* 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.
With 1,4-diaza-bicyclo[2.2.2]octane; TEMPOL; ammonia; copper(l) chloride In water; acetonitrile at 20℃; for 24 h;
General procedure: To a 25-mL Schlenk tube equipped with a magnetic stirrer, CuCl (0.05 mol, 5 molpercent), DABCO (0.10 mol, 10 molpercent), 4-HO-TEMPO (0.05 mmol, 5 molpercent) were added. Substrates 1 (1 mmol) and NH3 (aq, 25-28percent, 3 mmol, 3.0 equiv) in CH3CN (2 mL) were added subsequently. Then the reaction mixture was stirred at room temperature for 24 h in the presence of an air balloon. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4. Subsequently, the combined organic layer was concentrated under reduced pressure and the crude product was purified by column chromatography to afford the corresponding products.
Reference：
[1] Chinese Chemical Letters, 2018, vol. 29, # 3, p. 464 - 466
[2] Applied Organometallic Chemistry, 2018, vol. 32, # 4,
2
[ 705-76-0 ]
[ 57179-35-8 ]
Reference：
[1] Patent: WO2016/14529, 2016, A1,
3
[ 705-76-0 ]
[ 880-87-5 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1964, vol. 677, p. 21 - 33
4
[ 705-76-0 ]
[ 13388-75-5 ]
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[2] Journal of the American Chemical Society, 2004, vol. 126, # 19, p. 5942 - 5943
[3] Journal of the American Chemical Society, 1948, vol. 70, p. 662
[4] Archiv der Pharmazie, 1972, vol. 305, # 2, p. 124 - 134
[5] Canadian Journal of Chemistry, 1977, vol. 55, # 5, p. 785 - 791
[6] Patent: CN105503652, 2016, A,
5
[ 705-76-0 ]
[ 61367-62-2 ]
[ 74726-76-4 ]
Reference：
[1] Australian Journal of Chemistry, 1997, vol. 50, # 8, p. 831 - 840
6
[ 705-76-0 ]
[ 877-88-3 ]
Yield
Reaction Conditions
Operation in experiment
100%
With phosphorus tribromide In benzene at 20℃;
General procedure: benzyl alcohols (1 mmol) in dry benzene (15 mL) and phosphorus tribromides (0.5 mL) and stirred at room temperature to get respective benzyl bromides in quantitative yields, usual work-up.
98%
With pyridine; phosphorus tribromide In diethyl ether at 35℃; for 3 h; Inert atmosphere
To a solution of 3,5-dimethoxybenzylalcohol (1.5g, 8.918 mmol) in diethyl ether (45mL) under argon atmosphere was added pyridine (0.034mL, 0.445 mmol). Subsequently, phosphorous tribromide (0.83mL, 8.918 mmol) was added dropwise and the resulting reaction mixture was warmed to 35°C and stirred at that temperature for 3h. The reaction mixture was quenched with slow addition of ice-cold water and diluted with ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate (3x30mL). The organic phase was washed with brine, dried over Na2S04, filtered, and concentrated to afford the title compound (2.0g, yield: 98percent) as a white solid. 1H-NMR (D -d6, 300MHz): δ 6.54 (d, 2H), 6.39 (t, 1H), 4.42 (s, 2H), 3.79 (s, 6H).
97%
With pyridine; phosphorus tribromide In dichloromethane at 0 - 20℃; for 4 h;
PBr3 (18 ml) was added dropwise to a solution of 2 (32.6 g, 194 mmol) and pyridine (0.78 ml) in CH2Cl2 at0. After the mixture was slowly warmed to room temperature and stirred for 4 h, the reaction was quenched by the slowly addition of ice water, extracted with CH2Cl2, washed with brine, dried over Na2SO4, andconcentrated to provide 1-(bromomethyl)-3,5-dimethoxybenzene (3) as white solid ( 43.4g, yield 97percent). 1H NMR (400 MHz, CDCl3) δ 6.54 (s, 2H), 6.39 (s, 1H), 4.42 (s, 2H), 3.79 (s, 6H).
97%
With phosphorus tribromide In diethyl ether at 0℃; for 0.5 h;
PBr3 (3.10 mL) was addeddrop wise to a solution of (4) 9 g (53.545 mmol) in diethylether at 0 °C. The mixture was stirred at 0 °C for 30 min,and after completion of the reaction (monitored by TLC),the reaction mixture was quenched by slow addition ofpotassium bromide solution, extracted with diethyl ether,washed with brine, dried over Na2SO4 and concentrated toprovide the product (5).1-(Bromomethyl)-3,5-dimethoxybenzene (5) White solid;Yield: 97 percent; mp 68–70 °C;1H NMR (CDCl3, 400 MHz): δ 6.55–6.53 (2H, m, H–2, H–6), 6.40–6.38 (1H, m, H–4),4.42 (2H, s, –CH2–Br), 3.79 (6H, s, 2 X O–CH3); 13C NMR(CDCl3, 75 MHz): δ 161.1 (C, C–3, C–5), 139.7 (C, C–1),106.1 (CH, C–2, C–6), 98.2 (CH, C–4), 55.5 (O–CH3), 30.5(H2C–Br); for C9H11BrO2 MS (ESI) (m/z) 230 [M + H]+.
93%
With pyridine; phosphorus tribromide In diethyl ether at 25 - 40℃; for 3 h;
NaBH4 (1.11 g, 30.0 mmol, 2.0 equiv) was added slowly to a solution of3, 5-dimethoxybenzaldehyde (2.44 g, 15.0 mmol, 1.0 equiv) inMeOH (30 mL) at 0 0C. After 30 min of stirring at 0 0C, the reaction contents were quenched by the slow addition of water (20 mL) , poured into water (10 mL) , and extracted with EtOAc (3 x 20 mL) . The combined organic layers were then washed with water (20 mL) and brine (20 mL) , dried(MgSO4) , and concentrated to afford the desired alcohol intermediate (2.43 g, 99percent yield) as a white solid which was carried forward without further purification. Next, pyridine (0.017 mL, 0.212 mmol, 0.05 equiv) and PBr3 (0.400 mL, 4.25 mmol, 1.0 equiv) were added sequentially and <n="339"/>slowly to a portion of this newly-formed alcohol (0.715 g, 4.25 mmol, 1.0 equiv) in Et2O (20 inL) at 25 0C, and the resultant mixture was heated at 40 0C for 3 h. Upon completion, the reaction contents were quenched carefully with ice water (15 mL) , poured into water (10 mL) , and extracted with Et2O (3 x 20 mL) . The combined organic layers were then washed with water (15 mL) and brine (15 mL) , dried (MgSO4), and concentrated to afford alkyl halide Sl (1.50 g, 93percent yield) as an amorphous white solid which was carried forward without additional purification. Sl: Rf = 0.66 (silica gel, EtOAc/hexanes, 1:1); IR (film) vraaκ 3002, 2960, 2838, 1597, 1465, 1429, 1348, 1325, 1300, 1264, 1206, 1158, 1064, 992, 931, 836, 693, 650; 1H NMR (300 MHz, CDCl3) δ 6.54 (d, J = 2.1 Hz, 2 H), 6.39 (t, J = 2.1 Hz, 1 H), 4.42 (s, 2 H), 3.80 (s, 6 H); 13C NMR (75 MHz, CDCl3) δ 160.9, 139.7, 107.0 (2 C), 100.6, 55.4 (2 C), 33.6; HRMS (MALDI-FTMS) calculated for C5H11BrO2+ [M+] 229.9942, found 229.9937.
92%
With phosphorus tribromide In tetrahydrofuran at -10℃;
Phosphorus tribromide (0.4 eq) was added to the alcohol 304 (25 g, 0.13 mol) in THF (100 mL) very slowly at -10° C. and the mixture which resulted was stirred for 15-30 min at the same temperature. By this time all the starting material had disappeared (TLC). The reaction mixture was quenched by addition of ice-cold H2O (100 mL) and then filtered through a Buchner funnel. The filtrate was diluted with brine (100 mL) and extracted with EtOAc (3*300 mL). The combined organic extracts were dried (Na2S0.4) and concentrated in vacuum. The crude oil was purified by FCC (20percent ethylacetate in hexane) to afford the bromide 305 as a white solid (92percent)a.: 1HNMR (500 MHz, CDCl3) δ 6.61(2H, d, J=2.3 Hz), 6.46 (1H, t, J=2.3 Hz), 4.5 (2H, s), 3.85 (61-1, s). 13C NMR (125 MHz, CDCl3): δ 161.3, 140.2, 107.4, 101.0, 55.8, 34.1. The spectral data for 305 were in excellent accord with data previously reported on it (Seidel et al., 1990)1, This material was employed directly in the next step.
