mmol, 1.0equiv.), 4-(dimethylamino)-pyridin (DMAP, 1.0mmol, 0.25 equiv.) and vanillyl alcohol or 4-hydroxybenzyl alcohol (1.5mmol, 0.375 equiv.) in the presence of anhydrous dichloromethane (30mL) was thoroughly stirred at room temperature for 6-10h till the completion of reaction. The obtained product was extracted with sodium bicarbonate water solution and diluted hydrochloric acid. The organic layer was dried over anhydrous sodium sulphate and evaporated to dryness to give the crude product. The obtained residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (6:1, v:v) as original eluent to give the pure compounds 1-8 and 21-26 (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; | General procedure: General experimental procedure for the synthesis of vanillyl cinnamate derivatives (1-8 and 19-26): a mixture containing substituted cinnamic acids (4.0mmol, 1.0 equiv.), 1-(3-Dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (EDCI, 4.0mmol, 1.0equiv.), 4-(dimethylamino)-pyridin (DMAP, 1.0mmol, 0.25 equiv.) and vanillyl alcohol or 4-hydroxybenzyl alcohol (1.5mmol, 0.375 equiv.) in the presence of anhydrous dichloromethane (30mL) was thoroughly stirred at room temperature for 6-10h till the completion of reaction. The obtained product was extracted with sodium bicarbonate water solution and diluted hydrochloric acid. The organic layer was dried over anhydrous sodium sulphate and evaporated to dryness to give the crude product. The obtained residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (6:1, v:v) as original eluent to give the pure compounds 1-8 and 21-26 (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane | 4.1.1. Synthesis of compounds 1-8 and 19-26 General procedure: General experimental procedure for the synthesis of vanillyl cinnamate derivatives (1-8 and 19-26): a mixture containing substituted cinnamic acids (4.0mmol, 1.0 equiv.), 1-(3-Dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (EDCI, 4.0mmol, 1.0equiv.), 4-(dimethylamino)-pyridin (DMAP, 1.0mmol, 0.25 equiv.) and vanillyl alcohol or 4-hydroxybenzyl alcohol (1.5mmol, 0.375 equiv.) in the presence of anhydrous dichloromethane (30mL) was thoroughly stirred at room temperature for 6-10h till the completion of reaction. The obtained product was extracted with sodium bicarbonate water solution and diluted hydrochloric acid. The organic layer was dried over anhydrous sodium sulphate and evaporated to dryness to give the crude product. The obtained residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (6:1, v:v) as original eluent to give the pure compounds 1-8 and 21-26 (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane | 4.1.1. Synthesis of compounds 1-8 and 19-26 General procedure: General experimental procedure for the synthesis of vanillyl cinnamate derivatives (1-8 and 19-26): a mixture containing substituted cinnamic acids (4.0mmol, 1.0 equiv.), 1-(3-Dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (EDCI, 4.0mmol, 1.0equiv.), 4-(dimethylamino)-pyridin (DMAP, 1.0mmol, 0.25 equiv.) and vanillyl alcohol or 4-hydroxybenzyl alcohol (1.5mmol, 0.375 equiv.) in the presence of anhydrous dichloromethane (30mL) was thoroughly stirred at room temperature for 6-10h till the completion of reaction. The obtained product was extracted with sodium bicarbonate water solution and diluted hydrochloric acid. The organic layer was dried over anhydrous sodium sulphate and evaporated to dryness to give the crude product. The obtained residue was purified by silica gel chromatography using petroleum ether/ethyl acetate (6:1, v:v) as original eluent to give the pure compounds 1-8 and 21-26 (Scheme 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 10.4 %Chromat. 2: 88.7 %Chromat. | With hydrogen at 160℃; for 4h; Autoclave; Green chemistry; | |
1: 16.3 %Chromat. 2: 83.7 %Chromat. | With C25H23ClN7Ru(1+)*CF3O3S(1-); hydrogen at 100℃; for 1h; | |
1: 59 %Chromat. 2: 14 %Chromat. | With Ru-[{Im(Me)-py(4-OH)-Im(Me)}(CH3CN)2Cl]triflate; hydrogen; sodium carbonate at 100℃; for 4h; |
