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CAS No. : | 52010-97-6 | MDL No. : | MFCD11870191 |
Formula : | C8H8O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ZFHUHPNDGVGXMS-UHFFFAOYSA-N |
M.W : | 136.15 | Pubchem ID : | 556330 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 37.96 |
TPSA : | 37.3 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.19 cm/s |
Log Po/w (iLOGP) : | 1.39 |
Log Po/w (XLOGP3) : | -0.08 |
Log Po/w (WLOGP) : | 0.84 |
Log Po/w (MLOGP) : | 0.85 |
Log Po/w (SILICOS-IT) : | 1.83 |
Consensus Log Po/w : | 0.97 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.95 |
Solubility : | 15.4 mg/ml ; 0.113 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.25 |
Solubility : | 76.3 mg/ml ; 0.56 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.14 |
Solubility : | 0.977 mg/ml ; 0.00718 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-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 |
---|---|---|
95% | With hydrogen bromide In dichloromethane; acetic acid | 1.3 4-(Bromomethyl)benza]dehyde, 3.3 Alcohol 2 (6.46 g, 47.5) was dissolved in DCM (100 ml) before HBr in acetic acid (33 wtpercent, 42 ml, 243, 5 eq) was added and stirred overnight. Water (100 ml) was added to the reaction mixture and the phases were separated and the organic phase obtained was washed with a NaOH solution (2 M, 2 χ 100 ml), dried over Na2S04, and evaporated. The residue was washed through a silica plug to yield 3 as a white solid (9.04 g, 45.4 mmol, 95percent). Rf = 0.77 (DCM); m.p. = 100°C (recrystallised from hexane); vmax = 1682, 1604, 1209, 1200, 830, 770, 726 cm'1; NMR (300 MHz, CDC ) δ = 10.02 (s, 1H, CHO), 7.87 (d, 3J(H,H) = 8.2 Hz, 2H, ArCH a to CHO), 7.56 (d, 3J(H,H) = 8.2 Hz, 2H, ArCH a to C3/4Br), 4.52 (s, 2Η, C1/2Br); 13C NMR (75 MHz, CDC13) δ = 191.5 (CHO), 144.2 (ArCCBr), 136.2 (ArCCHO), 130.2 (ArCH a to ArCCHO), 129.7 (ArCH a to ArCCH2Br), 31.9 (C3/4Br); HRMS (EST): m/z calculated for C83/4BrO [M - H]" : 196.9602, found 196.9602; elemental analysis calcd (percent) for C8H7BrO (199.04): C 48.27, H 3.54; found: C 47.40, H 3.53. |
58% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane for 4.5 h; | N-Bromosuccinimide (NBS, 19.6 g) was added to a solution of 2a or 2b (10.0 g) in dichloromethane(120 mL). Triphenylphosphine (2.0 equiv, 38.5 g, 0.146 mol) was divided into four equal aliquots andan aliquot was added to the reaction every 30 min. After the reaction was completed, the solution wasmixed with cold water (120 mL). The aqueous phase was extracted two times with dichloromethaneand the organic phase was washed with a saturated NaCl solution and dried over Na2SO4 for 8 h.The mixture was purified by silica gel chromatography with petroleum ether–ethyl acetate = 25:1 aseluent to give compound 3a 8.5 g (58.0percent yield) and 3b 6.8 g (46.8percent yield), respectively. |
58% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane at 20℃; for 3 h; Cooling with ice | Take a 500mL eggplant-shaped bottle,Peeled 10.0 g of Intermediate II-1 (0.073 mol; 1.0 equiv)It was dissolved by adding 150 mL of methylene chloride, and 19.6 g of N-bromosuccinimide solid was added with stirring.Then under ice-cooling to the eggplant-shaped flask was added in four portions solid triphenylphosphine, a total of 38.5g (0.146mol; 2.0equiv), each batch half-hour intervals, until triphenyl phosphine addition was completed, the ice bath was removed ,The reaction was continued at room temperature for more than 3h, TLC TLC plate, UV analyzer (254nm) to monitor the progress of the reaction.After the raw material point II-1 disappears, the reaction is stopped and the reaction solution is poured into a beaker containing 150 ml of cold water,Then the aqueous phase was poured into the organic phase mixture separatory funnel extraction, the aqueous phase was extracted with 150ml of dichloromethane,The combined dichloromethane layers were washed with saturated aqueous sodium chloride solution. Then,The organic phase is dried over anhydrous sodium sulphate or anhydrous magnesium sulphate overnight. Filter out the desiccant,Weigh about 60-100 mesh size silica gel powder about 15g added to the filtrate, rotary evaporation to dry sand, silica gel column chromatography, the choice of elution system for petroleum ether: ethyl acetate = 99: 1, the resulting benzyl position Alcoholic hydroxyl brominated reaction products,A total of 8.5 g of a III-1 white solid was obtained in a yield of 58.0percent. |
58% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane at 20℃; for 3 h; Cooling with ice | Take a 500mL eggplant-shaped bottle,10.0 g of Intermediate II-1 (0.073 mol; 1.0 equiv) was weighed by peeling.Add 150 mL of dichloromethane to dissolve it,19.6 g of N-bromosuccinimide solid was added with stirring.Then, triphenylphosphine was added to the eggplant flask in four batches under ice-cooling conditions.A total of 38.5g (0.146mol; 2.0equiv),Each batch is separated by half an hour.After triphenylphosphine is added,Remove the ice bath,Continue to react at room temperature for more than 3 hours,Thin layer TLC board,An ultraviolet analyzer (254 nm) monitors the progress of the reaction.After the material point of II-1 disappears,Stop the reaction, Pour the reaction solution into a beaker containing 150 ml of cold water.Then, the aqueous organic phase mixture is poured into a separatory funnel for extraction.The aqueous phase is extracted with 150 ml of dichloromethane.Combine the dichloromethane layer,Add saturated aqueous sodium chloride solution.Then,The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight.Filter out the desiccant,Weigh about 15g of 60-100 mesh silica gel powder into the filtrate.Rotary to dry sand,Silica gel column chromatography separation,The elution system selected was petroleum ether:ethyl acetate = 99:1.The resulting benzylic hydroxyl alcohol bromo reaction product is collected,A total of 8.5 g of III-1 white solid was obtained.Yield: 58.0percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With hydrogen bromide In dichloromethane; acetic acid | 1.1.3 1.3 4-(Bromomethyl)benza]dehyde, 3.3 Alcohol 2 (6.46 g, 47.5) was dissolved in DCM (100 ml) before HBr in acetic acid (33 wt%, 42 ml, 243, 5 eq) was added and stirred overnight. Water (100 ml) was added to the reaction mixture and the phases were separated and the organic phase obtained was washed with a NaOH solution (2 M, 2 χ 100 ml), dried over Na2S04, and evaporated. The residue was washed through a silica plug to yield 3 as a white solid (9.04 g, 45.4 mmol, 95%). Rf = 0.77 (DCM); m.p. = 100°C (recrystallised from hexane); vmax = 1682, 1604, 1209, 1200, 830, 770, 726 cm'1; NMR (300 MHz, CDC ) δ = 10.02 (s, 1H, CHO), 7.87 (d, 3J(H,H) = 8.2 Hz, 2H, ArCH a to CHO), 7.56 (d, 3J(H,H) = 8.2 Hz, 2H, ArCH a to C¾Br), 4.52 (s, 2Η, C½Br); 13C NMR (75 MHz, CDC13) δ = 191.5 (CHO), 144.2 (ArCCBr), 136.2 (ArCCHO), 130.2 (ArCH a to ArCCHO), 129.7 (ArCH a to ArCCH2Br), 31.9 (C¾Br); HRMS (EST): m/z calculated for C8¾BrO [M - H]" : 196.9602, found 196.9602; elemental analysis calcd (%) for C8H7BrO (199.04): C 48.27, H 3.54; found: C 47.40, H 3.53. |
95% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane at 20℃; for 4h; | A Step A: 4- (bromomethyl) benzaldehyde To a stirred solution of 4- (hydroxymethyl) benzaldehyde (7 g, 50.7 mmol) in DCM (400 mL) , NBS (17.8 g, 100 mmol) and PPh3(27.3 g, 104 mmol) were added. After the addition, the reaction mixture was stirred at rt for 4hrs. The reaction mixture was washed by H2O (150 mL x 3) . The organic layers were washed with brine, dried over Na2SO4, concentrated and purified by column chromatography (petroleum ether/EtOAc=5: 1) to give 4- (bromomethyl) benzaldehyde (9.5 g, 95%) as white solids. MS: M/e 199 (M+1)+. |
88% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane at 20℃; for 10h; |
82% | With hydrogen bromide In toluene for 2h; Heating; | |
82% | With hydrogen bromide In water; toluene for 3h; Reflux; | |
80% | With boron tribromide In tetrahydrofuran at 0℃; for 2h; | General method A General procedure: To a solution of aryl benzyl alcohol in THF was added tribromoborane drop-wise at 0 °C. TLC showed the reaction was completed. The reaction was quenched by MeOH slowly and then concentrated under reduced pressure to give a residue. The residue was purified by slica gel column chromatography using a gradient from 0% to 20% of Ethyl acetate in Petroleum ether to yield the desired compound |
77% | With bromine; triphenylphosphine In dichloromethane at 20℃; for 0.583333h; | |
73% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane at 40℃; for 6h; | |
73% | With hydrogen bromide In water; toluene for 3h; Reflux; | |
65% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane at 0℃; for 0.333333h; | |
65% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane for 0.5h; | |
58% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane for 4.5h; | 3.2.2. Synthesis of 4-(Bromomethyl)benzaldehyde (3a) and 3-(Bromomethyl)benzaldehyde (3b) N-Bromosuccinimide (NBS, 19.6 g) was added to a solution of 2a or 2b (10.0 g) in dichloromethane(120 mL). Triphenylphosphine (2.0 equiv, 38.5 g, 0.146 mol) was divided into four equal aliquots andan aliquot was added to the reaction every 30 min. After the reaction was completed, the solution wasmixed with cold water (120 mL). The aqueous phase was extracted two times with dichloromethaneand the organic phase was washed with a saturated NaCl solution and dried over Na2SO4 for 8 h.The mixture was purified by silica gel chromatography with petroleum ether-ethyl acetate = 25:1 aseluent to give compound 3a 8.5 g (58.0% yield) and 3b 6.8 g (46.8% yield), respectively. |
58% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane at 20℃; for 3h; Cooling with ice; | 1.1.2 1.2 Synthesis of 4-bromomethylbenzaldehyde (III-1) Take a 500mL eggplant-shaped bottle,Peeled 10.0 g of Intermediate II-1 (0.073 mol; 1.0 equiv)It was dissolved by adding 150 mL of methylene chloride, and 19.6 g of N-bromosuccinimide solid was added with stirring.Then under ice-cooling to the eggplant-shaped flask was added in four portions solid triphenylphosphine, a total of 38.5g (0.146mol; 2.0equiv), each batch half-hour intervals, until triphenyl phosphine addition was completed, the ice bath was removed ,The reaction was continued at room temperature for more than 3h, TLC TLC plate, UV analyzer (254nm) to monitor the progress of the reaction.After the raw material point II-1 disappears, the reaction is stopped and the reaction solution is poured into a beaker containing 150 ml of cold water,Then the aqueous phase was poured into the organic phase mixture separatory funnel extraction, the aqueous phase was extracted with 150ml of dichloromethane,The combined dichloromethane layers were washed with saturated aqueous sodium chloride solution. Then,The organic phase is dried over anhydrous sodium sulphate or anhydrous magnesium sulphate overnight. Filter out the desiccant,Weigh about 60-100 mesh size silica gel powder about 15g added to the filtrate, rotary evaporation to dry sand, silica gel column chromatography, the choice of elution system for petroleum ether: ethyl acetate = 99: 1, the resulting benzyl position Alcoholic hydroxyl brominated reaction products,A total of 8.5 g of a III-1 white solid was obtained in a yield of 58.0%. |
58% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane at 20℃; for 3h; Cooling with ice; | 1.1.2 1.2 Synthesis of 4-bromomethylbenzaldehyde (III-1) Take a 500mL eggplant-shaped bottle,10.0 g of Intermediate II-1 (0.073 mol; 1.0 equiv) was weighed by peeling.Add 150 mL of dichloromethane to dissolve it,19.6 g of N-bromosuccinimide solid was added with stirring.Then, triphenylphosphine was added to the eggplant flask in four batches under ice-cooling conditions.A total of 38.5g (0.146mol; 2.0equiv),Each batch is separated by half an hour.After triphenylphosphine is added,Remove the ice bath,Continue to react at room temperature for more than 3 hours,Thin layer TLC board,An ultraviolet analyzer (254 nm) monitors the progress of the reaction.After the material point of II-1 disappears,Stop the reaction, Pour the reaction solution into a beaker containing 150 ml of cold water.Then, the aqueous organic phase mixture is poured into a separatory funnel for extraction.The aqueous phase is extracted with 150 ml of dichloromethane.Combine the dichloromethane layer,Add saturated aqueous sodium chloride solution.Then,The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight.Filter out the desiccant,Weigh about 15g of 60-100 mesh silica gel powder into the filtrate.Rotary to dry sand,Silica gel column chromatography separation,The elution system selected was petroleum ether:ethyl acetate = 99:1.The resulting benzylic hydroxyl alcohol bromo reaction product is collected,A total of 8.5 g of III-1 white solid was obtained.Yield: 58.0%. |
52% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane at 20℃; | |
35.76% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane at 20℃; for 3h; | 1.2 1.2 Synthesis of p-bromomethylbenzaldehyde (3a-1) and m-bromomethylbenzaldehyde (3a-2) Take one 100mL eggplant-shaped bottle, add 2.50g (18.36mmol) 2a-1 or 2a-2, dissolve it with 40mL dichloromethane, and add 4.90g (27.53mmol) N-bromosuccinimide under stirring The amine, followed by addition of 9.63 g (36.72 mmol) of triphenylphosphine in four times under ice bath conditions, and the reaction was completed at room temperature for more than 3 h. Monitor the progress of the reaction by TLC until the point 2a-1 or 2a-2 disappear completely, filter, add 40mL water to the filtrate, separate the liquid, extract the aqueous phase twice with dichloromethane, 20mL each time, combine the organic phases, anhydrous Sodium sulfate was dried, filtered to remove sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was sampled with 100-200 mesh silica gel and separated by column chromatography (PE:EA=10:1 elution) to obtain a white loose solid p-bromomethyl Benzaldehyde (3a-1, 1.30g, yield 35.76%) or m-bromomethylbenzaldehyde (3a-2, 1.09g, yield 30.07%). |
With phosphorus tribromide; benzene | ||
With hydrogen bromide In water; toluene | ||
With N-Bromosuccinimide; triphenylphosphine In dichloromethane for 2h; Reflux; | ||
With hydrogen bromide In water; toluene for 3h; Reflux; | ||
With N-Bromosuccinimide; triphenylphosphine In dichloromethane at 20℃; for 3h; Cooling with ice; | 3.2.2. Synthesis of 3a and 3b General procedure: Synthesis of 3-(bromomethyl)benzaldehyde (3a) or 4-(bromomethyl)benzaldehyde(3b): Compound 2a or 2b (2.50 g, 18.36 mmol) was dissolved in CH2Cl2 (40 mL), andn-bromosuccinimide (4.90 g, 27.53 mmol) was added to the solution. After cooling in anice bath, PPh3 (9.63 g, 36.72 mmol) was added to the solution. The mixture was stirred atroom temperature for at least 3 h. The reaction mixture was filtered, and water (40 mL) wasadded to the filtrate. The solution was extracted with CH2Cl2 (2 20 mL). The organiclayers were dried over anhydrous sodium sulfate, and the solvent was evaporated undera reduced pressure to obtain a residue. The residue was purified by silica gel columnchromatography (petroleum ether: EtOAc = 10:1) to afford 3-(bromomethyl)benzaldehyde(3a) or 4-(bromomethyl)benzaldehyde (3b) as a white porous solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 62% 2: 36% | With manganese(IV) oxide; oxygen In toluene at 110℃; for 8h; Green chemistry; | 3.1. Oxidation of benzhydrol 1a in the presence of substoichiometric amounts of activated MnO2: preparation of benzophenone 2 (Table 1, entry 6). General procedure General procedure: Benzhydrol 1 (0.3831 g, 2.08 mmol) was dissolved in toluene (15 mL) and activated MnO2 (purchased from Aldrich, 0.106 g, 1.92 mmol, 50 mg/mmol) was added to the solution. The reaction mixture was heated at 110 °C under oxygen atmosphere for 4 h. Supernatant of the reaction mixture was scooped by pipet. Additional toluene (5 mL) was added to solid residue and washed the solid then the supernatant was scooped by pipet. This washing procedure was repeated for four times. All of toluene solution was combined and concentrated. Crude product was purified by flash chromatography (silica gel/hexane-EtOAc 3:1) to give 2 in 98% yield (0.373 g, 2.05 mmol). MnO2 residue was examined for the recycling use of the oxidant (Scheme 4, see below). |