85.4%
With phosphorus tribromide In dichloromethane at 20℃; Inert atmosphere; Cooling with ice
In an ice bath and argon,Was dissolved in 20mL of dry CH2Cl2 4.088g (0.024mol) 3,5- dimethoxybenzene in 100mL methanol 3 neck round bottom flask,Slowly by syringe while stirring was dissolved in 10mL of dichloromethane was added dropwise a solution of 2.54mLPBr3,After 2h the reaction into an ice bath at room temperature,The reaction was continued 2-3h,TLC tracking and detection,The completion of the reaction, etc. The reaction solution was poured into ice water 50mL,Stirring,Lower for the milky white liquid,Plus sodium bicarbonate adjusted to pH 7,After separation of the aqueous layer was extracted with ethyl acetate,Dried over anhydrous sodium sulfate,The solvent was distilled off under reduced pressure,Dried to give compound 4The yield was 85.4percent,
78%
With 1H-imidazole; bromine; triphenylphosphine In dichloromethane at 0 - 20℃; for 24 h;
To a dry 250 mL rbf charged with 125 mL dry CH2Cl2 cooled to 0 °C was added in order, PPh3 (7.59 g, 28.9 mmol, 1.2 eq.), imidazole (1.97 g, 28.9 mmol, 1.2 eq.), Br2 (1.50 mL, 28.9 mmol, 1.2 eq.) and 3,5-dimethoxybenzyl alcohol (4.06 g, 24.1 mmol, 1.0 eq.). The reaction was stirred at r.t. for 24 h. Workup provided 3,5-dimethoxybenzyl bromide (4.35 g, 78percent) as a colourless oil.
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[3] Patent: WO2016/164703, 2016, A1, . Location in patent: Page/Page column 41
[4] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 24, p. 7683 - 7687
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[10] Angewandte Chemie - International Edition, 2007, vol. 46, # 43, p. 8186 - 8191
[11] Patent: WO2009/38731, 2009, A2, . Location in patent: Page/Page column 337-338
[12] Synlett, 2013, vol. 24, # 9, p. 1109 - 1112
[13] Marine Drugs, 2012, vol. 10, # 5, p. 1103 - 1125
[14] Patent: US2017/342047, 2017, A1, . Location in patent: Paragraph 0179-0180
[15] Journal of Medicinal Chemistry, 2002, vol. 45, # 12, p. 2534 - 2542
[16] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 21, p. 2603 - 2613
[17] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2016, vol. 55B, # 8, p. 1035 - 1038
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[19] Patent: CN105503652, 2016, A, . Location in patent: Paragraph 0046; 0047
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7
[ 705-76-0 ]
[ 4670-09-1 ]
Reference：
[1] Archiv der Pharmazie, 1972, vol. 305, # 2, p. 124 - 134
8
[ 705-76-0 ]
[ 22972-63-0 ]
Reference：
[1] Journal of the American Chemical Society, 1948, vol. 70, p. 662
With silica-supported Jones reagent In dichloromethane for 0.00269444h;
97%
With 1,2-dimethyl-3-[6-(methylsulfinyl)hexyl]-1H-imidazolium triflate; oxalyl dichloride; triethylamine In dichloromethane; acetonitrile at -78 - 20℃;
96%
With Dess-Martin periodane In dichloromethane at 0℃; Inert atmosphere;
96%
With fluorosulfonyl fluoride; potassium carbonate; dimethyl sulfoxide at 20℃; for 12h; chemoselective reaction;
95%
With benzyltriphenylphosphonium dichromate In acetonitrile for 0.333333h; Heating;
95%
With tert.-butylhydroperoxide; eosin y In decane; acetonitrile at 25℃; for 48h; Inert atmosphere; Irradiation; Molecular sieve; Green chemistry; chemoselective reaction;
General procedure for oxidation of alcohols:
General procedure: Oven dried round bottom flask was charged with Eosin Y (5 mmol) alcohol (1 mmol) and 3 equiv. of TBHP (5.5 M in decane) in dry ACN. The resulting mixture was degassed for 15 mins, followed by back filling N2, and then irradiated under Blue LED light (12W, 455 nm) at room temperature (25 oC). After reaction completion monitored through TLC, the mixture was diluted with 15 ml of 10% NaHCO3 solution, and extracted with EtOAc (3 × 20 ml). The combined organic extracts were washed with brine (20 ml), dried over Na2SO4, and concentrated on vacuo. Purification of the crude product on silica gel using EtOAc:Hexane as solvent system afforded the desired product.
94%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; copper(II) ferrite; oxygen In water at 100℃; for 24h; Schlenk technique; Sealed tube; Green chemistry;
94%
With 3Co(2+)*2C21H9NO8(4-)*2H2O*2C2H8N(1+)*2C3H7NO; <i>L</i>-proline In acetonitrile at 20℃; for 3h;
93%
With ammonium nitrate; hydrogenchloride; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; oxygen In water; acetonitrile at 60℃; for 5h; Green chemistry;
93%
With ammonium nitrate; hydrogenchloride; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In acetonitrile at 60℃; for 5h; Green chemistry; chemoselective reaction;
93%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; copper (II) dichloro(N,N,N',N'-tetramethylethylenediamine) In acetonitrile at 25℃; for 2h; chemoselective reaction;
2.3. Typical procedure for the Aerobic oxidation of alcohols using CuCl2/TMEDA/TEMPO2.3. Typical procedure for the Aerobic oxidation of alcohols using CuCl2/TMEDA/TEMPO
General procedure: Method A: A 20-mm culture tube with capacity to 15 mL andequipped with a magnetic stirrer was loaded with MeCN (2 mL), CuCl2(3.0 × 10 3 mmol, 0.4 mg) and TMEDA (3.0 × 10 3 mmol, 0.45 μL). Tothis slightly greenish blue solution, alcohol 1b (3 mmol, 320 μL) andTEMPO (3.0 × 10-2 mmol, 4.7 mg, 1.0 mol%) were added at roomtemperature (25 C). The opened flask reaction was stirred at 25 Cunder bubbled air (see apparatus on SI) where within 2 h, the totalconversion of 1b was confirmed by GC/FID. Then, the crude was filteredoff in a minimal amount of silica gel (ca. 10 mg) furnishing 353 mg ofthe pure p-tolualdehyde (2b) in 98 % of yield.Method B: Into a 20-mm culture tube with capacity to 15 mL andcharged with a solution of the alcohol 1b (3 mmol, 320 μL) in MeCN(2 mL), were sequentially added TEMPO (300 μL of a 0.1 M solution inacetonitrile, 1.0 mol%) and CuCl2/TMEDA (15 μL of a 0.1 M solution inacetonitrile, 0.1 mol%) via syringe in one portion. The reaction wasstirred at 25 C under bubbled atmospheric air in an opened flask andmonitored by GC/FID, where within 2 h, the total conversion of 1b wasconfirmed. Finally, the crude material was filtered off in a minimalamount of silica gel (ca. 10 mg) furnishing 2b in 98 % of yield. Thereactions using either Method A or Method B were able to produce 2bwith the same yield. A detailed solvent effect study and a scalable procedurecan be found in S.I. Moreover, the values of TON/TOF/E-factorare given in the Table 2.
92%
With dipotassium peroxodisulfate at 40℃; for 0.0833333h; Ionic liquid;
91%
With potassium phosphate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In tetrahydrofuran at 65℃; for 12h;
91%
With Dess-Martin periodane In dichloromethane for 1h;
To a solution of benzyl alcohol 4 (1.5 g, 8.9 mmol, 1 equiv.) inmethylene chloride (20 mL) was added Dess-Martin periodinane (3.8 g, 8.9 mmol,1 equiv.) at which point the reaction turned a cream colour. After 1 h thereaction mixture was filtered through Celite, rinsing with diethyl ether. Thecombined organic layers were subsequently washed with water, dried over sodiumsulphate anhydrous and concentrated under reduced pressure to afford the titlecompound. Yield 91%, White solid; Mp 43-44 °C {lit. [i]44-45 °C}; TLC (EtOAc/Hexane, 1:4 v/v): Rf = 0.40; 1H-NMR[CDCl3, 600 MHz] δ: 9.91 (s, 1H), 7.01 (d, J = 2.4 Hz, 2H), 6.71 (t, J= 2.2 Hz, 1H), 3.85 (s, 6H); 13C-NMR [CDCl3, 150 MHz] δ: 192.1,161.4, 138.6, 107.3(5) 107.2(9) 55.8.[i] Varseev, G. N.; Maier, M. E. Angew.Chem. Int. Ed. 2006, 45, 4767.
91%
With C30H56AgN4(1+)*C2F3O2(1-); potassium <i>tert</i>-butylate In toluene at 20℃; for 4h; Darkness;
90%
With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 1h;
General procedure I: Oxidation using Dess-Martin Periodinane (DMP)
General procedure: To a solution of alcohol (1.0 equiv) in DCM (2.2 mL per mmol of alcohol) was added DMP (1.2 equiv) at 0 °C. The reaction was then stirred at rt for 1 h.The reaction mixture was filtered through celite and the filter cake was washed with Et2O then H2O. The filtrate was concentrated in vacuo to afford the desired aldehyde.
