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CAS No. : | 171290-52-1 | MDL No. : | MFCD03839985 |
Formula : | C10H10O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | HUSBBWQIJMRKLI-UHFFFAOYSA-N |
M.W : | 162.19 | Pubchem ID : | 4661321 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.2 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 47.36 |
TPSA : | 18.46 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.79 cm/s |
Log Po/w (iLOGP) : | 2.58 |
Log Po/w (XLOGP3) : | 2.11 |
Log Po/w (WLOGP) : | 1.76 |
Log Po/w (MLOGP) : | 2.01 |
Log Po/w (SILICOS-IT) : | 2.47 |
Consensus Log Po/w : | 2.19 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.41 |
Solubility : | 0.627 mg/ml ; 0.00387 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.13 |
Solubility : | 1.21 mg/ml ; 0.00744 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.73 |
Solubility : | 0.306 mg/ml ; 0.00188 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.79 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H317-H319 | 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 |
---|---|---|
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). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With n-butyllithium In tetrahydrofuran; hexane at -50℃; Schlenk technique; Inert atmosphere | Solid 1-(2,2-dibromovinyl)-3,5-dimethoxybenzene (2.99 g, 9.28 mmol,1 equiv) was dissolved in dry THF (50 mL) under argon with stirring at −50 °C (dry ice/acetonitrilebath). A solution of nBuLi (24.0 mL, 1.6 M in hexanes, 38.4 mmol, 4.1 equiv) was added dropwiseafter which TLC indicated completion of the reaction. The mixture was quenched with saturatedammonium chloride (40 mL), extracted with CH2Cl2 (3 × 20 mL), dried (NaSO4), filtered andevaporated, giving an orange brown oil (1.61 g). Purification by flash column chromatography(pure pentane, followed by 19:1 pentane:Et2O) gave a pure colourless crystalline solid (1.22 g,81percent), Rf = 0.24 (pentane), m.p. 46–47 °C with literature properties.3 1H NMR (400.1 MHz, CDCl3):δ 6.72 (d, J = 2.3 Hz, 2H, ArH), 6.50 (t, J = 2.3 Hz, 1H, ArH), 3.76 (s, 6H, OCH3), 3.15 (s, 1H,CCH). 13C NMR (100.6 MHz, CDCl3): δ 160.6 (C), 123.4 (C), 110.0 (CH), 102.3 (CH), 83.7 (C),76.9 (CH), 55.4 (CH3). |
78.8% | Stage #1: With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78℃; for 2 h; Stage #2: With ammonium chloride In tetrahydrofuran; n-heptane; ethylbenzene |
General procedure: Lithium diisopropylamide solution (2 M in heptane/THF/ethylbenzene, 5 equiv) was slowly added to appropriate 2,2-dibromo-vinyl derivatives 40a3-d3 (1 equiv), dissolved in dry THF at -78 oC. The temperature was kept at -78 oC, and the mixture was stirred for 2 h. The reaction was quenched with saturated NH4Cl solution and extracted with CH2Cl2. The combined organic solutions were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel flash column chromatography. |
76% | With caesium carbonate In dimethyl sulfoxide at 115℃; Sealed tube; Inert atmosphere | General procedure: Following a modified literature procedure[10] dibromoalkenes S2 (1.0 equiv.), Cs2CO3 (2.5 equiv.) and DMSO (0.1M) are mixed in a sealed tube and heated to 115 °C overnight. The reaction is quenched by pouring the reaction mixture into brine (20 mL/mmol). The resulting mixture is extracted with tert-butyl methyl ether (3x10 mL/mmol) and the combined organic layers are washed with brine (15 mL/mmol) and dried over Na2SO4. Removal of all volatiles gives the crude product which is purified by flash column chromatography to afford the terminal alkynes S3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | at 20℃; for 2 h; | To a solution of arylethynyltrimethylsilanes (30 mmol) in methanol (30 ml) was added potassium fluoride (3.5 g, 60 mmol). The reaction mixture was stirred at room temperature for 2 hours. After removal of methanol, the product was extracted with ether (100 ml x 3) and purified by chromatography on silica gel using petroleum ether as eluent to afford pure products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72 mg | Stage #1: With triphenylphosphine In dichloromethane at 0 - 20℃; for 0.5 h; Stage #2: With lithium diisopropyl amide In tetrahydrofuran; n-heptane; ethylbenzene at -78℃; for 2 h; Stage #3: With ammonium chloride In tetrahydrofuran; n-heptane; ethylbenzene |
