* 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
[ 557-21-1 ]
[ 7051-16-3 ]
[ 19179-31-8 ]
Yield
Reaction Conditions
Operation in experiment
88%
With dmap; 1,1'-bis-(diphenylphosphino)ferrocene; nickel(II) chloride hexahydrate; zinc In acetonitrile at 60℃; for 7 h; Inert atmosphere; Sealed tube
General procedure: Under argon protection, NiCl2 · 6H2O (0.05mmo 1,11.9mg), dppf (0.06mmol, 33.3mg), Zn (0 · 2mmol, 13.0mg), DMAP (1.0mmol, 122.2mg), Zn (CN) 2 (0.8mmol) , 93.9mg),p-Chloroanisole (1.0 mmol, 140.6 mg) and acetonitrile (5.0 mL) were sequentially added in a 25.0 mL sealed tube, then directly put it into the oil bath at 60 °C, and heating was stopped after 6h, and cooled to room temperature, the reaction solution was directly filtered through a short silica gel column, washed with dichloromethane, concentrated and purified by silica gel column chromatography( given that the product is most easily pulled out, in order to avoid loss of sample mix, unless otherwise noted, both are wet method). Eluent: petroleum ether / ethyl acetate = 20:1, the product was 117.2 mg as a white solid, yield 88percent, and 1H NMR purity was greater than 98percent.
Reference：
[1] Organic Letters, 2017, vol. 19, # 8, p. 2118 - 2121
[2] Patent: CN108623495, 2018, A, . Location in patent: Paragraph 0043; 0045; 0061-0063
3
[ 171290-52-1 ]
[ 19179-31-8 ]
Yield
Reaction Conditions
Operation in experiment
52%
With N-Bromosuccinimide; silver(I) nitrite In 1,2-dichloro-ethane at 20℃; for 8 h; Sealed tube
3,5-dimethoxyphenylacetylene 81 mg (0.50 mmol), silver nitrite 154 mg (1 mmol), N-bromosuccinimide 178 mg (1 mmol)10 mL of a pressure-tight sealed container was sequentially added, and 5 mL of 1,2-dichloroethane was further added.The mixture was stirred at room temperature, and the reaction was checked by TLC. The reaction was completed in 8 hours.The reaction solution was diluted with 10 mL of dichloromethane, and filtered to give a clear liquid.Separation by column chromatography (extraction of petroleum ether/ethyl acetate in a volume ratio of 100:1)The eluate containing the desired product were collected and the solvent was evaporated to give a white solid 3,5-dimethoxy-benzonitrile 42.4mg (52percent yield).
Reference：
[1] Patent: CN107641088, 2018, A, . Location in patent: Paragraph 0064; 0065; 0066
4
[ 124-38-9 ]
[ 20469-65-2 ]
[ 19179-31-8 ]
Yield
Reaction Conditions
Operation in experiment
41 %Chromat.
Stage #1: With copper(l) iodide; sodium iodide; N,N`-dimethylethylenediamine In 1,4-dioxane at 120℃; for 24 h; Inert atmosphere; Sealed tube Stage #2: With 1,4-diaza-bicyclo[2.2.2]octane; copper(I) oxide; phenylsilane; ammonia In 1,4-dioxane; 1-methyl-pyrrolidin-2-one at 130℃; for 24 h; Sealed tube
General procedure: Under nitrogen atmosphere, Cu2O (10 mol percent), DABCO (25 mol percent), and a stirring bar were added into a 10 mL oven-dried sealed glass tube (as shown in Figure S1). Then NMP (0.5 mL), aryl iodides (0.125 mmol, 1.0 equiv.) and PhSiH3 (0.75 mmol, 6 equiv.) were injected by syringe. The tube wasthen sealed and CO2 (0.67 mmol, 5.4 equiv., 15 mL) as well as NH3 (0.67 mmol, 5.4 equiv., 15 mL) were injected by syringe after N2 was removed under vacuum. Finally, the mixture was stirred for 24 hr in a pre-heated-to-130 °C alloyed block. After the reaction was finished, the tube was cooled to room temperature and the pressure was carefully released. The yield of were measured by GC analysis using dodecane as the internal standard or by flash chromatography on silica gel (petroleumether/ethyl acetate).