89%
With potassium phosphate; carbon dioxide In dimethyl sulfoxide at 90℃; for 48h;
88%
With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78 - 25℃; for 6.5h;
87%
With sodium acetate; pyridinium chlorochromate In dichloromethane for 16h;
86%
With Quinuclidine; (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile; tetrabutylammonium dihydrogen phosphate In dimethyl sulfoxide; acetonitrile at 20℃; for 10h; Molecular sieve; Irradiation; Sealed tube; Green chemistry;
3. General procedure for oxidation of benzylic primary and secondary alcohols
General procedure: In a dry tube containing 4CzlPN (4.7 mg, 3mol%), quinuclidine (2.2mg, 10mol%), Bu4NH2PO4 (17mg, 25 mol%), MS (200 mg) in MeCN (1 ml) and DMSO (0.1 mL), benzyl primary and secondary alcohols (0.20 mmol) was added. The tube was sealed with an air balloon, and was left stirring under blue LEDs irradiation for 10 h. The desired product was isolated after purification by column chromatography.
85%
With dipyridinium dichromate In dichloromethane at 20℃; for 24h;
81%
With pyridine; chromium(VI) oxide In dichloromethane at 20℃; for 24h;
81%
With pyridinium chlorochromate In dichloromethane at 20℃;
77%
With C16H13ClIrNO(1-); sodium hydrogencarbonate In para-xylene for 20h; Reflux; Inert atmosphere;
71%
With m-iodosylbenzoic acid In water; acetonitrile at 20℃; for 3h;
17%
With [RhCl2(p-cymene)]2; water; sodium pivalate In tert-Amyl alcohol at 100℃; for 24h; Electrolysis;
With dicopper(II) pyrazole In acetonitrile at 30℃;
With potassium dichromate; sulfuric acid
With manganese(IV) oxide In chloroform
4.37 g
With pyridine; chromium(VI) oxide In dichloromethane for 0.25h; Ambient temperature;
With manganese(IV) oxide In toluene for 15h; Reflux;
With pyridinium chlorochromate
Multi-step reaction with 2 steps
1: CuO*Fe3O4; sodium hydroxide / toluene / 96 h / 100 °C / Inert atmosphere
2: hydrogenchloride; water / toluene; diethyl ether / 2 h / 20 °C / Inert atmosphere
> 99 %Chromat.
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; Ir(4,4'-di-tert-butyl-2,2'-bipyridyl)(2-phenylpyridine)<SUB>2</SUB>(PF<SUB>6</SUB>); tetrabutyl-ammonium chloride; oxygen; sodium hydrogencarbonate In dichloromethane; water at 20℃; for 48h; Irradiation; Green chemistry; chemoselective reaction;
With C19H18CrN4O3(2+)*2BF4(1-) In acetonitrile at -40.16℃;
2.57 g
With pyridinium chlorochromate In dichloromethane at 20℃; for 24h;
1.25 g
With dipyridinium dichromate In dichloromethane at 20℃; for 5h;
3.6
To a solution of 3,5-dihydroxybenzoic acid (2.00 g, 13.0 mmol) in DMF were added K2CO3 (27.0 g, 0.195 mol), CH3I (20.2 ml, 0.325 mol) and the mixture was stirred under reflux for 1h. The mixture was filtered and the filtrated solvent was evaporated in vacuo. The residue was dissolved in CH2Cl2, and the organic layer was washed with H2O and then dried over MgSO4. The solvent was evaporated in vacuo and the resulting precipitate was purified by silica-gel column chromatography (hexane:AcOEt=4:1) to give methyl ester (2.11 g, 10.7 mmol). To a solution of methyl ester (2.11 g, 10.7 mmol) in THF was added to LiAlH4 (0.812 g, 21.4 mmol) at 0. After being stirred for 1h at room temperature, H2Oand 1M NaOH added to the solution. The mixture was filtered and the organic layer was evaporated in vacuo to yield alcohol (1.40 g, 8.32 mmol). To a solution of alcohol (1.40 g, 8.32 mmol) in CH2Cl2 was added PDC (4.96 g, 8.32 mmol) and the mixture was stirred at room temperature for 5h. The mixture was filtered and the solvent was evaporated in vacuo. The residue was purified by silica-gel column chromatography (hexane:AcOEt=4:1) to give benzaldehyde (1.25 g, 7.52 mmol). To a solution of benzaldehyde (1.25 g, 7.52 mmol) were added ethyldiethylphosphonoacetate (3.01 ml, 15.4 mmol) and NaH (0.330 g, 8.27 mmol) at 0. After being stirred for 1h at room temperature, AcOEt and H2O were added to the solution. The organic layer was evaporated in vacuo and the residue was purified by silica-gel column chromatography (hexane:AcOEt=4:1) to give unsaturated ethyl ester (0.540 g, 2.03 mmol). To a solution of unsaturated ethyl ester (0.540 g, 2.03 mmol) in MeOH was added LiOH-H2O (1.22 g, 29.1 mmol).After being stirred under reflux for 2h, 1M HCl aq. and AcOEt were added to the mixture. The organic layer was washed with H2O and brine. The solvent was evaporated in vacuo to yield unsaturated carboxyl acid (1.35 g, 6.48 mmol, 89 %) as a white powder.
With dipyridinium dichromate In dichloromethane
With galactose oxidase M<SUB>3-5</SUB> from Fusarium; dihydrogen peroxide; copper(II) sulfate; catalase; horseradish peroxidase In aq. phosphate buffer; dimethyl sulfoxide at 20℃; Flow reactor; Enzymatic reaction;
With pyridinium chlorochromate In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere;
1,3-dimethoxy-5-vinylbenzene (29)
To a solution of alcohol 28 (4.5 g, 26.7 mmol) in DCM (50 mL) was added a suspension of PCC (11.5g, 53.5 mmol) in CH2Cl2 (100 mL) at 0 °C. The resulting mixture was stirred at room temperature until complete consumption of the starting material. The reaction was diluted with diethylether (150 mL) and filtered through a small pad of celite (with diethylether rinsing). The solvent was removed under reduced pressure at room temperature. The product was used without purification for the next step. KtOBu (5.49 g, 49.0 mmol) was added in one portion to a stirred suspension of methyltriphenylphosphonium iodide (22.6 g, 55.7 mmol) in dry diethyl THF (100 mL). The mixture was stirred for 2 h at room temperature and then cooled to 0 °C, followed by the addition of a solution of 3,5-dimethoxybenzaldehyde (3.7g, 22.0 mmol) in dry THF (40 mL) at the same temperature. The cooling bath was removed and the mixture was allowed to come to room temperature. Next, the reaction was quenched by addition of dry NH4Cl (10 mL). The solvents were removed under reduced pressure and the residue was passed through a short pad of silicagel (Hexanes/EtOAc) to afford 3,5-dimethoxystyrene 29 (3.2 g, 74% over two steps) as a colorless oil
With polymeric carbon nitride with hydrogen peroxide adduct In water for 4h; UV-irradiation;
With [bis(acetoxy)iodo]benzene; potassium bromide In 1,4-dioxane; water at 30℃; for 0.25h;
With [Ru(IV)(O)(N-methyl-N,N-bis(2-pyridylmethyl)amine)(2,2′-bipyridyl)](2+) In acetonitrile at 24.84℃;
With sodium tetrahydroborate; In methanol; at 20℃; for 1h;
General procedure: benzaldehyde derivatives (1 mmol) in methanol (15 mL), sodium borohydride (2 mmol) and stirred at room temperature for 1 h. Usual work-up, quantitative yield.
99%
With sodium tetrahydroborate; In methanol; at 0℃; for 0.5h;
NaBH4 (1.11 g, 30.0 mmol, 2.0 equiv) was added slowly to a solution of3, 5-dimethoxybenzaldehyde (2.44 g, 15.0 mmol, 1.0 equiv) inMeOH (30 mL) at 0 0C. After 30 min of stirring at 0 0C, the reaction contents were quenched by the slow addition of water (20 mL) , poured into water (10 mL) , and extracted with EtOAc (3 x 20 mL) . The combined organic layers were then washed with water (20 mL) and brine (20 mL) , dried(MgSO4) , and concentrated to afford the desired alcohol intermediate (2.43 g, 99% yield) as a white solid which was carried forward without further purification. Next, pyridine (0.017 mL, 0.212 mmol, 0.05 equiv) and PBr3 (0.400 mL, 4.25 mmol, 1.0 equiv) were added sequentially and <n="339"/>slowly to a portion of this newly-formed alcohol (0.715 g, 4.25 mmol, 1.0 equiv) in Et2O (20 inL) at 25 0C, and the resultant mixture was heated at 40 0C for 3 h. Upon completion, the reaction contents were quenched carefully with ice water (15 mL) , poured into water (10 mL) , and extracted with Et2O (3 x 20 mL) . The combined organic layers were then washed with water (15 mL) and brine (15 mL) , dried (MgSO4), and concentrated to afford alkyl halide Sl (1.50 g, 93% yield) as an amorphous white solid which was carried forward without additional purification. Sl: Rf = 0.66 (silica gel, EtOAc/hexanes, 1:1); IR (film) vraakappa 3002, 2960, 2838, 1597, 1465, 1429, 1348, 1325, 1300, 1264, 1206, 1158, 1064, 992, 931, 836, 693, 650; 1H NMR (300 MHz, CDCl3) delta 6.54 (d, J = 2.1 Hz, 2 H), 6.39 (t, J = 2.1 Hz, 1 H), 4.42 (s, 2 H), 3.80 (s, 6 H); 13C NMR (75 MHz, CDCl3) delta 160.9, 139.7, 107.0 (2 C), 100.6, 55.4 (2 C), 33.6; HRMS (MALDI-FTMS) calculated for C5H11BrO2+ [M+] 229.9942, found 229.9937.