1: 59 %Chromat. 2: 14 %Chromat. | With Ru-[{Im(Me)-py(4-OH)-Im(Me)}(CH3CN)2Cl]triflate; hydrogen at 100℃; for 4h; Sealed tube; | 2; 4.1.4; 4.1.8 1.4 General Procedures General procedure: To a 20 mL vial with a stir bar, 1OH (2 mg, 0.00321 mmol), vanillyl alcohol (49.5 mg, 0.321 mmol), and Na2CO3 (8.5 mg, 0.08025 mmol), were added. Methanol (5 mL) was injected into the vial by using a syringe and needle right before placing the vial in the Parr vessel. The reaction vial was semi submerged into about 350 mL methanol in a Parr vessel, which contained a metal frame to support the reaction vessel and stir bar at the bottom. The Parr vessel was sealed and purged with ultra-high purity H2 gas for 5 times. The Parr vessel was then pressurized to 290 psi (20 bar) and heated at 100° C. with stirring for 1 hr. After heating was completed, the Parr vessel was cooled with a water-ice bath to about 40° C. After releasing the pressure, a sample was taken from the reaction mixture for GC analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: 4-hydroxymethyl-2-methoxyphenol; epichlorohydrin With N-benzyl-N,N,N-triethylammonium chloride at 30℃; for 8h; Stage #2: With tetraethylammonium bromide; sodium hydroxide In dichloromethane; water at 25℃; for 3h; | 1.1; 1.2 In a first step, 100 g (0.65 mol) of vanillyl alcohol was mixed with 14.8 g (0.065 mol) of benzyl tri ethyl ammonium chloride (TEBAC) and 300 g (3.24 mol) of epichlorohydrin in a glass vessel. The reaction mixture was stirred for 8 hours at 30 °C. 200 g of dichloromethane was added to the mixture, and the mixture was washed with NaCl-saturated water. The organic phase was dried with anhydrous sodium sulphate and filtered. After filtration, the solvent and the unreacted epichlorohydrin were removed by vacuum distillation at 70 °C and 0.01 mbar.In a second step, the product obtained at the end of the first step was dissolved in 200 g of dichloromethane, and mixed with 104 g of demineralized water, 25.95 g (0.65 mol) sodium hydroxide, and 6.8 g (0.032 mol) of tetraethylammonium bromide. The mixture was vigorously stirred for 3 hours at room temperature (about 25 °C). After decantation, the organic phase was washed twice with NaCl- saturated water. The organic phase was dried, and the solvents were removed by vacuum distillation at 70 °C and 0.01 mbar. After drying, 130 g of a white crystalline product was isolated and identified by NMR as being vanillyl alcohol mono glycidyl ether. The NMR spectrum is shown in FIG. 1 A.The yield of the vanillyl alcohol glycidyl ether can be calculated as a percentage of a theoretical yield. In theory, one mole of vanillyl alcohol (having a molecular weight of 154 g/mol) produces one mole of vanillyl alcohol glycidyl ether (having a molecular weight of 209 g/mol). Thus, in theory, 100 g of vanillyl alcohol produces 135 g of vanillyl alcohol glycidyl ether. The calculated yield achieved in this example is 130 g/135 g = 96 %. |
55% | Stage #1: 4-hydroxymethyl-2-methoxyphenol; epichlorohydrin at 80℃; for 1h; Stage #2: With sodium hydroxide at 20℃; | Vanillyl alcohol (5 g), epichlorohydrin (25.43 mL) and TEBAC (0.74 g) were added to a three-neck round bottom equipped with a mechanical mixer. The reaction mixture was heated to 80° C. for 1 hour. After the 1 hour, the reaction was cooled to room temperature and a mixture of 5 M NaOH (25.9 mL) and TEBAC (0.74 g) was added dropwise. The reaction was then worked up and washed with a solution of equal parts DI water and ethyl acetate. Flash chromatography was used to purify the intermediate product, mono-glycidyl ether of vanillyl alcohol (MGEVA, 55% yield, white powder). (3-methoxy-4-(oxiran-2-ylmethoxy)phenyl)methanol (MGEVA, C11H14O4) White solid, mp. 71-73° C. 1H-NMR (CDCl3) 2.7 (1H, dd), 2.9 (1H, t), 3.4 (1H, m), 3.9 (3H, s), 4.0 (1H, dd), 4.2 (1H, dd), 4.6 (2H, s), 6.9 (3H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: methanol; 4-hydroxymethyl-2-methoxyphenol With tetra(n-butyl)ammonium hydroxide at 50℃; for 1h; Stage #2: 1-chloromethyl-4-fluorobenzene In acetonitrile at 50℃; | 3.5. Fluorobenzylation of Model Compounds General procedure: First, 100 mg of model compounds (vanillin: 0.657 mmol; acetovanillone: 0.602 mmol; guaiacol:0.806 mmol; vanillyl alcohol: 0.649 mmol; veratryl alcohol: 0.595 mmol and cellobiose: 0.292 mmol) were dissolved in 1 mL of NBu (3.198 mmol) and stirred for 1 h at 50 °C. Then, 10 mL of acetonitrilewas added, followed by 300 mg of 4-uorobenzyl chloride (2.076 mmol) (FBC), the derivatizing agent.The reaction mixture was stirred at 50 °C for overnight. Next, distilled water (30 mL) and EtOAc(30 mL) were added to the reaction mixture. The aqueous layer was separated and extracted withEtOAc (2 30mL). The combined EtOAc layer was washed with distilled H2O (2 30 mL) andsaturated sodium chloride solution (30 mL). The extracted EtOAc layer was dried with sodium sulfate,filtered, evaporated and analyzed without any further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h; | 4.2.2. 