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CAS No. : | 7417-21-2 | MDL No. : | MFCD00002894 |
Formula : | C10H14O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SRQAJMUHZROVHW-UHFFFAOYSA-N |
M.W : | 182.22 | Pubchem ID : | 81911 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.4 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 50.36 |
TPSA : | 38.69 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.68 cm/s |
Log Po/w (iLOGP) : | 2.2 |
Log Po/w (XLOGP3) : | 1.03 |
Log Po/w (WLOGP) : | 1.24 |
Log Po/w (MLOGP) : | 1.22 |
Log Po/w (SILICOS-IT) : | 2.03 |
Consensus Log Po/w : | 1.54 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.7 |
Solubility : | 3.67 mg/ml ; 0.0201 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.43 |
Solubility : | 6.73 mg/ml ; 0.0369 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.89 |
Solubility : | 0.236 mg/ml ; 0.0013 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.51 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.9% | With sodium tetrahydroborate; iodine In tetrahydrofuran at 20℃; for 0.583333 h; Cooling with ice | Take a dry and clean 100 mL round bottom flask, accurately weigh sodium borohydride (0.4 g, 7.65 mmol) and iodine (1.3 g, 5.10 mmol) in a bottle, add 10 mL of tetrahydrofuran, place in an ice bath, stir After 5 min, 21 (1.0 g, 5.10 mmol) was added in small portions. After the addition, the ice bath was removed and the reaction was carried out at room temperature. The reaction was monitored by TLC. After 30 min, the reaction was completed by TLC. 50 ml of a 5percent sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3), and the organic phase was combined and washed with brine (10 mL × 3). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporatedThe title compound (22) was obtained as a yellow oil.The yield was 98.9percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With toluene-4-sulfonic acid In methanol; dichloromethane at 20 - 25℃; for 0.333333 h; Flow reactor | General procedure: The system (Figure 4) was primed with solvent (DCM and 0.3 M aqueous NaOH) prior to the introduction of the substrates. Substrates were present as 0.034 M solutions (20 mL) in glass vials. These were placed in a square 4 x 4 rack. Following initiation of the computer-vision system (and checking to make sure the aqueous-out tap was opening/closing properly), activation of the autosampler/liquid-handling schedule was initiated by pressing ‘s’ on the computer keyboard. The outlet of the flow stream for each product was then collected until the autosampler moved to the waste position between each run. 5 mL of substrate was taken up during each run, 4 mL of which entered the holding loop (the line between the autosampler and 3-way-valve 1 was 1 mL in volume). Outlet collection flasks were changed manually. The products were isolated by removing solvent under reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Stage #1: With iodine; magnesium In tetrahydrofuran at 70℃; Inert atmosphere; Reflux Stage #2: at 0 - 70℃; Inert atmosphere Stage #3: With ammonium chloride In tetrahydrofuranInert atmosphere |
Example 2: Preparation of 2-(3.4-dimethoxyphenyl)ethanol (2) from 4-bromo-l ,2- dimethoxybenzene (1)Magnesium turnings (3.9 g, 0.160 mol, 1.0 equiv) and I2 (5 mg) was charged to a 250 mL three- neck round-bottom flask, one neck of which was equipped with a cooling condenser, one with a dropping funnel, the other with a thermometer. The reaction system was protected with N2 gas. A small portion of 4-bromo-l,2-dimethoxybenzene (35 g, 0.155 mol) in anhydrous THF (160 mL) was added to the flask. After the reaction was initiated by heating the reaction mixture at 70 °C, the residual solution of the bromide was added slowly at a rate sufficient to maintain the reaction solution under slight reflux. When the addition was finished, the mixture was maintained at 70 °C for 2 h and then cooled to 0 °C. Ethylene oxide (15 mL, 0.30 mol, 2.0 equiv) was added dropwise and the reaction mixture was heated to 70 °C for 1 h. When a sticky gel hat formed, a saturated NH4CI solution (100 mL) was added. After phase separation, the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water (2 * 50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and then evaporated under reduced pressure to give a red oil. Distillation yielded a colorless oil (15.3 g, b.p. 155-160 °C/10 mbar, 55percent), which solidified upon standing. 3/4 NMR (400 MHz, DMSO-^): δ 6.83 (d, J= 8.2 Hz, 1 H), 6.80 (d, J= 2.0 Hz, 1 H), 6.71 (dd, J= 8.2, 2.0 Hz, 1 H), 4.60 (t, J= 5.2 Hz, 1 H, -OH), 3.73 (s, 3 H), 3.70 (s, 3 H), 3.57 (m, 2 H), 2.65 (t, J= 7.2 Hz, 2 H). 13C MR (100 MHz, DMSO-afc): δ 148.7, 147.2, 132.1, 120.7, 113.0, 112.0, 62.5, 55.6, 55.4, 38.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.9% | With sodium tetrahydridoborate; iodine In tetrahydrofuran at 20℃; for 0.583333h; Cooling with ice; | 1.5 (5) Synthesis of Compound 22 Take a dry and clean 100 mL round bottom flask, accurately weigh sodium borohydride (0.4 g, 7.65 mmol) and iodine (1.3 g, 5.10 mmol) in a bottle, add 10 mL of tetrahydrofuran, place in an ice bath, stir After 5 min, 21 (1.0 g, 5.10 mmol) was added in small portions. After the addition, the ice bath was removed and the reaction was carried out at room temperature. The reaction was monitored by TLC. After 30 min, the reaction was completed by TLC. 50 ml of a 5% sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3), and the organic phase was combined and washed with brine (10 mL × 3). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporatedThe title compound (22) was obtained as a yellow oil.The yield was 98.9%. |
98% | With lithium aluminium hydride In tetrahydrofuran at 0 - 70℃; for 0.5h; | 2-(3,4-Dimethoxyphenyl)ethan-1-ol (6) To a suspension of LiAIH4 (0.19 g, 5.07 mmol) in 3 mL dry THF, a solution of 2-(3,4-dimethoxyphenyl)acetic acid (0.50 g, 2.55 mmol) in 7 mL dry THF was added at 0 °C. The reaction mixture was gradually warmed to ambient temperature and then was refluxed for 30 min. A mixture of THF/H2O (1 : 1) was added at 0 °C and then was diluted with ethyl acetate. Na2S04 was added to the mixture and was stirred for 15 min. Finally, it was filtered through a pad of Celite and the filtrate was concentrated in vacuo giving the desired product as a white solid, (0.45 g, 98%). 1H NMR (600 MHz, CDCb) d : 6.82-6.75 (m, 3H, Ar H), 3.87 (s, 3H, -OC ft), 3.85 (s, 3H, -OC/fc), 3.83 (t, J= 6.5 Hz, 2H, -C//2OH), 2.80 (t, .7=6.5 Hz, 2H, -CCH2OH). 13C NMR (75 MHz, CDC13) d: 148.5, 147.2, 130.9, 120.6, 1 12.0, 1 1 1.1 , 63.3, 55.7, 55.4, 38.4. MS m/z: 182.82 (M+H) 204.96 (M+Na) +, 386.64 (2M+Na)+ |
97% | With lithium aluminium hydride In tetrahydrofuran at 0℃; Reflux; |
93% | With lithium aluminium hydride In tetrahydrofuran at 20℃; for 0.5h; | |
91.2% | With sodium tetrahydridoborate; iodine In tetrahydrofuran for 18h; Heating; | |
90% | With sodium tetrahydridoborate; iodine In tetrahydrofuran for 24h; Reflux; | |
86% | With dimethylsulfide borane complex In tetrahydrofuran for 1h; Inert atmosphere; Reflux; | |
With lithium aluminium hydride | ||
With lithium aluminium hydride | ||
With dimethylsulfide borane complex | ||
Multi-step reaction with 2 steps 1: sulfuric acid 2: sodium | ||
With lithium aluminium hydride In tetrahydrofuran at 0 - 20℃; | ||
With lithium aluminium hydride In tetrahydrofuran at 0℃; | ||
With lithium aluminium hydride Inert atmosphere; | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 3 h / Reflux 2: diisobutylaluminium hydride / tetrahydrofuran; toluene / 20 °C | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 0.5 h / Reflux 2: sodium tetrahydridoborate; calcium(II) chloride / ethanol / 16 h / 0 - 20 °C | ||
With lithium aluminium hydride In tetrahydrofuran at 0 - 20℃; for 3h; Inert atmosphere; Reflux; | ||
With borane-THF In tetrahydrofuran at 0 - 20℃; for 2h; | ||
With lithium aluminium hydride In tetrahydrofuran Inert atmosphere; | ||
With lithium aluminium hydride In tetrahydrofuran | ||
With sulfuric acid In tetrahydrofuran; lithium hydroxide monohydrate | Preparation of 2-(3,4-dimethoxyphenyl)ethanol Preparation of 2-(3,4-dimethoxyphenyl)ethanol To a solution of 3,4-dimethoxyphenylacetic acid (2 g) in anhydrous THF (40 ml) at 0° C. under N2 was added dropwise borane-methyl sulfide complex (10 M, 1.5 ml). The mixture was stirred at room temperature for further 4 hrs. Cold water (5 ml) was added to destroy any excess of borane followed by the addition of H2SO4 (1 M, 50 ml). The mixture was extracted three time with ethyl acetate (50 ml). The organic layer was separated and evaporated off to give a colourless liquid which was then purified by column chromatography to afford a colourless solid in quantitative yield. 1H-NMR: δ6.76-6.82 (3H, m), 3.87 (8H, m), 2.82 (2H, t, J=6 Hz). | |
With borane-THF In tetrahydrofuran at 0 - 20℃; for 2h; Inert atmosphere; | ||
With lithium aluminium hydride In tetrahydrofuran at 0℃; for 2h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine In dichloromethane at 20℃; for 0.5h; | |
90% | With dmap; triethylamine In dichloromethane at 0 - 18℃; for 2h; | |
89% | With triethylamine In dichloromethane at 20℃; for 48h; |
73% | With dmap; triethylamine In dichloromethane at 20℃; for 15h; Inert atmosphere; | |
65% | With pyridine at 0℃; | |
65.2% | With triethylamine In dichloromethane at 20℃; for 2h; | |
With dmap; triethylamine In dichloromethane at 0 - 20℃; for 15h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With thionyl chloride In chloroform for 4h; Heating / reflux; | 28.2 The reaction mixture of 2-(3,4-dimethoxyphenyl)ethanoI (6.0 g, 32.8 mmol) and thionyl chloride (19 g, 164 mmol) in chloroform (20 mL) was stirred at reflux for 4 h, concentrated, and partitioned between water and ethyl acetate. The organic layer was washed with NaHCCb and brine, dried over anhydrous sodium sulfate, and concentrated to afford 4-(2-chloroethyl)- 1,2-flim.ethoxybenzene (K) quantitatively (6.6 g).A reaction mixture of 4-(2-chloroethyl)-l,2-dimethoxybenzene (3.6 g, 17.9 mmol), piρerazine-1-carboxylic acid f-butyl ester (4.0 g, 21.5 mmol), K2CO3 (4.97 g, 36 mmol), and NaI (2.7 g, 18 mmol) in DMF (20 mL) was stirred at 800C for 3 h, cooled to room temperature, and partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to afford 4-[2-(3,4-dimethoxy-phenyl)-ethyl]- piperazine-1-carboxylic acid *-butyl ester (4.8 g, 76%) which was dissolved in 4 N HCl in dioxane. This solution was stirred at room temperature for 4 h, concentrated, and dried in a high vacuum oven to give the title compound quantitatively. |
100% | With thionyl chloride In chloroform for 4h; Heating / reflux; | 28.2 The reaction mixture of 2-(3,4-dimethoxyphenyl)ethanol (6.0 g, 32.8 mmol) and thionyl chloride (19 g, 164 mmol) in chloroform (20 mL) was stirred at reflux for 4 h, concentrated., &hd partitioned between water and ethyl acetate. The organic layer was washed with NaHCO3 and brine, dried over anhydrous sodium sulfate, and concentrated to afford 4-(2-chloroethyl)-l ,2-dimethoxybenzene (K) quantitatively (6.6 g). |
62% | With phosphorus pentachloride; calcium carbonate In toluene at 0 - 20℃; for 4.16667h; Inert atmosphere; | To a stirring solution of 3 (5.0 g, 27.4 mmol) in dry toluene (80 mL) dry CaCO3 (8.24 g, 39.4 mmol) and PCl5 (5.47 g, 26.3 mmol) were added slowly over a period of 40 min under argon atmosphere at 0 °C. The mixture was stirred for another 30 min at 0 °C and 3 h at RT. The resulting solution was poured into saturated aqueous NaHCO3 solution containing ice (40 mL) and extracted twice with diethyl ether (100 mL). The organic layer was dried, filtered,concentrated and purified by silica gel column chromatography (n-hexane-ethyl acetate 90:10 (v/v)) to achieve 4 (3.42 g, 62 %) as a yellow solid. |
With tetrachloromethane; phosphorus pentachloride | ||
With hydrogenchloride; zinc(II) chloride | ||
With thionyl chloride; <i>N</i>,<i>N</i>-dimethyl-aniline In chloroform | ||
With thionyl chloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With carbon tetrabromide; triphenylphosphine In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere; | |
94% | With NBS; triphenylphosphine In dichloromethane at 0℃; for 1h; Inert atmosphere; | |
92% | With carbon tetrabromide; triphenylphosphine In dichloromethane at 20℃; for 12h; |
80% | With carbon tetrabromide; triphenylphosphine In dichloromethane at 20℃; | |
69% | With NBS; triphenylphosphine In benzene at 20℃; for 2h; | |
50% | With phosphorus tribromide In benzene | |
With phosphorus tribromide | ||
With NBS; triphenylphosphine In toluene at 20℃; for 12h; | ||
With bromine; triphenylphosphine In dichloromethane | d d) d) Preparation of 1-(2-bromoethyl)-3,4-dimethoxybenzene Triphenylphosphine (1.64 g, 6.2 mmol) was added to a solution of 2-(3,4-dimethoxyphenyl)-1-ethanol (1.027 g, 5.64 mmol) in dichloromethane (6 ml) at 0° C., followed by the dropwise addition of bromine (1.0 g, 6.2 mmol). The reaction was quenched with water after 2 hours. Usual work-up, including quenching with water after two hours, and then extracting with MTBE and then drying the organic extract obtained with MgSO4, and concentrating under pressure, gave the crude product (1.468 g), which was taken directly to the next step. | |
With phosphorus tribromide Inert atmosphere; | ||
With pyridine; phosphorus tribromide In dichloromethane at 0 - 20℃; for 1h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With silica-supported policresulen at 80℃; for 5h; Green chemistry; | SiO2/policresulen composite catalyzed oxa-Pictet-Spengler reaction. General procedure: All reactions were conducted in a 10-mL V-type vessel equipped with a triangular magnetic stirrer. In a typical reaction, 2-(3,4-dimethoxyphenyl)ethanol (91.1 mg, 0.5 mmol), benzaldehyde (64.8 mg, 0.6 mmol), and 1b (10 mg, 1 mol%) were mixed in 1,2-dichloroethane (1.0 mL) and stirred for 5 h at 80 °C. After the reaction, the mixture was cooled to room temperature and then centrifuged, and the liquid phase was subjected to isolation with PTLC (eluting solvent: ethyl acetate/petroleum ether = 1/8). The desired product, 7a, was obtained in a yield of 96%. Tests of the substrate scope were conducted in the same manner. The recycling of 1b was realized after doubling the dose. After washing the solid phase with PE (3.0 mL × 3) and drying under vacuum, the recovered 1b was used in the next run with a similar procedure. |
92% | With 2H(1+)*Mo12O40P(3-)*C8H14NOS(1+) at 70℃; for 0.416667h; Green chemistry; | |
86% | With toluene-4-sulfonic acid In water for 0.833333h; Reflux; |