95%
With tetrakis[3,5-bis(trifluoromethyl)phenyl]boric acid bis(diethyl ether) complex; (bis[(2-dicyclohexylphosphino)ethyl]amine)cobalt(II)(CH2SiMe3); hydrogen; In tetrahydrofuran-d8; at 25℃; under 760.051 Torr; for 48h;
General procedure: Under nitrogen, complex 1(6.1 mg, 10.0 tmol) and H[BAr?4].(Et2O)2 (10.1 mg, 10.0 jtmol) were dissolved in THF (2.0 mL) in a thick-walled glass vessel equipped with a TEFLON stopper and a stir bat Styrene (52.0 mg, 0.5 mmol) and Hg (606 mg, 3 mmol) were then added and hexamethylbenzene (0.1 mmol) was also added as internal standard. The bottle was degas sed by freeze-pump-thaw and charged with 1 atm of hydrogen gas. The resulting solution was stirred at 25 C. for 24 hours, afier which time the reaction mixture was exposed to air and diluted with dichloromethane. GC analysis revealed quantitative conversion to ethylbenzene.
94%
With sodium tetrahydroborate; In methanol; at 20℃; for 2h;
To an ice cold solution of 3,5-dimethoxybenzaldehyde (3) 10 g (60.175 mmol) inmethanol (100 mL) was added in small portions sodiumborohydride (179.751 mmol), and the mixture was stirredfor 2 h at rt. Methanol was distilled off under vacuum, andthe product diluted with cold water, and the solution wasextracted with EtOAc. The EtOAc layer was successivelywashed with water, 10 % sodium bicarbonate and brine.The organic layer was dried over Na2SO4, and evaporatedunder vacuum obtaining the compound (4) as a white solid.(3,5-Dimethoxyphenyl)methanol (4) White solid; Yield:94 %; mp 47-49 C;1H NMR (CDCl3, 500 MHz): delta 6.55-6.53 (2H, m, H-2, H-6), 6.42-6.40 (1H, m, H-4),4.52 (2H, s, -CH2-OH), 3.80 (6H, s, 2 X O-CH3); 13CNMR (CDCl3, 75 MHz): delta 160.9 (C, C-3, C-5), 143.6 (C,C-1), 104.6 (CH, C-2, C-6), 99.6 (CH, C-4), 65.1 (H2C-OH), 55.3 (O-CH3); for C9H12O3 MS (ESI) m/z) 169[M + H]+.
With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 2h;
To a stirred solution of 3,5-dimethoxybenzaldehyde (33.23 g, 200 mmol ) in 400 ml methanol, NaBH4 (15.13 g, 400 mmol ) was added in batches at 0oC. The reaction mixture was slowly warmed to room temperature and stirred for another 2 hours. The solvent was evaporated under vacuum and the residue was extracted with EtOAc, washed by water, dried over Na2SO4, and concentrated to give (3,5-dimethoxyphenyl)methanol (2) as white solid (32.6g, 97% yield). The product was used directly in the next step without further purification. 1H NMR (400 MHz, CDCl3) delta 6.52 (d, J = 1.6 Hz, 2H), 6.39 (s, 1H), 4.63 (d, J = 5.6 Hz, 2H), 3.79 (s, 6H
With sodium tetrahydroborate; In methanol; at 20℃; for 1h;Inert atmosphere;
General procedure: The carbonyl compound (1 mmol) and NaBH4 (2 mmol) were taken in a two-neck round bottomed flask and flashed with nitrogen gas. Then 5 mL of methanol was added to it and stirred at room temperature for 1h. After completion of the reaction, methanol was evaporated under reduced pressure and then the reaction mixture was diluted with saturated ammonium chloride solution and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, evaporated under reduced pressure. Then the crude product was purified by column chromatography using silica gel (60-120 mesh) and hexane/EtOAc as eluent.
With sodium tetrahydroborate; In ethanol; at 0℃; for 1h;Inert atmosphere;
To a mixture of 3,5-dimethoxybenzaldehyde (4.00 g, 24.1 mmol, 1.00 eq) in EtOH (40.0 mL) was added NaBH4 (1.82 g, 48.1 mmol, 2.00 eq) slowly at 0 C. The mixture was stirred at 0 C for 1 hour. TLC showed the starting material was consumed and a new spot with large polarity was detected. The reaction mixture was quenched by addition saturated NH4Cl aqueous solution (50 mL) at 0 C, and concentrated under reduced pressure to give a residue, then extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (20 mL × 2), then extracted with EtOAc (30 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a yellow liquid (4.92 g, crude). The crude product was not further purified and used for next step.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 1.33333h;Inert atmosphere;
Under N2 atmosphere, a solutionof LiAlH4 (2.1041 g, 55.44 mmol)in anhydrous THF (100 mL) wasadded dropwise to a solution of3,5-dimethoxybenzoic acid (11)(10.0 g, 54.9 mmol) in anhydrous THF (150 mL) at 0 C.After stirring for 20 min at 0 C and one hour at roomtemperature, the reaction was diluted with THF (90 mL)and water (4 mL) was added. The mixture was thenfiltered on celite, washed with ethyl acetate (4 × 65 mL)and concentrated under reduced pressure. The resultingclear yellow solid (9.14 g, 54.5 mmol, 99% yield) wasapplied to the next reaction without further purification. mp50.2-51.1 C; 1H NMR (300 MHz, CDCl3) delta 1.90 (s, 1H, OH), 3.80 (s, 6H, Ar-OCH3), 4.63 (s, 2H, Ar-CH2), 6.39 (t,1H, J 2.3 Hz, Ar-H), 6.53 (d, 2H, J 2.3 Hz, Ar-H); 13C NMR(126 MHz, CDCl3) delta 55.4 (2C), 65.4, 99.7, 104.6 (2C),143.4, 161.0 (2C); low resolution (LR)MS (EI (electronionization)) m/z 168 (M+, 100), 151 (12), 139 (45), 109(15). The spectra of compound 10 is in accordance withthose previously reported.33
92%
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 1h;Inert atmosphere;
3,5-dimethoxybenzoic acid 10 (6 g, 32.0 mmol) was added at 0 C to a stirred suspension of LAH (2.4g, 65.0mmol) in dry THF(120mL). The mixture was stirred at 0 C for 1 h and the reaction mixture was then carefully quenched with sat. Na2SO4 solution. It was then filtered and the solid was extracted with hot diethyl ether and concentrated under reduced pressure to furnish almost pure (3,5-dimethoxyphenyl) methanol 28 as a colorless oil, which crystallized when stored (5.0 g, 92% yield). Mp : 48-50 C. IR (KBr): numax 3400, 2940, 2839, 1596, 1461, 1429, 1201, 1151, 1061, 1035, 831, 691, 661 cm-1. 1H NMR (CDCl3, 300 MHz): delta/ppm = 6.50 (d, J = 2.3 Hz, 2H), 6.37 (t, J = 2.2, 4.5 Hz, 1H), 4.59 (bs, 2H ), 3.77 (s, 6H), 2.20 (brs, 1H). 13C NMR (CDCl3, 75 MHz): delta/ppm = 166.2, 164.6, 162.3, 156.4, 106.0, 97.0, 95.2, 91.2, 25.0 ppm. HRMS (ESI): calcd for C9H13O3 [M+H]+: 169.0859, found: 169.0866.
91%
With lithium aluminium tetrahydride; In tetrahydrofuran; for 13h;Reflux;
To a stirring solution of LiAlH4 (1.1-2.2 equiv) in anhydrous THF (1.0 mL per mmol of lactone, acid, diacid or phthalic anhydride) was added a solution of lactone, acid, diacid or phthalic anhydride (1.0 equiv) in anhydrous THF (0.5 mL per mmol of lactone, acid, diacid or phthalic anhydride) dropwise at 0 C. The reaction mixture was refluxed under a nitrogen atmosphere for 13-18 h. Upon completion of the reaction, the remaining LiAlH4 was quenched at 0 C using water (1.0 mL per gram of LiAlH4), an aqueous solution of NaOH (15 %, 2.0 mL per gram of LiAlH4) and H2O (3.0 mL per gram of LiAlH4). The organics were extracted with EtOAc, combined, washed with brine, dried over MgSO4 and concentrated in vacuo to afford the desired product.