1: 44% 2: 37% | With cucurbit[8]uril; 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In water for 0.25h; Reflux; | |
1: 37 %Chromat. 2: 16% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [Cu([bis(3-tert-butyl-2-hydroxybenzyl)](2-pyridylmethyl)amine)(acetate)(acetic acid)]; potassium carbonate In water at 25℃; for 24h; |
With manganese(IV) oxide In tetrahydrofuran at 45℃; other temperature, k2/k1; | ||
With sodium carbonate In acetonitrile at 15℃; electrolysis; | ||
1: 56 %Chromat. 2: 28.6 %Chromat. | With sodium bromate; acetic acid In water at 90℃; for 1.5h; | 13 In the same manner as in Example 3, the operation was conducted, except that 0.55 g (4 mmols) of p-xylylene glycol was used in place of m-methoxybenzyl alcohol and 1 ml (17.4 mmols) of acetic acid was used in place of 2 ml of acetic acid, and also 1 ml of water and 0.4 g (2.7 mmols) of sodium bromate were used. With respect to the components in the reaction solution, the intended p-phthalaldehyde was produced in an area ratio, as determined by gas chromatography, of 56.0% and p-hydroxymethylbenzaldehyde as a product at the intermediate stage (compound in which only one among two hydroxymethyl groups in a molecule of the raw material was replaced by a formyl group) was produced in an area ratio of 28.6%.Example 3 (An embodiment of the invention described in the above embodiment [1]): Production of m-methoxybenzaldehyde In a 15 ml test tube type reaction vessel equipped with a magnetic stirrer and a reflux condenser, 0.55 g (4 mmols) of m-methoxybenzyl alcohol, 0.18 g (1.2 mmols) of sodium bromate and 2 ml (34.8 mmols) of acetic acid were charged, and then the resultant mixture was stirred at 90°C for 1.5 hours. Along with the progress of the reaction, a small amount of bromine was produced. After the completion of the reaction, bromine completely disappeared. |
With 5,10,15,20-tetramesitylporphyrin In dichloromethane; acetonitrile for 72h; Irradiation; | ||
With recombinant 5-hydroxymethylfurfural oxidase In aq. phosphate buffer at 25℃; for 4h; Enzymatic reaction; | ||
With C14H36Cu2N4O2(2+)*2CF3O3S(1-) In dichloromethane at -40.16℃; for 5h; | 2.2 Oxidation of exogenous substrates General procedure: Solutions of OTMPDMeCN-(X)2 and OTMPDPhCN-(X)2 (10mM, 5mL in CH2Cl2) were prepared from the pre-mixed 1:1 Cu(I)-ligand precursors by addition of excess O2 (1atm) at 193K. Two equiv of substrate per oxidant were used unless otherwise noted. For anaerobic substrate oxidations, excess O2 was removed and the solution was flushed with N2 prior to substrate addition. Similar product distributions were obtained for alcohol oxidation reactions performed under O2 and N2 at 233K. Alcohol oxidations without NEt3 were carried out at 233K, and all other reactions were carried out under N2 at 193K unless otherwise noted. The resulting reaction mixtures were quenched by dropwise addition of aqueous ammonia (30%) until the CH2Cl2 layer turned colorless, and passed through a column of neutral activated alumina (Brockmann I, ∼150 mesh, 58Å) followed by MeOH (2mL). The copper product is retained, and the organic products elute. The reaction mixture was analyzed by GC/GC-MS. Mass recovery of the products was >90% based on addition of an internal calibrant (benzonitrile for alcohols, acetophenone for amines). | |
With oxygen In water at 120℃; for 24h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With sodium tetrahydridoborate In tetrahydrofuran; ethanol at 0℃; for 7h; | |
92% | With formic acid; [(η5-C5H5)Ru(κ1-P-PPh2Py)(PPh3)Cl]; sodium hydroxide In water monomer; acetonitrile at 80℃; for 8h; | |
91% | With bis(η5-cyclopentadienyl)hafnium dihydride In isopropanol at 80℃; for 8h; |
91% | With sodium tetrahydridoborate In ethanol at 0℃; for 1h; | 2 4-Hydroxymethylbenzaldehyde: To a suspension of terephthalaldehyde (MW 134.13; 14.92 mmol; 2.00 g; 1 eq) in anhydrous ethanol (50 mL) in a 250 mL (0314) Erlenmeyer flask (equipped with a magnetic stir bar) cooled to 0°C in an ice bath, powdered sodium borohydride (MW 37.83; 5.22 mmol; 0.200 g; 0.33 eq) was added in one portion, and the reaction continued to stir at 0°C. The suspension quickly became a light yellow solution in the first minute the sodium borohydride was added. A rubber septum was used to seal the flask, and the reaction was allowed to stir for one hour. The reaction was followed by TLC with 1 : 1 ethyl acetate and hexanes as the eluent. At the end of the experiment, the reaction was warmed to room temperature and deionized water was added. Ethyl acetate was added to this mixture, and it was vigorously shaken. The aqueous and organic layers were separated and the aqueous layer was extracted 3 x 20 mL with ethyl acetate. The combined organic layers were dried with sodium sulfate and dried under reduced pressure. When the crude residue was dissolved in (0315) dichloromethane, white crystals began to form in the reaction. The flask was cooled to 0°C to complete the crystallization and the crystals were filtered from the mother liquor. The remaining crude mixture was adsorbed onto silica gel for flash chromatography (0 to 30% ethyl acetate/hexanes) to afford 91% of the desired 4-hydroxymethylbenzadehyde product as a white solid. |
91% | With sodium tetrahydridoborate In ethanol at 0 - 20℃; for 1h; | |
90% | With methanol; sodium tertiary butoxide In 1,4-dioxane at 100℃; for 1h; | |
90% | With sodium tetrahydridoborate; acetylacetone In tetrahydrofuran at 0 - 20℃; for 2.25h; Inert atmosphere; | |
90% | With potassium-t-butoxide; hydrogen; C18H26Cl2MnN3P In methanol at 70 - 100℃; Inert atmosphere; Autoclave; chemoselective reaction; | |
88% | With sodium tetrahydridoborate; ethanol In tetrahydrofuran at -5 - 2℃; for 6.5h; | |
87% | With 5%-palladium/activated carbon; hydrogen In isopropanol at 20℃; for 6h; | |
86.1% | With sodium tetrahydridoborate In tetrahydrofuran; ethanol for 6h; Cooling with ice; | 3.2.1. Synthesis of 4-(Hydroxymethyl)benzaldehyde (2a) and 3-(Hydroxymethyl)benzaldehyde (2b) NaBH4 (1.7 g) was added to a solution of terephthalaldehyde (1a, 20.0 g) or isophthalaldehyde(1b, 20.0 g) in ethanol (100 mL) and tetrahydrofuran (150 mL). The reaction was stirred in an ice-bathfor 6 h. After reaction completion, the solution was quenched with 2Mhydrochloric acid to the pH 5-6.The solvent was evaporated, then water and ethyl acetate were added to the residue. The organicphase was washed with a saturated NaCl and dried with Na2SO4 for 8 h. The mixture was purifiedby silica gel chromatography with petroleum ether-ethyl acetate = 5:1 as eluent to give compound 2a17.6 g (86.1% yield) and 2b 16.4 g (80.2% yield), respectively. |
86.1% | With sodium tetrahydridoborate In tetrahydrofuran; ethanol for 6h; Cooling with ice; | 1.1.1 1.1 Synthesis of 4-hydroxymethylbenzaldehyde (II-1) Take a 500mL eggplant-shaped flask, 20g of terephthalaldehyde (0.15mol; 4.0equiv),100ml of ethanol and 150ml of tetrahydrofuran were added to the bottle, stirring to dissolve evenly.Subsequently, under ice-bath conditions, 1.7 g of sodium borohydride solid (9.3 mmol; 1.0 equiv) was slowly added to the bottle in one go. The reaction was carried out for 6 h, TLC TLC plate and ultraviolet analyzer (254 nm) to monitor the progress of the reaction.To be terephthalic formaldehyde material completely disappeared, stop the reaction,Dropping 2mol / L hydrochloric acid solution prepared before quenching, adjusting the pH to 4 to 5,The reaction mixture was then swirled to dryness. The resulting residue was re-dissolved in water and ethyl acetate and added to a separatory funnel.The aqueous phase is extracted with an equal volume of ethyl acetate 2 to 3 times, the combined ethyl acetate layers are washed with saturated aqueous sodium chloride solution.Subsequently, the organic phase is dried overnight over anhydrous sodium sulfate or anhydrous magnesium sulfate. Filter out the desiccant,Weigh about 60-100 mesh size silica gel powder about 30g added to the filtrate, and steam-dried to dry sand, silica gel column chromatography, the choice of elution system for petroleum ether: ethyl acetate = 3: 1, the resulting monomeric Based reduction reaction product,A total of 17.6 g of a II-1 white solid was obtained in a yield of 86.1%. |
86.1% | With sodium tetrahydridoborate In tetrahydrofuran; ethanol for 6h; Cooling with ice; | 1.1.1 1.1 Synthesis of 4-hydroxymethylbenzaldehyde (II-1) Take a 500mL eggplant-shaped bottle,20 g of terephthalaldehyde (0.15 mol; 4.0 equiv),100ml of ethanol and 150ml of tetrahydrofuran are added to the bottle in order.Stir and dissolve evenly.Then in an ice bath,Slowly add 1.7 g of sodium borohydride solid (9.3 mmol; 1.0 equiv) slowly into the bottle.Reaction more than 6h,Thin layer TLC board,An ultraviolet analyzer (254 nm) monitors the progress of the reaction.Until starting material terephthalaldehyde point completely disappeared,Stop the reaction, Pre-prepared 2mol/L hydrochloric acid solution was added for quenching.Adjust the pH to 4 to 5,Then the reaction solution was evaporated to dryness.The residue obtained with water,The ethyl acetate was re-dissolved and added to a separatory funnel.The aqueous phase is extracted 2 to 3 times with an equal volume of ethyl acetate.Combine the ethyl acetate layers,Add saturated aqueous sodium chloride solution.Then,The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate overnight.Filter out the desiccant,Weigh about 30g of 60-100 mesh silica gel powder into the filtrate.Rotary to dry sand,Silica gel column chromatography separation,The elution system selected was petroleum ether:ethyl acetate = 3:1,The resulting monoaldehyde-based reduction reaction product is collected,A total of 17.6 g of II-1 white solid was obtained.Yield: 86.1%. |
86% | With sodium tetrahydridoborate In tetrahydrofuran; ethanol at 0 - 20℃; for 1h; | |
86% | With Cs2CO3 In water monomer; isopropanol at 120℃; for 4h; | 2.5. Procedure for selective reduction of benzaldehydes General procedure: The selective reduction of various benzaldehydes was carriedout by dissolving 2 mmol of the corresponding benzaldehyde ina similar ratio of H2Oand ipr-OH followed by the addition of 2equivalents of Cs2CO3 and 25 mg of CoCr2O4-HNT. The reactionmixture was then refluxed for 4 h at 120 °C and the progress ofthe reaction was monitored by TLC analysis and the resultantbenzyl alcohol was separated by column chromatography. |
83% | With sodium tetrahydridoborate In tetrahydrofuran; ethanol; water monomer at -5 - 0℃; for 6h; | |
83% | With sodium tetrahydridoborate; ethanol In tetrahydrofuran at -10 - 20℃; for 6h; | 4 Example 4 Preparation of intermediate hydroxymethyl benzaldehyde Dissolve 2.0g (14.90mmol, 1eq.) terephthalaldehyde in 25mL absolute ethanol and 35mL tetrahydrofuran, add 140mg (3.72mmol, 0.25eq.) sodium borohydride in four batches while stirring at -10-5 After 1h is added, the reaction system is moved to room temperature, and the reaction is continued for 5h.After the reaction, add 1mol/L of dilute hydrochloric acid to the reaction solution to adjust the pH to 5, distill under reduced pressure to remove the solvent, add water to the residue and extract with ethyl acetate, retain the organic layer, wash with saturated brine, and anhydrous sulfuric acid The crude product was obtained by drying with sodium, filtering, and distillation under reduced pressure. Column chromatography gave a white solid 1.6g with a yield of 83.0%, mp 33-35°C. |
82% | With sodium tetrahydridoborate In tetrahydrofuran; ethanol; water monomer at -5 - 0℃; for 6.5h; | |
82% | With sodium tetrahydridoborate In tetrahydrofuran; ethanol at 20℃; for 5h; | |
81% | With sodium tetrahydridoborate In tetrahydrofuran; ethanol at -5 - 2℃; for 6.5h; Inert atmosphere; | Synthesis of 4-hydroxymethylbenzaldehyde (5) NaBH4 (0.85 g, 18.5 mmol) was added at -5 °C with continuous stirring for 30 min to a solution of terephthalaldehyde (10 g, 75 mmol) in a mixture of 95% EtOH (125 mL) and THF (175 mL). The mixture was allowed to stir for 6 h while the temperature was maintained in the range of 0-2 °C. The reaction mixture was then neutralized with 2 MHCl to pH 5 and the solvents were evaporated. Water (100 mL) was added to the residue and product was extracted into EtOAc, dried (MgSO4) and the solvent was evaporated. The product was purified by over silica gel column chromatography using EtOAc-hexane (1 : 1). Yield 81%, white solid; |
81% | With sodium tetrahydridoborate In tetrahydrofuran; ethanol at 5℃; for 1.5h; | |
81% | With sodium tetrahydridoborate In tetrahydrofuran at 0℃; for 0.5h; | Synthesis of compound 2 . To a stirred solution of compound 1 (1.5 g, 11.2 mmol) in 30 mL THF was added NaBH 4 (0.15 g, 4 mmol) portionwise at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h, then treated with water (50 mL), and extracted twice with CH 2 Cl 2 (40 mL ×2). The organic layers were washed twice with water and once with brine, then dried over anhydrous sodium sul- fate. After evaporation of the solvent under reduced pressure, the residue was purified by chromatography using hexane/PE (5/1, v/v) as an eluent to yield compound 2 as an white solid (1.2 g, 81%). 1 H NMR (600 MHz, CDCl 3 ) : 9.99 (s, 1H), 7.87 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 4.80 (d, J = 5.6 Hz, 2H), 2.10 (s, 1H). 13 C NMR (150 MHz, CDCl 3 ) : 192.51, 148.28, 135.35, 130.00, 126.94, 64.19. Anal. calcd for C 8 H 8 O 2 : C, 70.57; H, 5.92; found: C, 70.51; H, 5.96. |
80% | With methanol; sodium tetrahydridoborate at 0 - 20℃; for 3h; | |
78% | With hydrogen In methanol for 2.5h; | [0112] Terephthaldicarboxaldehyde (30.02 g, 224 mmol), methanol (200 mL), palladium on activated carbon, (10%, 3.02 g) and 2-(aminomethyl)pyridine (2.3 mL, 22 mol, 0.01 mol equiv) were combined in a hydrogenation vessel and the reaction mixture was shaken on a Parr hydrogenator for 2.5 hours at 40 psi of hydrogen. The mixture was filtered through celite, the cake washed with methanol and the solvent from the eluent removed in vacuo. Purification of the crude product by column chromatography on silica gel (EtOAc/Hexanes, 1:1) afforded the title compound (23.8 g, 78%) as a white solid. 1H NMR (CDCl3) δ 4.80 (s, 2H), 7.53 (d, 2H, J=9 Hz), 7.87 (d, 2H, J=9 Hz), 10.00 (s, 1H). |
74% | With sodium tetrahydridoborate In tetrahydrofuran; ethanol at 0℃; for 6.5h; | |