General procedure: PPh3 (4 equiv) was added at 0 oC to a solution of CBr4 (2 equiv) in dry CH2Cl2. At the same temperature, the appropriate aldehyde 40a2-d2 (1 equiv) dissolved in dry CH2Cl2 was dropped slowly into the reaction mixture. The cooling bath was removed and the reaction mixture was stirred at room temperature. After 30 min, water was added and the contents of the aqueous phase were extracted with CH2Cl2. The combined organic phases were dried over Na2SO4 and concentrated. The residue was purified by silica gel flash column chromatography.; General procedure: Lithium diisopropylamide solution (2 M in heptane/THF/ethylbenzene, 5 equiv) was slowly added to appropriate 2,2-dibromo-vinyl derivatives 40a3-d3 (1 equiv), dissolved in dry THF at -78 oC. The temperature was kept at -78 oC, and the mixture was stirred for 2 h. The reaction was quenched with saturated NH4Cl solution and extracted with CH2Cl2. The combined organic solutions were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel flash column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium carbonate; In methanol; at 20℃; for 2h; | ((3,5-Dimethoxyphenyl)ethynyl) trimethylsilane 1d (3.0 g, 12.8 mmol) was dissolved in methanol (100 mL) and potassium carbonate (3.5 g, 25.6 mmol) was added and stirred at room temperature for 2 hours; and filter and the resulting filtrate was concentrated under reduced pressure; the residue was purified by silica gel column chromatography (petroleum ether), so as to obtain the title product 1-ethynyl-3,5-dimethoxybenzene 1e (2 g, yellow solid), and the yield was 96%. |
96% | With potassium carbonate; In methanol; at 20℃; for 2h; | ((3,5-dimethoxyphenyl) ethynyl) trimethyl Monosilane 1d (3.0 g, 12.8 mmol) was dissolved in methanol (100 mL), potassium carbonate (3.5 g, 25.6 mmol) was added, and the mixture was stirred at room temperature for 2 hours.Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether) to obtain the target product 1-ethynyl-3,5-dimethoxybenzene 1e (2 g, yellow solid), yield: 96% . |
91% | With methanol; potassium fluoride; at 20℃; for 2h; | To a solution of arylethynyltrimethylsilanes (30 mmol) in methanol (30 ml) was added potassium fluoride (3.5 g, 60 mmol). The reaction mixture was stirred at room temperature for 2 hours. After removal of methanol, the product was extracted with ether (100 ml x 3) and purified by chromatography on silica gel using petroleum ether as eluent to afford pure products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With n-butyllithium; In tetrahydrofuran; hexane; at -50℃;Schlenk technique; Inert atmosphere; | Solid 1-(2,2-dibromovinyl)-3,5-dimethoxybenzene (2.99 g, 9.28 mmol,1 equiv) was dissolved in dry THF (50 mL) under argon with stirring at -50 C (dry ice/acetonitrilebath). A solution of nBuLi (24.0 mL, 1.6 M in hexanes, 38.4 mmol, 4.1 equiv) was added dropwiseafter which TLC indicated completion of the reaction. The mixture was quenched with saturatedammonium chloride (40 mL), extracted with CH2Cl2 (3 × 20 mL), dried (NaSO4), filtered andevaporated, giving an orange brown oil (1.61 g). Purification by flash column chromatography(pure pentane, followed by 19:1 pentane:Et2O) gave a pure colourless crystalline solid (1.22 g,81%), Rf = 0.24 (pentane), m.p. 46-47 C with literature properties.3 1H NMR (400.1 MHz, CDCl3):delta 6.72 (d, J = 2.3 Hz, 2H, ArH), 6.50 (t, J = 2.3 Hz, 1H, ArH), 3.76 (s, 6H, OCH3), 3.15 (s, 1H,CCH). 13C NMR (100.6 MHz, CDCl3): delta 160.6 (C), 123.4 (C), 110.0 (CH), 102.3 (CH), 83.7 (C),76.9 (CH), 55.4 (CH3). |
78.8% | General procedure: Lithium diisopropylamide solution (2 M in heptane/THF/ethylbenzene, 5 equiv) was slowly added to appropriate 2,2-dibromo-vinyl derivatives 40a3-d3 (1 equiv), dissolved in dry THF at -78 oC. The temperature was kept at -78 oC, and the mixture was stirred for 2 h. The reaction was quenched with saturated NH4Cl solution and extracted with CH2Cl2. The combined organic solutions were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel flash column chromatography. | |
76% | With caesium carbonate; In dimethyl sulfoxide; at 115℃;Sealed tube; Inert atmosphere; | General procedure: Following a modified literature procedure[10] dibromoalkenes S2 (1.0 equiv.), Cs2CO3 (2.5 equiv.) and DMSO (0.1M) are mixed in a sealed tube and heated to 115 C overnight. The reaction is quenched by pouring the reaction mixture into brine (20 mL/mmol). The resulting mixture is extracted with tert-butyl methyl ether (3x10 mL/mmol) and the combined organic layers are washed with brine (15 mL/mmol) and dried over Na2SO4. Removal of all volatiles gives the crude product which is purified by flash column chromatography to afford the terminal alkynes S3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine at 20℃; Inert atmosphere; | |
85% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine at 20℃; for 5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With copper(l) iodide;bis-triphenylphosphine-palladium(II) chloride; at 20℃; for 6h;Inert atmosphere; | To a solution of methoxy ethynylbenzenes (20 mmol) and methoxy substituted aryl iodide (22 mmol) in isopropylamine (120 ml) were added Pd(PPH3)2Cl2 (0.2 mmol) and CuI (0.4 mmol). The reaction mixture was stirred at ambient temperature for 6 hours under a slow stream of nitrogen. The reaction mixture was filtered and the residues were washed with ethyl acetate and the solvent evaporated from the combined filtrates. The crude product was purified by column chromatography on silica gel using petroleum ether/ethyl acetate (9:1) as an eluent to give methoxytolans. |