90%
To a solution of 3,5-dimethoxybenzoic acid (5.00 g, 27.5 mmol, 1.0 eq.) in dry THF (25 mL) cooled to 0 C was added NaBH4 (1.28 g, 34.0 mmol, 1.02 eq.). The solution was stirred until evolution of H2 stopped, and BF3*OEt2 (4.30 mL, 34.0 mmol, 1.02 eq) was added dropwise. The reaction was stirred at r.t. for 24 h. Upon completion, the reaction mixture was acidified with conc. HCl, and 50 mL DI H2O was added. The solution was extracted with EtOAc (3 x 25 mL), and the combined organic layers were washed with sat'd. aq. Na2CO3 (2 x 25 mL), sat'd aq. NaCl (1 x 50 mL) and dried over MgSO4. Recrystallization of the crude product from hexane provided the alcohol (4.16 g, 90%, m.p. 39-40 C, lit.[S3] m.p. 48-49 C) as white needles.
General procedure: benzyl alcohols (1 mmol) in dry benzene (15 mL) and phosphorus tribromides (0.5 mL) and stirred at room temperature to get respective benzyl bromides in quantitative yields, usual work-up.
> 99%
With phosphorus tribromide; In 1,4-dioxane; at 40℃; for 1h;Inert atmosphere;
Under N2 a t m o s p h e r e ,phosphorus tribromide (618 muL,6.58 mmol) was added dropwiset o a s o l u t i o n c o n t a i n i n g(3,5-dimethoxyphenyl)methanol(10) (1.00 g, 5.98 mmol) in dioxane (8 mL). The solutionwas stirred at 40 C for 1 h. After cooling to roomtemperature the reaction was quenched with a saturatedNaHCO3 solution (28 mL) and the resulting aqueousphase was extracted with ethyl acetate (3 × 28 mL). Thecombined organic extracts were dried with Na2SO4, filteredand concentrated under reduced pressure. The resultinglight yellow solid (1.38 g, 5.9 mmol, > 99% yield) wasapplied to the next reaction without further purification.mp 72.9-73.8 C; 1H NMR (500 MHz, CDCl3) delta 3.79 (s,6H, Ar-OCH3), 4.42 (s, 2H, Ar-CH2), 6.39 (t, 1H, J 2.2 Hz,Ar-H), 6.54 (d, 2H, J 2.2 Hz, Ar-H); 13C NMR (126 MHz,CDCl3) delta 33.6, 55.4 (2C), 100.6, 106.9 (2C), 139.7, 160.9(2C); LRMS (EI) m/z 232 (M+, 30), 230 (27), 152 (15),151 (100). The spectra of compound 12 is in accordancewith those previously reported.34
98%
With pyridine; phosphorus tribromide; In diethyl ether; at 35℃; for 3h;Inert atmosphere;
To a solution of 3,5-dimethoxybenzylalcohol (1.5g, 8.918 mmol) in diethyl ether (45mL) under argon atmosphere was added pyridine (0.034mL, 0.445 mmol). Subsequently, phosphorous tribromide (0.83mL, 8.918 mmol) was added dropwise and the resulting reaction mixture was warmed to 35C and stirred at that temperature for 3h. The reaction mixture was quenched with slow addition of ice-cold water and diluted with ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate (3x30mL). The organic phase was washed with brine, dried over Na2S04, filtered, and concentrated to afford the title compound (2.0g, yield: 98%) as a white solid. 1H-NMR (D -d6, 300MHz): delta 6.54 (d, 2H), 6.39 (t, 1H), 4.42 (s, 2H), 3.79 (s, 6H).
97%
With pyridine; phosphorus tribromide; In dichloromethane; at 0 - 20℃; for 4h;
PBr3 (18 ml) was added dropwise to a solution of 2 (32.6 g, 194 mmol) and pyridine (0.78 ml) in CH2Cl2 at 0. After the mixture was slowly warmed to room temperature and stirred for 4 h, the reaction was quenched by the slowly addition of ice water, extracted with CH2Cl2, washed with brine, dried over Na2SO4, and concentrated to provide 1-(bromomethyl)-3,5-dimethoxybenzene (3) as white solid ( 43.4g, yield 97%). 1H NMR (400 MHz, CDCl3) delta 6.54 (s, 2H), 6.39 (s, 1H), 4.42 (s, 2H), 3.79 (s, 6H).
97%
With phosphorus tribromide; In diethyl ether; at 0℃; for 0.5h;
PBr3 (3.10 mL) was addeddrop wise to a solution of (4) 9 g (53.545 mmol) in diethylether at 0 C. The mixture was stirred at 0 C for 30 min,and after completion of the reaction (monitored by TLC),the reaction mixture was quenched by slow addition ofpotassium bromide solution, extracted with diethyl ether,washed with brine, dried over Na2SO4 and concentrated toprovide the product (5).1-(Bromomethyl)-3,5-dimethoxybenzene (5) White solid;Yield: 97 %; mp 68-70 C;1H NMR (CDCl3, 400 MHz): delta 6.55-6.53 (2H, m, H-2, H-6), 6.40-6.38 (1H, m, H-4),4.42 (2H, s, -CH2-Br), 3.79 (6H, s, 2 X O-CH3); 13C NMR(CDCl3, 75 MHz): delta 161.1 (C, C-3, C-5), 139.7 (C, C-1),106.1 (CH, C-2, C-6), 98.2 (CH, C-4), 55.5 (O-CH3), 30.5(H2C-Br); for C9H11BrO2 MS (ESI) (m/z) 230 [M + H]+.
93%
With pyridine; phosphorus tribromide; In diethyl ether; at 25 - 40℃; for 3h;
NaBH4 (1.11 g, 30.0 mmol, 2.0 equiv) was added slowly to a solution of3, 5-dimethoxybenzaldehyde (2.44 g, 15.0 mmol, 1.0 equiv) inMeOH (30 mL) at 0 0C. After 30 min of stirring at 0 0C, the reaction contents were quenched by the slow addition of water (20 mL) , poured into water (10 mL) , and extracted with EtOAc (3 x 20 mL) . The combined organic layers were then washed with water (20 mL) and brine (20 mL) , dried(MgSO4) , and concentrated to afford the desired alcohol intermediate (2.43 g, 99% yield) as a white solid which was carried forward without further purification. Next, pyridine (0.017 mL, 0.212 mmol, 0.05 equiv) and PBr3 (0.400 mL, 4.25 mmol, 1.0 equiv) were added sequentially and <n="339"/>slowly to a portion of this newly-formed alcohol (0.715 g, 4.25 mmol, 1.0 equiv) in Et2O (20 inL) at 25 0C, and the resultant mixture was heated at 40 0C for 3 h. Upon completion, the reaction contents were quenched carefully with ice water (15 mL) , poured into water (10 mL) , and extracted with Et2O (3 x 20 mL) . The combined organic layers were then washed with water (15 mL) and brine (15 mL) , dried (MgSO4), and concentrated to afford alkyl halide Sl (1.50 g, 93% yield) as an amorphous white solid which was carried forward without additional purification. Sl: Rf = 0.66 (silica gel, EtOAc/hexanes, 1:1); IR (film) vraakappa 3002, 2960, 2838, 1597, 1465, 1429, 1348, 1325, 1300, 1264, 1206, 1158, 1064, 992, 931, 836, 693, 650; 1H NMR (300 MHz, CDCl3) delta 6.54 (d, J = 2.1 Hz, 2 H), 6.39 (t, J = 2.1 Hz, 1 H), 4.42 (s, 2 H), 3.80 (s, 6 H); 13C NMR (75 MHz, CDCl3) delta 160.9, 139.7, 107.0 (2 C), 100.6, 55.4 (2 C), 33.6; HRMS (MALDI-FTMS) calculated for C5H11BrO2+ [M+] 229.9942, found 229.9937.
92%
With phosphorus tribromide; In tetrahydrofuran; at -10℃;
Phosphorus tribromide (0.4 eq) was added to the alcohol 304 (25 g, 0.13 mol) in THF (100 mL) very slowly at -10 C. and the mixture which resulted was stirred for 15-30 min at the same temperature. By this time all the starting material had disappeared (TLC). The reaction mixture was quenched by addition of ice-cold H2O (100 mL) and then filtered through a Buchner funnel. The filtrate was diluted with brine (100 mL) and extracted with EtOAc (3*300 mL). The combined organic extracts were dried (Na2S0.4) and concentrated in vacuum. The crude oil was purified by FCC (20% ethylacetate in hexane) to afford the bromide 305 as a white solid (92%)a.: 1HNMR (500 MHz, CDCl3) delta 6.61(2H, d, J=2.3 Hz), 6.46 (1H, t, J=2.3 Hz), 4.5 (2H, s), 3.85 (61-1, s). 13C NMR (125 MHz, CDCl3): delta 161.3, 140.2, 107.4, 101.0, 55.8, 34.1. The spectral data for 305 were in excellent accord with data previously reported on it (Seidel et al., 1990)1, This material was employed directly in the next step.