73.89% | With sodium tetrahydridoborate; ethanol In tetrahydrofuran for 6h; Cooling with ice; | 1.1 1.1 Synthesis of p-hydroxymethylbenzaldehyde (2a-1) and m-hydroxymethylbenzaldehyde (2a-2) Take one 250mL eggplant-shaped bottle, add 10.00g (74.55mmol) of terephthalaldehyde 1a-1 or isophthalaldehyde 1a-2,Add 50 mL of ethanol and 80 mL of tetrahydrofuran to dissolve.Under stirring in an ice bath, 0.85 g (22.46 mmol) of sodium borohydride was added in three portions, and after the completion of the addition, the reaction was continued under ice bath conditions for more than 6 h.Monitor the progress of the reaction by TLC until the point 1a-1 or 1a-2 disappear completely, stop the reaction, and quench the reaction solution with 3mol/L hydrochloric acid.And adjust the pH to 4-5, filter, the filtrate is distilled under reduced pressure to remove the solvent,The residue is a brownish yellow oil. Dissolve the residue with 50 mL each of ethyl acetate and water. Separate the liquid. Extract the aqueous phase twice with ethyl acetate, 30 mL each time. Combine the organic phases and wash with saturated brine.Dry over anhydrous sodium sulfate, filter to remove sodium sulfate, the filtrate is distilled under reduced pressure to remove the solvent, and the residue is sampled with 100-200 mesh silica gel,Column chromatography separation (PE:EA=3:1 elution) to obtain colorless transparent liquid p-hydroxymethylbenzaldehyde (2a-1, 7.50g, yield 73.89%) or m-hydroxymethylbenzaldehyde (2a- 2, 5.63g, yield 55.57%). |
68% | With potassium hydroxide; aluminium In ethanol | |
67% | With sodium tetrahydridoborate In tetrahydrofuran; ethanol at 0 - 20℃; for 24h; Inert atmosphere; | |
66% | With sodium tetrahydridoborate; ethanol In tetrahydrofuran at 0 - 20℃; for 6.5h; Inert atmosphere; | |
66% | With sodium tetrahydridoborate; ethanol In tetrahydrofuran at 0℃; for 4.83h; Inert atmosphere; | 5.E E. Preparation of 4-(((tert-butyldimethylsilyl)oxy)methyl)benzaldehyde 69 Compound 68 is prepared by a literature procedure (Wang et al. (2017) Org. Lett. 19(3):632-635). More specifically, under inert atmosphere, terephthalaldehyde 67 (10.0 g, 74.6 mmol, 1 .00 equiv) is dissolved in anhydrous THF (124 mL, 0.60 M) and ethanol (41 mL, 1.8 M). At 0 °C, sodium borohydride (0.705 g, 18.6 mmol, 0.25 equiv) is added in small portions, over 20 minutes. The resulting mixture is stirred at 0 °C for 2.5 hours. More sodium borohydride (0.039 g, 1 .0 mmol, 0.014 equiv) is added at 0 °C. The resulting mixture is stirred at 0 °C for 2 hours. The reaction is quenched by addition of aqueous 2M HCI (10 mL). The resulting yellow solution, containing white solids is kept at 0 °C for the night. Solvent is evaporated under reduced pressure. Water (150 mL) is then added to the residue and the product is extracted with AcOEt (2 x 100 mL). Organic extracts are combined and washed with brine. The organic layer is dried over magnesium sulfate, filtered and solvent is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (Biotage SNAP, 100 g) eluting with 0-50% AcOEt/hexanes gradient. The desired product 68 is obtained as a white solid (6.68 g, 49.1 mmol, 66% yield).1H NMR (500 MHz, CDCI3) d (ppm) 10.02 (s, 1 H), 7.92-7.85 (m, 2H), 7.57- 7.52 (m, 2H), 4.82 (d, 2H, J = 5.5 Hz), 1 .85 (t, 1 H, J = 6.0 Hz). |
65% | With sodium tetrahydridoborate In tetrahydrofuran at 0℃; for 4h; Inert atmosphere; | |
65% | With sodium tetrahydridoborate In tetrahydrofuran; methanol at 0 - 20℃; for 12h; Inert atmosphere; | |
64% | With sodium tetrahydridoborate In ethanol at 0 - 20℃; for 4h; Sealed tube; | |
62% | With sodium tetrahydridoborate In tetrahydrofuran at 20℃; for 1h; | |
60% | With sodium tetrahydridoborate In tetrahydrofuran at 0 - 25℃; for 0.25h; Inert atmosphere; | Synthesis of 7 Derivative 6 (1.0 g, 7.45 mmol) wasdissolved in dry THF (20 mL) at room temperatureunder a nitrogen atmosphere. The mixture was cooled at 0°C and NaBH4 (0.28 g, 7.45 mmol) was added. Themixture was kept under stirring at 0°C and allowed towarm at room temperature and stirred for 15 min. Thereaction was quenched with water (30 mL) and theproduct 7 was extracted with ethyl acetate (50 mL)and washed with an aqueous saturated solution ofNaHCO3 (50 mL) and H2O (30 mL). The organic layerwas dried over Na2SO4, filtered and evaporated. Thecrude product was purified by column chromatographyon Silica gel (CH2Cl2/EP, 80/20, v/v), to give derivative 7as a white solid (0.61 g, 4.48 mmol, 60%). ESI(+) MS: m/z = 137 (MH+); 1H NMR (250 MHz, CDCl3, 298 K): δ 4.61(s, 2H), 7.55 (d, J = 7.5 Hz, 2H), 7.82 (d, J = 7.5 Hz, 2H),9.88 (s, 1H); 13C NMR (63 MHz, CDCl3, 298 K): δ 64.3,127.0, 130.1, 135.8, 150.1, 191.0. Anal. Calcd for C8H8O2:C, 70.58; H, 5.92. Found: C, 70.60; H, 5.93. |
56% | With sodium tetrahydridoborate; ethanol In tetrahydrofuran at 0 - 2℃; for 6h; Inert atmosphere; | 1.1.2-i Above in step (2-i), a 500 ml round bottom flask was charged with terephthaldehyde (10 g, 0.07462 mol, 1 eq), Sodium borohydride (0.8469 g, 0.02238 mol, 0.3 eq), 125 ml ethanol, 175 ml of THF was added, and the solution was degassed while blowing nitrogen gas at 0 to 2 ° C for 30 minutes, followed by stirring for 6 hours. After confirming that all of the reaction products disappeared using TLC, the pH of the solution was adjusted to 5 by neutralizing with 13 ml of 2M hydrochloric acid. The solvent was removed under reduced pressure, ethyl acetate and water were added, and the organic layer was separated using a separating funnel. After removal of the solvent under reduced pressure and then The reaction mixture was dissolved in dichloromethane and separated by column chromatography (silica, EtOAc 25% (v / v) + Hexane 75% (v / v)) to give 4- (hydroxymethyl) benzaldehyde. |
54% | With diisobutylaluminium hydride In tetrahydrofuran at 0℃; for 0.5h; | |
50% | With sodium tetrahydridoborate In tetrahydrofuran at 0 - 20℃; | 4.2.6.9. 4-(Hydroxymethyl)benzaldehyde (93) A solution of terephthalaldehyde (7.5 g, 56 mmol) in THF (50 ml) was cooled to 0 °C. Sodium borohydride (750 mg, 19.8 mmol) was added and the mixture was stirred at room temperature for 1 h. After evaporation of the solvent, the residue was taken up in ethyl acetate and the solution was washed with water and brine and dried over MgSO4. Upon removal of the solvent, the residue was purified by flash chromatography (cyclohexane/ethyl acetate) to obtain 93 as a white solid (3.85 g, 50%). 1H NMR (300 MHz, acetone-d6): δ = 4.49 (t, J = 5.3 Hz, 1H), 4.74, (d, J = 4.4 Hz, 2H), 7.58 (m, 2H), 7.88 (m, 2H), 10.01 (s, 1H) ppm; 13C NMR (75 MHz, acetone-d6): δ = 64.1, 127.5, 130.2, 136.5, 150.4, 192.6 ppm; HRMS (ESI): m/z [M+H]+ calcd for C8H9O2: 137.0597, found: 137.0612. |
49.2% | With sodium tetrahydridoborate In tetrahydrofuran; ethanol at 0℃; for 2h; | |
38% | With sodium tetrahydridoborate In tetrahydrofuran; ethanol at -5 - 0℃; | |
35% | With sodium tetrahydridoborate In tetrahydrofuran at 20℃; for 1h; | |
28% | With sodium tetrahydridoborate In tetrahydrofuran at 0℃; for 4h; Inert atmosphere; | p-hydroxymethylbenzaldehyde was prepared following literature procedures(Mak. C. C.; Bampos, N.; Darling, S. L.; Montalti, M.; Prodi, L.; Sanders, J.K. M. J. Org. Chem. 2001, 66, 4476-4486.): Terephtaldicarboxaldehyde(6.71 g, 50 mmol) wasdissolved in THF (50 mL). The mixture was cooled to 0°C, NaBH4 (0.66 g, 17.5 mmol) was addedand the reaction stirred for 4 h. After concentration of the reaction mixture,the residue was taken up in EtOAc, water was added and the layers separated. Theorganic layer was washed with water, sat. aq. NaCl, dried (Na2SO4),filtered and concentrated. The residue was purified by column chromatography(10 → 40% EtOAc/light petroleum) and the pure compound was obtained as an off-white solid (1.88 g,13.8 mmol, 28%). |
25% | With sodium tetrahydridoborate In tetrahydrofuran at 20℃; for 1h; | |
21% | With sodium tetrahydridoborate In tetrahydrofuran at 0 - 20℃; | |
19% | With sodium tetrahydridoborate In tetrahydrofuran at 20℃; for 1h; | |
Multistep reaction; | ||
25.2 g | With hydrogen In ethanol; water monomer for 3h; Ambient temperature; | |
In ethanol; water monomer | 1 Example 1 Example 1 Preparation of (+-)-BL-V8-310 and (+-)-epi-BL-V8-310 Terephthalaldehyde (25.0 g) was suspended in water (20 ml) and ethanol (80 ml). Pd/C (220 mg) was added to the suspension and then hydrogen gas (4.3 l) was introduced. The catalyst was removed by filtration and the filtrate was concentrated to give p-hydroxymethylbenzaldehyde (25.2 g). The product was dissolved in toluene (100 ml) and 48% HBr (50 ml) and the solution was refluxed for 2 hours. | |
With sodium borohydride In methanol | 1.a 4-Hydroxymethylbenzaldehyde (a) 4-Hydroxymethylbenzaldehyde 200 g (1.44 mols) of terephthalic dialdehyde are suspended in 2,000 ml of methanol, and 23.5 g (0.62 mol) of sodium borohydride are added, while cooling with ice. After the mixture has been heated to room temperature, it is evaporated down under reduced pressure to a quarter of its volume, and extracted 3 times with dichloromethane. After the solution has been dried with sodium sulphate and the dichloromethane stripped off, 4-hydroxymethylbenzyl alcohol crystallized from ether. After the filtrate had been evaporated down, 61.7 g of crystalline product were obtained. Yield: 61.7 g (34.5% of theory). Melting point: 48° C. | |
With hydrogenchloride In tetrahydrofuran; lithium tri-tert-butoxyaluminium hydride | 1.a a) a) 4-Hydroxymethylbenzaldehyde To a solution of 1,4-benzenedicarboxaldehyde (50.0 g, 0.373 mole) in dry tetrahydrofuran (200 mL) under nitrogen in an ice bath was added dropwise lithium tri(tert-butoxy)aluminum hydride (104.0 g, 0.410 mole) in 500 mL of tetrahydrofuran. After stirring for one half hour in an ice bath, the reaction mixture was poured into 2 L of ice cold 2 N hydrochloric acid. The aqueous solution was extracted with four 800 mL portions of ether. The combined ether layers were washed with sodium bicarbonate solution, brine and dried. Evaporation of the solvent afforded 46 g of crude material that was purified by chromatography (alumina, ether elution) to provide the title compound as a crystalline material (17.6 g, 35%): mp 44.5-46 °C | |
With sodium tetrahydridoborate In methanol | ||
With (η5-C5Me5)RhCl2(5-(3-pyridyl)dipyrromethane); water monomer; anhydrous sodium formate In acetonitrile at 80℃; for 5h; | ||
> 99 %Spectr. | With sodium tetrahydridoborate; nickel(II) phthalocyanine In PEG-400 at 20℃; for 0.25h; regioselective reaction; | |
With sodium tetrahydridoborate In methanol at 20℃; for 1h; | ||
With bis[dichlorido(η5-1,2,3,4,5-pentamethyl-cyclopentadienyl)iridium(III)]; C19H23N2O8PS(2-)*2Na(1+); anhydrous sodium formate In ethanol at 37℃; for 0.5h; | ||
With sodium tetrahydridoborate In tetrahydrofuran; ethanol at 0℃; for 6.5h; | ||
With sodium tetrahydridoborate In tetrahydrofuran; ethanol at 0 - 15℃; for 3h; | ||
1.51 g | With sodium tetrahydridoborate In tetrahydrofuran; ethanol at 0℃; for 6h; | |
With hydrogenchloride; Sodium hydrogenocarbonate In tetrahydrofuran; lithium tri-tert-butoxyaluminium hydride | 1 7β-(DL-α-Amino-p-hydroxymethylphenylacetamido)desacetoxycephalosporanic acid EXAMPLE 1 7β-(DL-α-Amino-p-hydroxymethylphenylacetamido)desacetoxycephalosporanic acid To a solution of 1,4-benzenedicarboxaldehyde (50.0 g., 0.373 mole) in 200 ml. of dry tetrahydrofuran under nitrogen in an ice bath was added dropwise lithium tri(t-butoxy)aluminum hydride (104.0 g., 0.410 mole) dissolved in 500 ml. of dry tetrahydrofuran. After stirring for one half hour in an ice bath, the reaction mixture was poured into 2 l. of ice cold 2N hydrochloric acid. The aqueous solution was extracted with four 800 ml portions of ether. The combined ether layers were washed with 500 ml of ice cold 5% sodium bicarbonate solution and then with 500 ml of saturated sodium chloride solution. After drying, the ether was removed under reduced pressure to give 46 g. of crude p-hydroxymethylbenzaldehyde. | |
With hydrogenchloride; Sodium hydrogenocarbonate In tetrahydrofuran; lithium tri-tert-butoxyaluminium hydride | 1 7β(DL-α-Amino-p-hydroxymethylphenylacetamido)desacetoxycephalosporanic acid EXAMPLE 1 7β(DL-α-Amino-p-hydroxymethylphenylacetamido)desacetoxycephalosporanic acid To a solution of 1,4-benzenedicarboxaldehyde (50.0 g., 0.373 mole) in 200 ml. of dry tetrahydrofuran under nitrogen in an ice bath was added dropwise lithium tri(t-butoxy)aluminum hydride (104.0 g., 0.410 mole) dissolved in 500 ml. of dry tetrahydrofuran. After stirring for one half hour in an ice bath, the reaction mixture was poured into 21. of ice cold 2N hydrochloric acid. The aqueous solution was extracted with four 800 ml portions of ether. The combined ether layers were washed with 500 ml of ice cold 5% sodium bicarbonate solution and then with 500 ml of saturated sodium chloride solution. After drying, the ether was removed under reduced pressure to give 46 g. of crude p-hydroxymethylbenzaldehyde. | |
With hydrogenchloride; Sodium hydrogenocarbonate In tetrahydrofuran; tri(t-butoxy)aluminum hydride | 1 7β-(DL-α-Amino-p-hydroxymethylphenylacetamido)desacetoxycephalosporanic acid EXAMPLE 1 7β-(DL-α-Amino-p-hydroxymethylphenylacetamido)desacetoxycephalosporanic acid To a solution of 1,4-benzenedicarboxaldehyde (50.0 g., 0.373 mole) in 200 ml. of dry tetrahydrofuran under nitrogen in an ice bath was added dropwise lithiun tri(t-butoxy)aluminum hydride (104.0 g., 0.410 mole) dissolved in 500 ml. of dry tetrahydrofuran. After stirring for one half hour in an ice bath, the reaction mixture was poured into 2 l. of ice cold 2N hydrochloric acid. The aqueous solution was extracted with four 800 ml portions of ether. The combined ether layers were washed with ml of ice cold 5% sodium bicarbonate solution and then with 500 ml of saturated sodium chloride solution. After drying, the ether was removed under reduced pressure to give 46 g. of crude p-hydroxymethylbenzaldehyde. | |
Multi-step reaction with 3 steps 1: ammonia hydrochloride / ethanol / 0 - 20 °C 2: sodium tetrahydridoborate; methanol / 1 h / 0 - 20 °C 3: hydrogenchloride / water monomer; tetrahydrofuran / 1 h / 20 °C | ||
With sodium tetrahydridoborate In tetrahydrofuran at 0℃; for 1h; | ||