93% | With pyrrolidine; palladium diacetate; triphenylphosphine; for 1h;Inert atmosphere; Reflux; | To a solution of 1.5 g (9.2 mmol) of <strong>[171290-52-1]1-ethynyl-3,5-dimethoxybenzene</strong> and 2.16 g (9.2 mmol) of 4-iodoanisole in 10.0 mL of pyrrolidine, 64 mg (0.246 mmol) of triphenylphosphine and 27 mg (0.123 mmol) of Pd(OAc)2 were added. The mixture was stirred under an Ar stream and heated at reflux temperature for 1.0 h. The mixture was frozen and poured into 60 mL of saturated ammonium chloride solution and then extracted with 30 mL of CH2Cl2. The organic layer was washed with brine and dried (Na2SO4). After filtration, the residue was purified by flash column chromatography on silica gel, with hexane-EtOAc, 9:1 as the eluent, to give pure (4) in 93% yield. |
75% | With pyrrolidine; triphenylphosphine;palladium 10% on activated carbon; at 85℃; for 17h;Inert atmosphere; | Example 3: Synthesis of 3,4',5-trimethoxydiphenylacetylene5 ml of pyrrolidine (99 %) were placed in a 10 ml glass tube fitted with a septum, a magnetic stirring bar and an argon supply. The pyrrolidine was degassed with argon for 30 minutes at room temperature. Afterwards 240 mg of 4-iodoanisol (98 %, 1 .01 mmol, 1 .00 eq.), 12 mg of triphenylphosphine (97 %, 0.044 mmol, 0.044 eq.), 40 mg of palladium on charcoal (10 %, 0.038 mmol, 0.037 eq.) and finally 249.3 mg of 1 -ethynyl-3,5-dimethoxybenzene (98 %, 1 .51 mmol, 1 .50 eq.) were added to the presented pyrrolidine.The mixture was stirred under argon at 85 0C (aluminum block temperature) for 17 hours. The reaction solution was cooled to room temperature and then 10 ml of ethyl acetate were added. Afterwards the suspension was filtrated with a membrane filter (0.45 mum).The solution was treated with 20 ml of a saturated ammonium chloride solution. Then an extraction was performed by extracting twice with 20 ml of ethyl acetate. The organic solutions were dried with sodium sulfate and afterwards concentrated at 40 0C and 180 mbar. The dark yellow crude material was purified by chromatography with ethyl acetate and n-heptane in a ratio of 5:95. The product containing fractions were collected and concentrated at 40 C and 90 mbar. The purified product was analyzed by GC-MS and NMR. The yield was 75 % based on the 4-iodoanisole. GC/MS: Retention time: 21 .61 min, Area %: 99.10 %; M: M+ 268, 253, 225, 210, 195, 182, 167, 152, 139.1H-NMR 300 MHz, d-Chloroform) delta 3.82 ppm (s, 6H, OCH3), 3.85 ppm (s, 3H, OCH3), 6.47 (t, J=2.31 Hz, 1 H, ArH), 6.70 ppm (d, J=2.31 Hz, 2H, ArH), 6.88 - 6.89 ppm (m, 2H, ArH), 7.48 - 7.52 ppm (m, 2H, ArH). 13C-NMR 75 MHz, d- Chloroform) delta 55.30 (OCH3), 56.42 (2xOCH3), 88.10 (C), 89.00 (C), 101 .57 (C), 109.22 (2xCH3), 1 14.02 (2xCH3), 1 15.20 (C), 124.91 (CH), 133.12 (2xCH), 159.71 (C), 160.55 (2xC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With [{Pd(mu-OH)Cl(1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene)}2]; potassium hydroxide; In ethanol; at 22℃; for 24h;Inert atmosphere; Schlenk technique; | General procedure: Glass reactor (3 mL) equipped with a condenser and a stirringbar was charged under argon with arylacetylene (9.11 104 mol),EtOH (99.8%) (2 mL) and catalyst 8 (0.25-2.0 mol% in relation toacetylene). The reaction mixture was stirred at 22 C for 24 h. Thenthe solventwas evaporated under reduced pressure and the residuewas purified by column chromatography (silica gel, hexane/CH2Cl2 = 4/1). Evaporation of the solvent gave an analytically pureproduct. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With pyrrolidine; triphenylphosphine;palladium 10% on activated carbon; at 85℃; for 17h;Inert atmosphere; | Example 1: Synthesis of 4'-Hydroxy-3,5-dimethoxydiphenylacetylene3 ml of pyrrolidine (99 %) were placed in a 10 ml glass tube fitted with a septum, a magnetic stirrer and an argon supply. The solution was degassed with argon for 30 minutes at room temperature. Then (the amount shown in table 1 ) of 4- halophenole (99 %), 10.8 mg (0.04 mmol) triphenylphosphine (97 %) and 248.2 mg (1 .5 mmol) 1 -ethynyl-3,5-dimethoxybenzene were added. Afterwards 35 mg of dried palladium on charcoal (10 %) were added.The mixture was stirred under argon at 85 0C (aluminum block temperature) for 17 hours. The reaction solution was cooled down to room temperature and then 10 ml of ethyl acetate were added. Afterwards the suspension was filtrated with a membrane filter (0.45 mum).The solution was treated 12 ml of hydrochloric acid solution (10 %, 34.3 mmol). Then an extraction was performed by extracting twice with 10 ml of ethyl acetate. The organic solutions were dried with sodium sulfate and afterwards concentrated at 40 0C at 180 mbar. The dark yellow crude material was purified by chromatography with ethyl acetate n-heptane in a ratio of 5:95. The fractions were collected and concentrated at 40 0C and 90 mbar. The isolated fractions were analysed by GC-MS and NMR.1H-NMR 300 MHz, d-Chloroform) delta 3.75-3-85 (m, 6H, OCH3), 4.97 (s, H, OH), 6.35-6.44 (m, 2H, ArH), 6.60 (dd, J=2.28 15.80 Hz, 1 H, ArH), 6.74 - 6.77 (m, 2H, ArH), 7.17 - 7.20 (m, 2H, ArH). 