79% | With hydrogenchloride In 1,4-dioxane for 1h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With silica-supported policresulen at 80℃; for 5h; Green chemistry; | SiO2/policresulen composite catalyzed oxa-Pictet-Spengler reaction. General procedure: All reactions were conducted in a 10-mL V-type vessel equipped with a triangular magnetic stirrer. In a typical reaction, 2-(3,4-dimethoxyphenyl)ethanol (91.1 mg, 0.5 mmol), benzaldehyde (64.8 mg, 0.6 mmol), and 1b (10 mg, 1 mol%) were mixed in 1,2-dichloroethane (1.0 mL) and stirred for 5 h at 80 °C. After the reaction, the mixture was cooled to room temperature and then centrifuged, and the liquid phase was subjected to isolation with PTLC (eluting solvent: ethyl acetate/petroleum ether = 1/8). The desired product, 7a, was obtained in a yield of 96%. Tests of the substrate scope were conducted in the same manner. The recycling of 1b was realized after doubling the dose. After washing the solid phase with PE (3.0 mL × 3) and drying under vacuum, the recovered 1b was used in the next run with a similar procedure. |
86% | With 1,1,1,3',3',3'-hexafluoro-propanol In water at 60℃; for 72h; | |
64% | In trifluoroacetic acid for 0.166667h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 1H-imidazole; iodine; triphenylphosphine In toluene at 20℃; for 24h; | |
With triphenylphosphine; methyl iodide Heating; | ||
With 1H-imidazole; iodine; triphenylphosphine In diethyl ether; acetonitrile for 1.5h; |
With 1H-imidazole; iodine; triphenylphosphine In dichloromethane | ||
With 1H-imidazole; iodine; triphenylphosphine | ||
With 1H-imidazole; iodine; triphenylphosphine In dichloromethane at 20℃; for 1h; | ||
Multi-step reaction with 2 steps 2: acetone; NaI | ||
Multi-step reaction with 2 steps 1: benzene; SOCl2 2: butanone; NaI | ||
Multi-step reaction with 2 steps 1: SOCl2, PhNMe2 / CHCl3 2: NaI / ethanol | ||
Stage #1: 2-(3,4-dimethoxyphenyl)ethyl alcohol With p-toluenesulfonyl chloride In dichloromethane Stage #2: With sodium iodide In acetone |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With diethylamino-sulfur trifluoride In dichloromethane at 25℃; for 2h; | |
77% | With tetrabutylammonium tetra(tert-butyl alcohol) coordinate fluoride; N-tosyl-4-chlorobenzenesulfonimidoyl fluoride; 1,8-diazabicyclo[5.4.0]undec-7-ene In toluene at 20℃; for 0.5h; Sealed tube; | |
76% | Stage #1: 2-(3,4-dimethoxyphenyl)ethyl alcohol With copper(l) chloride; diisopropyl-carbodiimide at 60℃; for 1h; Sealed tube; Microwave irradiation; Stage #2: With copper (II)-fluoride In water at 100℃; for 24h; Microwave irradiation; |
70% | With diethylamino-sulfur trifluoride In dichloromethane for 5h; Ambient temperature; | |
57% | With potassium fluoride; fluorosulfonyl fluoride; 18-crown-6 ether; 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 23℃; for 1h; Inert atmosphere; | General procedure C: General procedure: A 20 mL vial A and a 30 mL vial B were equipped with magnetic stir-bars, were capped with septum-fitted vial caps and connected by a polyethylene tube. Under nitrogen, Vial A was charged with SDI (5.53 mmol, 9.22 equiv) and anhydrous KF (14.7 mmol, 24.5equiv). To vial B was added THF (12 mL). A 3 mL syringe filled with excess of TFA (3.0 mL, 39.2 mmol) was added into the vial A at a rate of 9 mL/hr by a syringe pump. The tube in vial B was immersed into the solution after the first bubbles of SO2F2 appeared. Once bubbling of SO2F2 subsided, into vial B was inserted an empty balloon to increase the bubbling rate. When the bubbling had almost stopped, 6M NaOH (3.0mL) was slowly added into vial A. After completing generation of SO2F2, the tube was removed. Without opening the vial B, trifluorotoluene (1equiv) was added by a syringe into vial B as an internal standard. Without opening the vial B, an aliquot was taken by a syringe for quantitative 19F NMR analysis to confirm no TFA contaminant and quantify the amount of SO2F2 (Note: the chemical shift of the twoequivalent fluorines of SO2F2 appear at 33.8 ppm. Typically, about 1.5 to2.5 equivalents of SO2F2 were calculated to be in THF prior to additionof the other reagents). KF (4 equiv) and 18-crown-6 (4 equiv) were added into vial B. A reaction mixture of 3-Phenyl-1-propanol 1a (0.6mmol, 1 equiv), THF (4.0 mL), and DBU (1.8 mmol, 3 equiv) were added into vial B at 4 mL/hr by a syringe pump. An aliquot was taken for quantitative 19F NMR analysis after stirring for one hour (note: theamount of the aliquot is less than 0.1 mL which is less than 1% of the reaction solution). Caution: Reaction vials can become pressurized during the generation of SO2F2. Note: Picture of the assembly is availablein the SI |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-Bromosuccinimide In chloroform for 6h; Reflux; Inert atmosphere; | |
99.6% | With N-Bromosuccinimide In N,N-dimethyl-formamide at 0 - 20℃; | |
97% | With N-Bromosuccinimide In dichloromethane at 20℃; for 4h; Inert atmosphere; |
90% | With N-Bromosuccinimide In N,N-dimethyl-formamide at 0℃; for 22h; Inert atmosphere; | 2-(2-Bromo-4,5-dimethoxyphenyl)ethanol (23) Under an argon atmosphere, a solution of NBS (5.36g, 30.1 mmol) in DMF (20 mL) was added dropwise to a solution of 2-(3,4-dimethoxyphenyl)ethanol (5.00 g, 27.4 mmol) in DMF (10 mL) at 0 °C. After stirring for 22 h, the reaction mixture was quenched with water at the same temperature and allowed to warm to rt. The products were extracted with EtOAc and the extract was washed with water and brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography over silica gel 60N (hexane-EtOAc = 1:1) to give 23 as a colorless solid (6.45 g, 90%). IR (KBr) 3216, 1509, 1382, 1256, 1217, 1164, 1053, 859, 802 cm-1. 1H NMR(500 MHz, CDCl3): δ 1.46 (br s, 1H), 2.96 (t, J = 6.7 Hz, 2H), 3.84-3.89 (m, 8H), 6.78 (s, 1H), 7.02 (s,1H). 13C NMR (125 MHz, CDCl3): δ 39.0, 56.1, 56.2, 62.4, 113.8, 114.4, 115.7, 129.7, 148.3, 148.4.HRMS (m/z) Calcd for C10H14BrO3 [(M+H)+]: 261.01263. Found: 261.01146. |
76% | With N-Bromosuccinimide In chloroform for 5.5h; Reflux; | |
With bromine In acetic acid | ||
Multi-step reaction with 2 steps 1: bromine / 1 h 2: K2CO3 / methanol / 0.5 h | ||
With N-Bromosuccinimide In N,N-dimethyl-formamide at 0 - 20℃; for 3h; | XIV.1 XIVJV-Bromosuccinamide (NBS) (38 g) was added to a cool (0 0C) solution of dimethoxyphenyl ethanol (7) (39 g) in DMF (800 mL). The red solution was allowed to warm to ambient temperature over 3 h. The solution was poured into water and extracted with EtOAc. The combined organic extracts were washed with sodium thiosulfate (aq), NaHCO3 (aq), and brine. The organic solution was dried (MgSO4) and evaporated to give bromide 8 (56 g) as an orange oil that was used without further purification in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With iron(II) triflate In toluene at 70℃; for 2h; Green chemistry; | 2. Procedure for the synthesis of isochromans General procedure: β-Arylethanol 1 (1 mmol) and Fe(OTf)2 (0.01 mmol) were added sequentially to a solution of aldehyde, ketone, or ketal (1 eq, 1 mmol) in toluene (2 mL). The reaction mixture was warmed up slowly to the 70 oC and stirred for a few hours with monitoring by TLC plate. After completion the reaction, the mixture was cooled to room temperature. Then, the reaction mixture was washed with saturated NaHCO3 solution (5 mL), and the organic layer extracted with DCM (2×5 mL), dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography using PE-EtOAc mixture as eluent to afford the desired product. |
98% | With toluene-4-sulfonic acid In water for 0.833333h; Reflux; | |
97% | With Ersorb-4a In toluene at 110℃; for 15h; |
97% | With silica-supported policresulen at 80℃; for 5h; Green chemistry; | SiO2/policresulen composite catalyzed oxa-Pictet-Spengler reaction. General procedure: All reactions were conducted in a 10-mL V-type vessel equipped with a triangular magnetic stirrer. In a typical reaction, 2-(3,4-dimethoxyphenyl)ethanol (91.1 mg, 0.5 mmol), benzaldehyde (64.8 mg, 0.6 mmol), and 1b (10 mg, 1 mol%) were mixed in 1,2-dichloroethane (1.0 mL) and stirred for 5 h at 80 °C. After the reaction, the mixture was cooled to room temperature and then centrifuged, and the liquid phase was subjected to isolation with PTLC (eluting solvent: ethyl acetate/petroleum ether = 1/8). The desired product, 7a, was obtained in a yield of 96%. Tests of the substrate scope were conducted in the same manner. The recycling of 1b was realized after doubling the dose. After washing the solid phase with PE (3.0 mL × 3) and drying under vacuum, the recovered 1b was used in the next run with a similar procedure. |
94% | With 2H(1+)*Mo12O40P(3-)*C8H14NOS(1+) at 70℃; for 0.333333h; Green chemistry; | |
58% | With hydrogenchloride In 1,4-dioxane for 1h; Heating; | |
With hydrogenchloride In 1,4-dioxane for 1h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With bismuth(lll) trifluoromethanesulfonate; water In toluene at 80℃; | |
94% | With hydrogenchloride In 1,4-dioxane for 1h; Heating; | |
94% | With 2H(1+)*Mo12O40P(3-)*C8H14NOS(1+) at 70℃; for 0.333333h; Green chemistry; |
85% | With hydrogenchloride In 1,4-dioxane for 1h; Heating; | |
85% | With Ersorb-4a In toluene at 110℃; for 15h; | |
80% | With toluene-4-sulfonic acid In water for 0.916667h; Reflux; | |
With hydrogenchloride In 1,4-dioxane for 1h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With bismuth(lll) trifluoromethanesulfonate; water In toluene at 80℃; | |
99% | With bismuth(lll) trifluoromethanesulfonate In toluene at 20 - 80℃; for 1h; | |
99% | With iron(II) triflate In toluene at 70℃; for 2h; Green chemistry; | 2. Procedure for the synthesis of isochromans General procedure: β-Arylethanol 1 (1 mmol) and Fe(OTf)2 (0.01 mmol) were added sequentially to a solution of aldehyde, ketone, or ketal (1 eq, 1 mmol) in toluene (2 mL). The reaction mixture was warmed up slowly to the 70 oC and stirred for a few hours with monitoring by TLC plate. After completion the reaction, the mixture was cooled to room temperature. Then, the reaction mixture was washed with saturated NaHCO3 solution (5 mL), and the organic layer extracted with DCM (2×5 mL), dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography using PE-EtOAc mixture as eluent to afford the desired product. |
98% | With silica-supported policresulen at 80℃; for 3h; Green chemistry; | SiO2/policresulen composite catalyzed oxa-Pictet-Spengler reaction. General procedure: All reactions were conducted in a 10-mL V-type vessel equipped with a triangular magnetic stirrer. In a typical reaction, 2-(3,4-dimethoxyphenyl)ethanol (91.1 mg, 0.5 mmol), benzaldehyde (64.8 mg, 0.6 mmol), and 1b (10 mg, 1 mol%) were mixed in 1,2-dichloroethane (1.0 mL) and stirred for 5 h at 80 °C. After the reaction, the mixture was cooled to room temperature and then centrifuged, and the liquid phase was subjected to isolation with PTLC (eluting solvent: ethyl acetate/petroleum ether = 1/8). The desired product, 7a, was obtained in a yield of 96%. Tests of the substrate scope were conducted in the same manner. The recycling of 1b was realized after doubling the dose. After washing the solid phase with PE (3.0 mL × 3) and drying under vacuum, the recovered 1b was used in the next run with a similar procedure. |
96% | With 2H(1+)*Mo12O40P(3-)*C8H14NOS(1+) at 70℃; for 0.333333h; Green chemistry; | |
81% | With toluene-4-sulfonic acid In water for 0.916667h; Reflux; | |
77% | With hydrogenchloride In 1,4-dioxane for 1h; Heating; | |
77% | With hydrogenchloride In 1,4-dioxane for 1h; Heating; | |
With hydrogenchloride In 1,4-dioxane for 1h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With iron(II) triflate In toluene at 70℃; for 4h; Green chemistry; | 2. Procedure for the synthesis of isochromans General procedure: β-Arylethanol 1 (1 mmol) and Fe(OTf)2 (0.01 mmol) were added sequentially to a solution of aldehyde, ketone, or ketal (1 eq, 1 mmol) in toluene (2 mL). The reaction mixture was warmed up slowly to the 70 oC and stirred for a few hours with monitoring by TLC plate. After completion the reaction, the mixture was cooled to room temperature. Then, the reaction mixture was washed with saturated NaHCO3 solution (5 mL), and the organic layer extracted with DCM (2×5 mL), dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography using PE-EtOAc mixture as eluent to afford the desired product. 3. Analytic data of products 6,7-Dimethoxy-1-phenylisochroman (3a)1 was obtained under optimized conditions, reaction time: 4 h. White solid, 265 mg, 98% yield; 1H NMR (400 MHz, CDCl3)δ2.72-2.76 (m, 1H), 3.03-3.07 (m, 1H), 3.66 (s, 3H), 3.88 (s, 3H), 3.88-3.89 (m, 1H), 4.13-4.16 (m, 1H), 5.69 (s, 1H), 6.23 (s, 1H), 6.66 (s, 1H), 7.26-7.34 (m, 5H); 13C NMR(100 MHz, CDCl3) δ28.4, 56.0, 63.6, 79.2, 109.8, 111.2, 126.1, 128.2, 128.4, 129.0, 142.2, 147.3, 147.9; IR (KBr) 3071, 2918, 2861, 1505, 1453, 1261, 1214, 1095 cm-1HRMS (ESI) m/z calc. for C17H18O3 [M+Na]+ : 293.1154; found: 293.1147. |
96% | With silica-supported policresulen at 80℃; for 5h; Green chemistry; | SiO2/policresulen composite catalyzed oxa-Pictet-Spengler reaction. General procedure: All reactions were conducted in a 10-mL V-type vessel equipped with a triangular magnetic stirrer. In a typical reaction, 2-(3,4-dimethoxyphenyl)ethanol (91.1 mg, 0.5 mmol), benzaldehyde (64.8 mg, 0.6 mmol), and 1b (10 mg, 1 mol%) were mixed in 1,2-dichloroethane (1.0 mL) and stirred for 5 h at 80 °C. After the reaction, the mixture was cooled to room temperature and then centrifuged, and the liquid phase was subjected to isolation with PTLC (eluting solvent: ethyl acetate/petroleum ether = 1/8). The desired product, 7a, was obtained in a yield of 96%. Tests of the substrate scope were conducted in the same manner. The recycling of 1b was realized after doubling the dose. After washing the solid phase with PE (3.0 mL × 3) and drying under vacuum, the recovered 1b was used in the next run with a similar procedure. |
95% | With 1,1,1,3',3',3'-hexafluoro-propanol In water at 90℃; for 18h; |
93% | With 2H(1+)*Mo12O40P(3-)*C8H14NOS(1+) at 70℃; for 0.333333h; Green chemistry; | |
91% | With toluene-4-sulfonic acid In water for 0.666667h; Reflux; | |
87% | With hydrogenchloride In 1,4-dioxane for 1h; Heating; | |
83% | With Ersorb-4a In toluene at 110℃; for 15h; | |
With hydrogenchloride In 1,4-dioxane for 1h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With 2H(1+)*Mo12O40P(3-)*C8H14NOS(1+) at 70℃; for 0.5h; Green chemistry; | |