85.4%
With phosphorus tribromide; In dichloromethane; at 20℃;Inert atmosphere; Cooling with ice;
In an ice bath and argon,Was dissolved in 20mL of dry CH2Cl2 4.088g (0.024mol) 3,5- dimethoxybenzene in 100mL methanol 3 neck round bottom flask,Slowly by syringe while stirring was dissolved in 10mL of dichloromethane was added dropwise a solution of 2.54mLPBr3,After 2h the reaction into an ice bath at room temperature,The reaction was continued 2-3h,TLC tracking and detection,The completion of the reaction, etc. The reaction solution was poured into ice water 50mL,Stirring,Lower for the milky white liquid,Plus sodium bicarbonate adjusted to pH 7,After separation of the aqueous layer was extracted with ethyl acetate,Dried over anhydrous sodium sulfate,The solvent was distilled off under reduced pressure,Dried to give compound 4The yield was 85.4%,
78%
With 1H-imidazole; bromine; triphenylphosphine; In dichloromethane; at 0 - 20℃; for 24h;
To a dry 250 mL rbf charged with 125 mL dry CH2Cl2 cooled to 0 C was added in order, PPh3 (7.59 g, 28.9 mmol, 1.2 eq.), imidazole (1.97 g, 28.9 mmol, 1.2 eq.), Br2 (1.50 mL, 28.9 mmol, 1.2 eq.) and 3,5-dimethoxybenzyl alcohol (4.06 g, 24.1 mmol, 1.0 eq.). The reaction was stirred at r.t. for 24 h. Workup provided 3,5-dimethoxybenzyl bromide (4.35 g, 78%) as a colourless oil.
With phosphorus tribromide;
A) 22 g of 3,5-dimethoxybenzyl alcohol were reacted with 50 ml of phosphorus tribromide with ice cooling and the reaction mixture was heated for 30 minutes at 80 C. For workup, the reaction mixture was poured into ice water and extracted with methyl-tert-butyl ether. The organic phases were combined, dried, and concentrated. 23 g of 3,5-dimethoxybenzyl bromide were obtained as an oil.
With phosphorus tribromide; In dichloromethane; at 0 - 5℃; for 0.75h;
General procedure: crude product 2a which was then dissolved in anhydrous methylene chloride (50 mL) and cooled to 0-5 ºC by ice bath. To this solution was added dropwise phosphorus tribromide (0.5 mL, 5 mmol) over a period of 15 min and stirred for 0.5 h at the same temperature, and then washed with saturated brine (3 Chi 15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound 3a.
With sodium tetrahydridoborate In methanol; 1,2-dimethoxyethane for 3h; Heating;
99%
With lithium aluminium hydride In diethyl ether at 0℃; for 1h;
98%
With lithium aluminium hydride In diethyl ether Heating;
98%
With lithium aluminium hydride In tetrahydrofuran at 0 - 20℃; for 2h; Inert atmosphere;
97%
With lithium aluminium hydride In diethyl ether for 15h; Ambient temperature;
97%
With lithium aluminium hydride In tetrahydrofuran
97%
With lithium aluminium hydride In tetrahydrofuran at -20 - 20℃; for 12h;
96%
With lithium aluminium hydride In tetrahydrofuran
95%
With lithium aluminium hydride In tetrahydrofuran at 0℃; for 0.5h;
95%
Stage #1: 3,5-dimethoxybenzoic acid methyl ester With lithium aluminium hydride In tetrahydrofuran at 25℃; Cooling with ice;
Stage #2: With water monomer; sodium hydroxide In tetrahydrofuran at 20℃; for 8h;
3,5-Dimethoxybenzyl alcohol (4)
A round-bottomed flask (3 L) equipped with magnetic stirring bar and reflux condenser was charged with LAH (19 g, 500 mmol, 1 equiv). An addition funnel (500 mL) with N2 bubbler was connected to the top of the condenser. The addition funnel was charged anhydrous THF (500 mL) which was slowly added to the LAH to make a slurry. The reaction flask was cooled in an ice bath and the addition funnel was next charged with a solution of 3 (98 g, 500 mmol) in anhydrous THF (500 mL). The addition was made in a gentle stream so that the internal temperature did not exceed 25 °C. After the addition, the mixture was stirred overnight at rt. The mixture was cooled once again and carefully quenched by the sequential addition of: 1) H2O (19 mL); 2) 15% aqueous NaOH (19 g); 3) H2O (57 mL). After stirring 8 h at rt, the mixture was filtered through a medium porosity glass frit. The mixture was diluted with H2O (2 L) and extracted with Et2O (3 X 500 mL). The extracts were collected and washed with H2O (500 mL) followed by brine (500 mL). After drying over anhydrous MgSO4, the solvent was rotary evaporated leaving compound 4 as an off-white solid that did not require further purification. (79 g, 95%) Mp 46-48 °C [lit.Mauthner 47-48 °C]. 1H NMR (CDCl3): δ 6.47 (d, J = 2.3 Hz, 2H), 6.34 (t, J = 2.3 Hz, 1H), 4.55 (s, 2H), 3.74 (s, 6H), 2.79 (s, OH); 13C NMR (CDCl3): δ 160.99, 143.61, 104.66, 99.64, 65.14, 55.39. Elemental analysis calculated for C9H12O3: C, 64.27; H, 7.19. Found: C, 64.41; H, 7.03.
95%
With lithium aluminium hydride In tetrahydrofuran at 25℃; for 4.5 - 5.5h; Reflux;
93%
With lithium aluminium hydride In diethyl ether at 20℃; for 6h; Inert atmosphere;
93%
With sodium tetrahydridoborate In tetrahydrofuran; methanol at 70℃; for 2.5h;
92%
With lithium aluminium hydride In tetrahydrofuran for 10h; Ambient temperature;
92%
With lithium aluminium hydride In diethyl ether
92.3%
With lithium aluminium hydride In diethyl ether for 4h; Heating;
92.3%
With lithium aluminium hydride In diethyl ether for 4h; Reflux;
92%
With lithium aluminium hydride In tetrahydrofuran at 0 - 20℃; for 2.16667h;
91%
With lithium aluminium hydride In tetrahydrofuran at 20℃; for 6h; Inert atmosphere;
(2-bromo-3,5-dimethoxyphenyl) methanol (15)
To a 100 mL round bottom flask was added LAH (0.89 g, 23.45 mmol, 1.5 eq) in THF(55 mL). 14 (3.1 g, 15.8 mmol, 1.0 eq) in THF (10 mL) was added to solution by cannulaat 0 . The reaction mixture was stirred at room temperature for 6 hours. Aftercompletion of reaction (TLC), the reaction mixture was diluted with water (40 mL) andether (50 mL). The organic layer was separated and further extracted three times withethyl ether (30 mL x 3). The combined organic layer was washed with saturated NaClsolution (50 mL), dried over anhydrous MgSO4, and filtered, and the solvent was removedat reduced pressure to yield a product (3,5-dimethoxyphenyl) methanol (2.41 g, 14.33mmol, 91%, colorless liquid); 1H NMR (400 MHz, CDCl3) δ 6.55 - 6.50 (m, 2H), 6.39 (t, J =2.3 Hz, 1H), 4.64 (s, 2H), 3.79 (s, 6H). To a 250 mL round bottom flask was added (3,5-dimethoxyphenyl) methanol (2.41 g,14.33 mmol, 1.0 eq) in CHCl3 under argon atmosphere. N-bromosuccinimide (2.55 g,14.33 mmol, 1.0 eq) was added to solution at 0 . After stirring for 2 hours at ambienttemperature, add saturated NaHCO3/Na2S2O3 solutions (1:1, 100 mL in total) and dilutedwith water (40 mL) and methylene chloride (50 mL). The organic layer was separated andfurther extracted three times with methylene chloride (30 mL x 3). The combined organiclayer was washed with saturated NaCl solution (50 mL), dried over anhydrous MgSO4, andfiltered, and the solvent was removed at reduced pressure to yield a product 15 (3.15 g,12.75 mmol, 89 %, white solid); 1H NMR (400 MHz, CDCl3) δ 6.70 (d, J = 2.8 Hz, 1H), 6.44(d, J = 2.8 Hz, 1H), 4.73 (s, 2H), 3.87 (s, 3H), 3.82 (s, 3H)
82%
With lithium aluminium hydride In tetrahydrofuran at 0 - 20℃; for 3h;
3,5-Dimethoxy Benzylalcohol (304)
Ester 303 (25 g, 0.13 mol) in THF (50 mL) was added slowly to a dry stirred suspension of LiAlH4 (7.25 g 0.19 mol) in THF (550 mL) at 0° C., The reaction mixture was stirred for 3 h at rt at which time all the starting material had disappeared (TLC), The reaction mixture was quenched by addition of ice-cold H2O (1.0 eq), 10% act NaOH (3.0 eq), and H2O (1.0 eq), sequentially and then filtered through a Buchner funnel. The filtrate was diluted with brine (800 mL) and extracted with EtOAc (3*300 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuum. The crude oil was purified by FCC (20% ethylacetate in hexane) to afford a yellow oily alcohol 304 (17.5 g, 82%): 1H NMR (300 MHz, CDCl3) δ 6.53 (2H, d, J=6.0 Hz HAr), 6.35 (1H, t, J=2.4 Hz, HAr), 4.49 (214, s, H2COH), 3.80 (611, s, H3CO).