13C-NMR 75 MHz, d-Chloroform) delta 55.40 (OCH3), 88.32 (C), 92.02 (C), 104.45 (C), 109.22 (CH), 1 16.65 (2xCH), 1 15 (C), 124.9 (CH), 130.52 (CH), 160.52 (C), 160.96 (2xC). Table 1 : type and concentration of halophenols; yield of 4'-hydroxy-3,5- dimethoxydiphenylacetylene |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With pyrrolidine; triphenylphosphine;palladium 10% on activated carbon; at 85℃; for 17h;Inert atmosphere; | Example 1: Synthesis of 4'-Hydroxy-3,5-dimethoxydiphenylacetylene3 ml of pyrrolidine (99 %) were placed in a 10 ml glass tube fitted with a septum, a magnetic stirrer and an argon supply. The solution was degassed with argon for 30 minutes at room temperature. Then (the amount shown in table 1 ) of 4- halophenole (99 %), 10.8 mg (0.04 mmol) triphenylphosphine (97 %) and 248.2 mg (1 .5 mmol) 1 -ethynyl-3,5-dimethoxybenzene were added. Afterwards 35 mg of dried palladium on charcoal (10 %) were added.The mixture was stirred under argon at 85 0C (aluminum block temperature) for 17 hours. The reaction solution was cooled down to room temperature and then 10 ml of ethyl acetate were added. Afterwards the suspension was filtrated with a membrane filter (0.45 mum).The solution was treated 12 ml of hydrochloric acid solution (10 %, 34.3 mmol). Then an extraction was performed by extracting twice with 10 ml of ethyl acetate. The organic solutions were dried with sodium sulfate and afterwards concentrated at 40 0C at 180 mbar. The dark yellow crude material was purified by chromatography with ethyl acetate n-heptane in a ratio of 5:95. The fractions were collected and concentrated at 40 0C and 90 mbar. The isolated fractions were analysed by GC-MS and NMR.1H-NMR 300 MHz, d-Chloroform) delta 3.75-3-85 (m, 6H, OCH3), 4.97 (s, H, OH), 6.35-6.44 (m, 2H, ArH), 6.60 (dd, J=2.28 15.80 Hz, 1 H, ArH), 6.74 - 6.77 (m, 2H, ArH), 7.17 - 7.20 (m, 2H, ArH). 13C-NMR 75 MHz, d-Chloroform) delta 55.40 (OCH3), 88.32 (C), 92.02 (C), 104.45 (C), 109.22 (CH), 1 16.65 (2xCH), 1 15 (C), 124.9 (CH), 130.52 (CH), 160.52 (C), 160.96 (2xC). Table 1 : type and concentration of halophenols; yield of 4'-hydroxy-3,5- dimethoxydiphenylacetylene |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine; In 1,1-dichloroethane; at 20℃; for 24h;Inert atmosphere; Darkness; | General procedure: To a 50 mL round bottom flask equipped with a stir bar and covered with an aluminum foil was added 16 or 17 (0.5 mmol), substituted phenylacetylene (1.5 mmol), copper(I)iodide (20 mol %), tetrakis(triphenylphosphine)palladium(0) (10 mol %) and flask was sealed with a rubber septum. The flask was evacuated and back filled with nitrogen (repeated three times). Anhydrous triethylamine (0.15 mL) and anhydrous dichloroethane (10 mL) were then added with the help of a syringe. The yellow-brown solution was stirred at room temperature under nitrogen atmosphere in dark for 24 h (until disappearance of starting material; monitored by TLC). At the end of the reaction, silica gel (1 g) was added and solvents evaporated to make a silica gel plug which was loaded on top of a silica gel column (3 cm × 15 cm) pre-treated with triethylamine/ethyl acetate/hexanes (1:1:25) and continued with a gradient elution, collecting 10 mL fractions. For 19a, 19c, 19e and 19g-i (dipivalated compounds), the product eluted with triethylamine/ethyl acetate/hexanes (1:1:15); while for 19b, 19d and 19f (monopivalated compounds), the product eluted with triethylamine/ethyl acetate/hexanes (1:1:10). The fractions containing product spots (TLC) were pooled and evaporated under reduced pressure. The residual solvents were further removed using high vacuum oil pump. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In acetonitrile at 20℃; for 16h; Inert atmosphere; Darkness; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | General procedure: A 2 M solution of Me2Zn in toluene (0.375 mL, 0.75 mmol) was added dropwise to a solution of ligand L3 (11.2 mg, 0.025 mmol) and alkyne 2 (0.9 mmol) in toluene (0.2 mL) at rt under nitrogen. After stirring for 1 h, the reaction mixture was cooled to 0 C. After 15 min, a solution of imine 1 (0.125 mmol) in toluene (0.4 mL) was added via syringe. The solution was stirred until the reaction was complete (TLC). The reaction mixture was quenched with 1 M HCl (15 mL), extracted with CH2Cl2 (3×15 mL), dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with hexane/EtOAc mixtures afforded compound 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With copper(l) iodide; sodium tetrachloropalladate(II); triethylamine; tris(4,6-dimethyl-3-sulfonatophenyl)phosphine trisodium salt hydrate; In water; acetonitrile; at 80℃; for 16h;Inert atmosphere; | General procedure: 5-IdU (100 mg, 0.282 mmol), TXPTS (7.4 mg, 0.0113 mmol), triethylamine (400 muL, 2.846 mmol), copper(I) iodide (2.2 mg, 0.0113 mmol), and alkyne (0.849 mmol) were placed in 1 mL of mixture of 1:1 water:acetonitrile in a round-bottomed flask under nitrogen. Sodium tetrachloro-Palladium(II) (1.7 mg, 0.0057 mmol) was added to the reaction, which was heated at 80 C until completion (16 h). Then the mixture was dissolved in butanol and washed with water and a saturated solution of sodium chloride. The organic phase was dried over MgSO4 concentrated under vacuum. The crude product was then purified on silica gel chromatography (0-6% MeOH/CH2Cl2) to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium hydroxide In dimethyl sulfoxide at 120℃; Inert atmosphere; stereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With copper(l) iodide; nickel(II) chloride hexahydrate; N,N,N,N,-tetramethylethylenediamine; oxygen; In tetrahydrofuran; at 20℃; | General procedure: To a THF solution of CuI (5 mol%) and NiCl2·6H2O (5 mol%), tetramethylethylendiamine (20 mol%) was added. The solution was stirred 2 min at room temperature. C5-Ethynyl-nucleoside (1 eq.) and commercial alkyne (5 eq.) were added subsequently and the reaction mixture was stirred overnight at room temperature under oxygen atmosphere. After evaporation of all volatiles, the residue was purified by silica gel column chromatography (EtOAc/Petroleum ether) to yield the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With copper(l) iodide;bis-triphenylphosphine-palladium(II) chloride; at 20℃; for 6h;Inert atmosphere; | To a solution of methoxy ethynylbenzenes (20 mmol) and methoxy substituted aryl iodide (22 mmol) in isopropylamine (120 ml) were added Pd(PPH3)2Cl2 (0.2 mmol) and CuI (0.4 mmol). The reaction mixture was stirred at ambient temperature for 6 hours under a slow stream of nitrogen. The reaction mixture was filtered and the residues were washed with ethyl acetate and the solvent evaporated from the combined filtrates. The crude product was purified by column chromatography on silica gel using petroleum ether/ethyl acetate (9:1) as an eluent to give methoxytolans. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); N-butylamine; In diethyl ether; at 20℃; for 6h;Inert atmosphere; | General procedure: cis-1,2-dichloroethylene 6 (2.0 equiv.), terminal acetylenes(1.0 mmol, 1.0 equiv.), Pd(PPh3)4 (2.0 mol%), CuI (4.0mol%), n-butylamine (2.0 equiv.) and 4 mL diethyl ether were mixed together and stirred under nitrogen atmospherefor 6 h. Then the mixture was diluted with water and extracted with dichloromethane. The organic solvent was removed under vacuum and the residue was purified by flash column chromatography (n-hexane : ethyl acetate 10 : 1) to afford the corresponding (Z)-chloroenynes 6a-g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With piperidine; copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); In diethyl ether; at 20℃; for 6h;Inert atmosphere; | General procedure: trans-1,2-dichloroethylene 7(2.0 equiv.), terminal acetylenes (1.0 mmol, 1.0 equiv.), PdCl2(PPh3)2 (2.0 mol%), CuI (4.0 mol%), piperidine (2.0 equiv.) and 4 mL diethyl ether were mixed together and stirred under nitrogen atmosphere for 6 h. Then the mixture was diluted with water and extracted with dichloromethane. The organic solvent was removed under vacuum and the residue was purified by flash column chromatography (n-hexane : ethyl acetate 10 : 1) to afford the corresponding (E)-chloroenynes 7a-f. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With copper; copper(II) sulfate; In water; tert-butyl alcohol; at 20℃; for 8h; | General procedure: Procedure A: To a solution of alkyne (1.3equiv.) and (E)-4-azido-bis(POM)-but-2-enylphosphonate 22 (0.11mmol, 1.0equiv.) in t-BuOH/ H2O (1:1 ratio, 400muL) were added Cu powder (11.6mg, 0.40mmol, 5.0equiv.) and CuSO4 (5.0mg, 0.020mmol, 0.25equiv.). The resulting suspension was stirred 8h at room temperature, then the crude mixture was diluted in EtOAc (1mL), and directly transferred on a preparative thin layer silica plate to give (E)-4?-(1,2,3-triazol-1-yl)-bis(POM)-but-2?