With sodium tetrahydridoborate In tetrahydrofuran; ethanol at 0℃; for 6h; | 3.2.1. Synthesis of 2a and 2b General procedure: Synthesis of 3-(hydroxymethyl)benzaldehyde (2a) and 4-(hydroxymethyl)benzaldehyde(2b): Isophthalaldehyde (1a) or terephthalaldehyde (1b) (4.0 equivalent 10 g, 74.55 mmol)was dissolved in a mixture of ethanol (50 mL) and tetrahydrofuran (80 mL). After coolingin an ice bath, sodium borohydride (1 equivalent 0.85 g, 18.60 mmol) was added to thesolution. The reaction mixture was stirred at 0 C for at least 6 h until the disappearanceof 1a or 1b. Then the reaction was quenched with 3 M HCl (to pH 4-5). The solution wasfiltered and evaporated to dryness under a vacuum. The residue was mixed with waterand extracted with EtOAc (2 50 mL). The combined organic layers were washed withbrine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporatedto obtain a crude product. The crude product was purified by flash column chromatography(petroleum ether: EtOAc = 3:1) to afford 3-(hydroxymethyl)benzaldehyde (2a) or4-(hydroxymethyl)benzaldehyde (2b) as a colorless and transparent liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 83% 2: 17% | With C48H43ClN2P2Ru; ammonium formate In water; toluene at 90℃; for 9h; Schlenk technique; | 31 Example 31 Transfer hydrogenation in a biphasic system with formate salts as hydride donor on aldehyde substrates The selected aldehyde (2.5 mmol), HCOONH4 (10 mmol, 0.63 g) and complex (e.g. 1 .25 μηιοΙ, 1 mg; S/C = 2000) are transferred into a 50 ml Schlenk tube. Then toluene (1 .2 ml) and water (5 ml) are sequentially added. The biphasic mixture is subjected to four vacuum-argon cycles under vigorous stirring and then put into an oil bath at 90°C for the desired time. The reaction is sampled by removing ~1 ml of the mixture, diethyl ether (4 ml) is added, the organic phase separated, dried over MgS04, filtered and the solvent gently removed under reduced pressure. The crude residue was dissolved with CDCI3 and analyzed by H-NMR. Alternatively, the dried organic fraction is filtered over a short silica pad and the conversion determined by GC analysis. Table 11. TH of aldehydes catalyzed by complexes 13-15 with HC02NH4 in toluene/H20 at 90°C Aldehyde Complex S/C Substrate NH4-formate Time Alcohol By- molar molar;equivalents (h) (%) products (%L_ 13 5000 0.5 1 ; 2 16 60 0 13 5000 0.5 1 ; 2 22 76 0 14 5000 0.5 1 ; 2 15 96 0 14 5000 0.5 1 ; 2 24 97 0 14 5000 1 .0 1 ; 2 15 86 0 14 5000 1.0 1; 2 24 95 0 14 5000 0.5 1; 4 15 96 0 14 5000 0.5 1; 4 24 96 0 14 5000 1.0 1; 4 15 96 0 14 5000 1.0 1; 4 24 96 0 14 20000 2.0 2; 4 24 94 0 14 20000 2.0 2; 4 48 96 0 15 5000 0.5 1; 2 16 96 0 15 10000 2.0 1; 2 20 86 0 15 20000 2.0 1; 2 40 96 0 14 2000 0.5 1; 2 10 97 0 14 20000 2.0 2; 4 24 62 0 14 20000 2.0 2; 4 48 72 0 14 2000 0.5 2; 4 10 >99 0 14 2000 0.5 1; 2 3.5 >99 0 14 2000 0.5 1; 1.5 9 57: 83 0 58: 17 14 2000 0.5 1; 2 10 57: 71 0 58: 21 0 14 2000 0.5 1;4 10 57: 0 58: 99 14 2000 0.5 1; 2 10 97 54:10 14 5000 2.0 2; 4 16 78 0 14 5000 2.0 2; 4 24 86 0 14 5000 2.0 2; 4 48 97 0 14 5000 2.0 4; 4 16 84 0 14 5000 2.0 4; 4 24 91 0 14 5000 2.0 4; 4 48 94 0 14 10000 0.5 1;2 24 38 0 14 10000 0.5 1;2 38 49 0 With complexes 13-15 the transfer hydrogenation of aldehydes with NH4-formate is an improvement compared to using 2-propanol as hydride donor and K2C03 as base (examples 28 and 29). The use of less complex (higher S/C ratio) is possible and less by-products are formed. It is important to note that no primary amines are produced by reductive amination of the aldehyde. Interestingly, the presence of the toluene solvent as co-solvent is not entirely required, as shown in the table below. Toluene was not added to the reactions carried out on a 2.5 mmol substrate scale. Table 12. TH of aldehydes catalyzed by complex 14 with HC02NH4in H20 at 90°C Aldehyde Complex S/C Substrate NH4-formate Time Alcohol By- molar molar;equivalents (h) (%) products (%) 13 5000 0.5 1; 2 16 60 13 5000 0.5 1; 2 22 76 14 2000 2.5 mmol 1; 2 2 50 14 2000 2.5 mmol 1; 2 4 76 14 2000 2.5 mmol 1; 2 7 97 14 5000 2.5 mmol 1; 2 14 53 14 5000 2.5 mmol 1; 4 24 97 14 5000 2.5 mmol 2; 4 24 90 45 14 5000 0.5 1; 2 15 96 14 5000 0.5 1; 2 24 97 14 5000 1.0 1; 2 15 86 14 5000 1.0 1; 2 24 95 14 5000 0.5 1; 4 15 96 14 5000 0.5 1; 4 24 96 14 5000 1.0 1; 4 15 96 14 5000 1.0 1; 4 24 96 14 20000 2.0 2; 4 24 94 14 20000 2.0 2; 4 48 96 0 15 5000 0.5 1; 2 16 96 0 15 10000 2.0 1; 2 20 86 0 15 20000 2.0 1; 2 40 96 0 14 2000 2.5 mmol 1; 2 14 33 6 14 2000 2.5 mmol 1; 2 16 61 0 14 2000 0.5 1; 2 10 97 0 46 14 2000 2.0 2;4 11 97 0 14 10000 2.0 2;4 24 24 0 14 20000 2.0 2; 4 24 62 0 14 20000 2.0 2; 4 48 72 0 14 5000 2.0 2; 4 15 96 0 47 >99, 14 2000 0.5 2; 4 10 0 48 65[bl 14 2000 0.5 1; 2 3.5 >99 0 55 14 2000 2.0 2;4 3.5 99, 65[bl 0 14 2000 0.5 1; 1.5 9 57: 83 0 56 58: 17 14 2000 0.5 1; 2 10 57: 71 0 58: 21 14 2000 0.5 1;4 10 57: 0 0 58: 99 14 2000 0.5 1; 2 10 97 54:10 14 5000 2.0 2; 4 16 78 54:6 14 5000 2.0 2; 4 24 86 0 52 14 5000 2.0 2; 4 48 97 54:12 14 5000 2.0 4; 4 16 84 0 14 5000 2.0 4; 4 24 92 54:5 14 5000 2.0 4; 4 48 94 54:7 14 10000 0.5 1 ; 2 24 38 14 10000 0.5 1 ; 2 38 49 59 14 10000 2.0 4; 4 20 98 0 60 14 10000 2.0 2; 4 24 65 0 60 14 10000 2.0 4; 4 24 97 0 61 14 5000 2.0 4;4 20 98, 88[bl 62 14 5000 2.0 2;4 8 95 63 14 2000 2.0 4;4 9 96, 79[bl Conversion and product content were determined by GC analysis or by -NMR spectroscopy. Isolated yield. On 2.5 mmol scale, reduction of benzaldehyde 45 (0.5 molar in toluene) at S/C =2000, 90°C and 4 equivalents of 2M aqueous Na-formate gave only traces of benzylalcohol after 14 hours. Use of 4 equivalents of (NEt3H)-formate improves the yield to 50 % in 22 hours. Use of 5 equivalents of (NEt3H)-formate on frans-cinnamaldehyde 52 gives after 18 hours 80 % of allylic alcohol 53 and 15 % of saturated alcohol 54. NH4-formate is preferred over the other formate reagents. |
1: 3% 2: 74% | With hydrogen In ethanol Ambient temperature; | |
1: 40% 2: 36% | With Grubbs catalyst first generation; potassium hydroxide In 1,4-dioxane at 80℃; for 20h; |
With hydrogen In xylene at 110℃; effects of kind of catalyst; | ||
1: 36.5 % Chromat. 2: 62.5 % Chromat. | With potassium hydride In tetrahydrofuran for 1h; Heating; Title compound not separated from byproducts; | |
With sodium tetrahydroborate; water In tetrahydrofuran at 30℃; for 2.33333h; | 1 To a 2L three neck flask, fitted with an overhead agitator, thermometer and condenser, terephthalaldehyde (85.8 g) and THF (500 ml) were charged to give a pale yellow solution. Sodium borohydride (8.75 g) was dissolved in water (35 ml) and the resultant solution was charged to the three neck flask over 20 minutes maintaining the internal temperature below 30 0C. The reaction mixture was stirred for a further 2 hours; reaction was complete by GC (dialdehyde 0.5%, monoaldehyde 58.9%, diol 36.0%). Water (500 ml) and toluene (500 ml) were charged with stirring and then the layers were separated. The aqueous layer was further extracted with toluene and then the combined organics were backwashed with water. The organic layer was distilled at ambient pressure until the internal temperature reached 105 0C; approximately 600 ml of distillates were collected. The mixture was cooled to below 30 0C and then hexane (500 ml) was charged before cooling to 0-5 °C in order to precipitate the product from solution. The solid product was isolated by vacuum filtration and the solid cake was washed with a 50/50 mixture of toluene and hexane (200 ml total) and then dried at 40-45 °C under vacuum to give 69.02 g of (2). The solid melted in the vacuum oven. The product purity by GC was 66.2% with 27.9% of the diol impurity present. 1H NMR (400 MHz, CDCl3) δ ppm 10.00 (IH, s), 7.88 (2H, d, J = 8.0 Hz), 7.53 (2H, d, J = 8.0 Hz), 4.80 (2H, s) and 2.1 (IH, br s); 13C NMR (100 MHz, CDCl3) δ ppm 192.7, 148.4, 135.9, 130.4, 127.0 and 64.8. | |
With sodium tetrahydroborate In tetrahydrofuran; water at 30℃; for 2.33333h; | ||
With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; C19H23N2O8PS(2-)*2Na(1+); sodium formate; alkaline phosphatase In ethanol at 37℃; for 0.5h; | ||
With RuCl(4-phenyl-2-aminomethylbenzo[h]quinoline-H)(1,4-bis(diphenylphosphino)butane); ammonium formate In water; toluene at 90℃; for 4h; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: methyl 4-formylbenzoate With trimethylaluminum; isopropylmagnesium chloride; N,O-dimethylhydroxylamine*hydrochloride In tetrahydrofuran; diethyl ether; hexane at 0 - 20℃; for 2h; Stage #2: With diisobutylaluminium hydride In tetrahydrofuran; diethyl ether; hexane at 0 - 20℃; for 0.5h; | |
89% | Stage #1: methyl 4-formylbenzoate With trimethylaluminum; isopropylmagnesium chloride; N,O-dimethylhydroxylamine*hydrochloride Stage #2: With diisobutylaluminium hydride Stage #3: With water chemoselective reaction; | |
80% | Stage #1: methyl 4-formylbenzoate With trimethylsilyl trifluoromethanesulfonate; triphenylphosphine In dichloromethane at 20℃; for 1h; Inert atmosphere; Stage #2: With diisobutylaluminium hydride In hexane; dichloromethane at -78℃; for 8h; Inert atmosphere; Stage #3: With water; sodium hydrogencarbonate In methanol; hexane; dichloromethane at 40℃; for 2h; chemoselective reaction; |
80% | Stage #1: methyl 4-formylbenzoate With trimethylsilyl trifluoromethanesulfonate; triphenylphosphine In dichloromethane at 20℃; for 1h; Stage #2: With diisobutylaluminium hydride In hexane; dichloromethane at -78℃; regioselective reaction; | General Procedure for the Selective Reduction of Esterand Weinreb Amide in the Presence of Aldehyde General procedure: To a solutionof ald ester (or ald amide) (0.200 mmol, 1.0 eq) and PPh3 (63.0 mg, 0.240 mmol, 1.2 eq) in CH2Cl2 (2.0 mL, 0.1 M) wasadded TMSOTf (43 μL, 0.238 mmol, 1.2 eq) dropwise at rt. After being stirred for 1 h at rt, the reaction mixture was then cooled to -78°C, and DIBAL-H (0.59 mL of 1.02 M in hexane,0.602 mmol, 3.0 eq) was added slowly via syringe. Stirring was continued at -78°C until the starting material was consumed(TLC analysis was conducted after quenching a small amount of the reaction mixture with a drop of TBAF (1.0 M inTHF)). To the mixture were added saturated aqueous NaHCO3 solution (2.0 mL) and MeOH (1.0 mL), and the resulting solution was then stirred for 2 h at 40°C. After being cooled to rt,the mixture was extracted several times with EtOAc (50 mL).The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Purification was accomplished by flash column chromatography to afford the desired product. |
78% | Stage #1: methyl 4-formylbenzoate With N,O-dimethylhydroxylamine*hydrochloride; diisobutylaluminium hydride In tetrahydrofuran at 0 - 20℃; Inert atmosphere; Stage #2: With lithium triethylborohydride In tetrahydrofuran at -78℃; for 3h; | |
Yield given. Multistep reaction; | ||
With potassium hydroxide; lithium aluminium tetrahydride; n-butyllithium; o-carborane Yield given. Multistep reaction; | ||
Multi-step reaction with 3 steps 1: 4-toluenesulfonic acid / toluene 2: lithiumaluminium hydride / tetrahydrofuran 3: Acid hydrolysis | ||
Multi-step reaction with 3 steps 1: TsOH / benzene / 14 h / Heating 2: LiAlH4 / diethyl ether / 1 h / 0 °C 3: 3M aq. HCl / tetrahydrofuran / 6 h / 25 °C | ||
Multi-step reaction with 3 steps 1: toluene-4-sulfonic acid / toluene / 4 h / 160 °C / Dean-Stark 2: lithium aluminium tetrahydride / tetrahydrofuran / 4 h / 0 - 20 °C 3: hydrogenchloride / methanol / 1 h / 30 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With tert.-butylhydroperoxide In neat (no solvent) at 70℃; for 1.5h; | |
95% | With double-atom catalyst FeCo-DAC In o-dimethylbenzene at 140℃; for 36h; Inert atmosphere; Sealed tube; | |
91% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; nitromethane; oxygen; 1,10-ethyleneisoalloxazinium chloride at 40℃; for 14h; |
90% | With 9-fluorenone In dimethyl sulfoxide at 20℃; Irradiation; | |
89% | With ammonium hydroxide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; oxygen In ethanol at 50℃; for 30h; | 24 4.5. General procedure for the aerobic alcohol oxidation General procedure: Under an air atmosphere, a Schlenk tube was charged with MCM-41-bpy-CuI (40 mg, 0.025 mmol), alcohol (0.5 mmol), TEMPO (4 mg, 0.025 mmol), aqueous ammonia (0.5 mmol, 25e28%, w/w) and EtOH (1.0 mL). The mixture was stirred at 50 °C for 18-48 h. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and filtered. The MCM-41-bpy-CuI complex was washed with EtOH (2*5 mL), and Et2O (5 mL) and reused in the next run. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (petroleum/ethyl acetate=15:1 to 10:1) to provide the desired product. |
81% | With (NH4)4[CuMo6O18(OH)6]·5H2O; oxygen; sodium chloride In water monomer; acetonitrile at 60℃; for 20h; | |
With manganese(IV) oxide In tetrahydrofuran at 45℃; | ||
With oxygen; ozone; N-Methylmorpholine N-oxide In dichloromethane at -78℃; for 0.25h; Inert atmosphere; | General procedure General procedure: In a flame-dried round bottom flask under a positive pressure of argon, Zn, CBr4, and PPh3 (Z/C/P) (18.0 mmol of each) were suspended in methylene chloride (40 mL). This mixture was allowed to stir for 24 hours at room temperature. To an oven-dried 100 mL three-neck round bottom flask was added 3.0 mmol of methyl oleate, 20 mL of methylene chloride, and 3.0 mmol of N-methylmorpholine N-oxide (NMO). This solution was cooled to -78 oC and a stream of O2/O3 was bubbled through the solution at a rate of 2.0 L/min through a glass pipette for 15 minutes. The solution was then sparged with O2 for 30 minutes. This mixture was then put under a positive pressure of argon and transferred to the Z/C/P mixture via cannula. The ozonolysis flask S3was rinsed with 3x5 mL of methylene chloride. The reaction was stirred until completion, determined by TLC and 1H NMR. The solvent was partially removed in vacuo and the residue was filtered through a plug of silica gel using 5% ethyl acetate in hexane as eluent. The filtrate was concentrated on the rotovap. | |
With recombinant 5-hydroxymethylfurfural oxidase In aq. phosphate buffer at 25℃; for 4h; Enzymatic reaction; | ||
Stage #1: p-(hydroxymethyl)benzaldehyde With oxygen In water monomer; toluene at 20℃; for 1h; Darkness; Stage #2: In water monomer; toluene at 20℃; for 4h; Irradiation; | 2.7. Photocatalytic oxidation of aromatic alcohol General procedure: The photocatalytic oxidation of benzyl alcohol was carried outunder a 300W Xenon lamp (CEL-HXF300, a CEL-VisREF filter,350-780 nm), 10 cm to the reaction liquid) at ambient temperature(20 °C). In general, 100 mg of the as-prepared photocatalyst was dispersed in 20 mL of aromatic alcohol/toluene aqueous solution(0.05 mol·L-1) containing 0.035 mol·L-1 of naphthalene as the internalstandard under constant stirring. The choice of solvent toluene was dueto its inertness to oxidation and high solubility for molecular O2. Priorto illumination, the solution was kept in dark for 60 min under stirringto rule out the influence of adsorption. After illumination for 4 h, anequal volume of liquid sample was obtained by a syringe to filter thecatalysts with 0.22 μm filter. Then the analytical sample was analyzedby a GC (Agilent 7820) equipped with an FID and the HP-5 column. Toevaluate the stability, the spent catalyst was collected after the photocatalyticreaction by centrifugation, washing with ethanol and dryingfor the next test. | |
51.0 mg | With 3,3-dichloro-1,2-diphenylcyclopropene; triethylamine In dimethyl sulfoxide; acetonitrile at -20℃; for 0.666667h; Inert atmosphere; | General procedure for oxidation of alcohols General procedure: A solution of DMSO (234.4 mg, 0.21ml, 3.0 mmol, 3.0 equiv.) in MeCN (2.0 mL) was added to a solution of fresh 1 (390.0 mg, 1.5 mmol, 1.5 equiv.) in MeCN (10.0 mL) at -20 ° C, andthe reaction mixture was stirred for 20 minutes at the same temperature. The solution of alcohol substrate 2a - 2x (1.0 mmol, 1.0 equiv.) in MeCN (1.0 mL) was added, and the reaction mixture was stirred for another 20 minutes before the dropwise addition of triethyl amine (303.6 mg, 0.41 mL, 3.0 mmol, 3.0 equiv.). The cooling bath was removed and the reaction mixture was subsequently left to warm up to room temperature. Then,saturated aqueous NH4Cl-solution (15 mL) was added to the reaction mixture, the aqueous phase was extracted with EtOAc (3 x 30 mL), the combined organic phases were washed with brine (90 mL), dried over Na2SO4, and concentrated under reduced pressure.Afterwards, the product was isolated by column chromatography (SiO2, petroleum ether(PE)/ethyl acetate (EA)) to obtain the desired carbonyl product 3a - 3x. All aldehydes and ketones produced were characterized by 1H and 13C NMR and these spectral date matched literature values or that of authentic samples |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogenchloride; water In tetrahydrofuran for 1h; | 1.1.2 1.2 4-(HydroxymethyI)benzaIdehyde, 2.2Alcohol 1 (10.09 g, 48 mmol) was dissolved in a mixture of THF (100 ml) and 2 M HCl (100 ml) and stirred for 1 hour. The solvent was evaporated and the residue obtained was dissolved in ethyl acetate (100 ml) and water (100 ml). The phases were separated and the organic phase was washed with water (100 ml), dried over magnesium sulphate, and evaporated to yield 2 as a white solid (6.54 g, 48 mmol, 100%). /?/ = 0.54 (ethyl acetate/chloroform, 1 : 1); vmaj£ = 3327, 1689, 1607, 1206, 1010, 823 cm'1; ]H NMR (250 MHz, CDC13) 6 = 10.02 (s, 1H, CHO), 7.89 (d, 3J(H,H) = 8.1 Hz, 2H, ArCH a to CHO), 7.54 (d, 3J(H,H) = 8.1 Hz, 2H, ArCHa to CH OH), 4.82 (d, 3J(H,H) = 5.9 Hz, 2H, CH2OH), 1.94 (t, 3J(H,H) = 5.9 Hz, 1 H, CH2OH); 13C NMR (75 MHz, CDCI3) δ = 192.0 (CHO), 147.7 (ArCCOH), 135.7 (ArCCHO), 130.0 (ArCH a to ArCCHO), 127.0 (ArCH a to ArCCH2OH), 64.6 ( H2OH); HRMS (ESI'): m/z calculated for C8H702 [M - H]" : 135.0446, found 135.0448; elemental analysis calcd (%) for C8H802 (136.15): C 70.57, H 5.92; found: C 70.70, H 6.00. |