94% | With iron(II) triflate In toluene at 70℃; for 6h; Green chemistry; | 2. Procedure for the synthesis of isochromans General procedure: β-Arylethanol 1 (1 mmol) and Fe(OTf)2 (0.01 mmol) were added sequentially to a solution of aldehyde, ketone, or ketal (1 eq, 1 mmol) in toluene (2 mL). The reaction mixture was warmed up slowly to the 70 oC and stirred for a few hours with monitoring by TLC plate. After completion the reaction, the mixture was cooled to room temperature. Then, the reaction mixture was washed with saturated NaHCO3 solution (5 mL), and the organic layer extracted with DCM (2×5 mL), dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography using PE-EtOAc mixture as eluent to afford the desired product. |
92% | With Ersorb-4a In toluene at 110℃; for 15h; |
92% | With bismuth(lll) trifluoromethanesulfonate; water In toluene at 80℃; | |
91% | With bismuth(lll) trifluoromethanesulfonate In toluene at 20 - 80℃; for 1.5h; | |
88% | With silica-supported policresulen at 80℃; for 12h; Green chemistry; | SiO2/policresulen composite catalyzed oxa-Pictet-Spengler reaction. General procedure: All reactions were conducted in a 10-mL V-type vessel equipped with a triangular magnetic stirrer. In a typical reaction, 2-(3,4-dimethoxyphenyl)ethanol (91.1 mg, 0.5 mmol), benzaldehyde (64.8 mg, 0.6 mmol), and 1b (10 mg, 1 mol%) were mixed in 1,2-dichloroethane (1.0 mL) and stirred for 5 h at 80 °C. After the reaction, the mixture was cooled to room temperature and then centrifuged, and the liquid phase was subjected to isolation with PTLC (eluting solvent: ethyl acetate/petroleum ether = 1/8). The desired product, 7a, was obtained in a yield of 96%. Tests of the substrate scope were conducted in the same manner. The recycling of 1b was realized after doubling the dose. After washing the solid phase with PE (3.0 mL × 3) and drying under vacuum, the recovered 1b was used in the next run with a similar procedure. |
87% | With toluene-4-sulfonic acid In methanol for 2h; Reflux; | |
78% | With hydrogenchloride In 1,4-dioxane for 1h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With toluene-4-sulfonic acid In water for 0.75h; Reflux; | |
97% | With iron(II) triflate In toluene at 70℃; for 6h; Green chemistry; | 2. Procedure for the synthesis of isochromans General procedure: β-Arylethanol 1 (1 mmol) and Fe(OTf)2 (0.01 mmol) were added sequentially to a solution of aldehyde, ketone, or ketal (1 eq, 1 mmol) in toluene (2 mL). The reaction mixture was warmed up slowly to the 70 oC and stirred for a few hours with monitoring by TLC plate. After completion the reaction, the mixture was cooled to room temperature. Then, the reaction mixture was washed with saturated NaHCO3 solution (5 mL), and the organic layer extracted with DCM (2×5 mL), dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography using PE-EtOAc mixture as eluent to afford the desired product. |
91% | With hydrogenchloride In 1,4-dioxane for 1h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With silica-supported policresulen at 80℃; for 5h; Green chemistry; | SiO2/policresulen composite catalyzed oxa-Pictet-Spengler reaction. General procedure: All reactions were conducted in a 10-mL V-type vessel equipped with a triangular magnetic stirrer. In a typical reaction, 2-(3,4-dimethoxyphenyl)ethanol (91.1 mg, 0.5 mmol), benzaldehyde (64.8 mg, 0.6 mmol), and 1b (10 mg, 1 mol%) were mixed in 1,2-dichloroethane (1.0 mL) and stirred for 5 h at 80 °C. After the reaction, the mixture was cooled to room temperature and then centrifuged, and the liquid phase was subjected to isolation with PTLC (eluting solvent: ethyl acetate/petroleum ether = 1/8). The desired product, 7a, was obtained in a yield of 96%. Tests of the substrate scope were conducted in the same manner. The recycling of 1b was realized after doubling the dose. After washing the solid phase with PE (3.0 mL × 3) and drying under vacuum, the recovered 1b was used in the next run with a similar procedure. |
82% | With hydrogenchloride In 1,4-dioxane for 1h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With silica-supported policresulen at 80℃; for 3h; Green chemistry; | SiO2/policresulen composite catalyzed oxa-Pictet-Spengler reaction. General procedure: All reactions were conducted in a 10-mL V-type vessel equipped with a triangular magnetic stirrer. In a typical reaction, 2-(3,4-dimethoxyphenyl)ethanol (91.1 mg, 0.5 mmol), benzaldehyde (64.8 mg, 0.6 mmol), and 1b (10 mg, 1 mol%) were mixed in 1,2-dichloroethane (1.0 mL) and stirred for 5 h at 80 °C. After the reaction, the mixture was cooled to room temperature and then centrifuged, and the liquid phase was subjected to isolation with PTLC (eluting solvent: ethyl acetate/petroleum ether = 1/8). The desired product, 7a, was obtained in a yield of 96%. Tests of the substrate scope were conducted in the same manner. The recycling of 1b was realized after doubling the dose. After washing the solid phase with PE (3.0 mL × 3) and drying under vacuum, the recovered 1b was used in the next run with a similar procedure. |
93% | With 2H(1+)*Mo12O40P(3-)*C8H14NOS(1+) at 70℃; for 0.416667h; Green chemistry; | |
87% | With hydrogenchloride In 1,4-dioxane for 1h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With iodine; silver trifluoroacetate In chloroform at 20℃; for 0.5h; | |
97% | With iodine; silver trifluoroacetate In chloroform at 0℃; for 0.25h; | |
64% | With iodine; silver trifluoromethanesulfonate In tetrahydrofuran at 20℃; for 12h; |
54% | With Iodine monochloride In dichloromethane for 26.5h; | |
52% | With N-iodosaccharine at 20℃; Ionic liquid; Darkness; | General procedure: To a solution of 54 mg (0.5 mmol) of anisole in 1 mL of BMIM BF4 was added 158 mg (0.51 mmol) of N-iodosaccharin. The reaction was stirred at room temperature protected from light for 8-12 h. The product was then isolated by extraction with ether (3 × 3 mL), followed by evaporation of the solvent to afford the desired iodinated product. In some cases, the product was contaminated with small amounts of BMIM BF4. This could be removed via filtration with ether through a short plug of silica. Alternatively, it could be avoided entirely by extraction of the product from the reaction using 1:1 ether/hexanes in place of pure ether. The identity of all products were confirmed by comparison (spectral and mp) with either commercially available samples or data reported in the literature as indicated in Table 1. |
With iodine; silver trifluoroacetate In chloroform | ||
With iodine; silver trifluoroacetate In chloroform at 20℃; | ||
With iodine; silver trifluoroacetate In tetrahydrofuran Inert atmosphere; | ||
With iron(III) chloride; N-iodo-succinimide; 1-butyl-3-methylimidazolium trifluoromethanesulfonimide In toluene at 40℃; for 5h; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: 2-(3,4-dimethoxyphenyl)ethyl alcohol With aluminum (III) chloride In ethanethiol at 0 - 20℃; for 17h; Stage #2: With hydrogenchloride; water In ethanethiol Cooling with ice; | 3 Example 3: Preparation of hydroxytyrosol from 2-(3.4-dimethoxyphenyl)-ethanol (2)To a stirred solution of anhydrous aluminium chloride (29 g, 0.22 mol, 7.6 equiv) in ethanethiol (81 mL), cooled with an ice-water bath, was added 2-(3,4-dimethoxyphenyl)ethanol (5.2 g, 28.5 mmol). The mixture was stirred at 0 °C for 2 h and at room temperature for 1 h. The mixture was poured into ice water (100 mL) and acidified with dilute HC1 (20 mL). Ethanethiol was removed by evaporation and brine was added. The mixture was extracted with ethyl acetate (3 x 100 mL). The combined extracts were dried over anhydrous sodium sulfate and concentrated to give a red oil (4.2 g, 95%). 'H NMR (400 MHz, DMSO-/&): δ 8.69 (br s, 1 H), 8.59 (br s, 1 H), 6.60 (d, J= 7.8 Hz, 1 H), 6.58 (d, J= 2.0 Hz, 1 H), 6.42 (dd, J= 7.8, 2.0 Hz, 1 H), 4.55 (t, J= 5.2 Hz, 1 H, -OH), 3.50 (m, 2 H), 2.53 (t, J= 7.3 Hz, 2 H). 13C NMR (100 MHz, DMSO-ofc): δ 144.9, 143.4, 130.31, 119.6, 116.4, 115.5, 62.7, 38.6.2 |
With aluminium trichloride In benzene Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With conc. HNO3 In acetic acid | 9.a EXAMPLE 9 a) 2-(4,5-dimethoxy-2-nitrophenyl)ethanol [1] For 6 min, conc. HNO3 (4.8 ml, 65%, d=1.4) was added dropwise to a mixture of homoveratryl alcohol (3.02 g, 16.6 mmol) in glacial acetic acid (30 ml) under stirring, this mixture having been cooled to -10° C. (common salt/ice) It was then allowed to warm up to 23° C. in 30 min. After being stirred for 1 h at this temperature, the mixture was diluted with H2 O, neutralized with NaHCO3 and extracted with EtOAc (3*30 ml). The combined organic phases were dried over Na2 SO4, filtered and concentrated under reduced pressure. The residue (3.25 g) was purified by column chromatography (90 g SiO2 toluene/EtOAc 4:1 500 ml, toluene/EtOAc 3:1 400 ml, toluene/EtOAc 2:1 300 ml). 2-(4,5-dimethoxy-2-nitrophenyl)ethanol (2.13 g, 56%) was obtained as a yellow solid. Rf (SiO2, toluene/EtOAc 2:1) 0.24 UV(MeOH), λmax [nm] (log ε): 202 (4.18), 216 (4.06), 242 (3.97), 297 (3.63), 340 (3.70) 1 H-NMR-Spektrum (250 MHz, CDCl3): 7.61 (s, H--C(3)); 6.80 (s, H--C(6)); 3.97 (s, OCH3); 3.96 (m, α-CH2, unresolved); 3.95 (s, OCH3); 3.21 (t, β-CH2), 1.70 (s (br), OH) Anal. calcd. for C10 H13 NO5 (227.216): C 52.86, H 5.77, N 6.16; found: C 52.87, H 5.82, N 6.12 |
With nitric acid In acetic acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With silica-supported policresulen at 80℃; for 3h; Green chemistry; | SiO2/policresulen composite catalyzed oxa-Pictet-Spengler reaction. General procedure: All reactions were conducted in a 10-mL V-type vessel equipped with a triangular magnetic stirrer. In a typical reaction, 2-(3,4-dimethoxyphenyl)ethanol (91.1 mg, 0.5 mmol), benzaldehyde (64.8 mg, 0.6 mmol), and 1b (10 mg, 1 mol%) were mixed in 1,2-dichloroethane (1.0 mL) and stirred for 5 h at 80 °C. After the reaction, the mixture was cooled to room temperature and then centrifuged, and the liquid phase was subjected to isolation with PTLC (eluting solvent: ethyl acetate/petroleum ether = 1/8). The desired product, 7a, was obtained in a yield of 96%. Tests of the substrate scope were conducted in the same manner. The recycling of 1b was realized after doubling the dose. After washing the solid phase with PE (3.0 mL × 3) and drying under vacuum, the recovered 1b was used in the next run with a similar procedure. |
93% | With 2H(1+)*Mo12O40P(3-)*C8H14NOS(1+) at 70℃; for 0.333333h; Green chemistry; | |
44% | With hydrogenchloride In 1,4-dioxane for 1h; Heating; |
With hydrogenchloride In 1,4-dioxane for 1h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With silica-supported policresulen at 80℃; for 5h; Green chemistry; | SiO2/policresulen composite catalyzed oxa-Pictet-Spengler reaction. General procedure: All reactions were conducted in a 10-mL V-type vessel equipped with a triangular magnetic stirrer. In a typical reaction, 2-(3,4-dimethoxyphenyl)ethanol (91.1 mg, 0.5 mmol), benzaldehyde (64.8 mg, 0.6 mmol), and 1b (10 mg, 1 mol%) were mixed in 1,2-dichloroethane (1.0 mL) and stirred for 5 h at 80 °C. After the reaction, the mixture was cooled to room temperature and then centrifuged, and the liquid phase was subjected to isolation with PTLC (eluting solvent: ethyl acetate/petroleum ether = 1/8). The desired product, 7a, was obtained in a yield of 96%. Tests of the substrate scope were conducted in the same manner. The recycling of 1b was realized after doubling the dose. After washing the solid phase with PE (3.0 mL × 3) and drying under vacuum, the recovered 1b was used in the next run with a similar procedure. |
99% | With iron(II) triflate In toluene at 70℃; for 2h; Green chemistry; | 2. Procedure for the synthesis of isochromans General procedure: β-Arylethanol 1 (1 mmol) and Fe(OTf)2 (0.01 mmol) were added sequentially to a solution of aldehyde, ketone, or ketal (1 eq, 1 mmol) in toluene (2 mL). The reaction mixture was warmed up slowly to the 70 oC and stirred for a few hours with monitoring by TLC plate. After completion the reaction, the mixture was cooled to room temperature. Then, the reaction mixture was washed with saturated NaHCO3 solution (5 mL), and the organic layer extracted with DCM (2×5 mL), dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography using PE-EtOAc mixture as eluent to afford the desired product. |
98% | With bismuth(lll) trifluoromethanesulfonate; water In toluene at 80℃; |
96% | With 2H(1+)*Mo12O40P(3-)*C8H14NOS(1+) at 70℃; for 0.333333h; Green chemistry; | |
92% | With hydrogenchloride In 1,4-dioxane for 1h; Heating; | |
With hydrogenchloride In 1,4-dioxane for 1h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With boron trifluoride diethyl etherate In dichloromethane for 2h; Ambient temperature; | |
89% | With boron trifluoride diethyl etherate In dichloromethane at 20℃; for 2h; | 1 Example 1; methyl 2-Hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionate 7 g (27.5 mmol) of methyl 3,3-diphenyl-2,3-epoxypropionate and 5.5 g (30.2 mmol) of 2-(3,4-dimethoxyphenyl)ethanol were dissolved in 20 ml of dichloromethane and, at room temperature, 5 drops of boron trifluoride etherate were added.. The solution was stirred for 2 hours.. The solvent was then distilled off, and the residue (10.7 g, 89%) was immediately reacted further. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43 g | With toluene-4-sulfonic acid In dichloromethane at 60℃; for 5h; | |
With toluene-4-sulfonic acid at 60℃; for 5h; Neat (no solvent); | 12.A Example 12; Methyl (S)-2-Hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-diphenylpropionate; Variant A: 27.9 g of methyl (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionate (100 mmol) were mixed with 1 g of p-toluenesulfonic acid and 18.2 g of 2-(3,4-dimethoxyphenyl)ethanol (100 mmol) in a flask and heated to 60° C. The pressure in the flask is reduced in order to distill out the methanol which is produced, and the mixture is stirred at 60° C. for a further 5 hours. For workup, the mixture is cooled and diluted with 300 ml of ether, and the organic phase is washed first with sodium bicarbonate solution and then several times with water. It is then dried with magnesium sulfate, and the desiccant is filtered off and the solvent is distilled off. A residue of 43 g of oil was isolated and could be employed immediately for the subsequent synthesis. | |
With toluene-4-sulfonic acid In dichloromethane at 60℃; for 5h; | 12.B Variant B: 27.9 g of methyl (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionate (100 mmol), 1 g of p-toluenesulfonic acid and 18.2 g (100 mmol) of 2-(3,4-dimethoxyphenyl)ethanol were dissolved in 75 ml of dichloromethane in a flask. The solution was heated and the dichloromethane was distilled out while simultaneously adding dichloromethane dropwise, in order to distill out the methanol which was produced, and the mixture was stirred at 60° C. for a further 5 hours. For workup, the mixture is cooled and diluted with 300 ml of ether, and the organic phase is washed first with sodium bicarbonate solution and then several times with water. It is then dried with magnesium sulfate, and the desiccant is filtered off and the solvent is distilled off. A residue of 43 g of oil was isolated and could be used immediately in the subsequent synthesis. |