-enylphosphonate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; diethylamine; triphenylphosphine; In N,N-dimethyl-formamide; at 80℃; for 2h;Inert atmosphere; | Synthesis of 5-((3 ,5-dimethoxyphenyl)ethynyl)-N- (2-methyl-6-nitrophenyl)pyrimidin-2-amine. A mixture of 5-bromo-N-(2-methyl-6-nitrophenyl)pyrimidin-2-amine (573 mg, 3.0 mmol), 1- ethynyl-3,5-dimethoxybenzene (483 mg, 3.0 mmol), triphenylphosphine (157 mg, 0.60 mmol), bis(triphenylphosphine)palladium(II) chloride (210 mg, 0.30 mmol), copper(I) iodide (57 mg,0.30 mmol) and diethylamine (1.50 ml, 15.0 mmol) in N,N-dimethylformamide (10 mL) was degassed with nitrogen three times, and then stirred at 80 C for 2 hrs. LCMS showed the reaction was completed. The mixture was coolded to RT, quenched with water (20 mL) and extracted with ethyl acetate (3 x 80 mL). The combined organic layers were separated, washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue waspurified by silica gel chromatography (petroleum ether:ethyl acetate = 4:1) to afford the title compound as a yellow solid (460 mg, 39%). MS (ES+) C21H,8N404 requires: 390, found: 391 [M |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7% | With Selectfluor; In acetonitrile; at 0 - 20℃;Inert atmosphere; | 3-Ethynyl-2,4-difluoro-1,5-dimethoxybenzene Selectfluor (24.57 g, 69.37 mmol) was added portion wise to a stirred solution of <strong>[171290-52-1]1-ethynyl-3,5-dimethoxybenzene</strong> (5.00 g, 30.83 mmol) in MeCN (40 ml) at 0C under nitrogen. Solution was allowed to warm slowly to ambient temperature and stirred for 18 h. Reaction mixture was quenched by addition of water and then partitioned between EtOAc and water. Organics were combined, dried, filtered and concentrated. Crude material was purified by FCC on Biotage (20 - 80% EtOAc / Heptane) to give the title compound (420.0 mg, 7%). 1H NMR (500 MHz, Chloroform-d) delta 6.65 (t, J= 8.0 Hz, 1H), 3.88 (s, 6H), 3.52 (s, 1H). M/Z: 198.05, M+1: 198.85, tR= 1.32 min (System 1). |
6.5 g | With Selectfluor; In acetonitrile; at 0 - 20℃; for 12h; | Selectfluor (22g, 62.1mmol) was added lot wise to a solution of l-ethynyl-3,5- dimethoxybenzene (5g, 30.8mmol) in acetonitrile (200mL) at 0 C. The reaction mass was stirred at ambient temperature for 12h. Concentrated the reaction mass and diluted the reaction mass with ethyl acetate and NaHC03 solution. Dried and concentrated and purified the crude to afford the desired title compound (6.5g crude ). (Poor ionisationin LCMS). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With pyridine; copper(l) iodide; In tetrahydrofuran; at 60℃; for 4.5h;Inert atmosphere; Sealed tube; | Under argon atmosphere,3,5-dimethoxyphenylacetylene(97 mg, 0.60 mmol), trifluoromethylthio reagent (85 mg, 0.3 mmol), cuprous iodide (60 mg, 0.60 mmol)Pyridine(72 l, 0.90 mmol) was placed in a 25 ml sealed tube and then 2 ml tetrahydrofuran solution was added and reacted at 60C for 4.5 hours.After completion of the reaction, the reaction mixture was cooled to room temperature and the solvent was removed by rotary evaporation under reduced pressure. The residue was purified by flash silica gel column to give the corresponding product e3 (64 mg, 81%). The purity was more than 95% by 1H-NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With copper(II) sulfate; sodium L-ascorbate; In water; tert-butyl alcohol; at 20℃; for 2h;Inert atmosphere; | General procedure: Azide 13 (300 mumol), alkyne (750 mumol), CuSO4 (9.6 mg, 60 mumol) and sodium ascorbate (60.0 mg, 300 mumol) were dissolved in 1:1 t-BuOH/H2O (3 mL). The mixture was stirred for 2 h at rt. After the completion of the reaction, the mixture was filtered and washed with H2O (70 mL) (solid A). The filtrate was extracted with EtOAc (3 * 70 mL). The combined organic extracts were dried over anhyd MgSO4, filtered, and concentrated by rotary evaporation (residue B). The solid A and residue B were combined and purified by column chromatography to afford 8 or 9. |
98% | With copper(II) sulfate; sodium L-ascorbate; In water; tert-butyl alcohol; at 20℃; for 2h; | Formula 7 of the azide compound (300 mumol), alkynyl (750 mumol), CuSO4 (9.6 mg, 60 mumol) and Na. An ascorbate (60.0 mg, 300 mumol) 1: was dissolved in 1 t-BuOH / H2O (3 mL). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was filtered of and washed using H2O (70 mL) (solid A). The filtrate was extracted with EtOAc (3 × 70 mL). The combined organic extracts were then dried using anhydrous MgSO4, filtered and concentrated by rotaryevaporation (residue B). It was combined and the solid residue A and B, was purified by column chromatography to give the compound of formula 2 and 3. Formula 2 for the general method in accordance with, 1:1 t-BuOH/H2O (3 mL) in a compound 7a (95.8 mg, 300 mumol), 1-ethynyl -3,5-dimethoxybenzene (121 mg, 750 mumol), CuSO4 (9.6 mg, 60 mumol) and Na. Using ascorbate (60.0 mg, 300 mumol) was prepared in the desired compound. After stirring at room temperature the reaction mixture for 2 hours, was purified by column chromatography (5: 1 hexane / EtOAc ? 