81.1%
With lithium aluminium hydride In tetrahydrofuran at 20℃; for 4h; Inert atmosphere; Cooling with ice;
1 Synthesis of Intermediate 3,5-dimethoxyphenylmethanol 3
Under argon atmosphere and ice-cooling,Followed by lithium aluminum hydride was added 1.251g (0.033mol) in 100mL of anhydrous tetrahydrofuran and 20mL three-necked flask,Stirring,Dripped with a syringe 5.886g (0.03mol)Compound 2Tetrahydrofuran 20mL,The ice bath was removed,The reaction was continued at room temperature for 4h,TLC tracking and detection,And so the reaction was complete the reaction mixture was slowly poured into 200mL of ice water,Stirring,Flocculent precipitate,The precipitate was dissolved with dilute hydrochloric acid,Ethyl acetate,Dried over anhydrous sodium sulfate,Ethyl acetate was distilled off under reduced pressure,Dried to give compound 3,The yield was 81.1%,
80%
Stage #1: 3,5-dimethoxybenzoic acid methyl ester With phenylsilane; potassium hydroxide at 20℃; for 3h;
Stage #2: With hydrogenchloride; water monomer In tetrahydrofuran at 20℃; for 1h;
75%
Stage #1: 3,5-dimethoxybenzoic acid methyl ester With lithium aluminium hydride In tetrahydrofuran at 0 - 20℃; Inert atmosphere;
Stage #2: With water monomer In tetrahydrofuran; methanol; ethyl acetate at 0 - 20℃; Inert atmosphere; Molecular sieve;
With lithium aluminium hydride In diethyl ether
With lithium aluminium hydride
4.58 g
With lithium aluminium hydride In diethyl ether for 3h; Heating;
With lithium tetrahydridoborate
With lithium aluminium hydride
100 % Chromat.
With sodium tetrahydridoborate In methanol; 1,2-dimethoxyethane for 1h; Heating;
With lithium aluminium hydride In tetrahydrofuran at 20℃; for 4h;
With sodium tetrahydridoborate In tetrahydrofuran; methanol for 1.66667h; Reflux;
With lithium aluminium hydride In diethyl ether for 6h; Reflux; Inert atmosphere;
2 4.2. Synthesis of 3,5-dimethoxybenzyl chloride (2) [27]
To a suspension of AlLiH4 (0.6 g; 15.8 mmol) in dry ethyl eter (15 mL) under nitrogen atmosphere, a solution of commercial methyl-3,5-dimethoxybenzoate (1) (2 g; 10.0 mmol) in 10 mL of anhydrous ethyl eter was added dropwise with stirring. After 6 h of refluxing, the mixture was quenched with HCl 10% (20 mL). The organic layer was separated and dried over anhydrous MgSO4. The solvent was removed under reduced pressure and the crude product (1.71 g, quantitative yield, 10.2 mmol) was dissolved in CH2Cl2 (48 mL) under nitrogen atmosphere and, with magnetic stirring, tionyl chloride freshly distilled (1.5 mL; 20.4 mmol) was added dropwise. The reaction mixture was heated to reflux and then a solution of triethylamine (6 mL) in CH2Cl2 (48 mL) was added during 2 h. The reaction mixture was quenched with saturated NaHCO3 (100 mL) and was extracted with ether (40 mL * 3). The organic layer was separated and dried over anhydrous MgSO4 and concentrated. The crude residue was purified by flash column chromatography with alumina and 3,5-dimethoxybenzyl chloride (2) eluted as a yellowish solid (1.8 g, 9.6 mmol, 94%, m.p.: 45-46 °C, lit.
With sodium tetrahydridoborate In tetrahydrofuran; methanol for 1.66667h;
To a mixture of methyl ester 3 (12.0 g, 61.2 mmol, 1 equiv.) andNaBH4 (12.7 g, 336 mmol, 5.5 equiv.) in THF (260 mL) was added MeOH(74 mL) dropwise under reflux over 1 h. After heating under reflux for 40 min,the reaction was cooled down to room temperature, and the pH was adjusted to 7by the dropwise addition of 1 M HCl. The reaction mixture was filtered througha Celite pad. The filtrate was extracted with EtOAc (4 x 30mL), and thecombined organic extracts were washed with brine (100 mL), dried over Na2SO4,and concentrated under reduced pressure to give alcohol 4 which was used for the subsequent reaction without purification.An analytical quantity may be further purified by recrystallization fromcyclohexene. Yield 92%, White crystalline solid; Mp 47-48 °C {lit. [i]47-48 °C}; TLC (EtOAc/Hexane, 1:4 v/v): Rf = 0.08; 1H-NMR[CDCl3, 600 MHz] δ: 6.52 (d, J= 2.2 Hz, 2H), 6.39 (t, J = 2.2 Hz,1H), 4.64 (s, 2H), 3.80 (s, 6H); 13C-NMR [CDCl3, 150 MHz]δ: 161.2, 143.5, 104.7, 99.8, 65.6, 55.5.
With lithium aluminium hydride In tetrahydrofuran at 0 - 20℃; for 11h;
2.4 g
With lithium aluminium hydride In diethyl ether at 0℃;
1.4 g
With lithium aluminium hydride In tetrahydrofuran at 0 - 20℃; for 1h;
3.5
To a solution of 3,5-dihydroxybenzoic acid (2.00 g, 13.0 mmol) in DMF were added K2CO3 (27.0 g, 0.195 mol), CH3I (20.2 ml, 0.325 mol) and the mixture was stirred under reflux for 1h. The mixture was filtered and the filtrated solvent was evaporated in vacuo. The residue was dissolved in CH2Cl2, and the organic layer was washed with H2O and then dried over MgSO4. The solvent was evaporated in vacuo and the resulting precipitate was purified by silica-gel column chromatography (hexane:AcOEt=4:1) to give methyl ester (2.11 g, 10.7 mmol). To a solution of methyl ester (2.11 g, 10.7 mmol) in THF was added to LiAlH4 (0.812 g, 21.4 mmol) at 0. After being stirred for 1h at room temperature, H2Oand 1M NaOH added to the solution. The mixture was filtered and the organic layer was evaporated in vacuo to yield alcohol (1.40 g, 8.32 mmol). To a solution of alcohol (1.40 g, 8.32 mmol) in CH2Cl2 was added PDC (4.96 g, 8.32 mmol) and the mixture was stirred at room temperature for 5h. The mixture was filtered and the solvent was evaporated in vacuo. The residue was purified by silica-gel column chromatography (hexane:AcOEt=4:1) to give benzaldehyde (1.25 g, 7.52 mmol). To a solution of benzaldehyde (1.25 g, 7.52 mmol) were added ethyldiethylphosphonoacetate (3.01 ml, 15.4 mmol) and NaH (0.330 g, 8.27 mmol) at 0. After being stirred for 1h at room temperature, AcOEt and H2O were added to the solution. The organic layer was evaporated in vacuo and the residue was purified by silica-gel column chromatography (hexane:AcOEt=4:1) to give unsaturated ethyl ester (0.540 g, 2.03 mmol). To a solution of unsaturated ethyl ester (0.540 g, 2.03 mmol) in MeOH was added LiOH-H2O (1.22 g, 29.1 mmol).After being stirred under reflux for 2h, 1M HCl aq. and AcOEt were added to the mixture. The organic layer was washed with H2O and brine. The solvent was evaporated in vacuo to yield unsaturated carboxyl acid (1.35 g, 6.48 mmol, 89 %) as a white powder.