Stage #1: (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester; 2-(3,4-dimethoxyphenyl)ethyl alcohol In dichloromethane; toluene Large scale; Stage #2: With sulfuric acid In toluene at 50 - 55℃; for 6h; Large scale; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With iron(II) triflate In toluene at 70℃; for 4h; Green chemistry; | 2. Procedure for the synthesis of isochromans General procedure: β-Arylethanol 1 (1 mmol) and Fe(OTf)2 (0.01 mmol) were added sequentially to a solution of aldehyde, ketone, or ketal (1 eq, 1 mmol) in toluene (2 mL). The reaction mixture was warmed up slowly to the 70 oC and stirred for a few hours with monitoring by TLC plate. After completion the reaction, the mixture was cooled to room temperature. Then, the reaction mixture was washed with saturated NaHCO3 solution (5 mL), and the organic layer extracted with DCM (2×5 mL), dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography using PE-EtOAc mixture as eluent to afford the desired product. |
97% | With toluene-4-sulfonic acid In water for 0.75h; Reflux; | |
95% | With 2H(1+)*Mo12O40P(3-)*C8H14NOS(1+) at 70℃; for 0.333333h; Green chemistry; |
With hydrogenchloride In 1,4-dioxane for 1h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With 1H-imidazole In dichloromethane at 0℃; for 2h; | |
97% | Stage #1: 2-(3,4-dimethoxyphenyl)ethyl alcohol With 1H-imidazole In dichloromethane for 0.0833333h; Stage #2: tert-butyldimethylsilyl chloride In dichloromethane at 20℃; for 1h; | General Procedure for the formation of silyl ethers (1a). The starting material, 2-(3,4-dimethoxyphenyl)-ethan-1-ol (521 mg, 2.86 mmol, 1.0 equiv) was dissolved in dichloromethane (20 mL) and imidazole (583 mg, 8.58 mmol, 3.0 equiv) was added. The mixture was stirred for 5 minutes. tert-Butyldimethylsilyl chloride (518 mg, 3.43 mmol, 1.2 equiv) was added and the reaction mixture was stirred at room temperature for 1 hr. Water (20 mL) and dichloromethane (20 mL) were added and the mixture was shaken in a separating funnel. The aqueous layer was separated and washed with dichloromethane (2 x 5 mL). The combined organic layers were washed with water (20 mL), brine (20 mL) and dried over MgSO4. Following filtration, the solvent was removed under reduced pressure. The crude material was purified by column chromatography on silica gel (eluting with a gradient from petroleum ether to 1:1 petroleum ether : ether) to afford 820mg of 1a (97%). |
96% | With 4-methylpyridine-1-oxide In dichloromethane at 20℃; for 1h; Molecular sieve; |
With 1H-imidazole In dichloromethane at 0 - 20℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With triethylamine In dichloromethane at 0 - 20℃; for 3h; | 3.4-Dimethoxyphenethyl methanesulfonate (7) To a solution of 2-(3,4-dimethoxyphenyl)ethan-l-ol (6) in 10 mL dry CH2CI2, Et3N (0.4 mL) and CH3SO2CI (0.2 mL, 2.42 mmol) were added at 0 °C and the reaction mixture was stirred at ambient temperature for 3 h. After completion of the reaction, water was added and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaHCCL, NaCl, dried over Na2S04, filtered and the solvent was evaporated in vacuo. The desired product was obtained after purification by flash-column chromatography (PE/EtOAc, 60:40) as colorless oil, (0.46 g, 87%). NMR (600 MHz, CDCI3) d: 6.82-6.74 (m, 3H, Ar H), 4.39 (t, 7=7.0 Hz, 2H, -C//2OSO2CH3), 3.87 (s, 3H, -OCH3), 3.85 (s, 3H, -OC//3), 2.99 (t, J= 7.0 Hz, 2H, -G%CH20S02CH3), 2.87 (s, 3H, - OSO2C//3). 3C NMR (75 MHz, CDCb) d: 148.8, 147.9, 128.6, 120.9, 1 12.0, 1 1 1.2, 70.4, 55.8, 55.7, 37.2,35.0. MS m/z: 282.88 (M+Na) +, 542.53 (2M+Na)+ |
76% | With triethylamine In dichloromethane at 20℃; for 8h; | |
70% | With triethylamine In dichloromethane at 0 - 20℃; for 2h; | 3 The synthesis of 3,4-dimethoxyphenethyl methanesulfonate (0143-2). To a stirred solution of compound 0143-1 (1 g, 5.5 mmol) in DCM (10 ml) was added MsCI (0.7 ml, 8.2 mmol) and TEA (3.0 ml, 16.5 mmol) under ice-water. The resulting reaction mixture was stirred at 0 °C for 1 h. Then added water, the aqueous phase was extracted with DCM, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the desired product 0143-2 (1.0 g, yield: 70%) as yellow oil. |
70% | With triethylamine In dichloromethane for 1.58333h; Inert atmosphere; | |
With triethylamine In dichloromethane at 0 - 20℃; | ||
With triethylamine In dichloromethane | 3.a a. a. 2-(3,4-Dimethoxyphenyl)ethyl methanesulfonate A solution of 18.2 g (0.1 mole) of 3,4-dimethoxyphenethyl alcohol in 150 ml of methylene chloride was cooled to -5° C. To the solution was added 13.9 ml (0.1 mole) of triethylamine followed by 7.7 ml (0.1 mole) of methanesulfonyl chloride keeping the temperature below 0° C. The reaction was stirred for 4 hr, poured into water, washed with brine, dried over Na2 SO4, and evaporated to give 26.7 g of product as a yellow oil. | |
With triethylamine In dichloromethane | 3.a a. a. 2-(3,4-Dimethoxyphenyl)ethyl methanesulfonate A solution of 18.2 g (0.1 mole) of 3,4-dimethoxyphenethyl alcohol in 150 ml of methylene chloride was cooled to -5°C. To the solution was added 13.9 ml (0.1 mole) of triethylamine followed by 7.7 ml (0.1 mole) of methanesulfonyl chloride keeping the temperature below 0°C. The reaction was stirred for 4 hr, poured into water, washed with brine, dried over Na2SO4, and evaporated to give 26.7 g of product as a yellow oil. | |
With triethylamine In dichloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With Dess-Martin periodane In dichloromethane | |
95% | With Dess-Martin periodane In dichloromethane at 20℃; for 3h; | 107A (3,4-Dimethoxyphenyl)acetaldehyde 18 g (96.81 mmol) of 2-(3,4-dimethoxyphenyl)ethanol were initially charged in 395 ml of dichloromethane and 50.8 g (116.17 mmol) of Dess-Martin reagent were added in portions. The temperature was held at 20° C. The reaction mixture was stirred at RT for 3 h. The suspension was admixed with 200 ml of saturated aqueous sodium hydrogencarbonate solution and 200 ml of saturated aqueous sodium dithionite solution. It was stirred for 30 minutes and then the organic phase was separated off. The aqueous phase was extracted three times with dichloromethane and the combined organic phases were washed once with sodium hydrogencarbonate solution and once with water. After drying using sodium sulphate and removal of the solvent, 16.6 g of product were obtained (95% of theory), which was directly reacted further. [1885] LCMS (Method 1): Rt=0.74 min; m/z=181 (M+H)+ [1886] 1H-NMR (300 MHz, CDCl3): δ=3.66 (d, 2H), 3.91 (s, 6H), 6.73 (d, 1H), 6.81 (t, 1H), 6.90 (d, 1H), 9.75 (t, 1H). |
94% | With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In acetonitrile at 80℃; for 2h; |
86% | With Dess-Martin periodane In dichloromethane at 20℃; for 3h; Inert atmosphere; | |
84% | With Dess-Martin periodane In dichloromethane | |
76.7% | With 2-iodoxybenzoic acid In acetonitrile at 80℃; for 2h; Inert atmosphere; | |
64% | With Dess-Martin periodane In dichloromethane for 4h; Inert atmosphere; | |
38% | With sulphur trioxide pyridine complex; N-ethyl-N,N-diisopropylamine In dichloromethane; dimethyl sulfoxide at -15℃; for 0.5h; Inert atmosphere; | |
With Dess-Martin periodane In dichloromethane at 20℃; Inert atmosphere; | General procedure for the synthesis of aromatic and aliphatic acetaldehydes: General procedure: The alcohol (1.0 eq) was added to a suspension of Dess-Martin periodinane (1.2 eq) in CH2Cl2(100 mM) under an argon atmosphere at room temperature. The mixture was allowed to stir for0.5 - 20 hours, while consumption of starting material was monitored by TLC. After the reactionwas complete, 1M Na2S2O3 (equal volume to CH2Cl2) was added. After stirring for 15 minutes,the phases were separated and the aqueous phase was extracted with CH2Cl2 twice. Thecombined organic layers were washed with 5% NaHCO3 and brine, and dried over Na2SO4. Thesolvent was evaporated under reduced pressure and the residue was purified by columnchromatography to afford analytically pure aldehydes.b) alcohol precursors for aldehydes 13, 14, 20 (solid alcohols)The alcohol (1.0 eq) was dissolved in CH2Cl2 (200 mM) and the solution was added to asuspension of Dess-Martin periodinane (1.2 eq) in CH2Cl2 (200 mM) under an argon atmosphereat room temperature. The mixture was allowed to stir for 0.5 - 20 hours (TLC monitoring). Then,Et2O (equal volume to CH2Cl2), 1M Na2S2O3 and saturated NaHCO3 (both equal volume toCH2Cl2) were added. After stirring for 15 minutes, the phases were separated and the aqueousphase was extracted with Et2O twice. The combined organic layers were washed with sat.NaHCO3 and brine, and dried over Na2SO4. The solvent was evaporated under reduced pressureand the residue was purified by column chromatography to afford analytically pure aldehydes. | |
With Dess-Martin periodane In dichloromethane at 20℃; for 0.25h; | ||
16.6 g | Stage #1: 2-(3,4-dimethoxyphenyl)ethyl alcohol With Dess-Martin periodane In dichloromethane at 20℃; for 3h; Stage #2: With sodium dihydrosulfite; Sodium hydrogenocarbonate In dichloromethane; lithium hydroxide monohydrate for 0.5h; | 107A (3,4-Dimethoxyphenyl)acetaldehyde 18 g (96.81 mmol) of 2-(3,4-dimethoxyphenyl)ethanol were initially charged in 395 ml of dichloromethane and 50.8 g (116.17 mmol) of Dess-Martin reagent were added in portions. The temperature was held at 20° C. The reaction mixture was stirred at RT for 3 h. The suspension was admixed with 200 ml of saturated aqueous sodium hydrogencarbonate solution and 200 ml of saturated aqueous sodium dithionite solution. It was stirred for 30 minutes and then the organic phase was separated off. The aqueous phase was extracted three times with dichloromethane and the combined organic phases were washed once with sodium hydrogencarbonate solution and once with water. After drying using sodium sulphate and removal of the solvent, 16.6 g of product were obtained (95% of theory), which was directly reacted further. |
With Dess-Martin periodane In dichloromethane for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With oxygen; sodium carbonate In water at 49.85℃; for 2h; | ||
With sodium chlorite; Me-AZADO+Cl- In acetonitrile at 25℃; for 0.17h; aq. phosphate buffer; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With 3 A molecular sieve; potassium carbonate In toluene for 24h; Heating; | |
87% | With 1,1'-bis(diphenylphosphino)ferrocene; [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; potassium carbonate In toluene at 20℃; for 24.1667h; Inert atmosphere; Molecular sieve; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With iron(II) triflate In toluene at 70℃; for 4h; Green chemistry; | 2. Procedure for the synthesis of isochromans General procedure: β-Arylethanol 1 (1 mmol) and Fe(OTf)2 (0.01 mmol) were added sequentially to a solution of aldehyde, ketone, or ketal (1 eq, 1 mmol) in toluene (2 mL). The reaction mixture was warmed up slowly to the 70 oC and stirred for a few hours with monitoring by TLC plate. After completion the reaction, the mixture was cooled to room temperature. Then, the reaction mixture was washed with saturated NaHCO3 solution (5 mL), and the organic layer extracted with DCM (2×5 mL), dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography using PE-EtOAc mixture as eluent to afford the desired product. |
93% | With 1,1,1,3',3',3'-hexafluoro-propanol In water at 20℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With boron trifluoride diethyl etherate In dichloromethane at 20℃; for 1.5h; | 5 Example 5; methyl 2-Hydroxy-3-(2-(3,4-dimethoxyphenyl)ethoxy)-3,3-di-(4-ethyl-phenyl)propionate 6 g (19.3 mmol) of methyl 3,3-di(4-ethylphenyl)-2,3-epoxypropionate (crude) and 3.52 g (19.3 mmol) of 2-(3,4-dimethoxyphenyl)ethanol were dissolved in 20 ml of dichloromethane and, at room temperature, 5 drops of boron trifluoride etherate were added.. The solution was stirred for 1.5 hours.. The solvent was then distilled off, and the residue, a pale yellow oil (8.66 g, 91%), was immediately reacted further. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: 2-(3,4-dimethoxyphenyl)ethyl alcohol With sodium hydride In dichloromethane; mineral oil at 0 - 5℃; for 2h; Stage #2: trichloroacetonitrile In dichloromethane; mineral oil for 0.5h; | 3 Example 3 Preparation of 3,4-dimethoxyphenethyl 2,2,2-trichloroacetimidate (Compound B) Three-necked flask was added dichloromethane 100ml, was added under stirring3,4-dimethoxyphenethyl alcohol (Compound B-1, 9.1 g, 50 mmol) was added and dissolved completely.The reaction solution was cooled to 0 ° C to 5 ° C, and sodium hydride (4.0 g, 100 mmol,60% mineral oil). The mixture was stirred at 0 ° C to 5 ° C for 2 hours,Trichloroacetonitrile (10.8 g, 75 mmol) was added dropwise rapidly and stirring was continued for 0.5 h,HPLC detection of 3,4-dimethoxyphenethyl alcohol, the basic consumption is completed,The reaction solution was carefully poured into ice water to quench the reaction, stirred for 30 minutes,The organic phase was extracted twice with saturated brine, dried over anhydrous sodium sulfate,The solvent was distilled off under reduced pressure to obtain 15.5 g of 3,4-dimethoxyphenethyl 2,2,2-trichloroacetimidate as a brown oil,After standing it was solid, 95% yield, HPLC purity 95.0%. |
95% | Stage #1: 2-(3,4-dimethoxyphenyl)ethyl alcohol With sodium hydride In mineral oil at 0 - 5℃; for 2h; Stage #2: trichloroacetonitrile In dichloromethane; mineral oil for 0.5h; | 3 Example 3 Preparation of 2-(3,4-dimethoxyphenyl)ethyl 2,2,2-trichloroethanimidate (Compound B) Dichloromethane (100ml) was added to a three-neck bottle.2-(3,4-dimethoxyphenyl)ethan-1-ol (compound B-1,9.1g, 50mmol), completely dissolved,The reaction solution was cooled to 0 °C. to 5 °C. and sodium hydride (4.0 g, 100 mmol, 60% in mineral oil) was carefully added in portions.Maintain 0 °C ~ 5 °C, stirring for 2 hours,Trichloroacetonitrile (10.8 g, 75 mmol) was rapidly added dropwise.Continue stirring for 0.5 hours. After basic consumption of 2-(3,4-dimethoxyphenyl)ethan-1-ol as raw material by HPLC, carefully pour the reaction mixture into ice water to quench the reaction, stir for 30 minutes, and separate the liquid.The organic phase is extracted twice with saturated brine,After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 15.5 g of 2-(3,4-dimethoxyphenyl)ethyl 2,2,2-trichloroethanimidate as a brown oil, which became solid after standing. Yield 95%, HPLC purity 95.0%. |