40: 1 CH2Cl2 / MeOH) to compound 2a using a was obtained as a brown solid (138 mg, 98%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With copper(II) sulfate; sodium L-ascorbate; In water; tert-butyl alcohol; at 20℃; for 48h;Inert atmosphere; | General procedure: Azide 13 (300 mumol), alkyne (750 mumol), CuSO4 (9.6 mg, 60 mumol) and sodium ascorbate (60.0 mg, 300 mumol) were dissolved in 1:1 t-BuOH/H2O (3 mL). The mixture was stirred for 2 h at rt. After the completion of the reaction, the mixture was filtered and washed with H2O (70 mL) (solid A). The filtrate was extracted with EtOAc (3 * 70 mL). The combined organic extracts were dried over anhyd MgSO4, filtered, and concentrated by rotary evaporation (residue B). The solid A and residue B were combined and purified by column chromatography to afford 8 or 9. |
73% | With copper(II) sulfate; sodium L-ascorbate; In water; tert-butyl alcohol; at 20℃; for 18h; | Formula 7 of the azide compound (300 mumol), alkynyl (750 mumol), CuSO4 (9.6 mg, 60 mumol) and Na. An ascorbate (60.0 mg, 300 mumol) 1: was dissolved in 1 t-BuOH / H2O (3 mL). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was filtered of and washed using H2O (70 mL) (solid A). The filtrate was extracted with EtOAc (3 × 70 mL). The combined organic extracts were then dried using anhydrous MgSO4, filtered and concentrated by rotaryevaporation (residue B). It was combined and the solid residue A and B, was purified by column chromatography to give the compound of formula 2 and 3. Following the general method for the general formula 2, 1: 1 t-BuOH / H2O (3 mL) in a compound 7b (76.7 mg, 300 mumol), -3,5- dimethoxybenzene (121 mg 1-ethynyl, 750 mumol), CuSO4 (9.6 mg, 60 mumol) and Na. Using ascorbate (60.0 mg, 300 mumol) was prepared in the desired compound. The reaction mixture was stirred at room temperature for 48 hours, was purified by column chromatography (5: 1 hexane / EtOAc ? 20: 1 CH2Cl2 / MeOH) Compound 2b was obtained by using as a brown solid (90.6mg, 73%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With copper(II) sulfate; sodium L-ascorbate; In water; tert-butyl alcohol; at 20℃; for 5.5h;Inert atmosphere; | General procedure: Azide 13 (300 mumol), alkyne (750 mumol), CuSO4 (9.6 mg, 60 mumol) and sodium ascorbate (60.0 mg, 300 mumol) were dissolved in 1:1 t-BuOH/H2O (3 mL). The mixture was stirred for 2 h at rt. After the completion of the reaction, the mixture was filtered and washed with H2O (70 mL) (solid A). The filtrate was extracted with EtOAc (3 * 70 mL). The combined organic extracts were dried over anhyd MgSO4, filtered, and concentrated by rotary evaporation (residue B). The solid A and residue B were combined and purified by column chromatography to afford 8 or 9. |
80% | With copper(II) sulfate; sodium L-ascorbate; In water; tert-butyl alcohol; at 20℃; for 5.5h; | Formula 7 of the azide compound (300 mumol), alkynyl (750 mumol), CuSO4 (9.6 mg, 60 mumol) and Na. An ascorbate (60.0 mg, 300 mumol) 1: was dissolved in 1 t-BuOH / H2O (3 mL). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was filtered of and washed using H2O (70 mL) (solid A). The filtrate was extracted with EtOAc (3 × 70 mL). The combined organic extracts were then dried using anhydrous MgSO4, filtered and concentrated by rotaryevaporation (residue B). It was combined and the solid residue A and B, was purified by column chromatography to give the compound of formula 2 and 3. Formula 2 for the general method in accordance with, 1:1 t-BuOH/H2O (3 mL) in a compound 7c (80.8 mg, 300 mumol), 1-ethynyl -3,5-dimethoxybenzene (121 mg, 750 mumol), CuSO4 (9.6 mg, 60 mumol) and Na. Using ascorbate (60.0 mg, 300 mumol) was prepared in the desired compound. After stirring at room temperature for 5.5 hours the reaction mixture was purified by column chromatography (5: 1 hexane / EtOAc ? 20: 1 CH2Cl2 / MeOH) Compound 2c was obtained using as a brown solid (104mg, 80%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With copper(II) sulfate; sodium L-ascorbate; In water; tert-butyl alcohol; at 40℃; for 47h;Inert atmosphere; | General procedure: Azide 13 (300 mumol), alkyne (750 mumol), CuSO4 (9.6 mg, 60 mumol) and sodium ascorbate (60.0 mg, 300 mumol) were dissolved in 1:1 t-BuOH/H2O (3 mL). The mixture was stirred for 2 h at rt. After the completion of the reaction, the mixture was filtered and washed with H2O (70 mL) (solid A). The filtrate was extracted with EtOAc (3 * 70 mL). The combined organic extracts were dried over anhyd MgSO4, filtered, and concentrated by rotary evaporation (residue B). The solid A and residue B were combined and purified by column chromatography to afford 8 or 9. |