96% | In water at 30℃; for 0.0833333h; | |
With hydrogenchloride In diethyl ether at 25℃; for 1h; Yield given; |
With hydrogenchloride In water at 20℃; for 2h; | ||
With hydrogenchloride In 1,4-dioxane; water at 20℃; for 21h; | ||
2.4 g | With hydrogenchloride In tetrahydrofuran; water at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With 1H-imidazole In dichloromethane at 20℃; for 1h; Inert atmosphere; | 5.E Under inert atmosphere, compound 68 (1 .00 g, 7.35 mmol, 1 .00 equiv) is dissolved in anhydrous DCM (40 mL, 0.18 M). TBDMSCI (1 .33 g, 8.82 mmol, 1 .20 equiv) is added, followed by imidazole (0.600 g, 8.82 mmol, 1 .20 equiv) and the resulting mixture is stirred at rt for 1 hour. The reaction mixture is diluted in AcOEt. This organic layer is washed with 10% aqueous citric acid, sat. aqueous NH4CI and then with brine. The washed organic layer is dried over sodium sulfate, filtered and solvent is evaporated under reduced pressure. The desired product 69 is obtained as colourless oil (1 .8 g, 7.2 mmol, 98% yield).1H NMR (500 MHz, CDCI3) d (ppm) 10.0 (s, 1 H), 7.87-7-82 (m, 2H), 7.52- 7.47 (m, 2H), 4.82 (s, 2H), 0.96 (s, 9H), 0.12 (s, 6H). |
87% | With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; for 4h; Inert atmosphere; | 2. Synthesis of aldehyde building blocks 33 and 34 General procedure: The silyl-protected aldehyde wasprepared according to literature procedures (Azuma, H.; Miyasaka, K.; Yokotani,T.; Tachibana, T.; Kojima-Yuasa, A.; Matsui-Yuasa, I.; Ogino, K. Bioorg. Med.Chem. 2006, 14, 1811-1818): 4-hydroxybenzaldehyde (1.22 g, 10 mmol) wasdissolved in DMF (25 mL), imidazole (0.95 g, 14 mmol) was added and the recationmixture cooled to 0 C. A solution of TBDMS-Cl (1.8 g, 12 mmol) in DMF (5 mL)was added dropwise and the reaction stirred at rt for 4 h. After removal of thesolvent, the residue was taken up in EtOAc and washed with sat. aq. NaHCO3and sat. aq. NaCl, dried (Na2SO4), filtered andconcentrated. The crude product was subjected to column chromatography (0 → 5%EtOAc/light petroleum) and obtained as a pale yellow oil (2.12 g, 9.0 mmol, 90%). |
84% | Stage #1: 4-(hydroxylmethyl)benzaldehyde With 1H-imidazole In dichloromethane at 20℃; for 0.5h; Inert atmosphere; Stage #2: tert-butyldimethylsilyl chloride In dichloromethane at 20℃; for 24h; Inert atmosphere; |
With 1H-imidazole In acetonitrile at 25℃; for 8h; Yield given; | ||
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In tetrahydrofuran at 25℃; for 6h; | ||
Acid hydrolysis; | ||
With hydrogenchloride In methanol at 30℃; for 1h; | Procedure O for Preparation of Compounds SSA 48036 and TTA 46118C General procedure: Procedure O for Preparation of Compounds SSA 48036 and TTA 46118C-Chloro-6-methoxy-quinoline-3-carbaldehyde or TTA 46118B was dissolved in H2O or MeOH then an HCl solution was added (see conditions table 6). The reaction mixture was stirred according to the conditions described in table 6. For the reaction involving 2-chloro-6-methoxy-quinoline-3-carbaldehyde, a precipitate appeared that was filtered and washed with a minimum amount of water, to give, after further drying under vacuum and in presence of P2O5, LPO 43136A (see table 6). For the reaction involving TTA 461188 (see table 6), the reaction mixture was evaporated. The obtained colorless oil was taken back in CH2Cl2 (180 mL) and the resulting solution was washed with H2O (2×40 mL), brine (30 mL), dried over MgSO4, filtered and concentrated to dryness to give crude TTA 46118C (see table 6) that was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: terephthalaldehyde mono(diethylacetal) With lithium aluminium tetrahydride In diethyl ether for 2h; Heating; Stage #2: With hydrogenchloride In diethyl ether; water for 0.0333333h; | |
Multi-step reaction with 2 steps 1: sodium bis(2-methoxyethoxy)aluminum hydride / toluene / 1 h / 0 °C 2: HCl / diethyl ether / 1 h / 25 °C | ||
Stage #1: terephthalaldehyde mono(diethylacetal) With sodium tetrahydroborate In methanol for 3h; Stage #2: With hydrogenchloride; methanol; water at 0 - 20℃; for 24h; | 2.A Example 2 Step A: To a cold (0° C.) solution of 4-(diethyoxymethyl)benzaldehyde (5.2 g, 24 mmol) in MeOH (50 mL) was added NaBH4 (0.93 g, 24 mmol), and the reaction mixture was stirred for 3 hours. The MeOH was removed and the residue was taken up in DCM and diluted with water. The aqueous layer was extracted with DCM (3×50 mL). The combine organic layers were dried, filtered and concentrated. The crude oil was dissolved in MeOH (50 mL) and cooled to 0° C. To this was added 2N HCl (10.0 mL) in ether. The reaction mixture was left at room temperature for 24 hours. The MeOH was removed and the crude product was purified by flash column chromatography, eluting with EtOAc/Hexane (3:7) to yield 2.92 g of 4-(hydroxymethyl)benzaldehyde (11) as a colorless oil. |
Multi-step reaction with 2 steps 1: sodium tetrahydroborate; methanol / 1 h / 0 °C 2: hydrogenchloride; water / tetrahydrofuran / 1 h | ||
Multi-step reaction with 2 steps 1.1: potassium hydroxide / methanol / 0.08 h 1.2: 16 h / 0 - 20 °C 2.1: hydrogenchloride / 1,4-dioxane; water / 21 h / 20 °C | ||
Multi-step reaction with 2 steps 1: sodium tetrahydroborate; methanol / 1 h / 0 - 20 °C 2: hydrogenchloride / water; tetrahydrofuran / 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In 1,2-dichloro-ethane at 50℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
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Multistep reaction.; |
Yield | Reaction Conditions | Operation in experiment |
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Multistep reaction.; |
Yield | Reaction Conditions | Operation in experiment |
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Multistep reaction.; |
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Multistep reaction.; |
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Multistep reaction.; |
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Multistep reaction.; |
Yield | Reaction Conditions | Operation in experiment |
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Multistep reaction.; |
Yield | Reaction Conditions | Operation in experiment |
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Multistep reaction.; |
Yield | Reaction Conditions | Operation in experiment |
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Multistep reaction.; |
Yield | Reaction Conditions | Operation in experiment |
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Multistep reaction.; |
Yield | Reaction Conditions | Operation in experiment |
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Multistep reaction.; |
Yield | Reaction Conditions | Operation in experiment |
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Multistep reaction.; |
Yield | Reaction Conditions | Operation in experiment |
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Multistep reaction.; |
Yield | Reaction Conditions | Operation in experiment |
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99% | With sodium sulfate In dichloromethane at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
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37% | In ethanol at 0 - 20℃; for 3.5h; | 2.A Example 2 Synthesis of [(E)-4-CHLOROMETHYL-4'-HEXYLOXYSTILBENE] (3). [A : (E)-4-HYDROXYMETHYL-4'-HEXYLOXYSTILBENE (7).] 115 mg (16.5 mmole) of Li were dissolved in 75 ml of ethanol under nitrogen atmosphere. Then 2.05 g (15 mmole) of aldehyde 4-hydroxymethylbenzaldehyde were added and the mixture was cooled in an ice bath. Then 5.148 g (15 mmole) of (4-hexyloxy-benzyl)- triphenyl-phosphonium bromide were added. The mixture was stirred in the ice bath under nitrogen for 30 min, and then stirred at room temperature for 3 h. 2.5 ml of water were added and the precipitate was collected on a filter and washed with 10 ml of ethanol. After drying over silica in a dessicator 1.75g of white powder was obtained. Yield: [37 %.] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine In ethanol at 50℃; | B2.a A mixture of intermediate 3 (0.028 mol), [4- (HYDROXYMETHYL)-BENZALDEHYDE] (0.031 mol) and Net3 (0.057 mol) in [ETOH (280ML)] was stirred at [50°C] overnight. The solvent was evaporated. The residue was taken up in THF (200ml). [MGS04] [(5G)] was added. The mixture was stirred at 50°C for 2 hours, then brought to room temperature. The precipitate was filtered off and dried. Yielding: 15g of intermediate 5 [(>100%).] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 5℃; for 2h; | A8.a DIAD (0. [0238] mol) was added dropwise at 5°C to a solution [OF 4-HYDROXYBENZALDEL1YDE] (0. [017] mol), [2- (4, 4-ETHYLENEDIOXYPIPERIDINO)] ethanol (CA No : 37443-73-5) (0.0204 mol) and P (Ph3) 4 (0.0289 mol) in THF (60ml). The mixture was stirred at [5°C] for 2 hours. [H90 (SML)] was added. The mixture was extracted with HCI 3N, washed with EtOAc, basified with [K2CO3] and extracted with EtOAc. The organic layer was separated, dried [(MGS04),] filtered, and the solvent was evaporated. Yielding: 7.6g of intermediate 27. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; | DIAD (0. [0195 MOL)] was added dropwise at a temperature between 0 and [5°C] to a mixture of 4-hydroxybenzaldehyde (0.015 mol), [5-HYDROXYMETHYL-1-METHYL-1H-] imidazole (CA No: 38993-84-9) (0.018 mol) and [PPH3] (0.0225 mol) in THF (40ml) under [N2] flow. The mixture was stirred at room temperature overnight, then stirred for a week end, diluted in EtOAc, extracted with [HC1] 3N, washed with EtOAc, alkalinized with [K2CO3] and extracted with EtOAc. The organic layer was separated, dried [(MGS04),] filtered, and the solvent was evaporated. Yielding: 1.6g of intermediate 38 (49percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With hydrogen iodide | 7 EXAMPLE 7 EXAMPLE 7 According to Example 6, 17.13 g of 84 percent pure 4-hydroxymethylbenzaldehyde (0.106 moles) (remaining impurity: 10% of 1,4-bis-hydroxymethylbenzene+5% of terephthaldialdehyde) were reacted with 38.8 ml of 57 percent hydriodic acid (0.294 moles). After standing at 4° C., 24.7 g of crude product, which were immediately sublimed at 90° C. and 0.01 mm Hg without further drying, were obtained from the organic layer. This gave 21.95 g of sublimed product which, according to NMR, contained 88.8 mole-% of 4-iodomethylbenzaldehyde. By evaporation of the organic mother liquor in a waterpump vacuum and drying at 50° C. and 0.1 mm Hg, a second fraction with 68.5 mole-% of 4-iodomethylbenzaldehyde was obtained. This gives a calculated total 4-iodomethylbenzaldehyde yield of 23.6 g corresponding to 89% of the theoretical yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In ethanol; water; | b) 1-(4-hydroxymethylphenyl)-1,4-pentanedione To a solution of 4-hydroxymethylbenzaldehyde (1.94 g) obtained in Example 20 a) in ethanol (20 ml) were added methyl vinyl ketone (2.5 ml), triethylamine (0.85 ml) and 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (0.410 g), and the mixture was refluxed for 8 hr. Distilled water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was dried over magnesium sulfate, concentrated and purified by silica gel column chromatography to give the title compound (1.32 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-Aminopyrazine; 4-(hydroxylmethyl)benzaldehyde With scandium tris(trifluoromethanesulfonate) In methanol; dichloromethane for 1h; Stage #2: 5-isocyano-2,3-dihydroinden-1-one O-tert-butyldimethylsilyl oxime In methanol; dichloromethane at 20℃; | 2.B Step B: Pyrazin-2-amine (12) (0.10 g, 1.1 mmol) was combined with 0.21 g (1.3 mmol) of 4-(hydroxymethyl)benzaldehyde (11) and Sc(OTf)3 (0.053 g, 0.11 mmol) and the combination was dissolved in DCM/MeOH (1:1) and stirred for 1 hours. To this was added 0.310 g (1.1 mmol) of 5-isocyano-2,3-dihydroinden-1-one O-tert-butyldimethylsilyl oxime (7) and the reaction mixture was left at room temperature overnight. The reaction mixture was concentrated and purified by flash column chromatography, eluting with DCM, DCM/MeOH (50:1) and DCM/MeOH (25:1) to provide 0.175 g of the desired product (13). MS (APCI) m/z 386.0(M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1,1-dibromo-3,3,3-trifluoroacetone With sodium acetate In water at 115℃; for 0.5h; Stage #2: 4-(hydroxylmethyl)benzaldehyde With ammonia In methanol; water at 20℃; for 5h; | 3.1 Example 3 2-r4-f3'-Methyl-2-trifluoromethyl-biphenyl-4-yloxymethyl)-phenyl1-lH-imidazole-4- carboxylic acid [00125] Step 1: To a solution of NaOAc-3H2O (0.66 g, 2.4 mmol) in H2O (2.2 ml) is added l,l,l-trifluoro-3,3-dibromoacetone (0.66 g, 4.8 mmol). The mixture is stirred and heated in a 1150C oil bath for 30 minutes. After cooling to room temperature, this solution is added into a solution of 4-hydroxymethyl-benzaldehyde (0.30 g, 2.2 mmol) in methanol (11 ml) with concentrated ammonium hydroxide (2.8 ml). The mixture is stirred for 5 hours at and then concentrated. Water is added to the residue and the mixture is extracted with ethyl acetate; The ethyl acetate layers- are combined and dried. [4-(4-Trifluoromethyl-lH- imidazol-2-yl)-phenyl] -methanol 9 is obtained after removing the solvent: 1H NMR (DMSO- d6) δ 13.1 (s, 1 H), 7.92 (d, 2 H, J = 8.0 Hz), 7.90 (s, 1 H), 7.42 (d, 2 H, J = 8.0 Hz), 5.28 (t, 1 H, J = 6.0 Hz), 4.54 (d, 2 H, J = 6.0 Hz); LC-MS m/z 243.0 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With sodium acetate; acetic anhydride In ethyl acetate Reflux; | |