95% | Stage #1: 2-(3,4-dimethoxyphenyl)ethyl alcohol With sodium hydride In dichloromethane; mineral oil at 0 - 5℃; for 2h; Stage #2: trichloroacetonitrile In dichloromethane; mineral oil for 0.5h; | 1-7; 1 Comparative Example 1 Preparation of 3,4-dimethoxyphenethyl 2,2,2-trichloroacetimide ester (sodium hydride method) 100 ml of dichloromethane was added to the three-necked flask, and 3,4-dimethoxyphenylethanol (9.1 g, 50 mmol) was added thereto with stirring. After completely dissolved, the reaction solution was cooled to 0 ° C to 5 ° C.Sodium hydride (4.0 g, 100 mmol, 60% mineral oil) was added in portions.After maintaining 0 ° C ~ 5 ° C, stirring for 2 hours, rapid addition of trichloroacetonitrile (10.8 g, 75 mmol), stirring for 0.5 hours, HPLC detection of the raw material 3,4-dimethoxyphenyl alcohol after the basic consumption, the reaction The mixture was poured into ice water to quench the reaction, and the mixture was stirred for 30 minutes, and the organic phase was extracted twice with saturated brine and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure to give 15.5 g.3,4-Dimethoxyphenethyl 2,2,2-trichloroacetimide ester, brown oil, solid after standing, yield 95%, HPLC purity 95.0%. |
90% | With sodium hydroxide; methyl tributylammonium chloride In methyl tert-butyl ether (MTBE); water at 9 - 15℃; for 1 - 4h; | 5a.4a Step 4A: 3,4-(Dimethoxyphenethoxy)trichloracetimidate (16).To a reaction flask was charged 3,4-dimethoxyphenethyl alcohol (DMPE, 1O g, Aldrich cat No.197653, CAS No. 7417-21-2) and MTBE (50 mL), and the resultant mixture was stirred at 12°C (9-15°C). Solid potassium hydroxide (5.0 g, 1.6 equiv) and methyl tributyl ammonium chloride (75 wt% solution in water; 0.4 g, 0.02 equiv) were successively charged to the reaction flask. Under maximum agitation, trichloroacetonitrile (10.0 g, 1.26 mole equiv, Aldrich cat No.T53805, CAS No. 545-06-2) was charged slowly to the reaction flask via an addition funnel, while the pot temperature was maintained <1°C. Residual trichloroacetonitrile in the addition funnel was rinsed into the flask with MTBE (5 mL). The reaction mixture was agitated at 12°C (9-15 °C) until the reaction was judged complete (1-4 h) by HPLC analysis (DMPE <1%, E-DMPE ester >96%).Upon completion of the reaction, the reaction mixture was diluted with MTBE (20 mL) and then cooled to 3°C (0-60C). The MTBE layer was washed with water (3 x 20 mL) cooled at 3°C (0-60C).The ratio of the E and Z isomers in the MTBE layer can alternatively be determined by 1H-NMR (~l-mL solution is concentrated to dryness, and the residue is EPO analyzed by 1H-NMR (CDCl3). The chemical shift of the CH2O methylene groups is4.45 ppm for the E isomer and 4.55 ppm in the Z isomer, respectively)- If the E isomer is less than 98%, the MTBE layer is washed further with 0.4 M KOH solution.The MTBE solution was concentrated to dryness under reduced pressure at a maximum bath temperature of 4O0C. Ethanol (55 mL) was added to the remaining residue and the mixture was agitated at 25°C (22-28°C) until a clear solution was achieved (-30-60 min). The ethanolic solution was cooled to O0C (-3 to 3°C) to allow product crystallization (The E-DMPE ester crystallizes out at 7-10°C ). The slurry was diluted with water (77 mL) and the mixture was agitated at 0°C (-3 to 3°C) for ~1 hr. The slurry was filtered and rinsed with cold (0-6°C) water (36 mL). The wet cake was dried under vacuum at ambient temperature (15-250C) until the moisture content (KF) was lower than 0.05% to give the E-DMPE ester (16) as an off-white crystalline solid (90-95% yield) with 99.0+% purity by HPLC); R/ = 0.33 for 3,4-dimethoxyphenethyl alcohol (EtOAc-hexanes, 1:1 v/v); R/= 0.76 for (E)-trichloroacetirnidic acid 2-(3,4- dimethoxyphenyl)ethyl ester (16) (ΕtOAc-hexanes, 1 :1 v/v); 1H-NMR (300 MHz,CDCl3) δ: 8.22 (br s, IH, NH), 6.77-6.75 (m, 3H, Ar), 4.42 (t, 2H, J7 Hz, CH2O), 3.81 & 3.79 (2 s, 6H, 2 x OCH3), 2.97 (t, 2H, J 7 Hz, CH2). |
90% | With potassium hydroxide; methyl tributylammonium chloride In water at 9 - 15℃; for 1 - 4h; | 4 PREPARATION 4; 3,4-(Dimethoxyphenethoxy)trichloracetimidate (5a); To a reaction flask was charged 3,4-dimethoxyphenethyl alcohol (50 mL), and EPO the resultant mixture was adjusted to 12 0C (9-15 0C). Solid potassium hydroxide (5.0 g, 1.62 equiv), and methyltributylammonium chloride (75 wt% solution in water; 0.4 g, 0.02 equiv) were charged to the reaction flask. Under maximum agitation, trichloroacetonitrile (10.0 g, 1.26 equiv) was charged slowly to the reaction flask via an addition funnel, while the pot temperature was maintained <15 0C. The reaction mixture was agitated at 12°C (9-15 0C) for 1-4 hours. The reaction mixture was diluted with methyl terf-butyl ether (MTBE) (20 ml_), then cooled to 3°C (0-60C). Next, the MTBE layer was washed with water (3 x 20 mL) at 3°C (0-60C). The MTBE solution was concentrated under reduced pressure to dryness at a maximum bath temperature of 4O0C, and ethanol (55 mL) was added to the remaining residue and the mixture was agitated at 25 0C (22-28 0C) until a clear solution was achieved. The ethanolic solution was cooled to 00C (-3 to 3°C) to allow product crystallization. The slurry was diluted with water (77 mL) and the mixture was agitated at 00C (-3 to 3°C) for ~1 h. The slurry was filtered and rinsed with cold (0-60C) water (36 mL). The wet cake was dried under vacuum at ambient temperature (15-25°C) until the moisture content (KF) was lower than 0.05% to give 3,4-(dimethoxyphenethoxy)trichloracetimidate (5a), as an off-white crystalline solid (90-95% yield); 1H-NMR (300 MHz, CDCI3) δ 2.97 (t, 2H, J = 7 Hz, CH2), 3.81 & 3.79 (2 s, 6H, 2 x OCH3), 4.42 (t, 2H, J = 7 Hz, CH2O), 6.77-6.75 (m, 3H, Ar), 8.22 (br s, 1 H1 NH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With MgCl2; magnesium chloride; In tetrahydrofuran; water; ethyl acetate; acetonitrile; | 16) Removal of triphenylphosphine oxide from 1-bromo-2-(3.4-dimethoxyphenyl)-ethane reaction mixture using MgCl2 (1 eq) A mixture of 2-(3,4-dimethoxyphenyl)ethyl alcohol (3.64 g) and <strong>[1034-39-5]dibromotriphenylphosphorane</strong> (8.44 g) in acetonitrile (30 ml) was stirred at 0-5 C. for 2.5 days. The solvent was removed Th vacuo and the residue was dissolved in ethyl acetate (50 ml) and water (20 ml). The organic layer was separated and dried (MgSO4), and the solvent then removed in vacuo. A sample was analyzed by Gc for triphenylphosphine oxide content. Magnesium chloride (1.9 g) and tetrahydrofuran (15 ml) were added to the residue. The mixture was heated under reflux for 3 hours, left to stand for 16 hours at ambient temperature, cooled to 0 C. for 3 hours, filtered and the filter pad washed with tetrahydrofuran (10 ml). The solvent was removed from the filtrate in vacuo and the residue extracted with ethyl acetate (20 ml). The extract was filtered, washed with water (20 ml), and the solvent then removed in vacuo to yield a residue which was analyzed by Gc for triphenylphosphine oxide content. % Triphenylphosphine oxide content by normalisation by Gc analysis | |
With MgCl2; magnesium chloride; In tetrahydrofuran; water; ethyl acetate; acetonitrile; | 16) Removal of triphenylphosphine oxide from 1-bromo-2-(3.4-dimethoxyphenyl)-ethane reaction mixture using MgCl2(1 eq) A mixture of 2-(3,4-dimethoxyphenyl)ethyl alcohol (3.64 g) and <strong>[1034-39-5]dibromotriphenylphosphorane</strong> (8.44 g) in acetonitrile (30 ml) was stirred at 0-5C for 2.5 days. The solvent was removed Th vacuo and the residue was dissolved in ethyl acetate (50 ml) and water (20 ml). The organic layer was separated and dried (MgSO4), and the solvent then removed in vacuo. A sample was analyzed by Gc for triphenylphosphine oxide content. Magnesium chloride (1.9 g) and tetrahydrofuran (15 ml) were added to the residue. The mixture was heated under reflux for 3 hours, left to stand for 16 hours at ambient temperature, cooled to 0C for 3 hours, filtered and the filter pad washed with tetrahydrofuran (10 ml). The solvent was removed from the filtrate in vacuo and the residue extracted with ethyl acetate (20 ml). The extract was filtered, washed with water (20 ml), and the solvent then removed in vacuo to yield a residue which was analyzed by Gc for triphenylphosphine oxide content. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With (R)-3,3'-bis(9-anthracenyl)-1,1'-binaphthyl-2,2'-diyl hydrogenphosphate In ethyl acetate at 20℃; for 24h; optical yield given as %ee; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; bis[2-(diphenylphosphino)phenyl] ether In toluene at 20℃; Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With bismuth(lll) trifluoromethanesulfonate; water In toluene at 80℃; | |
53% | With iron(II) triflate In toluene at 70℃; for 24h; Green chemistry; | 2. Procedure for the synthesis of isochromans General procedure: β-Arylethanol 1 (1 mmol) and Fe(OTf)2 (0.01 mmol) were added sequentially to a solution of aldehyde, ketone, or ketal (1 eq, 1 mmol) in toluene (2 mL). The reaction mixture was warmed up slowly to the 70 oC and stirred for a few hours with monitoring by TLC plate. After completion the reaction, the mixture was cooled to room temperature. Then, the reaction mixture was washed with saturated NaHCO3 solution (5 mL), and the organic layer extracted with DCM (2×5 mL), dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography using PE-EtOAc mixture as eluent to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With trifluorormethanesulfonic acid In toluene at 80℃; for 1h; | |
22% | With iron(II) triflate In toluene at 70℃; for 24h; Green chemistry; | 2. Procedure for the synthesis of isochromans General procedure: β-Arylethanol 1 (1 mmol) and Fe(OTf)2 (0.01 mmol) were added sequentially to a solution of aldehyde, ketone, or ketal (1 eq, 1 mmol) in toluene (2 mL). The reaction mixture was warmed up slowly to the 70 oC and stirred for a few hours with monitoring by TLC plate. After completion the reaction, the mixture was cooled to room temperature. Then, the reaction mixture was washed with saturated NaHCO3 solution (5 mL), and the organic layer extracted with DCM (2×5 mL), dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography using PE-EtOAc mixture as eluent to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With iron(II) triflate In toluene at 70℃; for 6h; Green chemistry; | 2. Procedure for the synthesis of isochromans General procedure: β-Arylethanol 1 (1 mmol) and Fe(OTf)2 (0.01 mmol) were added sequentially to a solution of aldehyde, ketone, or ketal (1 eq, 1 mmol) in toluene (2 mL). The reaction mixture was warmed up slowly to the 70 oC and stirred for a few hours with monitoring by TLC plate. After completion the reaction, the mixture was cooled to room temperature. Then, the reaction mixture was washed with saturated NaHCO3 solution (5 mL), and the organic layer extracted with DCM (2×5 mL), dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography using PE-EtOAc mixture as eluent to afford the desired product. |
97% | With bismuth(lll) trifluoromethanesulfonate; water In toluene at 80℃; | |
95% | With 2H(1+)*Mo12O40P(3-)*C8H14NOS(1+) at 70℃; for 0.5h; Green chemistry; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With bismuth(lll) trifluoromethanesulfonate; water In toluene at 80℃; | |
53% | With iron(II) triflate In toluene at 70℃; for 24h; Green chemistry; | 2. Procedure for the synthesis of isochromans General procedure: β-Arylethanol 1 (1 mmol) and Fe(OTf)2 (0.01 mmol) were added sequentially to a solution of aldehyde, ketone, or ketal (1 eq, 1 mmol) in toluene (2 mL). The reaction mixture was warmed up slowly to the 70 oC and stirred for a few hours with monitoring by TLC plate. After completion the reaction, the mixture was cooled to room temperature. Then, the reaction mixture was washed with saturated NaHCO3 solution (5 mL), and the organic layer extracted with DCM (2×5 mL), dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography using PE-EtOAc mixture as eluent to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With iron(II) triflate In toluene at 70℃; for 6h; Green chemistry; | 2. Procedure for the synthesis of isochromans General procedure: β-Arylethanol 1 (1 mmol) and Fe(OTf)2 (0.01 mmol) were added sequentially to a solution of aldehyde, ketone, or ketal (1 eq, 1 mmol) in toluene (2 mL). The reaction mixture was warmed up slowly to the 70 oC and stirred for a few hours with monitoring by TLC plate. After completion the reaction, the mixture was cooled to room temperature. Then, the reaction mixture was washed with saturated NaHCO3 solution (5 mL), and the organic layer extracted with DCM (2×5 mL), dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography using PE-EtOAc mixture as eluent to afford the desired product. |