With lithium aluminium hydride In tetrahydrofuran at 0 - 80℃; for 4h; Inert atmosphere;
Multi-step reaction with 3 steps
1: Et3N / tetrahydrofuran / 1 h / 0 - 20 °C
2: 33 percent / Li, naphthalene / tetrahydrofuran / 2 h / 0 °C
3: dimethylsulfoxide / 2 h / Heating
Multi-step reaction with 3 steps
1: pyridine; thionyl chloride / diethyl ether / 20 °C / Cooling with ice
2: 4 h / 130 °C / Inert atmosphere
3: potassium <i>tert</i>-butylate / tetrahydrofuran / 1.25 h / Reflux
Multi-step reaction with 3 steps
1: Dess-Martin periodane / dichloromethane / 0 °C / Inert atmosphere
2: Methyltriphenylphosphonium bromide; sodium hydride / tetrahydrofuran; mineral oil / 20 °C / Inert atmosphere
3: sodium acetate; palladium diacetate / methanol / 12 h / 20 °C / Inert atmosphere
Multi-step reaction with 3 steps
1.1: phosphorus tribromide / dichloromethane / 2 h / 0 °C
2.1: 7 h / 135 °C
3.1: sodium hydride / tetrahydrofuran / 1 h / 0 °C
3.2: 17 h / 0 - 20 °C
Multi-step reaction with 2 steps
1: dmap; triethylamine / dichloromethane / 0.25 h / 0 - 20 °C
2: bis(1,5-cyclooctadiene)nickel (0); 1,3-bis-(diphenylphosphino)propane; potassium <i>tert</i>-butylate / 1,4-dioxane / 12 h / 200 °C / Inert atmosphere; Glovebox; Schlenk technique; Sealed tube
With nickel In tetrahydrofuran for 12h; Reflux; optical yield given as %de;
12 % de
at 70℃; for 1h; diastereoselective reaction;
4 Application of Rucat for Wittig Type Olefination Reaction
General procedure: 50 mL round bottom flask was charged with Rucat (0.250 g), alcohol (0.1 mol) and phosphorus ylide (0.11 mol) was added to the reaction mixture. The combined reaction mass was allowed to react at 70 °C for 1 h. Again, after removing all the volatile organic impurities from the reaction mass, product was isolated by ether washing (5 × 2 mL). The diastereomeric selectivity was calculated using 1H NMR spectroscopic analyses. After the successful isolation of product, catalytic system was further reduced under hydrogen atmosphere (4 bar) at 50 °C for 3 h before going to the next catalytic run. Sequential addition of reactants was carried out as per above mentioned protocol for the same.
Stage #1: (4-methoxybenzyl)triphenylphosphonium bromide With n-butyllithium In tetrahydrofuran; hexane at 0℃;
Stage #2: 3,5-dimethoxybenzyl alcohol With 4,4'-di-tert-butylbiphenyl; lithium; nickel dichloride In tetrahydrofuran; hexane for 12h; Inert atmosphere; Reflux;
Stage #3: With iodine In hexane for 48h; Reflux;
Stage #1: (4-methoxybenzyl)triphenylphosphonium bromide With n-butyllithium In tetrahydrofuran; hexane at 0℃;
Stage #2: 3,5-dimethoxybenzyl alcohol With 4,4'-di-tert-butylbiphenyl; lithium; nickel dichloride In tetrahydrofuran; hexane for 12h; Inert atmosphere; Reflux; optical yield given as %de;
With tetraethylammonium bromide; oxygen; potassium carbonate In water; dimethyl sulfoxide at 100℃; for 16h;
70%
With copper (II)-fluoride In water; dimethyl sulfoxide at 120℃; for 12h; Schlenk technique; Inert atmosphere; Green chemistry;
Experimental Procedure for Cu-catalyzed Methyl Esterification of Benzoic Alcohol
General procedure: To a 50 mL Schlenk tube equipped with a stir bar was added 0.5 mmol of benzylic alcohol followed by 0.05 mmol of CuF2 (0.1 equiv). The mixture of DMSO (1.5 mL) and H2O (1.5 mL) was added, followed by 6 mmol of TBHP(12 equiv). The glass tube was vacuumed and purged with argon three times before it was tightly screw-capped. The reaction mixture was stirred at 120 Cfor 12 h, cooled to room temperature, poured into brine and extracted with EtOAc. The combined extracts were dried over MgSO4, filtered, and evaporated. The residue was purified by column chromatography (petroleumether/EtOAc) to afford the methyl ester
With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; benzyl chloride In tetrahydrofuran at 65 - 70℃; for 20h; Inert atmosphere; Schlenk technique;
91%
With bismuth(lll) trifluoromethanesulfonate; dichloro bis(acetonitrile) palladium(II); oxygen; potassium carbonate at 60℃; for 3h; Schlenk technique;
3.13 4.2.1 General procedure for the synthesis of 2 in Table2
General procedure: To a 25-mL Schlenk tube equipped with a magnetic stirrer, PdCl2(CH3CN)2 (0.05mol, 5mol%), Bi(OTf)3 (0.05mol, 5mol%), K2CO3 (1mmol) were added. Substrates 1 (1mmol) and MeOH (2mL) were added subsequently. The reaction tube was vacuumed and backfilled with oxygen (3 times). Then the reaction mixture was stirred at 60°C for 3h in the presence of an oxygen balloon. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. Subsequently, the combined organic layer was concentrated under reduced pressure and the crude product was purified by column chromatography with hexane/ethyl acetate to afford the corresponding products 2.
36%
With palladium 10% on activated carbon; oxygen; sodium carbonate at 120℃; for 1.5h; Microwave irradiation; Green chemistry;
General procedure for aerobic aldehyde and alcohol esterification
General procedure: Na2CO3 (2 equiv) was dissolved in MeOH (1 mL) and sonicated with a US bath for 10 sec (20.3 kHz, 60 W). The substrate (aldehyde or alcohol, 1 mmol) and 10% Pd/C (5% Pd/mol of substrate) were added to this mixture. The reaction was carried out under magnetic stirring in a MW reactor Synth-Wave. The 1 L pressure-resistant PTFE cavity (up to 200 bar) equipped with a 15 position vial rack was loaded with O2 (2.5 bar) followed by the addition of N2 up to 20 bar total pressure. The reaction was irradiated for an appropriate reaction temperature ranging from 90 to 120 °C (average power 300 W), and for 1 to 2 hours (see Table 2 and Table 3). The mixture was then filtered off through celite, the catalyst washed with MeOH and the solvent evaporated under vacuum. Isolated yields for all substrates reported were obtained using these conditions.
(3,4-Dimethoxy-benzylidene)-triphenyl-λ5-phosphane[ No CAS ]
[ 705-76-0 ]
cis-3,3',4',5-tetramethoxystilbene[ No CAS ]
[ 83088-26-0 ]
Yield
Reaction Conditions
Operation in experiment
80 % de
at 70℃; for 1h; Overall yield = 64 %; diastereoselective reaction;
4 Application of Rucat for Wittig Type Olefination Reaction
General procedure: 50 mL round bottom flask was charged with Rucat (0.250 g), alcohol (0.1 mol) and phosphorus ylide (0.11 mol) was added to the reaction mixture. The combined reaction mass was allowed to react at 70 °C for 1 h. Again, after removing all the volatile organic impurities from the reaction mass, product was isolated by ether washing (5 × 2 mL). The diastereomeric selectivity was calculated using 1H NMR spectroscopic analyses. After the successful isolation of product, catalytic system was further reduced under hydrogen atmosphere (4 bar) at 50 °C for 3 h before going to the next catalytic run. Sequential addition of reactants was carried out as per above mentioned protocol for the same.
With potassium carbonate In N,N-dimethyl-formamide at 20 - 50℃; for 2h;
Take 3,5-dihydroxybenzyl alcohol 140g, potassium carbonate 300g added to 500ml reaction flask, add 200ml DMF stirring dissolved,Methyl iodide (300 g) was added dropwise at room temperature. After completion of the dropwise addition, the reaction was carried out at room temperature for one hour and the temperature was raised to 50° C. for one hour. Pour the reaction solutionIn 2000 ml ice water, the liquid was separated with a separatory funnel, and the lower layer was extracted with 3*100 ml of toluene, combined with the upper layer, and transferred to 1000 ml.bottle. 200 ml of concentrated hydrochloric acid and 20 g of tetrabutylammonium bromide were added to the reaction flask and refluxed for 5 hours. Cool the reaction solution to roomThe mixture was warmed, separated, and the lower layer was extracted with 3*100 ml of toluene, combined with the upper layer, washed with 2*200 ml of saturated sodium bicarbonate solution, and thenWashed to neutrality, dried with 4A molecular sieves and transferred to a 1000ml reaction flask. The toluene was evaporated to dryness at 90°C and 0.01MPa.Add trimethyl phosphite 150g reflux for 7h,The unreacted trimethyl phosphite was evaporated under reduced pressure and 300 ml of DMSO was added.Sodium hydride25g,In the absence of evolution of hydrogen gas, 325 g of a 50% solution of allyloxybenzaldehyde in DMSO was added dropwise. After completion of the dropwise addition, the reaction was carried out at room temperature for two hours. The reaction solution was poured into 2000 ml of ice water and suction filtered. The cake was washed with water and dried to give 3,5-dimethoxy-4'-allyl.Oxime 207g, total yield 70
With 1,4-diaza-bicyclo[2.2.2]octane; TEMPOL; ammonia; copper(l) chloride; In water; acetonitrile; at 20℃; for 24h;
General procedure: To a 25-mL Schlenk tube equipped with a magnetic stirrer, CuCl (0.05 mol, 5 mol%), DABCO (0.10 mol, 10 mol%), 4-HO-TEMPO (0.05 mmol, 5 mol%) were added. Substrates 1 (1 mmol) and NH3 (aq, 25-28%, 3 mmol, 3.0 equiv) in CH3CN (2 mL) were added subsequently. Then the reaction mixture was stirred at room temperature for 24 h in the presence of an air balloon. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4. Subsequently, the combined organic layer was concentrated under reduced pressure and the crude product was purified by column chromatography to afford the corresponding products.
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