Stage #1: acetic anhydride; 4-(hydroxylmethyl)benzaldehyde With sodium acetate In ethyl acetate at 104 - 106℃; for 0.25h; Heating / reflux; Stage #2: N-acetylglycine In ethyl acetate at 93 - 95℃; for 18h; Heating / reflux; | 2 To a 2 L three neck flask, fitted with an overhead agitator, thermometer and condenser sodium acetate (59.2 g), (4-hydroxymethyl)benzaldehyde (2) (69.0 g), ethyl acetate (100 ml) and acetic anhydride (120ml) were charged. The slurry was heated to reflux (104-106 °C) and maintained at reflux for 15 minutes before cooling to below 40 0C. iV-acetylglycine (42.2 g) and ethyl acetate (100 ml) were charged, the resultant mixture was heated to reflux (93-95 °C) and maintained for 18 hours. The batch was cooled to below 60 0C at which point it solidified and water (400ml) was added, the resultant solid was isolated by vacuum filtration, the slurry washed in water (300 ml), then washed in MTBE (300 ml) and then displacement washed with MTBE (100 ml). The yellow solids were dried under vacuum at 45 0C to give 56.2 g of (3); purity by GC was 96.1%; 1H NMR (400 MHz, CDCl3) δ ppm 8.08 (2H, d, J= 7.8 Hz), 7.42 (2H, d, J= 7.8 Hz), 7.13 (IH, s), 5.14 (2H, s), 2.41 (3H, s) and 2.13 (3H, s); 13C NMR (100 MHz, CDCl3) 6 ppm 171.2, 168.1, 166.7, 139.4, 133.4, 133.2, 132.7, 131.1, 128.7, 66.1, 21.4 and 16.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With hydrogen In methanol | Preparation of 4-hydroxymethylbenzaldehyde: Preparation of 4-hydroxymethylbenzaldehyde: Terephthaldicarboxaldehyde (30.02 g, 224 mmol), methanol (200 mL), palladium on activated carbon, (10%, 3.02 g) and 2-(aminomethyl)pyridine (2.3 mL, 22 mol, 0.01 mol equiv) were combined in a hydrogenation vessel and the reaction mixture was shaken on a Parr hydrogenator for 2.5 hours at 40 psi of hydrogen. The mixture was filtered through celite, the cake washed with methanol and the solvent from the eluent removed in vacuo. Purification of the crude product by column chromatography on silica gel (EtOAc/Hexanes, 1:1) afforded the title compound (23.8 g, 78%) as a white solid. 1H NMR (CDCl3) δ 4.80 (s, 2H), 7.53 (d, 2H, J=9 Hz), 7.87 (d, 2H, J=9 Hz), 10.00 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35.4% | Stage #1: 4-(hydroxylmethyl)benzaldehyde With sodium hydride In tetrahydrofuran at 20℃; for 0.25h; Stage #2: methyl iodide In tetrahydrofuran at 20℃; for 16h; | 36 Intermediate 36: 4-(methoxymethyl)benzaldehyde; To a mixture of sodium hydride (220 mg, 5.51 mmol) in THF (6 mL) was added a solution of 4-(hydroxymethyl)benzaldehyde (500 mg, 3.67 mmol) in THF (6.00 mL) at rt, the reaction mixture was stirred for 15 minutes. Iodomethane (0.344 mL, 5.51 mmol) was added and the reaction mixture was stirred at rt for 16 h. Water was added and the mixture was extracted with EtOAc (3x), washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-50% EtOAc in heptane) to give the title compound (195 mg, 35.4 %) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.32 - 3.39 (m, 9H), 3.41 (s, 3H), 4.43 (s, 7H), 4.52 (s, 2H), 7.47 (d, J= 6.64 Hz, 3H), 7.85 (d, J = 6.64 Hz, 2H), 9.99 (s, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sulfuric acid; water In tetrahydrofuran at 20℃; for 3h; | 35 Intermediate 35: 4-(hydroxymethyl)benzaldehyde; To (4-(dimethoxymethyl)phenyl)methanol (1.50 g, 8.23 mmol) in THF (3 mL) was added a 3% aqueous solution OfHiSO4 (3 mL). The mixture was stirred at rt for 3 h, then saturated aqueous solution OfNaHCO3 (10 mL) was added and the mixture was extracted with EtOAc (3x), washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to give the titlle compound (1.17 g, 104 %) as a solid. 1U NMR (400 MHz, CDCl3) δ ppm 2.10 (br. s., IH), 4.81 (d, J= 4.69 Hz, 2H), 7.53 (d, J= 7.81 Hz, 2H), 7.88 (d, J= 7.81 Hz, 2H), 10.00 (s, IH). |
With sulfuric acid In tetrahydrofuran at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With hydroxylamine hydrochloride; sodium carbonate In ethanol; water at 60℃; for 12h; | |
With hydroxylamine hydrochloride; sodium hydroxide In ethanol; water at 20℃; Cooling with ice; | ||
With hydroxylamine hydrochloride; sodium hydroxide In ethanol; water at 20℃; for 1.5h; Cooling; | 1 N-hydroxy-4-(hydroxymethyl)benzimidoyl chloride (Compound 13): To a solution of 4-(hydroxymethyl)benzaldehyde as reported by Zaidi, et al. (3.4 g, 25 mmol) and NH2OH.HCl (1.9 g, 27 mmol) in a 1 to 1 mixture of water and ethanol (14 mL) was added ice (10 g) as reported by Liu, et al. Zaidi, S. H. H.; Loewe, R. S.; Clark, B. A.; Jacob, M. J.; Lindsey, J. S., Organic Process Research & Development (2006), 10, 304-314; Liu, K.-C.; Shelton, B. R.;, Howe, R. K., J. Org. Chem., (1980), 45, 3916-3918. To this stirred solution was added NaOH (2.5 g in 2.5 mL water, 60 mmol) slowly. After stirring at room temperature for 1.5 hours the solution was washed with Et2O (25 mL) and the Et2O was discarded. The aqueous layer was acidified with HCl (1 N in water) and extracted with CH2Cl2 (three times with 25 mL) and Et2O (two times with 25 mL). The organic layers were dried over MgSO4, filtered and concentrated in vacuo to a white solid that was used without further purification. To a solution of the oxime (500 mg, 3.3 mmol), in DMF (2.5 mL) was added N-chlorosuccinimide (440 mg, 3.3 mmol) portionwise as reported by Liu, et al. Liu, K.-C.; Shelton, B. R.;, Howe, R. K., J. Org. Chem., (1980), 45, 3916-3918. A small portion (˜0.2 mL) of HCl gas from the headspace above a solution of conc. HCl was bubbled into the solution to ensure initiation of the reaction. After the reaction warmed and subsequently cooled back to room temperature, water (10 mL) was added and the product was extracted with Et2O (three times with 20 mL) The organic layer was dried over MgSO4, filtered and concentrated in vacuo to yield a white solid (330 mg, 1.8 mmol, 55%), which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | Stage #1: 2,4-dimethyl pyrrole; p-(hydroxymethyl)benzaldehyde With trifluoroacetic acid In dichloromethane at 20℃; for 12h; Inert atmosphere; Stage #2: boron trifluoride diethyl ether complex With triethylamine; 2,3-dicyano-5,6-dichloro-p-benzoquinone In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere; | 1.1 (1) Synthesis of 1,3,5,6-tetramethyl 8- (4 (hydroxymethylphenyl)) boron fluoride dipyrrole (2) Take a dry 500ml two-necked flask, the bottle was replaced with nitrogen, 2,4-dimethylpyrrole (2.2mL,Benzaldehyde (1.4 g, 10.0 mmol), trifluoroacetic acid (0.11 mL, 1 mmol) and CH2Cl2 (150 mL) were stirred at room temperature for 12 h before 2,3-dichloro-5,6-dicyanobenzene Quinone (2.3 g, 10.0 mmol), stirred for 1 h at room temperature,Et3N (30 mL) was added and the mixture was cooled to 0 ° C. in an ice bath. BF 3 .Et 2 O (30 mL) was added and the mixture was stirred at rt for 3 h, washed with saturated NaHCO 3 and extracted with CH 2 Cl 2.The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated.Purification by silica gel column chromatography (petroleum ether: dichloromethane = 2: 1) gave a yellow solid (0.9 g, 2.5 mmol) in a yield of 50%. |
41.3% | With CF3COOH; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; (C2H5)3N In dichloromethane (N2); drop of TFA was added to soln. of aldehyde and pyrrole in CH2Cl2, stirred overnight, treated with DDQ, stirred for 30 min, Et3N was added,after15 min BF3*Et2O was added at 0°C, stirred at r.t. for 3 h; washed with satd. aq. NaHCO3, organic layer was eparated, dried over MgSO4, filtered, concd., column chromy., (silica, CH2Cl2/hexane); | |
26% | Stage #1: 2,4-dimethyl pyrrole; p-(hydroxymethyl)benzaldehyde With trifluoroacetic acid In dichloromethane at 20℃; Inert atmosphere; Stage #2: With 2,3-dicyano-5,6-dichloro-p-benzoquinone In dichloromethane for 0.5h; Inert atmosphere; Stage #3: boron trifluoride diethyl ether complex Further stages; | Synthesis of compound 3 . To a stirred solution of compound 2 (1.36 g, 10 mmol) and 2,4-dimethylpyrrole (1.60 g, 20.0 mmol) in anhydrous CH 2 Cl 2 (100 mL), one drop of TFA was added as a catalyst. The resulting mixture was stirred overnight under N 2 at room temperature. DDQ (2.28 g, 10 mmol) was added to the reac- tion mixture, and stirred for additional 30 min. Et 3 N (30 mL) was added and stirred for 15 min. BF 3 ·Et 2 O (60 mL) was added at 0 °C, and the mixture was stirred for 3 h. 50 mL of water was added to the reaction mixture and exacted with DCM, the organic layer was washed with aq. NaHCO 3 and brine, dried over anhydrous MgSO 4 . Evaporation of the solvent under reduced pressure, the residue was purified by chromatography using CH 2 Cl 2 /hexane as an eluent to afford compound 3 (0.92 g, 26%). 1 H NMR (600 MHz, CDCl 3 ) : 7.49 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 5.98 (s, 2H), 4.81 (d, J = 5.5 Hz, 2H), 2.55 (s, 6H), 1.38 (s, 6H). 13 C NMR (100 MHz, CDCl 3 ) 155.45, 143.16, 141.99, 141.63, 134.06, 132.26, 131.47, 128.09, 127.40, 127.00, 121.25, 64.63, 14.58, 14.49. Anal. calcd for C 20 H 21 BF 2 N 2 O: C, 67.82; H, 5.98; N, 7.91; found: C, 67.79; H, 6.01; N, 7.89. |
Stage #1: 2,4-dimethyl pyrrole; p-(hydroxymethyl)benzaldehyde With trifluoroacetic acid In dichloromethane at 20℃; Inert atmosphere; Stage #2: boron trifluoride diethyl ether complex With triethylamine; 2,3-dicyano-5,6-dichloro-p-benzoquinone | ||
With triethylamine; trifluoroacetic acid; 2,3-dicyano-5,6-dichloro-p-benzoquinone In dichloromethane at 20℃; for 24h; | ||
With 2,3-dimethyl-5,6-dicyanobenzoquinone; triethylamine In dichloromethane at 0 - 50℃; | (1) Mix methylpyrrole (206mg, 2.2mmol), benzaldehyde (106mg, 1.0mmol), and triethylamine (0.5ml) into dichloromethane, stir overnight at room temperature, and slowly add trifluoride at 0°C. Boron diethyl ether (0.5ml), stir for 10 minutes, add 2,3-dimethyl-5,6-dicyanobenzoquinone (227mg, 1mmol), extract with dichloromethane, dry with anhydrous Na2SO4, and spin at 50°C under vacuum. The solvent is evaporated, and a chromatographic column is used for separation and purification to obtain the orange-yellow solid product BODIPY. | |
Stage #1: 2,4-dimethyl pyrrole; p-(hydroxymethyl)benzaldehyde With triethylamine In dichloromethane at 20℃; Stage #2: boron trifluoride diethyl ether complex In dichloromethane at 0℃; for 0.166667h; | 1 The NB preparation method used in the following examples is as follows: (1) 2,4-dimethylpyrrole (1.1 mmol), p-methylhydroxybenzaldehyde (0.5 mmol), and triethylamine (0.2 ml) were mixed and dissolved in dichloromethane, stirred at room temperature overnight, and slowly added dropwise at 0°C with borontrifluoride etherate (0.2ml), stirred for 10 minutes, added 2,3-dimethyl-5,6-dicyanobenzoquinone (0.5mmol), extracted with dichloromethane, dried over anhydrous Na2SO4, and vacuum rotary evaporated at 50°C. The solvent was removed, and the product was separated and purified by a chromatographic column to obtain BODIPY as an orange-yellow solid product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26.3% | With piperidine In toluene byproducts: H2O; aldehyde and indacene were ferluxed overnight in mixt. of toluene and piperidine in Dean-Stark apparatus; evapd., column chromy. (silica, CH2Cl2/hexane); | |
With piperidine; toluene-4-sulfonamide In toluene at 140℃; Dean-Stark; | 1 Example 1 Dissolving X1(0.5mmol), 4-N, N-diphenylamine benzaldehyde (1.0mmol), and p-toluenesulfonamide (0.01mmol) in a mixed solution of toluene (20mL) and piperidine (1mL), placing in a round-bottomed flask equipped with a Dean-Stark apparatus, heating at 140 deg.C under reflux until all solvents are collected by the Dean-Stark apparatus, adding toluene (20mL) and piperidine (1mL) to the reaction medium, continuing heating at 140 deg.C under reflux until all solvents are collected by the Dean-Stark apparatus, repeating the addition of toluene (20mL) and piperidine (1mL) and heating under reflux for 3 times, which is followed by TLC, after the reaction of starting materials is completed, performing column chromatography, removing the solvent by distillation under reduced pressure to obtain a black solid product BDP, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With oxygen In dimethyl sulfoxide at 20℃; for 24h; Irradiation; | |
88.9% | With sodium tetrahydroborate In tetrahydrofuran; ethanol at 0 - 2℃; | |
70% | With dihydrogen peroxide In neat (no solvent) at 70℃; for 7h; Green chemistry; chemoselective reaction; |
46% | With manganese(IV) oxide In dichloromethane for 48h; Inert atmosphere; Reflux; | 4.13. 4-(Hydroxymethyl)benzaldehyde (19) Under nitrogen atmosphere, a suspension of 1,4-benzenedimethanol (1 eq, 1.00 mmol, 138 mg) and MnO2 (1.5 eq,1.50 mmol, 130 mg) in 17 mL of anhydrous dichloromethane was stirred at reflux for two days. The resulting mixture was filtrated under vacuum, the solid was washed with dichloromethane and ethyl acetate and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography(petroleum ether/ethyl acetate: 80/20 to 70/30) to give 4-(hydroxymethyl)benzaldehyde 19 (63 mg, 46%) as a colorless solid;Rf (ethyl acetate/petroleum ether: 40/60) 0.44; 1H NMR (300 MHz,CDCl3) d (ppm): 10.00 (s, 1H), 7.87 (d, J 8.2 Hz, 2H), 7.53 (d,J 8.2 Hz, 2H), 4.80 (s, 2H). The spectral data was in accordance with the literature [31]. |
16% | With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In water at 20℃; for 60h; | |
With dihydrogen peroxide In water at 20℃; for 7h; | ||
100 g | With acetic acid; 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione at 20 - 35℃; for 16h; | 2 Example 2: Synthesis of Int-2 1,4-Phenylenedimethanol (250 g) in acetonitrile (ACN, 7.5 L), mixed at 0°C, added 2-iodoxybenzoic acid (IBX) (0.7 eq), AcOH (1.0 eq), raised to room temperature. After 16 hours the reaction was filtered through CELITE bed and washed with EtOAc (6 L). The filtrate was concentrated, the residue was dissolved in EtOAc (4 L) and washed with saturated aqueous NaHCCb solution. The organic layer was dried over Na2S04, filtered, concentrated, and purified on silica [20% EtOAc:hexane] to afford 100 g of 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-methylbenzyl-triethylphosphonium bromide With lithium hydroxide In water for 0.05h; Inert atmosphere; Stage #2: 4-(hydroxylmethyl)benzaldehyde In water at 80℃; for 3h; Inert atmosphere; stereoselective reaction; | General experimental procedure for the synthesis of (2-phenyIethenyl) phenylmethanol (4a-4e) General procedure: Into a flame-dried microwave vial, containing a magnetic stirring bar was weighed corresponding benzyl alcohol (2 mmol, 1 equiv) under Ar. Triethylphosphane hydrochloride (2 mmol, 1 equiv) was added to the vial. The vial was septa-sealed and stirred at 100 °C for 8 h. The septum was removed and water (800 μL) was added to make a 2.5 M solution. Powdered lithium hydroxide (8 mmol, 4 equiv) was added to the vial which was subsequently magnetically stirred for 3 min prior to the addition of 4-hydroxymethylbenzaldehyde (LI) (2 mmol, 1 equiv). The reaction was stirred vigorously at 80 °C for 3 hours The oil bath was removed and the flask was left to attain room temperature. 6 mL water was added to the reaction mixture and the flask was stirred for 10 min. The slurry was vacuum filtered and dried to yield the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2-bromobenzyl-triethylphosphonium bromide With lithium hydroxide In water for 0.05h; Inert atmosphere; Stage #2: 4-(hydroxylmethyl)benzaldehyde In water at 80℃; for 3h; Inert atmosphere; stereoselective reaction; | General experimental procedure for the synthesis of (2-phenyIethenyl) phenylmethanol (4a-4e) General procedure: Into a flame-dried microwave vial, containing a magnetic stirring bar was weighed corresponding benzyl alcohol (2 mmol, 1 equiv) under Ar. Triethylphosphane hydrochloride (2 mmol, 1 equiv) was added to the vial. The vial was septa-sealed and stirred at 100 °C for 8 h. The septum was removed and water (800 μL) was added to make a 2.5 M solution. Powdered lithium hydroxide (8 mmol, 4 equiv) was added to the vial which was subsequently magnetically stirred for 3 min prior to the addition of 4-hydroxymethylbenzaldehyde (LI) (2 mmol, 1 equiv). The reaction was stirred vigorously at 80 °C for 3 hours The oil bath was removed and the flask was left to attain room temperature. 6 mL water was added to the reaction mixture and the flask was stirred for 10 min. The slurry was vacuum filtered and dried to yield the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With lithium hydroxide In water at 80℃; for 4h; Inert atmosphere; stereoselective reaction; | Synthesis 12 Into a flame-dried microwave vial, containing a magnetic stirring bar was weighed the phosphomum salt 11 (82 mg,,0.2 mmol). To this was added water (0.1 mL), LiOH (19 mg, 0.8 mmol), and 5 (27 mg, 0.2 mmol). The reaction was heated to 80 °C with stirring for 4 hours. The reaction was cooled to room temperature, water (x mL) was added and the reaction stirred for another 10 minutes at which point the precipitated stilbene (12) was filtered off. Yield 96%, Yellow solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With 1-methyl-piperazine In methanol at 20℃; for 20h; | 4.2.1. General procedure for the preparation of compounds 1, 5-15, 18-21, 23-33, 35-44, 46-54, 61, 62, 65, 67-69, 72-75, 92 General procedure: A solution of arylaldehyde (1 equiv), 2-cyanoacetamide or derivative (1.0-1.5 equiv) and N-methylpiperazine (0.05-1.05 equiv) in methanol (2-10 ml) was stirred at room temperature overnight. After addition of an equivalent volume of water/methanol (1:1) or 1 N HCl/methanol (1:1) for acidic products, the precipitate was collected by filtration and washed with water/methanol (1:1). If precipitation did not occur, the mixture was evaporated and the residue was purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In water at 20℃; | I (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-amino-tetrahydro-2H-pyran-2,4,5-triyl triacetate hydrochloride (4) was prepared from compound 1 according to publication: D. J. Silva etc. J. Org. Chem., 1999, 64(16), 5926-5929. | |