90% | With toluene-4-sulfonic acid In water for 0.666667h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9%; 31% | Reference Example 20; Ethyl 3-(2-(2-(3,4-dimethoxyphenyl)ethoxy)pyrimidin-4-yl)benzoate and ethyl 3-(4-(2-(3,4-dimethoxyphenyl)ethoxy)pyrimidin-2-yl)benzoate; Sodium hydride (60% liquid paraffin dispersion, 324 mg, 8.12 mmol) was added at 0C to a DMF (50 mL) solution of 2,4-dichloropyrimidine (1.0 g, 6.71 mmol) and 2-(3,4-dimethoxyphenyl)ethanol (1.35 g, 7.38 mmol), and the mixture was stirred for 3 hours at 60C. Water was added to the reaction solution, and the product was extracted with ethyl acetate. An ether mixture (1.06 g) was obtained. A 2 N sodium carbonate aqueous solution (20 mL)-1,2-dimethoxyethane (20 mL) mixture of tetrakis(triphenylphosphine)palladium (0) (125 mg, 0.11 mmol), <strong>[4334-87-6](3-(ethoxycarbonyl)phenyl)boronic acid</strong> (837 mg, 4.32 mmol), and the above mixture was reacted for 16 hours at 90C in a nitrogen atmosphere. Water was added to the reaction solution, and the product was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, then dried over anhydrous sodium sulfate, and then concentrated at reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane 1:1) to give 840 mg (yield: 31%) of ethyl 3-(4-(2-(3,4-dimethoxyphenyl)ethoxy)pyrimidin-2-yl)benzoate and 240 mg (yield: 9%) of ethyl 3-(2-(2-(3,4-dimethoxyphenyl)ethoxy)pyrimidin-4-yl)benzoate.Ethyl 3-(4-(2-(3,4-dimethoxyphenyl)ethoxy)pyrimidin-2-yl)benzoate Melting point: 101 - 102 C. (Ethyl acetate-hexane). 1H-NMR (CDCl3 ) delta : 1.41 (3H, t, J = 7.2 Hz), 3.10 (2H, t, J = 7.2 Hz), 3.86(3H, s), 3.88 (3H, s), 4.42 (2H, q, J = 7.2 Hz), 4.71 (2H, t, J = 7.2 Hz), 6.64 (1H, d, J = 5.4 Hz), 6.79 - 6.90 (3H, m), 7.54 (1H, t, J = 7.5 Hz), 8.15 (1H, d, J = 7.5 Hz), 8.52 (1H, d, J = 5.7 Hz), 8.60 (1H, d, J = 8.1 Hz), 9.07 (1H, s).Ethyl 3-(2-(2-(3,4-dimethoxyphenyl)ethoxy)pyrimidin-4-yl)benzoate Melting point: 94 - 95 C. (Ethyl acetate-hexane). 1H-NMR (CDCl3 ) delta : 1.42 (3H, t, J = 7.2 Hz), 3.14 (2H, t, J = 6.9 Hz), 3.86(3H, s), 3.88 (3H, s), 4.42 (2H, q, J = 7.2 Hz), 4.66 (2H, t, J = 6.9 Hz), 6.79 - 6.90 (3H, m), 7.41 (1H, d, J = 5.1 Hz), 7.56 (1H, t, J = 7.8 Hz), 8.17 (1H, d, J = 7.8 Hz), 8.32 (1H, d, J = 7.8 Hz), 8.57 (1H, d, J = 5.1 Hz), 8.69 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With sodium hydride In paraffin oil (nujol); N,N-dimethyl-formamide at 0 - 20℃; for 16h; | 17 Reference Example 17; 2-(2-(3,4-Dimethoxyphenyl)ethoxy)-4-iodopyridine; Sodium hydride (60% liquid paraffin dispersion, 358 mg, 8.96 mmol) was added at 0°C to a DMF (3 mL) solution of 2-fluoro-4-iodopyridine (1.0 g, 4.48 mmol) and 2-(3,4-dimethoxyphenyl)ethanol (0.9 g, 5.0 mmol), and the mixture was stirred for 16 hours at room temperature. Water was added to the reaction solution, and the product was extracted with ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate, and then concentrated at reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate 1:1) to give 0.88 g of the titled compound (yield: 51 %). Oily substance. 1H-NMR (CDCl3 ) δ : 3.00 (2H, t, J = 6.9 Hz), 3.86 (3H, s), 3.87 (3H, s), 4.46 (2H, t, J = 6.9 Hz), 6.77 - 6.80 (3H, m), 7.13 - 7.21 (2H, m), 7.79 (1H, d, J = 5.4 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃; for 1h; | 7 Reference Example 7; 2-Chloro-6-(2-(3,4-dimethoxyphenyl)ethoxy)pyridine; A tetrahydrofuran (30 mL) solution of 6-chloropyridin-2-ol (1.0 g, 7.72 mmol), 2-(3,4-dimethoxyphenyl)ethanol (1.55 g, 8.44 mmol), triphenylphosphine (2.23 g, 8.44 mmol), and diethyl azodicarboxylate (1.61 g, 8.44 mmol) was stirred for 1 hour at room temperature. The reaction mixture was concentrated at reduced pressure, and the residue was chromatographed on a silica gel column (hexane-ethyl acetate 80:20) to give 1.76 g of the titled compound (yield: 78%). Oily substance. 1H-NMR (CDCl3 ) δ : 3.01 (2H, t, J = 6.9 Hz), 3.86 (3H, s), 3.88 (3H, s), 4.49 (2H, t, J = 6.9 Hz), 6.60 - 6.89 (5H, m), 7.45- 7.92 (1H, m). |
78% | With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃; for 1h; | 121 2-chloro-6-(2-(3,4-dimethoxyphenyl)ethoxy)pyridine Reference Example 121 2-chloro-6-(2-(3,4-dimethoxyphenyl)ethoxy)pyridine A solution of 6-chloropyridin-2-ol (1.0 g, 7.72 mmol), 2-(3,4-dimethoxyphenyl)ethanol (1.55 g, 8.44 mmol), triphenylphosphine (2.23 g, 8.44 mmol) and diethyl azodicarboxylate (1.61 g, 8.44 mmol) in tetrahydrofuran (30 mL) was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate 80:20) to give the title compound (1.76 g, yield 78%) as an oil. 1H-NMR (CDCl3) δ : 3.01 (2H, t, J = 6.9 Hz), 3.86 (3H, s), 3.88 (3H, s), 4.49 (2H, t, J = 6.9 Hz), 6.60-6.89 (5H, m), 7.45-7.92 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydride In paraffin oil (nujol); N,N-dimethyl-formamide at 0 - 20℃; for 1h; | 16 Reference Example 16; 2-Chloro-4-(2-(3,4-dimethoxyphenyl)ethoxy)pyridine; A DMF (10 mL) suspension of 2-chloro-4-nitropyridine (1.10 g, 6.31 mmol) and 2-(3,4-dimethoxyphenyl)ethanol (1.23 g, 6.75 mmol) was added at 0°C to a DMF (30 mL) suspension of sodium hydride (60% liquid paraffin dispersion, 504 mg, 12.6 mmol), and the mixture was stirred for 1 hour at room temperature. Water was added to the reaction solution, and the product was extracted with ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate, and then concentrated at reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate 1:1) to give 1.87 g of the titled compound (yield: quantitative). Melting point: 116 - 117°C. (Ethyl acetate-hexane). 1H-NMR (CDCl3 ) δ : 3.05 (2H, t, J = 6.9 Hz), 3.87 (3H, s), 3.88 (3H, s), 4.19 (2H, t, J = 6.9 Hz), 6.70 - 6.83 (5H, m), 8.17 (1H, d, J = 5.7 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Stage #1: 4-Bromoveratrole With iodine; magnesium In tetrahydrofuran at 70℃; Inert atmosphere; Reflux; Stage #2: oxirane In tetrahydrofuran at 0 - 70℃; Inert atmosphere; Stage #3: With ammonium chloride In tetrahydrofuran Inert atmosphere; | 2 Example 2: Preparation of 2-(3.4-dimethoxyphenyl)ethanol (2) from 4-bromo-l ,2- dimethoxybenzene (1)Magnesium turnings (3.9 g, 0.160 mol, 1.0 equiv) and I2 (5 mg) was charged to a 250 mL three- neck round-bottom flask, one neck of which was equipped with a cooling condenser, one with a dropping funnel, the other with a thermometer. The reaction system was protected with N2 gas. A small portion of 4-bromo-l,2-dimethoxybenzene (35 g, 0.155 mol) in anhydrous THF (160 mL) was added to the flask. After the reaction was initiated by heating the reaction mixture at 70 °C, the residual solution of the bromide was added slowly at a rate sufficient to maintain the reaction solution under slight reflux. When the addition was finished, the mixture was maintained at 70 °C for 2 h and then cooled to 0 °C. Ethylene oxide (15 mL, 0.30 mol, 2.0 equiv) was added dropwise and the reaction mixture was heated to 70 °C for 1 h. When a sticky gel hat formed, a saturated NH4CI solution (100 mL) was added. After phase separation, the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water (2 * 50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and then evaporated under reduced pressure to give a red oil. Distillation yielded a colorless oil (15.3 g, b.p. 155-160 °C/10 mbar, 55%), which solidified upon standing. ¾ NMR (400 MHz, DMSO-^): δ 6.83 (d, J= 8.2 Hz, 1 H), 6.80 (d, J= 2.0 Hz, 1 H), 6.71 (dd, J= 8.2, 2.0 Hz, 1 H), 4.60 (t, J= 5.2 Hz, 1 H, -OH), 3.73 (s, 3 H), 3.70 (s, 3 H), 3.57 (m, 2 H), 2.65 (t, J= 7.2 Hz, 2 H). 13C MR (100 MHz, DMSO-afc): δ 148.7, 147.2, 132.1, 120.7, 113.0, 112.0, 62.5, 55.6, 55.4, 38.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.2% | With triethylamine In dichloromethane at 20℃; for 6h; Cooling with ice; | 1.6 (6) Synthesis of Compound 23 A dry, clean 100 mL round bottom flask was taken and accurately weighed 22 (2.5 g, 13.72 mmol) in a vial and dissolved in 25 mL of dichloromethane. Under ice bath, triethylamine (2.08 g, 20.58 mmol) and slow pivaloyl chloride (2.65 g, 21.95 mmol) were added. After the addition, the ice bath was removed and the reaction was carried out at room temperature. The reaction was monitored by TLC. After 6 hours, the material was basically reacted by TLC. 25 mL of water was added to the reaction mixture, and the organic phase was separated and the aqueous phase was extracted with dichloromethane (10 mL×2). After the organic phases were combined, they were washed with brine (10 mL×3). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporatedThe title compound (23) 3.3 g was obtained as a yellow oil.The yield was 89.2%. |
1.4 g | With pyridine In dichloromethane at 0 - 20℃; for 18h; | |
With pyridine In dichloromethane at 0 - 20℃; for 18h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With silica-supported policresulen at 80℃; for 16h; Green chemistry; | SiO2/policresulen composite catalyzed oxa-Pictet-Spengler reaction. General procedure: All reactions were conducted in a 10-mL V-type vessel equipped with a triangular magnetic stirrer. In a typical reaction, 2-(3,4-dimethoxyphenyl)ethanol (91.1 mg, 0.5 mmol), benzaldehyde (64.8 mg, 0.6 mmol), and 1b (10 mg, 1 mol%) were mixed in 1,2-dichloroethane (1.0 mL) and stirred for 5 h at 80 °C. After the reaction, the mixture was cooled to room temperature and then centrifuged, and the liquid phase was subjected to isolation with PTLC (eluting solvent: ethyl acetate/petroleum ether = 1/8). The desired product, 7a, was obtained in a yield of 96%. Tests of the substrate scope were conducted in the same manner. The recycling of 1b was realized after doubling the dose. After washing the solid phase with PE (3.0 mL × 3) and drying under vacuum, the recovered 1b was used in the next run with a similar procedure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With boron trifluoride diethyl etherate In dichloromethane at -10℃; for 2h; | trans-tert-Butyl (2-(3,4-dimethoxyphenethoxy)cyclohexyl)carbamate ((±)-8) To a solution of 2-(3,4-dimethoxyphenyl)ethan-1-ol (313 mg, 1.72 mmol) and BF3·OEt2 (22 μL; 0.172 mmol) in anhydrous dichloromethane (0.5 mL) was slowly added a solution of aziridine (±)-7 (340 mg; 1.72 mmol) in anhydrous dichloromethane (5 mL) over a period of 45 min at -10 °C. The resulting reaction mixture was stirred at the same temperature until completion of the reaction (monitored by TLC, 2 h). The reaction mixture was quenched by adding saturated aqueous NaHCO3 (5 mL). The aqueous layer was extracted with dichloromethane (3 × 25 mL) and the combined organic layers were dried over sodium sulfate. Dichloromethane was filtered and concentrated under vacuo to obtain a residue, which was purified by column chromatography (silica gel, 1:3 EtOAc:Pet. ether) to furnish pure product (±)-8 (490 mg, 75% yield) as a semi-solid: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 48h; chemoselective reaction; | 4.3.1. Preparation of analogs 5-9 and 13-47 by chemoselective Mitsunobu esterification General procedure: Triphenylphosphine (TPP) (280 mg, 1.07 mmol) was added in portions to a freshly prepared solution of the designated alcohol (1.0 mmol) and the specified phenolic acid (1.0 mmol equivalent) in anhydrous THF (3.5 mL) at 0 °C. Diisopropylazodicarboxylate (DIAD) (208 mL, 1.0 mmol) was then added dropwise to the mixture. The reaction mixture was stirred at 0 °C for 30 min. The mixture was then warmed and stirring was continued for 48 h at rt [19]. Reactions were monitored till completion by TLC. The reaction mixture was then worked up by removal of the solvent under reduced pressure, saturated solution of NaHCO3 (10 mL) was added, and then the mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated under reduced pressure to dryness. The crude product was collected and purified by column chromatography(CC) on Sephadex LH-20 using isocratic CH2Cl2 followed by chromatography on Si gel 60 using n-hexane-EtOAc system, gradient elution, to afford 5-9 and 13-47 (Supplementary Information). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 48h; chemoselective reaction; | 4.3.1. Preparation of analogs 5-9 and 13-47 by chemoselective Mitsunobu esterification General procedure: Triphenylphosphine (TPP) (280 mg, 1.07 mmol) was added in portions to a freshly prepared solution of the designated alcohol (1.0 mmol) and the specified phenolic acid (1.0 mmol equivalent) in anhydrous THF (3.5 mL) at 0 °C. Diisopropylazodicarboxylate (DIAD) (208 mL, 1.0 mmol) was then added dropwise to the mixture. The reaction mixture was stirred at 0 °C for 30 min. The mixture was then warmed and stirring was continued for 48 h at rt [19]. Reactions were monitored till completion by TLC. The reaction mixture was then worked up by removal of the solvent under reduced pressure, saturated solution of NaHCO3 (10 mL) was added, and then the mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated under reduced pressure to dryness. The crude product was collected and purified by column chromatography(CC) on Sephadex LH-20 using isocratic CH2Cl2 followed by chromatography on Si gel 60 using n-hexane-EtOAc system, gradient elution, to afford 5-9 and 13-47 (Supplementary Information). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With 4-methyl-morpholine In dichloromethane at 20℃; | Vinylogous Esters 5a-f; General Procedure General procedure: To a solution of the corresponding alcohol (1.0 mmol) in CH2Cl2 (3 mL) were added N-methylmorpholine (101 mg, 1.0 mmol) and ethyl propiolate (108 mg, 1.1 mmol). The reaction mixture was stirred at r.t., and the progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was removed on a rotary evaporator and the residue was extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with brine (30 mL), and dried over anhyd Na2SO4. The solvent was removed on a rotary evaporator, and the crude product was purified by silica gel column chromatography using EtOAc and hexane as eluents. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With toluene-4-sulfonic acid In methanol; dichloromethane at 20 - 25℃; for 0.333333h; Flow reactor; | General Procedure for the flow deprotection of silyl ethers (3a-j). General procedure: The system (Figure 4) was primed with solvent (DCM and 0.3 M aqueous NaOH) prior to the introduction of the substrates. Substrates were present as 0.034 M solutions (20 mL) in glass vials. These were placed in a square 4 x 4 rack. Following initiation of the computer-vision system (and checking to make sure the aqueous-out tap was opening/closing properly), activation of the autosampler/liquid-handling schedule was initiated by pressing ‘s’ on the computer keyboard. The outlet of the flow stream for each product was then collected until the autosampler moved to the waste position between each run. 5 mL of substrate was taken up during each run, 4 mL of which entered the holding loop (the line between the autosampler and 3-way-valve 1 was 1 mL in volume). Outlet collection flasks were changed manually. The products were isolated by removing solvent under reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Stage #1: 4-carboxymethyl-5-ethylidene-6-(3,4,5-triacetoxy-6-acetoxymethyl-tetrahydropyran-2-yloxy)-5,6-dihydro-4H-pyran-3-carboxylic acid methyl ester With 2,4,6-trichlorobenzoyl chloride; triethylamine In dichloromethane at 0 - 20℃; for 2h; Stage #2: 2-(3,4-dimethoxyphenyl)ethyl alcohol With dmap In dichloromethane at 0 - 20℃; for 2h; | 2 4.4.3. General procedure for esterification General procedure: To a solution of oleoside 11-methylester tetraacetate 3 or oleoside tetraacetate 5 (1 equiv.) in dichloromethane were added at 0°C 1.2 equiv of trichlorobenzoyl chloride and 1.4 equiv triethylamine. After 2h stirring at room temperature, the mixture was cooled to 0°C and a solution of alcohol/thiol/amine (1.5 equiv.) in dichloromethane and DMAP (1.4 equiv.) were added. After stirring for 2hat room temperature, the mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with dichloromethane and ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (cyclohexane/ethylacetate 1:1) led to the acetylated derivatives. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 74h; Inert atmosphere; Schlenk technique; | 4-[2-(3,4-dimethoxyphenyl)ethoxy]phthalonitrile (1) 4-Nitrophthalonitrile (1 g, 5.78 mmol) was dissolved in dry DMF(40 mL) and dimethoxyphenyl (1.80 g, 8.45 mmol) was added. After stirring for 15 min, finely ground anhydrous K2CO3 (2.35 g,17.3 mmol) was added in small portions for 2 h with efficient stirring.The reaction mixture was stirred magnetically at 50 °C for 72 h. After reaction completion (observed by TLC), the mixture was poured intoan ice-water mixture (200 mL) and the precipitate was filtered and washed with water until the filtrate was neutral, and dried in a vacuum. Finally, the precipitate was crystallised from ethanol to give compound 1 as: White solid; m.p. 220 °C; yield 1.44 g (78%); FTIR (KBr) (ncm-1): 1568 (C=C), 2233 (C≡N), 3049 (C-Harom); 1H NMR (400 MHz,DMSO-d6, tamb): δ 3.00 (t, 3J = 6.00 Hz, 2H, H2¢), 3.72 (s, 3H, OCH3(a)),3.75 (s, 3H, OCH3(b)), 4.35 (t, 3J = 6.20 Hz, 2H, H1¢); 6.81-8.04 (m,6H, Harom); 13C NMR (100 MHz, DMSO-d6, tamb): δ 39.2 (C2¢), 60.6(OCH3(b)), 60.7 (OCH3(a)), 74.8 (C1¢), 111.1 (C1), 117.1 (C5¢), 118.1 (C8¢),120.9 (C2), 121.5 (CN), 121.4 (CN), 125.3 (C3), 125.5 (C5), 126.1 (C4¢),135.1 (C3¢), 140.9 (C6), 152.7 (C6¢), 153.8 (C7¢), 167,1 (C4); ES-SM m/z:308.33 [M]+. Anal. calcd for C18H16N2O3: C, 70.11; H, 5.23; N, 9.08;found: C, 70.1; H, 5.2; N, 9.1%. |