4-(Azidomethyl)-2-methoxyphenol (6) In a round bottomed flask, alcohol 5 (1 g, 6.50 mmol, 1 eq.) was reacted with thionyl chloride (1mL, 2 eq.) and DMF (4 drops) in CH2Cl2 (15 mL). The reaction mixture was kept under magneticstirring for approximately two hours until TLC analysis indicated the completion of the reaction. Thesolvent and the excess of thionyl chloride were removed under vacuum. Subsequently, a 0.5 Msolution of NaN3 (26 mL, 13 mmol, 2 eq.) in DMSO was added to the flask, and the resulting solutionwas kept under magnetic stirring for approximately 16 h [23]. When TLC analysis indicated the endof the reaction, distilled H2O (20 mL) was added, followed by exhaustive extraction with chloroform.The organic phase was concentrated under vacuum and the resulting crude product was purified byflash chromatography in silica gel, eluted with ethyl acetate: hexane (9:1) to give a brown oil (827 mg,4.62 mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 53% 2: 47% | With orcinol; Acetobacterium dehalogenans veratrol-O-demethylase; Desulfitobacterium hafniense methyltransferase dhaf4611 In aq. buffer at 35℃; for 24h; Inert atmosphere; Enzymatic reaction; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With boron trifluoride diethyl etherate; acetic acid at 20℃; | 5.2. General preparation of compounds (3a-i) General procedure: The respective benzyl alcohol (1.96 μmol) was dissolved in acetic acid (3 mL). BF3.OEt2 (3.5 mL, 3.528 μmol) was added to the reaction mixture at room temperature. Sodium methyl sulfinate (200 mg, 1.96 μmol) was added to the reaction mixture and stirred for 30 min. Reaction mixture completion was confirmed by the TLC. After completion of the reaction, the reaction mixture was quenched with NaHCO3 solution (10 mL). The organic compound was extracted with dichloromethane (20 mL) and water (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by the silica gel chromatography to give the compounds 3a-3i. Yield, IR, NMR, ESI MS (M+H) data, and CHNS/O elemental analysis (Perkin-Elmer 2400) data of each product are given below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; caesium carbonate In dimethyl sulfoxide at 110℃; for 15h; Sealed tube; | |
69% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; 1,1,1,3',3',3'-hexafluoro-propanol; [bis(acetoxy)iodo]benzene; caesium carbonate at 100℃; for 15h; Microwave irradiation; Sealed tube; | General procedure for the preparation of pyrimidine fused uracils (3) from Nuracilamidines (1) and benzyl alcohols (2) using PhI(OAc)2/TEMPO ascatalytic system General procedure: N-Uracil amidine (0.5 mmol, 1.0 equiv.), benzyl alcohol (0.55 mmol, 60 mg), PhI(OAc)2(0.6 mmol, 193 mg), TEMPO (0.05 mmol, 8 mg) and Cs2CO3 (0.75 mmol, 244 mg) wereadded in an oven-dried microwave vial (10 mL) equipped with a magnetic stirring bar.To this mixture 1mL of HFIP was added via syringe and the tube was sealed with aseptum without inserting any gas protection. The reaction mixture was stirred in a preheatedoil bath at 100 C for 15 hours. After completion of reaction, the mixture wascooled to room temperature. The mixture was then partitioned between ethyl acetate(10 mL) and brine (10 mL). The aqueous layer was extracted with ethyl acetate(210 mL). Finally, the combined organic layers were washed with brine and driedover anhydrous Na2SO4 and concentrated under reduced pressure. The crude productwas purified by column chromatography on silica gel (60-120 mesh) using a mixture ofhexane-ethyl acetate (1:9) as the eluent to afford the pyrimidine fused uracils |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With immobilized Candida antarctica Lipase B at 60℃; for 0.25h; Molecular sieve; Flow reactor; Enzymatic reaction; | 2.1. General procedure for the flow esterification and in-line work up General procedure: A glass column (i.d.: 6.6 mm) was packed with a previously preparedmixture of Novozyme 435 (692 mg) and powder molecular sieves 4 Å(692 