With sodium hydroxide In water at 20℃; | I (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-amino-tetrahydro-2H-pyran-2,4,5-triyl triacetate hydrochloride (4) was prepared from compound 1 according to publication: D. J. Silva etc. J. Org. Chem., 1999, 64(16), 5926-5929. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With 1,11-bis(3-methyl-3H-imidazolium-1-yl)-3,6,9-trioxaundecane di(methanesulfonate) In methanol at 20℃; for 1.33333h; | General procedure for deprotection of TBDMS ether using [tetraEG(mim)2][OMs]2 General procedure: A mixture of TBDMS ether (1.0 mmol) and [tetraEG(mim)2][OMs]2 IL (0.2 mmol) in methanol (4 mL) was stirred at room temperature up to the completion of reaction. Reaction progress was monitored by thin layer chromatography (TLC). After completion of the reaction, methanol was removed under reduced pressure and the residue was extracted with diethyl ether and dried over sodium sulfate. The diethyl ether was evaporated under reduced pressure to afford respective products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With 4H3N*4H(1+)*CuMo6O18(OH)6(4-); water monomer; oxygen; anhydrous sodium carbonate at 50℃; for 12h; | |
95% | With NADH oxidase and 3-succinoylsemialdehyde-pyridine dehydrogenase co-expressed in Escherichia coli cells In aq. phosphate buffer at 30℃; for 3h; Microbiological reaction; | |
85% | With C20H25N2(1+)*Cl(1-); water monomer; oxygen; 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 20℃; for 16h; Schlenk technique; chemoselective reaction; |
With water monomer; copper atom; potassium hydroxide at 40℃; Electrochemical reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | Stage #1: bis(trichloromethyl) carbonate; 1-aminopyrene In 1,4-dioxane at 70℃; for 5h; Stage #2: 4-(hydroxylmethyl)benzaldehyde With dmap; triethylamine In N,N-dimethyl-formamide at 25℃; for 12h; | III General Procedure III: General Procedure III: [0175] To amine (0.69 mmol) in 3.5 ml anhydrous dioxane was added triphosgene (0.068 g, 0.23 mmol) and the resulting mixture was stirred at 70° C. for 5 h before concentration. The solid residue was dissolved in 3.5 ml dimethylformamide, to which 4-(hydroxylmethyl)benzaldhyde (0.066 g, 0.49 mmol), triethylamine (0.19 ml, 1.39 mmol) and 4-(dimethylamino)pyridine were added. The reaction mixture was stirred at 25° C. for 12 h before concentration. The solid was dissolved in ethyl acetate and the organic phase was washed with water (5 times), brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | Stage #1: 2-acetylpyridine; 4-(hydroxylmethyl)benzaldehyde With sodium hydroxide at 0℃; for 2h; Stage #2: With ammonia In water at 100℃; for 2h; | |
34% | Stage #1: 2-acetylpyridine With sodium hydroxide at 0℃; for 0.0833333h; Stage #2: 4-(hydroxylmethyl)benzaldehyde at 0℃; for 2h; | Synthesis of 4′-(4-Hydroxymethylphenyl)-2,2′:6′2′′-terpyridine starting material [41]. To a mixture of crushed sodium hydroxide (1.00 g, 25.0 mmol) and poly(ethylene glycol) (PEG-400) (15 mL) at 0 °C was added 2-acetylpyridine (3.78 g, 31.0 mmol). After 5 min, 4-(hydroxymethyl)benzaldehyde (2,1.80 g, 13.0 mmol) was added and stirred at 0 °C for 2 h. Aqueous ammonia (15 mL, 25%) was then added and was heated to 100 °C for an additional 2 h. The resulting precipitate was collected by filtration and washed with water and cold ethanol. Recrystallisation from ethanol gave the terpyridine4′-(4-Hydroxymethylphenyl)-2,2′:6′2′′-terpyridine as an off-white solid (1.50 g, 34%) |
25% | With ammonium hydroxide; sodium hydroxide In ethanol; water at 35℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With boron trifluoride diethyl etherate In dichloromethane for 0.5h; Inert atmosphere; Schlenk technique; | |
With copper(II) sulfate In dichloromethane at 20℃; | 4.2 Representative procedure for preparation of 1,3-dithianes 4.2.1 Method A General procedure: CuSO4 (3.5g, 22.0mmol) was added to a mixture of 4-methoxybenzaldehyde (2.7g, 19.7mmol) and 1,3-propandithiol (2.3g, 21.0mmol) in CH2Cl2 (100mL) at room temperature and stirred at the same temperature until the starting aldehyde had been completely consumed (checked by TLC analysis). The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (eluent: hexane/AcOEt=5:1) followed by recrystallization (AcOEt/hexane) to give 2-(4-methoxyphenyl)-1,3-dithiane 1a (3.2g, 71%) as colorless prisms. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With p-benzoquinone; sodium iodide In water; acetonitrile at 100℃; for 48h; | 4.3.1 Representative procedure for deprotection of 1,3-dithianes (Table 2, entry 3) General procedure: A mixture of 2-(2-methoxyphenyl)-1,3-dithiane (1c) (0.11 g, 0.50mmol), 1,4-benzoquinone (64.8 mg, 0.60 mmol), and NaI (0.70 mg, 0.005 mmol) in MeCN (2mL) and H2O (0.2mL) was stirred at 100°C for 24 h. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (eluent: hexane/AcOEt=15/1) to give 2-methoxybenzaldehyde (2c, 66.5mg, 98%) as colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: 4-(diethylaminocarbonyl)benzoic acid With lithium tri-t-butoxyaluminum hydride In tetrahydrofuran at 20℃; for 0.25h; Inert atmosphere; Stage #2: With zirconocene dichloride In tetrahydrofuran at 20℃; for 0.0333333h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 80% 2: 6 %Spectr. | With Iron(III) nitrate nonahydrate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; potassium chloride; oxygen In 1,2-dichloro-ethane at 25℃; for 48h; Schlenk technique; | General procedure: To a Schlenk tube were added Fe(NO3)3·9H2O (40.6 mg, 0.1 mmol), TEMPO (15.8 mg, 0.1 mmol), KCl (7.5 mg, 0.1 mmol), 1a (108.5 mg, 1.0 mmol), and DCE (4.0 mL) sequentially under an atmosphere of oxygen (gas bag, commercial size: 2 L, which could be expanded to 5 L). The mixture was then stirred at 25 °C until completion of the reaction as monitored by TLC (petroleum ether/EtOAc = 5:1) (48h). The crude reaction mixture was filtered through a short column of silica gel (height: 2 cm, diameter: 3 cm) eluting with Et2O (3 × 25 mL). After evaporation, the residue was purified by chromatography on silica gel [petroleum ether/EtOAc = 15:1 (500 mL) to 2:1 (300 mL)] to afford benzoic acid (2a)14 (69.9 mg, 57%) as a pale yellow solid. Yields of 57% of 2a and 38% of benzaldehyde (3a)15 were observed by NMR analysisof the crude product using CH2Br2 as an internal standard and by comparison with spectra reported in the literature. |
Multi-step reaction with 2 steps 1: recombinant 5-hydroxymethylfurfural oxidase / aq. phosphate buffer / 24 h / 25 °C / pH 8 / Enzymatic reaction 2: recombinant 5-hydroxymethylfurfural oxidase / aq. phosphate buffer / 4 h / 25 °C / pH 7 / Enzymatic reaction | ||
Multi-step reaction with 2 steps 1: recombinant 5-hydroxymethylfurfural oxidase / aq. phosphate buffer / 4 h / 25 °C / pH 8 / Enzymatic reaction 2: recombinant 5-hydroxymethylfurfural oxidase / aq. phosphate buffer / 4 h / 25 °C / pH 7 / Enzymatic reaction |
Multi-step reaction with 2 steps 1: recombinant 5-hydroxymethylfurfural oxidase / aq. phosphate buffer / 4 h / 25 °C / pH 8 / Enzymatic reaction 2: recombinant 5-hydroxymethylfurfural oxidase / aq. phosphate buffer / 4 h / 25 °C / pH 7 / Enzymatic reaction |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | Compound 8 (50.0 mg, 0.26 mmol) was dissolved in 1,2-dichloroethane(10 mL), followed by addition of 4-(hydroxymethyl)benzaldehyde(40.0 mg, 0.29 mmol). The mixture was stirred at roomtemperature for 2 h, followed by addition of NaBH(OAc)3(63.0 mg, 0.30 mmol). The mixture was stirred for an additional48 h. Then the reaction was quenched with saturated NaHCO3,evaporated to remove the organic solvent, and extracted with ethylacetate. The combined organic layers were dried with MgSO4, andconcentrated under vacuum. The residue was purified by silica gelchromatography (ethyl acetate/petroleum ether = 2/1, v/v) to provide11 as colorless oil (27.0 mg, 33%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4% | Stage #1: C18H18N2O3; 4-(hydroxylmethyl)benzaldehyde In methanol at 60℃; Stage #2: With 2,3-dicyano-5,6-dichloro-p-benzoquinone In dichloromethane at 20℃; for 0.5h; | Procedure J for Preparation of Benzoxazoles LPO 55056D, ANP 53142B, ANP 53192A, 114, 115, 153 and 170 General procedure: Procedure J for Preparation of Benzoxazoles LPO 55056D, ANP 53142B, ANP 53192A, 114, 115, 153 and 170To a solution of ANP 49184A or ECO 59064 in MeOH was added the corresponding aldehyde at RT in an ace pressure tube (see aldehyde and conditions in tables 6 and 7). The reaction mixture was stirred according to the conditions described in tables 6 and 7. After cooling to RT, the solvent was evaporated and the residue was dissolved in CH2Cl2 and DDQ was added (see exact conditions in table 7). This reaction mixture was stirred at RT for 30 min and CH2Cl2 (100 mL) and a 1 M K2CO3 aqueous solution (20 mL) were added. The separated organic layer was washed with brine (50 mL), dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography (SiO2, see exact conditions in tables 6 and 7) to give, after evaporation and further drying under vacuum, the benzoxazole LPO 55056D, ANP 53142B, ANP 53192A, 114, 115, 153 or 170 (see table 7). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With 1-pyrrolidinecarboxaldehyde; benzoyl chloride; In 1,4-dioxane; at 20 - 40℃; for 24.25h;Sealed tube; | General procedure: As described in general procedure II a solution of 4-formylbenzyl alcohol (163,136.2 mg, 1.00 mmol, 1.0 equiv) and FPyr (9.8 ilL, 10.2 mg, 0.10 mmol,10 mol%) in dioxane (500 ilL) was treated with BzCI (176 mg, 213 mg,1.50 mmol, 1.5 equiv) and allowed to stir for 15 mm at ambient temperatureand 24 h at 40 C. After work up with CH2CI2 (instead of Et20) the crude material (223 mg, 98% cony., 263/363 97:3) was dissolved in toluene (0.5 mL) and loaded onto a silica gel column. Finally, chromatographic purification on silica gel (crude mass/Si02 1:20) with Et20/toluene 0.5:99.5, concentration with chloroform (3 x 2 mL) to remove residual toluene anddrying at 20 mbar furnished chloride 263 as a colorless solid (108.3 mg, 0.70 mmol, 70%). M (C8H7CIO) = 154.594 g/mol; HR-MS (El, [C8H70]j calc. 119.0491 u found 119.0500 u. |
45.5% | With thionyl chloride; In dichloromethane; at 0 - 10℃; for 3h; | In a 1000 ml flask, 4-hydroxymethylbenzaldehyde (70.5 g, 0 . 518 mol) in methylene chloride (500 ml) Thionyl chloride (80.1 g, 0.673 mol) was added dropwise at 0 C. to 10 C., And the mixture was stirred at 0 C. to 10 C. for 3 hours. The reaction mixture was concentrated under reduced pressure and toluene (50 ml × 3) Azeotropic with water. The residue was purified by silica gel chromatography (Kieselgel 60; n-heptatane / toluene) To give chloride (261-e) (36.4 g, 0.235 mol; yield 45.5% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With aluminum oxide In dichloromethane at 20℃; Reflux; Inert atmosphere; | 4.1.1. General procedure for the synthesis of 2-benzylidenebenzofuran-3(2H)-one (method A) General procedure: To a solution of benzofuran-3(2H)-one (1.0 mmol) and benzaldehyde(1.0 mmol) in dichloromethane (6 mL) was added aluminum oxide (30.0 mmol) at room temperature. After stirring for 6 h, the reaction mixture was filtered off. The filtrate was concentrated under vacuum and the residue was purified by flash chromatography on silica gel to give the desired compound |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | Stage #1: di(pyrrol-2-yl)methane; benzaldehyde; 4-(hydroxylmethyl)benzaldehyde With trifluoroacetic acid at 20℃; for 24h; Inert atmosphere; Darkness; Stage #2: With chloranil for 1h; Inert atmosphere; | 1.1.1-i In the step (1-i) 1L round bottom flask Dipyrromethane (Dipyrromethane) (0.5 g, 0.003424 mol, 2 eq), benzaldehyde (Benzaldehyde) (0.1815 g (0.174 ml), 0.001712 mol, 1 eq), 4 - (hydroxymethyl) benzaldehyde (4- (hydroxymethyl) benzaldehyde) ( 0.233 g, 0.001712 mol, 1 eq), trifluoroacetic acid (trifluoroacetic acid, TFA) (0.234 g, 0.00205 mol, 1.2 eq), dichloromethane ( dichloromethane, DCM) into a 700 ml block the light and then di gaesing (degassing) and the solution while blowing nitrogen gas for 30 minutes at room temperature and stirred for 12 hours. The reaction with an acid to TFA (0.234 g (0.16 ml) , 0.00205 mol, 0.6 eq) were cyclized catalyst. To block the light to the flask and stirred for 12 hours. using chloranil p- (p-chloranil) (1.05 g , 0.00428 mol, 1.25 eq) was oxidized with an oxidizing agent to the porphyrin intermediates. Triethyl amine (triethylamine) 3 ml in order to remove residual TFA was slowly added dropwise (dropping). Dichloromethane and the reaction mixture was dissolved in methane was purified by column chromatography (silica, CHCl 3 and separated by 100% (v / v)) 5- (4'-hydroxymethylphenyl) - 15-phenyl-21H, 23H-porphine [5- (4'-Hydroxymethylphenyl) -15-phenyl-21H, 23H-porphine]. |