With potassium carbonate In dimethyl sulfoxide at 50℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; for 21.5h; Inert atmosphere; | 2-[3,4-bis(methoxyphenyl)ethyl 3,4-bis[[(2-nitrophenyl)sulfonyl]oxy]cinnmamate (11c) To a cooled (0 °C) solution of 6a (45.0 mg, 81.8 µmol) and 2-(3,4-dimethoxyphenyl)ethanol (10b, 10.4 mg, 57.1 µmol) in dry THF (0.13 mL) were added PPh3 (37.7 mg, 0.14 mmol) and DEAD (22.0 µL, 0.14 mmol). The reaction mixture was stirred at room temperature for 21.5 h. Then, the reaction was worked up by removal of the solvent, redissolved on AcOEt and extracted with sat. NaHCO3. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (AcOEt-CHCl3) (1:30 v/v) to give a title compound (35.9 mg, 88%) as a white solid. Mp: 61-65 °C, IRν : 3096, 1710, 1543, 1500, 1392, 1372, 1235, 1192, 909, 817, 780 cm-1. 1H NMR (500 MHz, CDCl3): δ 8.03-8.00 (m, 2H), 7.87-7.84 (m, 2H), 7.80-7.73 (m, 4H), 7.55 (d, 1H, J = 16.0 Hz), 7.47-7.45 (m, 2H), 7.33, (d, 1H, J = 8.9 Hz), 6.84-6.77 (m, 3H), 6.38 (d, 1H, J = 16.0 Hz), 4.40 (t, 2H, J = 7.2 Hz), 3.88 (s, 3H), 3.87 (s, 3H), 2.96 (t, 2H, J = 7.2 Hz). 13C NMR (125 MHz, CDCl3): δ 165.9, 148.8, 148.3, 148.2, 147.7, 141.7, 141.4, 141.1, 135.9, 135.8, 135.1, 132.5, 131.8, 130.1, 128.33, 128.26, 127.8, 124.9, 124.8, 123.5, 121.0, 120.8, 112.0, 111.2, 65.4, 55.82, 55.81, 34.6. High-resolution MS calcd for C31H26N2O14S2 (M+): 714.0826. Found: 714.0845. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 18h; Inert atmosphere; | 2-(3,4-Dimethoxyphenyl)ethyl 3-phenylpropanoate (13d) To a cooled (0 C) solution of 2-(3,4-Dimethoxyphenyl)ethanol (10b, 92.0 mg, 0.51 mmol) and 3-phenylpropionic acid (14, 113.2 mg, 0.75 mmol) in dry THF (1.2 mL) were added PPh3 (332.0 mg, 1.27 mmol) and DIAD (272.1 µL, 1.27 mmol). The reaction mixture was stirred at room temperature for 18 h. Then, the reaction was worked up by removal of the solvent, redissolved on AcOEt and extracted with sat. NaHCO3. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (CHCl3-n-hexane) (1:3 v/v) and column chromatography on silica gel (n-hexane-AcOEt) (10:1 v/v) to give a title compound (140.9 mg, 89%) as a white solid. Mp: 49-51 °C, IR : 3004, 2969, 2937, 2838, 1725, 1515, 1235, 1155, 1028 cm-1. 1H NMR (500 MHz, CD3OD) δ: 7.27-7.23 (m, 2H), 7.19-7.15 (m, 2H), 6.78 (d, 1H, J = 8.6 Hz), 6.73-6.71 (m, 2H), 4.25 (t, 2H, J = 7.2 Hz), 3.84 (s, 3H), 3.83 (s, 3H), 2.92 (t, 2H, J = 7.8 Hz), 2.84 (t, 2H, J = 7.2 Hz), 2.60 (t, 2H, J = 7.8 Hz). 13C NMR (125 MHz, CD3OD) δ: 172.5, 148.7, 147.5, 140.2, 130.1, 128.3, 128.0, 126.0, 120.6, 111.9, 111.0, 64.9, 55.63, 55.58, 35.7, 34.5, 30.7. High-resolution MS calcd for C19H22O4 (M+): 314.1519. Found: 314.1525. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With iron(II) triflate In toluene at 70℃; for 4h; Green chemistry; | 2. Procedure for the synthesis of isochromans General procedure: β-Arylethanol 1 (1 mmol) and Fe(OTf)2 (0.01 mmol) were added sequentially to a solution of aldehyde, ketone, or ketal (1 eq, 1 mmol) in toluene (2 mL). The reaction mixture was warmed up slowly to the 70 oC and stirred for a few hours with monitoring by TLC plate. After completion the reaction, the mixture was cooled to room temperature. Then, the reaction mixture was washed with saturated NaHCO3 solution (5 mL), and the organic layer extracted with DCM (2×5 mL), dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography using PE-EtOAc mixture as eluent to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With iron(II) triflate In toluene at 70℃; for 4h; Green chemistry; | 2. Procedure for the synthesis of isochromans General procedure: β-Arylethanol 1 (1 mmol) and Fe(OTf)2 (0.01 mmol) were added sequentially to a solution of aldehyde, ketone, or ketal (1 eq, 1 mmol) in toluene (2 mL). The reaction mixture was warmed up slowly to the 70 oC and stirred for a few hours with monitoring by TLC plate. After completion the reaction, the mixture was cooled to room temperature. Then, the reaction mixture was washed with saturated NaHCO3 solution (5 mL), and the organic layer extracted with DCM (2×5 mL), dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography using PE-EtOAc mixture as eluent to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With iron(II) triflate; In toluene; at 70℃; for 4h;Green chemistry; | General procedure: beta-Arylethanol 1 (1 mmol) and Fe(OTf)2 (0.01 mmol) were added sequentially to a solution of aldehyde, ketone, or ketal (1 eq, 1 mmol) in toluene (2 mL). The reaction mixture was warmed up slowly to the 70 oC and stirred for a few hours with monitoring by TLC plate. After completion the reaction, the mixture was cooled to room temperature. Then, the reaction mixture was washed with saturated NaHCO3 solution (5 mL), and the organic layer extracted with DCM (2×5 mL), dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography using PE-EtOAc mixture as eluent to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With iron(II) triflate In toluene at 70℃; for 6h; Green chemistry; | 2. Procedure for the synthesis of isochromans General procedure: β-Arylethanol 1 (1 mmol) and Fe(OTf)2 (0.01 mmol) were added sequentially to a solution of aldehyde, ketone, or ketal (1 eq, 1 mmol) in toluene (2 mL). The reaction mixture was warmed up slowly to the 70 oC and stirred for a few hours with monitoring by TLC plate. After completion the reaction, the mixture was cooled to room temperature. Then, the reaction mixture was washed with saturated NaHCO3 solution (5 mL), and the organic layer extracted with DCM (2×5 mL), dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography using PE-EtOAc mixture as eluent to afford the desired product. |
94% | With 2H(1+)*Mo12O40P(3-)*C8H14NOS(1+) at 70℃; for 0.75h; Green chemistry; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With iron(II) triflate In toluene at 70℃; for 6h; Green chemistry; | 2. Procedure for the synthesis of isochromans General procedure: β-Arylethanol 1 (1 mmol) and Fe(OTf)2 (0.01 mmol) were added sequentially to a solution of aldehyde, ketone, or ketal (1 eq, 1 mmol) in toluene (2 mL). The reaction mixture was warmed up slowly to the 70 oC and stirred for a few hours with monitoring by TLC plate. After completion the reaction, the mixture was cooled to room temperature. Then, the reaction mixture was washed with saturated NaHCO3 solution (5 mL), and the organic layer extracted with DCM (2×5 mL), dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography using PE-EtOAc mixture as eluent to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | 2-(3,4-Dimethoxyphenyl)ethanol (2.10?g, 11.56?mmol) was stirred in dry DMSO in the presence of finely ground anhydrous K2CO3 (?2.00?g, excess). After stirring for 30?min under an N2 atmosphere, <strong>[51762-67-5]3-nitrophthalonitrile</strong> (2.00?g, 11.56?mmol) was added to this mixture dropwise. The reaction mixture was monitored by TLC (CHCl3) for 3?days at ca. 50?C. The mixture was then cooled to ambient temperature and poured into ca. 250?mL ice-water. After completion of the precipitation, the solid product was filtered and purified by column chromatography using a mixture of CHCl3:MeOH (2:1 v/v) as the eluent. The obtained products are excellently soluble in CHCl3, THF, DMF and DMSO. Yield of 2: 0.69?g (78%), m.p.: 138?C. Anal. Calc. for C18H16N2O3 (308.33?g/mol): C, 70.12; H, 5.23; N, 9.09. Found: C, 70.09; H, 5.20; N, 9.05%. FT-IR (thin film) nu/cm-1: 3094, 2968, 2832, 2241, 1608, 1582, 1530, 1464, 1405, 1378, 1269, 1159, 1033, 960, 813, 459. 1H NMR ([d6]-DMSO) delta, ppm: 8.10, 7.80, 7.62, 6.85, 6.80, 6.65, 4.40, 3.80, 3.00. 13C NMR ([d6]-DMSO) delta, ppm: 161.5, 149.1, 148.1, 137.1, 130.7, 121.3, 119.1, 116.4, 116.0, 113.6, 113.4, 112.4, 71.1, 63.1, 56.1, 55.9, 34.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With sodium hydride In N,N-dimethyl-formamide at 20℃; for 10h; Inert atmosphere; | 4.2.1. General procedure for the preparation of ω-bromoalkylderivatives 10-27 General procedure: To a solution of the phenethyl alcohol (1.82 mmol for 1, 4;0.66 mmol for 2, 3, 5, 6, 1.0 equiv.) in anhydrous DMF (8.0 mL for 1,4; 5.0 mL for 2, 3, 5, 6) were added 95% NaH (8.0 equiv. for 1-4; 6.0equiv. for 5, 6), followed by the corresponding α,ω-dibromoalkane(6.0 equiv. for 1-4; 8.0 equiv. for 5, 6). The mixturewas kept stirringat rt and inert atmosphere for 10 h. Then, it was concentrated todryness under reduced pressure and the residue was subjected to1:1 CH2Cl2-H2O partitioning (30 mL); aqueous layer was furtherextracted with CH2Cl2 (2x15 mL). Combined organic fractions weredried over Na2SO4, filtered and the filtrate was concentrated todryness. The residue was purified by column chromatography, usingthe eluant indicated in each case, to afford derivatives 10-27. |
72% | With sodium hydride In N,N-dimethyl-formamide at 20℃; for 10h; Inert atmosphere; | 4.2.1. General procedure for the preparation of ω-bromoalkylderivatives 10-27 General procedure: To a solution of the phenethyl alcohol (1.82 mmol for 1, 4;0.66 mmol for 2, 3, 5, 6, 1.0 equiv.) in anhydrous DMF (8.0 mL for 1,4; 5.0 mL for 2, 3, 5, 6) were added 95% NaH (8.0 equiv. for 1-4; 6.0equiv. for 5, 6), followed by the corresponding α,ω-dibromoalkane(6.0 equiv. for 1-4; 8.0 equiv. for 5, 6). The mixturewas kept stirringat rt and inert atmosphere for 10 h. Then, it was concentrated todryness under reduced pressure and the residue was subjected to1:1 CH2Cl2-H2O partitioning (30 mL); aqueous layer was furtherextracted with CH2Cl2 (2x15 mL). Combined organic fractions weredried over Na2SO4, filtered and the filtrate was concentrated todryness. The residue was purified by column chromatography, usingthe eluant indicated in each case, to afford derivatives 10-27. |
50% | With sodium hydride In dimethyl sulfoxide at 20℃; for 4.5h; Inert atmosphere; | 4.2.20. 4-{2’-[(5''-Bromopentyl)oxy]ethyl}-1,2-dimethoxybenzene(39) To a solution of 2-(3,4-dimethoxyphenyl)ethanol (102.5 mg,0.55 mmol) in anhydrous DMSO (4 mL) were added NaH (84.5 mg,3.4 mmol, 6.1 equiv.) and 1,5-dibromopentane (630 mL, 4.5 mmol,8.2 equiv.). The resulting mixture was stirred at rt and under Ar for4.5 h. After that, it was partitioned between 1:1 Et2OeH2O (30 mL);the aqueous phasewas extracted further with Et2O (2 x15 mL). Thecombined organic fractions were dried over Na2SO4, filtered andconcentrated to dryness. The residue was purified by columnchromatography (cyclohexane / 1:5 Et2Ocyclohexane). Yield:92.1 mg, 50%. Rf 0.31 (1:2 Et2Ocyclohexane). 1H NMR (300 MHz,CDCl3) δ 6.77 (m, 3H, H-3, H-5, H-6), 3.86 (s, 3H, s, OMe), 3.85 (s, 3H,OMe), 3.60 (t, 2H, JH,H 7.1 Hz, CH2), 3.44 (t, 2H, JH,H 7.1 Hz, CH2),3.39 (t, 2H, JH,H 7.1 Hz, CH2), 2.82 (t, 2H, JH,H 7.1 Hz, CH2), 1.86(quint, 2H, CH2), 1.64e1.43 (m, 4H, 2CH2) ppm; 13C NMR (75.5 MHz,CDCl3) δ 148.9, 147.6 (C-1, C-2), 131.8 (C-4), 120.9 (C-5), 112.4, 111.3(C-3, C-6), 72.2 (Ar-CH2-CH2), 70.8 (C-100), 56.0 (OMe), 55.9 (OMe),36.1, 33.9, 32.7, 29.0, 25.1 (CH2) ppm; HRESI-MS calcd. forC15H2379BrNaO3 ([M+Na]+): 353.0723, found: 353.0721; calcd. forC14H2181BrNaO2 ([M+Na]+): 355.0702, found 355.0700. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sodium hydride In N,N-dimethyl-formamide for 0.5h; | 3.2.9. Synthesis of 2-(3,4-dimethoxyphenyl)ethan-1-ol (14) To a mixture of 7 (1.68 g, 10 mmol), NaH (0.24 g, 10 mmol) in 20 ml dry DMF, asolution of CH3I (2.16 g, 15 mmol) in 10 ml DMF was added in 20 min. Then the stirringwas continued for further 10 min. The reaction was quenched by water (20 ml),extracted with ethyl acetate (350 ml), and the organic layers were collected, washedwith brine, dried over Na2SO4, and evaporated in vacuo. The residue was purified byflash chromatography using ethyl acetate/petroleum ether 1:4 as eluent, to give pure14 (1.70 g, 93%) as a colorless oil. 1H NMR (600 MHz, CD3OD) d: 6.80-6.77 (m,2H), 6.68-6.66 (m, 1H), 3.69 (s, 3H), 3.66 (s, 3H), 3.55 (t, J7.3 Hz, 2H), 2.62 (t,J7.3 Hz, 2H); 13C NMR (150 MHz, CD3OD) d: 149.0, 147.6, 132.5, 121.2, 113.3,112.3, 62.9, 56.0, 55.9, 39.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: O-(2,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyl)trichloroacetimidate; 2-(3,4-dimethoxyphenyl)ethyl alcohol In dichloromethane at -78℃; for 0.5h; Molecular sieve; Inert atmosphere; Stage #2: With trimethylsilyl trifluoromethanesulfonate at -78 - 0℃; for 0.5h; Inert atmosphere; | 3.2.10. Synthesis of (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(3,4-dimethoxyphenethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (15) General procedure: A mixture of 8 (0.336 g, 1.6 mmol), 13 (1.47 g, 3 mmol), and 4Å molecular sieves(1.0 g) was added to dry CH2Cl2 (30 ml) under argon atmosphere at 78 C. Themixture was stirred for 30 min and TMSOTf (cat., 10 ll) was added. Then the stirringwas continued for further 30 min after which the temperature was brought up to0 C. The reaction mixture was neutralized by the addition of Et3N and concentrated.The crude product was purified by column chromatography (petroleum ether: EtOAc1:2 V/V) to give 15 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With tetrakis(triphenylphosphine) palladium(0); Potassium benzoate In o-xylene at 140℃; for 27h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With sodium hydride In N,N-dimethyl-formamide at 20℃; for 10h; Inert atmosphere; | 4.2.1. General procedure for the preparation of ω-bromoalkylderivatives 10-27 General procedure: To a solution of the phenethyl alcohol (1.82 mmol for 1, 4;0.66 mmol for 2, 3, 5, 6, 1.0 equiv.) in anhydrous DMF (8.0 mL for 1,4; 5.0 mL for 2, 3, 5, 6) were added 95% NaH (8.0 equiv. for 1-4; 6.0equiv. for 5, 6), followed by the corresponding α,ω-dibromoalkane(6.0 equiv. for 1-4; 8.0 equiv. for 5, 6). The mixturewas kept stirringat rt and inert atmosphere for 10 h. Then, it was concentrated todryness under reduced pressure and the residue was subjected to1:1 CH2Cl2-H2O partitioning (30 mL); aqueous layer was furtherextracted with CH2Cl2 (2x15 mL). Combined organic fractions weredried over Na2SO4, filtered and the filtrate was concentrated todryness. The residue was purified by column chromatography, usingthe eluant indicated in each case, to afford derivatives 10-27. |