Reference：
[1] Chem, 2018, p. 2883 - 2893
5
[ 557-21-1 ]
[ 20469-65-2 ]
[ 19179-31-8 ]
Reference：
[1] Organic Letters, 2015, vol. 17, # 2, p. 202 - 205
[2] Journal of Organic Chemistry, 2017, vol. 82, # 13, p. 7040 - 7044
6
[ 7311-34-4 ]
[ 19179-31-8 ]
Reference：
[1] Synthesis, 1989, # 6, p. 451 - 452
[2] Journal of Organic Chemistry, 2015, vol. 80, # 17, p. 8657 - 8667
[3] Journal of Heterocyclic Chemistry, 2009, vol. 46, # 5, p. 980 - 987
Reference：
[1] Chinese Journal of Chemistry, 2013, vol. 31, # 1, p. 27 - 30
11
[ 20469-65-2 ]
[ 19179-31-8 ]
Yield
Reaction Conditions
Operation in experiment
2.3 g
at 160 - 170℃; for 10 h; Inert atmosphere
A mixture of l-bromo-3,5-dimethoxybenzene (5 g, 23 mmol) and CuCN (6 g, 67 mmol) in DMF (60 mL) was heated to reflux (160 -170 °C) for 10 h under N2. After cooling to r.t., the mixture was diluted with ethyl acetate, poured into 10 percent aqueous NH4OH extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column (petroleum ether/ethyl acetate (15: 1) as eluent) to afford 3,5-dimethoxybenzonitrile (2.3 g). 1H NMR (CDC13, 400 MHz): δ 6.76 (d, J= 2.0 Hz, 2H), 6.65 (t, J= 2.0 Hz 3.81 (s, 6H).
3,5-Dimethoxy-benzamidine Dry HCl gas was bubbled through a cooled (-15 C.) solution of <strong>[19179-31-8]3,5-dimethoxybenzonitrile</strong> (1.50 g, 9.20 mmol) for 30 minutes. The reaction mixture was placed in a refrigerator overnight. After evaporation of the solvent, a white solid was obtained which was dissolved in ethanol.
Reference Example 22 1-Bromo-2,4-dimethoxy-6-cyanobenzene To a solution of <strong>[19179-31-8]3,5-dimethoxybenzonitrile</strong> (2 g) in CH2Cl2 (100 mL) was added pyridinium tribromide (4 g). The mixture was stirred for 24 h at room temperature then washed successively with aqueous NaHCO3, water and brine, dried (MgSO4) filtered and evaporated. The residue was crystallized from CH2Cl2 and hexane to yield the title compound (1.8 g).
With magnesium; In tetrahydrofuran; water; ethyl acetate;
i. Synthesis of Compound (4) Now in more specific terms, the synthesis of 1-phenoxy-5-(3,5-dimethoxyphenyl)pentane (4) was accomplished as follows. To a mechanically stirred Grignard reagent (prepared from 91.6 g, 0.4 mmol of 4-bromophenoxybutane and 14.6 g, 0.6 mmol of magnesium turnings in 400 mL of anhydrous THF), added 48.9 g, 0.3 mmol of <strong>[19179-31-8]3,5-dimethoxybenzonitrile</strong> (3) all at once and heated to reflux for 3 hours. The reaction was cooled to 0 C. with an ice bath for 15 minutes followed by the slow addition of 6N HCL (150 mL), and then allowed to stir at reflux overnight. The THF was removed in vacuo and the residue dissolved in ethyl acetate (300 mL) and 6N HCL (50 mL). The layers were separated and the aqueous fraction extracted with ethyl acetate (4*150 mL). The combined ethyl acetate extract was washed with saturated NaHCO3, followed by water and brine. After drying, it was concentrated and the residue was chromatographed on silica gel (650 g), eluding with 5%-25% ether/hexanes, to yield 79.8 g (85%) of compound (4).
As an overview of Reaction Scheme 1, a Grignard reagent prepared from 4-bromophenoxybutane in tetrahydrofuran (THF) was treated with the nitrile compound (3) to produce the ketone compound (4) (85% yield), which, on further treatment, with diemthyl zinc and TiCl4 in CH2 Cl2 at -40 C. gave the resorcinal compound (5)(63% yield).