mg) to obtain a packed bed reactor (PBR) with a final volume of3.0 mL. A 0.1 M solution of the phenolic alcohol in CPME (20 mL) and a0.3 M solution of the fatty acid in CPME (20 mL) were mixed in a T-piece and the resulting flow stream was directed into the reactor column keptat 60 C. The total flow rate was 0.2 mL/min (residence time: 15 min).The exiting flow stream was flowed through a column (i.d.: 10 mm)packed with Amberlite IRA67 (2.8 g, total exchange capacity ≥ 1.60 eq/L FB form, PBR volume: 5.5 mL) at a total flow rate of 0.4 mL/min thanksto an inlet of CPME delivered through a third peristaltic pump. Theorganic solvent was collected and evaporated under pressure and, ifnecessary, the crude was purified by flash chromatography. |
67% | With immobilized Candida antarctica Lipase B at 60℃; for 0.25h; Molecular sieve; Flow reactor; Enzymatic reaction; | 2.1. General procedure for the flow esterification and in-line work up General procedure: A glass column (i.d.: 6.6 mm) was packed with a previously preparedmixture of Novozyme 435 (692 mg) and powder molecular sieves 4 Å(692 mg) to obtain a packed bed reactor (PBR) with a final volume of3.0 mL. A 0.1 M solution of the phenolic alcohol in CPME (20 mL) and a0.3 M solution of the fatty acid in CPME (20 mL) were mixed in a T-piece and the resulting flow stream was directed into the reactor column keptat 60 C. The total flow rate was 0.2 mL/min (residence time: 15 min).The exiting flow stream was flowed through a column (i.d.: 10 mm)packed with Amberlite IRA67 (2.8 g, total exchange capacity ≥ 1.60 eq/L FB form, PBR volume: 5.5 mL) at a total flow rate of 0.4 mL/min thanksto an inlet of CPME delivered through a third peristaltic pump. Theorganic solvent was collected and evaporated under pressure and, ifnecessary, the crude was purified by flash chromatography. |
With lipase B from Candida antarctica In tert-butyl methyl ether at 37℃; for 48h; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With N-doped carbon supported bimetallic catalyst Fe10Pd1/NC500 derived by pyrolisis of MOF NH2-MIL-101(Fe10Pd1) at 500°C at 120℃; for 16h; Inert atmosphere; | |
With 3.3 wt% niobium oxide supported on cubic spinel cobalt oxide In neat (no solvent) at 140℃; for 20h; Sealed tube; | 2.3 Catalytic Reactions General procedure: A dehydrogenative coupling reaction was carried out in a35 mL screw-cap Borosil glass test tube. Typically, 1 mmolof alcohol, 3 mmol of aniline, and 25 mg freshly preparedcatalyst were added and tightly screw-capped. The reactiontube was heated to the desired reaction temperaturethrough the oil bath. The reaction mixture was stirredby using a magnetic stirrer. The progress of the reactionwas monitored periodically by withdrawing samples and quantified by Gas Chromatography (Agilent-7890B) andGC-MS (Shimadzu QP-2010, Japan) with HP-5 column,which consists of 5% diphenyl and 95% dimethyl polysiloxanecapillary column and FID as a detector). After thereaction, the solid catalyst was collected by centrifuge,washed with methanol and dried in an oven at 70 °C overnightand reuse for the further cycle. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 22% 2: 11% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 6h; | General procedure of the Steglich esterifi cation. General procedure: 1-Adamantanecarboxylic or 1-adamantaneacetic acid was dissolved in CH2Cl2 (5-10 mL), and an equivalent amount of alcohol, an equivalent amount of DCC, and a catalytic amount of DMAP (0.05 g) were added. The mixture was stirred at ~20 °C for 6 h, and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (10 mL), and the solution was kept at 4°C for 1 h. The precipitate was filtered off and washed with cold ethyl acetate, and the solvent was removed under reduced pressure. The residue was chromatographed (eluent is indicatedfor each compound). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 24h; | 2 1.0 g of monomethyl fumarate was suspended in 20 ml of tetrahydrofuran, and 0.59 g (0.5 eq.) of 4-(hydroxymethyl)-2-methoxyphenol, 3.68 g (2.5 eq.) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.94 g (1.0 eq.) of 4-dimethylaminopyridine were added. After stirring at room temperature for 24 hours, the mixture was concentrated and diluted with 20 ml of ethyl acetate. After washing with 20 ml of water, drying over anhydrous magnesium sulfate, concentration, and crystallization with a mixed solvent of ethyl acetate and n-hexane (1:5, v/v), 0.96 g of the title compound as a white solid was obtained. (Yield: 66%) 1H NMR (400 MHz, DMSO-d6) δ 3.71 (s, 3H), 3.74(s, 6H), 5.20 (s, 2H), 6.81 (s, 2H), 6.95 (s, 2H), 7.00 (d, 1H), 7.15 (d, 1H), 7.20 (s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: 4-hydroxymethyl-2-methoxyphenol; boron trifluoride diethyl ether complex In tetrahydrofuran at 20℃; for 12h; Inert atmosphere; Stage #2: n-butyllithium In hexane at 20℃; for 6h; Inert atmosphere; | 2 Example 2: Raw material M2 Preparation method: Under argon atmosphere, the raw materials 4-hydroxy-3-methoxybenzyl alcohol (1.54g, 0.01mol) and boron trifluoride ether complex (2.98g, 0.021mol) were dissolved in 15ml THF (tetrahydrofuran). Mix well and react at room temperature for 12 hours. The obtained mixed solution was dried under reduced pressure under the conditions of 30° C. and a vacuum degree of about -0.1 MPa to remove the solvent to obtain an intermediate.14ml of butyllithium in hexane solution (c=1.6mol/L) was added to the intermediate, the reaction was stirred at room temperature for 6 hours, and the resulting mixed solution was dried under reduced pressure at 40°C and a vacuum degree of about -0.1MPa, The obtained crude product was washed three times with cyclohexane, filtered and dried to obtain product M2. The yield was 85%, and the NMR is shown in Figure 2. |
85% | Stage #1: 4-hydroxymethyl-2-methoxyphenol; boron trifluoride diethyl ether complex In tetrahydrofuran at 20℃; for 12h; Inert atmosphere; Stage #2: n-butyllithium In hexane at 20℃; for 6h; Inert atmosphere; | 2 Example 2: Raw material M2 Preparation method: Under argon atmosphere, the raw materials 4-hydroxy-3-methoxybenzyl alcohol (1.54g, 0.01mol) and boron trifluoride ether complex (2.98g, 0.021mol) were dissolved in 15ml THF (tetrahydrofuran). Mix well and react at room temperature for 12 hours. The obtained mixed solution was dried under reduced pressure under the conditions of 30° C. and a vacuum degree of about -0.1 MPa to remove the solvent to obtain an intermediate.14ml of butyllithium in hexane solution (c=1.6mol/L) was added to the intermediate, the reaction was stirred at room temperature for 6 hours, and the resulting mixed solution was dried under reduced pressure at 40°C and a vacuum degree of about -0.1MPa, The obtained crude product was washed three times with cyclohexane, filtered and dried to obtain product M2. The yield was 85%, and the NMR is shown in Figure 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With immobilized Candida antarctica Lipase B at 60℃; for 1.25h; Molecular sieve; Flow reactor; Enzymatic reaction; | 2.2. General procedure for the flow esterification with sorbic acid General procedure: A glass column (i.d.: 6.6 mm) was packed with a previously preparedmixture of Novozyme 435 (692 mg) and powder molecular sieves 4 Å(692 mg) (PBR volume: 3.0 mL). A 0.1 M solution of the phenolic alcoholin CPME (20 mL) and a 0.3 M solution of the sorbic acid in CPME (20mL) were mixed in a T-piece and the resulting flow stream was directedinto the reactor column kept at 60 C. The total flow rate was 0.04 mL/min (residence time: 75 min). The organic solvent was collected andevaporated under pressure and the crude was purified by flashchromatography. |
30% | With immobilized Candida antarctica Lipase B at 60℃; for 1.25h; Molecular sieve; Flow reactor; Enzymatic reaction; | 2.2. General procedure for the flow esterification with sorbic acid General procedure: A glass column (i.d.: 6.6 mm) was packed with a previously preparedmixture of Novozyme 435 (692 mg) and powder molecular sieves 4 Å(692 mg) (PBR volume: 3.0 mL). A 0.1 M solution of the phenolic alcoholin CPME (20 mL) and a 0.3 M solution of the sorbic acid in CPME (20mL) were mixed in a T-piece and the resulting flow stream was directedinto the reactor column kept at 60 C. The total flow rate was 0.04 mL/min (residence time: 75 min). The organic solvent was collected andevaporated under pressure and the crude was purified by flashchromatography. |
Tags: 498-00-0 synthesis path| 498-00-0 SDS| 498-00-0 COA| 498-00-0 purity| 498-00-0 application| 498-00-0 NMR| 498-00-0 COA| 498-00-0 structure
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