63% | With sodium hydride In N,N-dimethyl-formamide at 20℃; for 10h; Inert atmosphere; | 4.2.1. General procedure for the preparation of ω-bromoalkylderivatives 10-27 General procedure: To a solution of the phenethyl alcohol (1.82 mmol for 1, 4;0.66 mmol for 2, 3, 5, 6, 1.0 equiv.) in anhydrous DMF (8.0 mL for 1,4; 5.0 mL for 2, 3, 5, 6) were added 95% NaH (8.0 equiv. for 1-4; 6.0equiv. for 5, 6), followed by the corresponding α,ω-dibromoalkane(6.0 equiv. for 1-4; 8.0 equiv. for 5, 6). The mixturewas kept stirringat rt and inert atmosphere for 10 h. Then, it was concentrated todryness under reduced pressure and the residue was subjected to1:1 CH2Cl2-H2O partitioning (30 mL); aqueous layer was furtherextracted with CH2Cl2 (2x15 mL). Combined organic fractions weredried over Na2SO4, filtered and the filtrate was concentrated todryness. The residue was purified by column chromatography, usingthe eluant indicated in each case, to afford derivatives 10-27. |
Stage #1: 2-(3,4-dimethoxyphenyl)ethyl alcohol With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere; Stage #2: 1 ,6-dibromohexane In N,N-dimethyl-formamide at 20℃; for 5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With methanesulfonic acid In chloroform at 60℃; for 1h; | 1-4 Add 0.055g (0.3mmol) 2-(3,4-dimethoxyphenyl)ethanol and 0.3mL chloroform into a 50mL reaction tube,Stir at room temperature to dissolve all the raw materials, and then add 0.029 g (0.3 mmol) of methanesulfonic acid and 84 μL (0.6 mmol) of heptaldehyde. Stir the reaction at 60°C for 1 hour, stop heating, add 2mL saturated sodium bicarbonate aqueous solution to the system, extract three times with 10mL ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, filter with suction, concentrate, and proceed with the crude product. Column chromatography separation (solvents are ethyl acetate and n-hexane) to obtain a white viscous solid product with a yield of 71%. The resulting product was characterized by a Bruker Avance superconducting Fourier digital nuclear magnetic resonance spectrometer, and the characterization data were: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With methanesulfonic acid In chloroform at 80℃; for 1h; | 5 General procedure: Add 0.055g (0.3mmol) 2-(3,4-dimethoxyphenyl)ethanol and 0.3mL chloroform into a 50mL reaction tube,Stir at room temperature to dissolve all the raw materials, and then add 0.029 g (0.3 mmol) of methanesulfonic acid and 84 μL (0.6 mmol) of heptaldehyde. Stir the reaction at 60°C for 1 hour, stop heating, add 2mL saturated sodium bicarbonate aqueous solution to the system, extract three times with 10mL ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, filter with suction, concentrate, and proceed with the crude product. Column chromatography separation (solvents are ethyl acetate and n-hexane) to obtain a white viscous solid product with a yield of 71%. The resulting product was characterized by a Bruker Avance superconducting Fourier digital nuclear magnetic resonance spectrometer, and the characterization data were: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With methanesulfonic acid In chloroform at 80℃; for 1h; | 6 General procedure: Add 0.055g (0.3mmol) 2-(3,4-dimethoxyphenyl)ethanol and 0.3mL chloroform into a 50mL reaction tube,Stir at room temperature to dissolve all the raw materials, and then add 0.029 g (0.3 mmol) of methanesulfonic acid and 84 μL (0.6 mmol) of heptaldehyde. Stir the reaction at 60°C for 1 hour, stop heating, add 2mL saturated sodium bicarbonate aqueous solution to the system, extract three times with 10mL ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, filter with suction, concentrate, and proceed with the crude product. Column chromatography separation (solvents are ethyl acetate and n-hexane) to obtain a white viscous solid product with a yield of 71%. The resulting product was characterized by a Bruker Avance superconducting Fourier digital nuclear magnetic resonance spectrometer, and the characterization data were: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; | 2 Compound 10-4: methyl 3-(2-(4-(2-((3,4-dimethoxyphenethoxy)carbonyl)adamantan-1-yl)phenoxy)acetamido)benzoate ( Methyl 3-(2-(4-(2-((3,4-dimethoxyphenethoxy)carbonyl)adamantane-1-yl)phenoxy)acetamido)benzoate) (10d): Compound 9 (0.31 g, 0.66 mmol), 2- (3,4-dimethoxyphenyl) ethanol (0.18 g, 0.99 mmol), EDC.HCl (0.19 g, 0.99 mmol), HOBt (0.13 g, 0.99 mmol) and DIPEA (0.17 ml, 0.99 mmol) was dissolved in DMF at room temperature and stirred overnight. Upon completion of stirring, water was added to terminate the reaction, followed by extraction with EA. The extracted organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The concentrated reaction was purified by column chromatography on silica gel (DCM/EA) to give the target compound 10d as a white solid (0.36 g, 58 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sodium hydride In N,N-dimethyl-formamide at 20℃; for 10h; Inert atmosphere; | 4.2.1. General procedure for the preparation of ω-bromoalkylderivatives 10-27 General procedure: To a solution of the phenethyl alcohol (1.82 mmol for 1, 4;0.66 mmol for 2, 3, 5, 6, 1.0 equiv.) in anhydrous DMF (8.0 mL for 1,4; 5.0 mL for 2, 3, 5, 6) were added 95% NaH (8.0 equiv. for 1-4; 6.0equiv. for 5, 6), followed by the corresponding α,ω-dibromoalkane(6.0 equiv. for 1-4; 8.0 equiv. for 5, 6). The mixturewas kept stirringat rt and inert atmosphere for 10 h. Then, it was concentrated todryness under reduced pressure and the residue was subjected to1:1 CH2Cl2-H2O partitioning (30 mL); aqueous layer was furtherextracted with CH2Cl2 (2x15 mL). Combined organic fractions weredried over Na2SO4, filtered and the filtrate was concentrated todryness. The residue was purified by column chromatography, usingthe eluant indicated in each case, to afford derivatives 10-27. 4.2.1.1. 4-[2’-(12’’-Bromododecyloxy)ethyl]-1,2-dimethoxybenzene(18). 2-(3', 4'-Dimethoxyphenyl)ethanol (3) (122.8 mg, 0.66 mmol)and 1,12-dibromododecane (1.3 g, 3.99 mmol, 6.0 equiv.) were used.Column chromatography (cyclohexane/ 1:10 Et2Ocyclohexane)afforded 18 as a brown syrup. Yield: 420.6 mg, 82%. Rf 0.40 (1:5EtOAc/Cyclohexane). 1H NMR (300 MHz, CDCl3) δ 6.84-6.74 (m,3H, H-3, H-5, H-6), 3.87 (s, 3H, OMe), 3.85 (s, 3H, OMe), 3.60 (t, 2H,JH,H 7.0 Hz, CH2), 3.43 (t, 2H, JH,H 6.8 Hz, CH2), 3.38 (t, 2H,JH,H 6.9 Hz, CH2), 2.83 (t, 2H, JH,H 7.2 Hz, CH2), 1.85 (quint, 2H,JH,H 6.9 Hz, CH2), 1.64-1.52 (m, 2H, CH2), 1.47-1.37 (m, 2H, CH2),1.31-1.27 (m, 14H, 7CH2) ppm; 13C NMR (75.5 MHz, CDCl3) δ 148.9(C-2), 147.5 (C-1), 131.9 (C-4), 120.9 (C-5), 112.4 (C-3), 111.3 (C-6),72.1 (C-20), 71.3 (C-1’’), 56.0, 55.9 (2OMe), 36.1 (C-10), 34.2, 33.0,29.9, 29.7 (x2), 29.6, 29.5, 28.9, 28.3, 26.3 (CH2) ppm; HRESIMScalcd. for C22H3779BrNaO3 ([M + Na]+): 451.1818, found: 451.1825. |
82% | With sodium hydride In N,N-dimethyl-formamide at 20℃; for 10h; Inert atmosphere; | 4.2.1. General procedure for the preparation of ω-bromoalkylderivatives 10-27 General procedure: To a solution of the phenethyl alcohol (1.82 mmol for 1, 4;0.66 mmol for 2, 3, 5, 6, 1.0 equiv.) in anhydrous DMF (8.0 mL for 1,4; 5.0 mL for 2, 3, 5, 6) were added 95% NaH (8.0 equiv. for 1-4; 6.0equiv. for 5, 6), followed by the corresponding α,ω-dibromoalkane(6.0 equiv. for 1-4; 8.0 equiv. for 5, 6). The mixturewas kept stirringat rt and inert atmosphere for 10 h. Then, it was concentrated todryness under reduced pressure and the residue was subjected to1:1 CH2Cl2-H2O partitioning (30 mL); aqueous layer was furtherextracted with CH2Cl2 (2x15 mL). Combined organic fractions weredried over Na2SO4, filtered and the filtrate was concentrated todryness. The residue was purified by column chromatography, usingthe eluant indicated in each case, to afford derivatives 10-27. 4.2.1.1. 4-[2’-(12’’-Bromododecyloxy)ethyl]-1,2-dimethoxybenzene(18). 2-(3', 4'-Dimethoxyphenyl)ethanol (3) (122.8 mg, 0.66 mmol)and 1,12-dibromododecane (1.3 g, 3.99 mmol, 6.0 equiv.) were used.Column chromatography (cyclohexane/ 1:10 Et2Ocyclohexane)afforded 18 as a brown syrup. Yield: 420.6 mg, 82%. Rf 0.40 (1:5EtOAc/Cyclohexane). 1H NMR (300 MHz, CDCl3) δ 6.84-6.74 (m,3H, H-3, H-5, H-6), 3.87 (s, 3H, OMe), 3.85 (s, 3H, OMe), 3.60 (t, 2H,JH,H 7.0 Hz, CH2), 3.43 (t, 2H, JH,H 6.8 Hz, CH2), 3.38 (t, 2H,JH,H 6.9 Hz, CH2), 2.83 (t, 2H, JH,H 7.2 Hz, CH2), 1.85 (quint, 2H,JH,H 6.9 Hz, CH2), 1.64-1.52 (m, 2H, CH2), 1.47-1.37 (m, 2H, CH2),1.31-1.27 (m, 14H, 7CH2) ppm; 13C NMR (75.5 MHz, CDCl3) δ 148.9(C-2), 147.5 (C-1), 131.9 (C-4), 120.9 (C-5), 112.4 (C-3), 111.3 (C-6),72.1 (C-20), 71.3 (C-1’’), 56.0, 55.9 (2OMe), 36.1 (C-10), 34.2, 33.0,29.9, 29.7 (x2), 29.6, 29.5, 28.9, 28.3, 26.3 (CH2) ppm; HRESIMScalcd. for C22H3779BrNaO3 ([M + Na]+): 451.1818, found: 451.1825. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran; toluene at 20℃; for 0.5h; Inert atmosphere; | Ethyl 4,5-Dibromo-1-(3,4-dimethoxyphenethyl)-1H-pyrrole-2-carboxylate (10) A 50-mL round-bottomed flask equipped with a Teflon-coated magneticstirring bar, a rubber septum, and a three-way stopcock wascharged with ethyl 4,5-dibromo-1H-pyrrole-2-carboxylate (1.256 g,5.09 mmol, 1.0 equiv), 3,4-dimethoxyphenylethanol (1.123 g, 6.16mmol, 1.2 equiv), and PPh3 (1.609 g, 6.14 mmol, 1.2 equiv). After theflask was evacuated and backfilled with N2, anhydrous THF (10 mL)and 1.9 M DIAD in toluene (3.3 mL, 6.3 mmol, 1.2 equiv) were addedto the flask. The solution was stirred at r.t. for 30 min, after which thereaction mixture was treated with H2O (10 mL). The resulting mixturewas extracted with Et2O (2 × 15 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a crudeproduct, which was purified by column chromatography (silica gel,hexane/Et2O = 20:1 to 6:1, gradient) to provide 10.Yield: 1.965 g (4.28 mmol, 84%); colorless solid; mp 56-58 °C; Rf =0.12 (hexane/Et2O = 3:1).IR (ATR): 1707, 1516, 1417, 1405, 1328, 1262, 1233, 1178, 1158, 1094,1031 cm-1.1H NMR (400 MHz, CDCl3): = 7.03 (s, 1 H), 6.80 (d, J = 8.1 Hz, 1 H),6.75 (dd, J = 8.1, 1.9 Hz, 1 H), 6.63 (d, J = 1.9 Hz, 1 H), 4.63 (t, J = 7.7 Hz,2 H), 4.27 (q, J = 7.0 Hz, 2 H), 3.86 (s, 3 H), 3.85 (s, 3 H), 2.91 (t, J = 7.7Hz, 2 H), 1.34 (t, J = 7.0 Hz, 3 H).13C NMR (100 MHz, CDCl3): = 159.5, 148.9, 147.9, 130.2, 123.6,121.1, 119.6, 112.8, 112.2, 111.3, 99.1, 60.5, 56.0, 55.9, 49.9, 36.7,14.4.HRMS (ESI/TOF): m/z [M + Na]+ calcd for C17H1979Br2NO4Na: 481.9579;found: 481.9562. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran; toluene at 20℃; for 0.333333h; Inert atmosphere; | Ethyl 4,5-Dibromo-1-(3,4-dimethoxyphenethyl)-3-iodo-1H-pyrrole-2-carboxylate (16) A 50-mL round-bottomed flask equipped with a Teflon-coated magneticstirring bar, a rubber septum, and a three-way stopcock wascharged with dibromoiodopyrrole S1 (3.855 g, 9.12 mmol, 1.0 equiv),3,4-dimethoxyphenylethanol (2.000 g, 11.0 mmol, 1.2 equiv), andPPh3 (2.872 g, 10.9 mmol, 1.2 equiv). After the flask was evacuatedand backfilled with N2, anhydrous THF (18 mL) and 1.9 M DIAD in toluene(5.8 mL, 11 mmol, 1.2 equiv) were added to the flask. The solutionwas stirred at r.t. for 20 min, after which the reaction mixturewas treated with H2O (20 mL). The resulting mixture was extractedwith Et2O (2 x 20 mL). The combined organic extracts were washedwith brine (40 mL), dried over Na2SO4, and filtered. The filtrate wasconcentrated under reduced pressure to give a crude product, whichwas purified by column chromatography (silica gel, hexane/CH2Cl2 =1:1 to 1:4, gradient), followed by recrystallization from EtOH to provide16.Yield: 4.623 g (7.88 mmol, 86%); colorless solid; mp 96-98 °C; Rf =0.33 (hexane/Et2O = 1:1). IR (ATR): 2953, 2832, 1699, 1516, 1420, 1397, 1382, 1261, 1237, 1157,1100, 1030 cm-1.1H NMR (400 MHz, CDCl3): = 6.80 (d, J = 8.2 Hz, 1 H), 6.73 (dd, J = 8.2,2.0 Hz, 1 H), 6.58 (d, J = 2.0 Hz, 1 H), 4.66 (t, J = 7.7 Hz, 2 H), 4.33 (q, J =7.3 Hz, 2 H), 3.86 (s, 3 H), 3.85 (s, 3 H), 2.91 (t, J = 7.7 Hz, 2 H), 1.42 (t,J = 7.3 Hz, 3 H).13C NMR (100 MHz, CDCl3): = 158.8, 148.9, 148.0, 129.8, 125.7,121.0, 112.08, 112.05, 111.3, 109.6, 77.0, 61.2, 56.0, 55.9, 51.6, 36.7,14.3.HRMS (ESI/TOF): m/z [M + Na]+ calcd for C17H1879Br81BrINO4Na:609.8525; found: 609.8555. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran; toluene at 20℃; for 1h; Inert atmosphere; | Ethyl 3,4,5-Tribromo-1-(3,4-dimethoxyphenethyl)-1H-pyrrole-2-carboxylate (18) A 50-mL round-bottomed flask equipped with a Teflon-coated magneticstirring bar, a rubber septum, and a three-way stopcock wascharged with tribromopyrrole S2 (1.128 g, 3.00 mmol, 1.0 equiv), 3,4-dimethoxyphenylethanol (656.0 mg, 3.60 mmol, 1.2 equiv), and PPh3(948.8 mg, 3.62 mmol, 1.2 equiv). After the flask was evacuated andbackfilled with N2, anhydrous THF (6 mL) and 1.9 M DIAD in toluene(1.9 mL, 3.6 mmol, 1.2 equiv) were added to the flask. The solutionwas stirred at r.t. for 1 h, after which the reaction mixture was treatedwith H2O (6 mL). The resulting mixture was extracted with EtOAc (2 ×10 mL). The combined organic extracts were washed with brine (10mL), dried over Na2SO4, and filtered. The filtrate was concentrated underreduced pressure to give a crude product, which was purified bycolumn chromatography (silica gel, hexane/CH2Cl2 = 1:3) followed byrecrystallization from EtOH to provide 18.Yield: 1.214 g (2.25 mmol, 75%); colorless solid; mp 113-115 °C; Rf =0.19 (hexane/CH2Cl2 = 1:3).IR (ATR): 2939, 1701, 1516, 1455, 1424, 1398, 1383, 1323, 1262, 1237,1173, 1157, 1141, 1100, 1030, 801, 767, 645, 620 cm-1.1H NMR (400 MHz, CDCl3): = 6.80 (d, J = 8.3 Hz, 1 H), 6.73 (dd, J = 8.3,1.9 Hz, 1 H), 6.60 (d, J = 1.9 Hz, 1 H), 4.65 (t, J = 7.6 Hz, 2 H), 4.32 (q, J =7.3 Hz, 2 H), 3.86 (s, 3 H), 3.85 (s, 3 H), 2.91 (t, J = 7.6 Hz, 2 H), 1.40 (t,J = 7.3 Hz, 3 H). 13C NMR (100 MHz, CDCl3): = 159.1, 149.0, 148.0, 129.8, 122.4,121.1, 112.3, 112.1, 111.4, 107.2, 104.5, 61.1, 56.0, 55.9, 51.2, 36.7,14.3. HRMS (ESI/TOF): m/z [M + Na]+ calcd for C17H1879Br281BrNO4Na:561.8663; found: 561.8645. |
Tags: 7417-21-2 synthesis path| 7417-21-2 SDS| 7417-21-2 COA| 7417-21-2 purity| 7417-21-2 application| 7417-21-2 NMR| 7417-21-2 COA| 7417-21-2 structure
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