Preparation of 3-chloro-5-(3,5-dimethoxyphenyl)-6-(2-fluorophenyl)-4-(2,4,6- trifluorophenyl)pyridazine (Compound 45) Step A: Preparation of l-(3,5-dimethoxyphenyl)-2-(2-fluorophenyl)ethanoneTo a mixture of magnesium turnings (5.7 g, 0.2 mol), iodine (catalytic amount) and 1 ,2-dibromoethane (2 drops) in diethyl ether (150 mL) at reflux was added dropwise a solution of l-(bromomethyl)-2-fluorobenzene (31.45 g, 0.17 mol) in diethyl ether (140 mL) over 105 minutes. The reaction mixture was cooled 10 0C, and a solution of 3,5- dimethoxybenzonitrile (22.51 g, 0.14 mol) in diethyl ether (130 mL) and tetrahydrofuran (80 mL) was added dropwise. The reaction mixture was heated at reflux for 5 h and then allowed to stand at room temperature overnight. The reaction mixture was diluted with hydrochloric acid (1 N, 300 mL), water (75 mL), ethyl acetate (500 mL) and more hydrochloric acid (I N, 200 mL). After stirring for 1 h, the layers were separated, and the aqueous layer was extracted with ethyl acetate (2x). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was triturated with hexanes to provide the title compound as a solid (31.3 g).1H NMR (CDCl3): delta 7.4-7.3 (m, 2H), 7.17 (s, 2H), 7.17-7.10 (m, 2H), 6.66 (s, IH), 4.28 (s,2H), 3.83 (s, 3H), 3.80 (s, 3H).
Step 1: Cyclopentyl-(3,5-dimethoxy-phenyl)-methanone To a solution of <strong>[19179-31-8]3,5-dimethoxybenzonitrile</strong> (5.0 g) in anhydrous THF (60 mL) were added a solution of cyclopentylmagnesium chloride (20 mL of 2 M solution in diethyl ether) and cuprous bromide (88 mg). The resulting reaction mixture was refluxed for 1 h. Then water (10 mL) and 10% sulfuric acid (20 mL) were added and the resulting mixture was stirred at room temperature overnight. Then the reaction mixture was diluted with diethyl ether and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield 5.9 of the title compound (82% yield). HRMS calcd for C14H18O3 [M+H]+ 253.1329, observed 253.1328.
With n-butyllithium; In tetrahydrofuran; hexane; at -78 - -60℃;Inert atmosphere;
General procedure: An oven-dried three-necked flask was sealed with septa and evacuated/backfilled with N2 several times before starting the reaction. To a mixture of 2.5 M n-BuLi in hexane (4.2 mL, 10.45 mmol) and dry THF, maintained at below -70 C, a solution of N,N-diethyl-2-methylbenzamide (1 g, 5.23 mmol) and <strong>[19179-31-8]3,5-dimethoxybenzonitrile</strong> (1.11 g, 6.79 mmol) in dry THF was added dropwise, maintaining the temperature below -60 C. The reaction mixture was stirred at -78 C. The reaction mixture was warmed to room temperature and quenched with water. The resulting mixture was extracted with CH2Cl2, the organic extract washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was then purified by column chromatography (n-hexane:EtOAc = 1:1) to obtain compound 5b as white crystals (1.1 g, 74%).
3-(3,5-dimethoxyphenyl)-6,7-dimethoxyisoquinolin-1(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
With n-butyllithium; In tetrahydrofuran; hexane; at -78 - -60℃;Inert atmosphere;
General procedure: An oven-dried three-necked flask was sealed with septa and evacuated/backfilled with N2 several times before starting the reaction. To a mixture of 2.5 M n-BuLi in hexane (4.2 mL, 10.45 mmol) and dry THF, maintained at below -70 C, a solution of N,N-diethyl-2-methylbenzamide (1 g, 5.23 mmol) and <strong>[19179-31-8]3,5-dimethoxybenzonitrile</strong> (1.11 g, 6.79 mmol) in dry THF was added dropwise, maintaining the temperature below -60 C. The reaction mixture was stirred at -78 C. The reaction mixture was warmed to room temperature and quenched with water. The resulting mixture was extracted with CH2Cl2, the organic extract washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was then purified by column chromatography (n-hexane:EtOAc = 1:1) to obtain compound 5b as white crystals (1.1 g, 74%).
With sodium azide; In N,N-dimethyl-formamide; at 110℃; for 6h;
General procedure: A mixture of nitrile (1 mmol), sodium azide (1.5 mmol), Cu complex catalyst (0.4 mol%) and DMF (3 mL) was taken in a round-bottomed flask and stirred at 110 C temperature. After completion of the reaction the catalyst was separated from the reaction mixture with an external magnet and reaction mixture was treated with ethyl acetate (2 × 20 mL) and 1 N HCl (20 mL). The resultant organic layer was separated and the aqueous layer was again extracted with ethyl acetate (2 × 15 mL). The combined organic layers were washed with water, concentrated, and the crude material was chromatographed on silica gel (Hexane-EtoAc, 1:1) to afford the pure product.