14% | Stage #1: di(pyrrol-2-yl)methane; benzaldehyde; 4-(hydroxylmethyl)benzaldehyde With trifluoroacetic acid In dichloromethane at 20℃; Inert atmosphere; Darkness; Stage #2: With chloranil In dichloromethane for 1h; Inert atmosphere; Darkness; | 1.1 [Reaction Scheme 1] Specifically, the synthesis process is as follows In the above step (i), a porphyrin derivative [5- (4'-hydroxymethylphenyl) -15-phenyl porphyrin] having a reactive group at the 5th carbon of porphyrin was synthesized. To a dichloromethane solvent (700 ml) was added benzaldehyde, Hydroxymethyl benzaldehyde, 2.4 mM (1 equivalent), 2.4 mM (1 equivalent), and 4.9 mM (2 equivalents) of dipyyromethane were added, respectively, and then The composition was a nitrogen atmosphere. Trifluoroacetic acid (TFA) was used as an acid catalyst and stirred in a dark room for 6 hours, and Then, chloranil (1.25 eq) was added thereto and stirred for 1 hour. The acid was then neutralized with triethylamine and stirred until completion of the reaction. As a result, the porphyrin derivative [5- (4'-hydroxymethylphenyl) -15-phenyl porphyrin], and [5,15-bis (4'- hydroxymethylphenyl) porphyrin] with the porphyrin derivative of the general formula (I), Porphyrin derivatives of general formula 3 [5,15-diphenyl porphyrin] was obtained, and the porphyrin derivative was separated using column chromatography (developing solvent: chloroform) to obtain a porphyrin derivative of formula (2) in a yield of 14%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With 1H-imidazole; triethylamine In dichloromethane at 20℃; for 1h; | 2 4-(Triisopropylsiloxy)methylbenzaldehyde: The triisopropylsilyl protection began by preparing a suspension of 4-hydroxymethylbenzaldehyde (MW 136.15, 13.66 mmol, 1.86 g, 1 eq) in dichloromethane (20 mL) at room temperature. To this suspension was added imidazole (MW 68.08, 27.32 mmol, 1.86 g, 2 eq) and (0317) triethylamine (5 mL). Triisopropylchlorosilane (MW 192.80, 15.03 mmol, 2.89 g, 3.2 mL, 1.1 eq) was added in one portion, and the reaction was allowed to stir at room temperature for one hour. The disappearance of starting material was monitored by TLC (20% EtOAc/hexane). At the end of the reaction, an aqueous sodium bicarbonate solution was added and the mixture was shaken in a separatory funnel. The aqueous and organic layers were separated, and the organic layer was extracted (3 x 20 mL) with ethyl acetate. The organic layers were combined, dried with sodium sulfate, and concentrated under reduced pressure. The resulting organic residue was dissolved in the minimum amount of dichloromethane and was filtered through silica gel to remove the baseline polar material. The eluted organic solution was adsorbed onto silica and purified using chromatography (0 to 35% DCM/hexanes) to give a 90% yield of the desired TIPS -protected benzyl ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate; trifluoroacetic acid In methanol; dichloromethane at 45℃; for 4h; | 5.1.2. General procedure 1: Hantzschester-involved reductive amination General procedure: TFA (0.1 equiv.) were added to the solution of substituted anilins (1.0 equiv.), different aromatic aldehydes (1.2 equiv.), and Hantzschester (1.2 equiv.) in DCM/MeOH (3:1) at room temperature, and thereaction was warmed to 45 °C and reacted for about 4 h. After completion (monitored by TLC), the solution was adjusted to pH 7-8 byaddition of NaHCO3, and the crude residue was obtained by concentrating in vacuo. Finally, the crude residue was purified by columnchromatography to give the intermediate or target compounds in high yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With piperidine In ethanol at 80℃; for 4h; | 1.1.2-ii Above Step (2-ii) was performed by adding 4- (hydroxymethyl) benzaldehyde (5.6 g, 0.04113 mol, 1 eq) to a 250 ml round bottom flask, malononitrile (3.0 g, 0.04524 mol, 1.1 eq), 50 ml of ethanol and 2 drops of piperidine were added and the mixture was stirred under reflux conditions of 80 ° C for 4 hours. TLC was used to confirm the progress of the reaction and when the reaction was completed, the solvent was removed under reduced pressure. The reaction mixture was dissolved in dichloromethane and separated by column chromatography (silica, EtOAc 30% (v / v) + Hexane 70% (v / v)) to obtain 2 - [4- (hydroxymethyl) phenyl] methylidene} propanedinitrile Respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With nido-decaborane; In 1,4-dioxane; methanol; at 20℃; for 2h; | To a solution of 4-amino-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (25.0 g, 91.5 mmol) in 20% MeOH-dioxane (600 mL) was added 4-(hydroxymethyl)benzaldehyde (25.0 g, 184 mmol) and B10H14 (22.5 g, 184 mmol). The mixture was stirred at ambient temperature for 2 hours with venting (pressure) and was concentrated. The residue was diluted with ethanol (500 mL) and the mixture stirred for 1 hour. The resulting suspension was filtered, the collected solid cake was washed with ethyl acetate (200 mL) and dried in vacuum to give crude 2-(2,6-dioxopiperidin-3-yl)-4-((4-(hydroxymethyl)benzyl)amino)isoindoline-1,3-dione (28.0 g) as a yellow-green solid which was used in next step without further purification. LCMS (ESI) m/z 376.2 [MH-18]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | General procedure: Substrate (0.4 mmol) in 1 mL of acetone and catalyst (0.5 mol%)were taken in a round bottom flask. 2 mL of acetone and 2 mL of H2Owere added to it. NaIO4 (213 mg, 1.0 mmol) was dissolved in 1 mL ofH2O and transferred to the reaction mixture. The reaction mixture wasstirred at room temperature for?15 min-240 min. After this time,Na2SO3 (2.0 mmol) was added to the reaction mixture followed byaddition of 2 mL of DCM and 3 mL of H2O. The reaction mixture wasfurther stirred for 10 min. A GC standard (ethylbenzene or mesityleneor stilbene or acetophenone) was added as a reference and the reactionmixture was again stirred for 5 min. It was then transferred to a separatingfunnel with the help of 3 mL of H2O and 8 mL of DCM. Theorganic layer was separated and aqueous layer was again extracted with5 mL of DCM (2 times). The combined organic layer was washed with20 mL of brine solution. Products and unreacted substrates were analyzedby GCMS. The yields were calculated by GC analyses. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With potassium phosphate; bis(triphenylphosphine)nickel(II) chloride; 1,3-bis[2,6-diisopropylphenyl]imidazolium chloride In toluene at 110℃; for 8h; Inert atmosphere; | 3.2. General Procedure for Ni-catalyzed 1,2-Addition of Aryl Aldehydes to Arylboronic Acids General procedure: An oven-dried 25-mL three-necked flask was charged with K3PO4 (0.53 g, 2.5 mmol), Ni(PPh3)2Cl2 (0.033 g, 0.05 mmol) and IPr·HCl (0.043 g, 0.1 mmol). Then the aryl aldehyde(1.0 mmol, 1a: 0.106 g; 1b: 0.196 g; 1c: 0.186 g; 1d:0.149 g; 1e: 0.151 g; 1f: 0.185 g; 1g: 0.136 g; 1h: 0.178g; 1i:0.072 g; 1j: 0.12 g) and the arylboronic acid (1.5 mmol, 2a:0.183 g; 2b: 0.258 g; 2c: 0.228 g; 2d: 0.204 g; 2e: 0.21 g; 2f:0.285 g) were added. The flask was evacuated and backfilled with nitrogen, with the operation being repeated twice. Dried toluene (5 mL) was added via syringe at this time. The reaction mixture was heated in an oil bath of 110 °C for 8 h and then allowed to cool to room temperature; it was then filtered through a silica-gel pad that was washed with ethyl acetate.The combined organic phases were evaporated under reduced pressure and the residue was purified by column chromatography (silica-gel, Petroleum ether/Ethyl Acetate)to give the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With sodium tris(acetoxy)borohydride; sodium sulfate In dichloromethane at 20℃; Inert atmosphere; | 18.I Step I, tert- butyl 4-(4-(hydroxymethyl)benzyl)piperazine-l-carboxylate To a solution of 4-(hydroxymethyl)benzaldehyde (620 mg, 4.55 mmol) in dry DCM (7 mL) was added /er/-butyl piperazine- 1-carboxylate (1.02 g, 5.46 mmol) and anhydrous Na2S04 (~0.5 g) and NaBH(OAc)3 (1.16 g, 5.46 mmol) and the reaction mixture was stirred overnight at rt. The reaction mixture was diluted with DCM and then washed with brine (2 x 10 mL). The organic layer was collected, dried over anhydrous Na2S04, then filtered and concentrated. The residue was purified by flash chromatography on silica gel using a gradient of MeOH in DCM (0-30%) to afford the title compound (1.1 g, 79%) as a colourless oil. 'H NMR (400 MHz, CDCh) d 7.32 (d, J = 2.0 Hz, 4H), 4.68 (s, 2H), 3.52 (s, 2H), 3.44 3.39 (m, 4H), 2.43 2.34 (m, 4H), 1.45 (s, 9H)* missing OH signal. LRMS, m/z, calculated, 306.194, found 307.36 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.6% | With sodium hydroxide In ethanol; water for 1h; | 1.1 1. Synthesis of 3-(4-ethoxyphenyl)-1-(4-hydroxyphenyl)-2-en-1-one A 100 mL three-necked flask containing a magnetic rotor was added with acetophenone (12.00 g, 0.10 mol), 4-hydroxymethyl benzaldehyde (13.62 g, 0.10 mol) and solvent absolute ethanol (30 mL), and stirred at room temperature. Subsequently, an aqueous solution of sodium hydroxide (12.00 g, 0.30 mol, 12 mL) was prepared and added dropwise to the reaction system through a constant pressure dropping funnel. The reaction process was monitored by a silica gel chromatography plate. After the reaction was completed, it was filtered, and the filtrate was concentrated and then filtered. The solid obtained by the two filtrations was washed once with water, washed twice with anhydrous ethanol and dried, and then recrystallized with anhydrous ethanol to obtain yellow crystals with a yield of 89.6%. |
88.6% | With sodium hydroxide In ethanol; water at 20℃; for 2h; | 1.1 1. Synthesis of 1-phenyl-3-(4-hydroxymethyl)phenyl-2-en-1-one A 100 mL three-necked flask containing a magnetic rotor was added with acetophenone (12.00 g, 0.10 mol), 4-hydroxymethyl benzaldehyde (13.62 g, 0.10 mol) and solvent absolute ethanol (25 mL), and stirred at room temperature.An aqueous solution of sodium hydroxide (8.00 g, 0.20 mol, 10 mL) was added dropwise to the reaction system through a constant pressure dropping funnel.After the addition was completed, the reaction was carried out for 2 h, monitored by TLC.After the completion of the reaction, the filtered solid was washed once with water, washed twice with anhydrous ethanol and then dried, and recrystallized with anhydrous ethanol to obtain yellow crystals with a yield of 88.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.6% | With sodium hydroxide In ethanol for 2h; | 4.1 1. Synthesis of 1-(4-trifluoromethylphenyl)-3-(4-hydroxymethylphenyl)-2-en-1-one Using 4-trifluoromethyl acetophenone and 4-hydroxymethyl benzaldehyde to react in sodium hydroxide and absolute ethanol, the yield was 88.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 1H-imidazole In dichloromethane at 20℃; for 1.25h; Cooling with ice; | 83.83-1 Example 83 (83-1) 4-([tert-butyl (biphenyl) silyl] oxy} methyl) benzaldehyde (Example compound 83-1) 4- (Hydroxymethyl) benzaldehyde (1.20 g) is dissolved in dichloromethane (30 mL), imidazole (1.44 g) is added under ice-cooling, and tert-butylchlorodiphenylsilane (2.75 mL) is added dropwise. The mixture was stirred at room temperature for 75 minutes. Under ice-cooling, water was added to the reaction solution, the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100: 0-87: 13) to give the title compound (quant.) As a white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium phosphate; cobalt(II) chloride hexahydrate; diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate; (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile; bis[2-(diphenylphosphino)phenyl] ether In tetrahydrofuran at 20℃; for 4h; Schlenk technique; Sealed tube; Inert atmosphere; Irradiation; diastereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: 4-(hydroxylmethyl)benzaldehyde With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 1h; Inert atmosphere; Stage #2: carbon disulfide In tetrahydrofuran; mineral oil at 0℃; for 1h; Inert atmosphere; Stage #3: methyl iodide In tetrahydrofuran; mineral oil at 0℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tetrahydroborate; copper(II) ion In water at -5℃; for 0.0333333h; Green chemistry; chemoselective reaction; | Method C. General procedure for the reduction of benzoyl halides (Table 6) General procedure: The three-neck round bottom flask containing copper(II)salt (2 mol % of Cu(OAc)2 or CuCO3 or Cu(NO3)2 or 3 mol % of Cu(OH)2 or CuSO4 or 4 mol % of CuO or 6 mol%o f CuCl2 catalyst, as per Table 3) in water (1.2 mL) was equipped with a thermo pocket, magnetic needle, and an addition funnel fitted with calcium chloride guard tube, was stirred and cooled at 5 °C under atmospheric environment followed by simultaneousslow addition of NaBH4 (2.0-2.5 molar ratio to the substrate, as per Table 2) and benzoylchloride (140.57 mg, 1 mmol) was carried out, respectively. Subsequently within 2 min, after the completion of the reaction (as evidenced by TLC) the reaction mixture was filtered using Büchner funnel to remove the black precipitate. The filtered reaction mass was diluted by 5mL methylene dichloride and washed with aqueous 5% NaHCO3 solution (5mL 2), then washed with water (5mL 2). Thus, the obtained organic phase was dried over anhydrous sodium sulfate. Further upon filtration of the dry ingagent, the solvent from the obtained organic layer was removed under vacuo affording desired benzyl alcohol. It was observed that the purity of the crude product was more than 99% by 1H NMR, henceforth, to obtain pure product no column or flash chromatographic separation technique was needed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With C21H25IN2Ru; potassium hydroxide In m-xylene at 145℃; for 12h; Schlenk technique; | 2.4.1. A typical reaction under the optimized reaction condition General procedure: To a 25mL Schlenk flask, an NHC-Ru complex (one of [Ru-1]-[Ru-7], 1.56 μmol), an alcohol (25mmol), KOH (1.68g, 30mmol), a stirring bar, and m-xylene (3.0mL) were added. The flask was equipped with a reflux condenser, and the reaction mixture was stirred at a refluxing temperature in open air. After the assigned reaction period, the flask was cooled to room temperature. Water (10mL) and ethyl acetate (20mL) were added, and the two layers were separated. The organic layer was collected, and the aqueous layer was further extracted with ethyl acetate (3× 20mL). Subsequently, the organic layers were combined, dried over Na2SO4, concentrated via a rotary evaporator, dried with a vacuum pump to afford the unreacted alcohol, which was weighed to obtain its yield. Afterwards, 3N HCl (around 12mL) was added to the aqueous layer, which was extracted with ethyl acetate (3× 20mL). The organic layers were combined, dried over Na2SO4, concentrated and dried to afford the desired carboxylic acid, which was weighed to determine its yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sulfur(VI) fluoride; ammonium fluoride; triethylamine In acetonitrile at 40℃; for 6h; | 5 Example 5: Preparation of 4-(fluoromethyl)benzaldehyde In a 100ml single-necked flask, 2.72g (20mmol) of 4-(hydroxymethyl)benzaldehyde (formula I, R=CHO), 0.74g (20mmol) of ammonium fluoride, 6.06g (60mmol) of Et 3 N and 40ml of acetonitrile was stirred at 40°C for 6h in a sulfonyl fluoride atmosphere. After the reaction was completed, 50ml of water was added to dilute it, and then 50ml of ethyl acetate was added for extraction three times. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. suction filtration, and concentration to obtain 2.44 g of 4-(fluoromethyl)-benzaldehyde with a purity of 97% and a yield of 86%. |
Tags: 52010-97-6 synthesis path| 52010-97-6 SDS| 52010-97-6 COA| 52010-97-6 purity| 52010-97-6 application| 52010-97-6 NMR| 52010-97-6 COA| 52010-97-6 structure
[ 99-04-7 ]
3-Methylbenzoic acid(Flakes or Chunks or Granular)
Similarity: 0.88
[ 163164-47-4 ]
4-(2-Hydroxyethyl)benzaldehyde
Similarity: 0.81
[ 75633-63-5 ]
1-(4-(Hydroxymethyl)phenyl)ethanone
Similarity: 0.85
[ 163164-47-4 ]
4-(2-Hydroxyethyl)benzaldehyde
Similarity: 0.81
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