85%
With sodium azide; In dimethyl sulfoxide; at 140℃; for 3h;
General procedure: A mixture of benzonitrile (1 mmol), sodium azide (1 mmol),and alum NPs (0.05 g) in DMSO (5 mL) was stirred at140 C for 30 min. The progress of the reaction was carefullymonitored by TLC (thin layer chromatography). After completionof the reaction, the reaction mixture was cooled, andthe catalyst was filtered. The filtrate was treated with HCl(4 N, 10 mL) and then with ethyl acetate (210 mL). Theresulting organic layer was washed with distilled water andextracted, then was dried over anhydrous sodium sulfate,and concentrated to give the crude solid crystalline 5-phenyl-1H-tetrazole. The product was recrystallized from n-hexane/ethyl acetate (1:1) to obtain white crystals.
80%
With sodium azide; copper(II) ferrite; In N,N-dimethyl-formamide; at 120℃; for 12h;
General procedure: A mixture of nitrile (1 mmol), sodium azide (1.5 mmol), catalyst (40 mol%) and DMF (3 mL) was taken in a round-bottomed flask and stirred at 120 C temperature for 12 h. After completion of the reaction the catalyst was separated from the reaction mixture with an external magnet and reaction mixture was treated with ethyl acetate (30 mL) and 5 N HCl (20 mL). The resultant organic layer was separated and the aqueous layer was again extracted with ethyl acetate (20 mL). The combined organic layers were washed with water, concentrated, and the crude material was chromatographed on silica gel (Hexane-EtoAc, 1:1) to afford the pure product. refText
With [2,2]bipyridinyl; aluminum (III) chloride; bis(acetylacetonate)nickel(II); zinc(II) oxide; In 1,2-dimethoxyethane; at 140℃; for 12h;Sealed tube;
General procedure: No special protection is required. In the air, a magnetic stirrer is added to the clean single-mouth reaction tube.p-Bromoanisole (IIa, 0.2 mmol, 1.0 equiv),Nickel diacetylacetonate (Ni(acac) 2, 0.01 mmol, 5 mol%),Aluminum chloride (AlCl3, 0.02 mmol, 10 mol%),Bipyridine(dipy, 0.04 mmol, 20 mol%),Zinc oxide (ZnO, 0.2 mmol, 1.0 equiv), formamide (1.0 mL)Sealing the reaction tube with ethylene dimethoxide (1,2-dimethoxyethane, 0.5 mL);After reacting at 140 C for 12 hours,Thin layer chromatography analysis showed complete consumption of the crude bromoanisole.Stop heating, cooling; extract, direct wet loading,200-300 mesh silica gel column chromatography,A mixed solvent of ethyl acetate and petroleum ether (1:10) was rinsed.Separating the compound of formula Ia22.6mg,The yield was 85%.
81
[ 100-59-4 ]
[ 19179-31-8 ]
[ 628263-26-3 ]
Yield
Reaction Conditions
Operation in experiment
75%
Example 1 Synthesis of 3,5--dimethoxybenzophenone[0068] Neat <strong>[19179-31-8]3,5-dimethoxybenzonitrile</strong> (16.0 g, 98.1 mmol) was added to a 2.0 M solution of phenylmagnesium chloride in THF (98.0 mL, 196.1 mmol). The reaction mixture was refluxed for 24 hours at 70 C. The solution was then transferred into a mixture of concentrated aqueous HC1 (100 mL) and ice (300 g). The mixture was allowed to warm up to room temperature and stirred for 24 hours. The product was extracted with ether (3 x 300 mL) and the combined organic layers were washed with brine (200 mL) and water (150 mL) before being dried with anhydrous magnesium sulfate. The filtrate was dried in vacuo to afford 3,5-dimethoxybenzophenone as a yellow solid in 75 % yield. ¾ NMR (CDCI3): delta 7.84 (d, 3JH- H = 7.2 Hz, 1H), 7.61 (t, 3JH-H = 7.6 Hz, 2H), 7.50 (t, JH-H = 7.6 Hz, 2H), 6.95 (d, 3JH-H = 2.4 Hz, 1H), 6.70 (t, 3JH-H = 2.4 Hz, 2H), 3.85 (s, 6H).
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