74% | With copper(II) sulfate; sodium L-ascorbate; In water; tert-butyl alcohol; at 40℃; for 47h; | Formula 7 of the azide compound (300 mumol), alkynyl (750 mumol), CuSO4 (9.6 mg, 60 mumol) and Na. An ascorbate (60.0 mg, 300 mumol) 1: was dissolved in 1 t-BuOH / H2O (3 mL). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was filtered of and washed using H2O (70 mL) (solid A). The filtrate was extracted with EtOAc (3 × 70 mL). The combined organic extracts were then dried using anhydrous MgSO4, filtered and concentrated by rotaryevaporation (residue B). It was combined and the solid residue A and B, was purified by column chromatography to give the compound of formula 2 and 3. Following the general method for the general formula 2, 1: 1 t-BuOH / H2O (3 mL) in the compound 7d (85.3 mg, 300 mumol),1-ethynyl -3,5-dimethoxy-benzene (121 mg, 750 mumol), CuSO4 (9.6 mg, 60 mumol) and Na. Using ascorbate (60.0 mg, 300 mumol) was prepared in the desired compound. The reaction mixture was stirred at 40 for 47 hours, was purified by column chromatography (5: 1 hexane / EtOAc ? 20: 1 CH2Cl2 / MeOH) to yield a compound 2d as a brown solid using (98.8mg, 74%) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With copper(II) sulfate; sodium L-ascorbate; In water; tert-butyl alcohol; at 20℃; for 66h;Inert atmosphere; | General procedure: Azide 13 (300 mumol), alkyne (750 mumol), CuSO4 (9.6 mg, 60 mumol) and sodium ascorbate (60.0 mg, 300 mumol) were dissolved in 1:1 t-BuOH/H2O (3 mL). The mixture was stirred for 2 h at rt. After the completion of the reaction, the mixture was filtered and washed with H2O (70 mL) (solid A). The filtrate was extracted with EtOAc (3 * 70 mL). The combined organic extracts were dried over anhyd MgSO4, filtered, and concentrated by rotary evaporation (residue B). The solid A and residue B were combined and purified by column chromatography to afford 8 or 9. |
51% | With copper(II) sulfate; sodium L-ascorbate; In water; tert-butyl alcohol; at 20℃; for 66h; | Formula 7 of the azide compound (300 mumol), alkynyl (750 mumol), CuSO4 (9.6 mg, 60 mumol) and Na. An ascorbate (60.0 mg, 300 mumol) 1: was dissolved in 1 t-BuOH / H2O (3 mL). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was filtered of and washed using H2O (70 mL) (solid A). The filtrate was extracted with EtOAc (3 × 70 mL). The combined organic extracts were then dried using anhydrous MgSO4, filtered and concentrated by rotaryevaporation (residue B). It was combined and the solid residue A and B, was purified by column chromatography to give the compound of formula 2 and 3. Following the general method for the general formula 2, 1: 1 t-BuOH / H2O (3 mL) in a compound 7e (29.5 mg, 100 mumol),1-ethynyl -3,5-dimethoxy-benzene (40.6 mg, 250 mumol), CuSO4 (3.2 mg, 20 mumol) and Na. ascorbate (20.0 mg, 100mumol) theOf the desired compound was prepared using. After stirring at room temperature the reaction mixture for 66 hours, was purified by column chromatography (5: 1 hexane / EtOAc ? 30: 1 CH2Cl2 / MeOH) Compound 2e by using as a brown solid form (23.1mg, 51%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With copper(II) sulfate; sodium L-ascorbate; In water; tert-butyl alcohol; at 20℃; for 3.5h;Inert atmosphere; | General procedure: Azide 13 (300 mumol), alkyne (750 mumol), CuSO4 (9.6 mg, 60 mumol) and sodium ascorbate (60.0 mg, 300 mumol) were dissolved in 1:1 t-BuOH/H2O (3 mL). The mixture was stirred for 2 h at rt. After the completion of the reaction, the mixture was filtered and washed with H2O (70 mL) (solid A). The filtrate was extracted with EtOAc (3 * 70 mL). The combined organic extracts were dried over anhyd MgSO4, filtered, and concentrated by rotary evaporation (residue B). The solid A and residue B were combined and purified by column chromatography to afford 8 or 9. |
82% | With copper(II) sulfate; sodium L-ascorbate; In water; tert-butyl alcohol; at 20℃; for 3.5h; | Formula 7 of the azide compound (300 mumol), alkynyl (750 mumol), CuSO4 (9.6 mg, 60 mumol) and Na. An ascorbate (60.0 mg, 300 mumol) 1: was dissolved in 1 t-BuOH / H2O (3 mL). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was filtered of and washed using H2O (70 mL) (solid A). The filtrate was extracted with EtOAc (3 × 70 mL). The combined organic extracts were then dried using anhydrous MgSO4, filtered and concentrated by rotaryevaporation (residue B). It was combined and the solid residue A and B, was purified by column chromatography to give the compound of formula 2 and 3. Following the general method for the general formula 2, 1: 1 t-BuOH / H2O in the compound (3 mL) 7f (34.6 mg, 100 mumol), 1-Ethynyl -3,5-dimethoxy-benzene (40.1 mg, 250 mumol), CuSO4 (3.2 mg, 20 mumol) and Na. Using ascorbate (20.0 mg, 100mumol) was prepared the desired compound. The reaction mixture was stirred at room temperature for 3.5 h, purified by column chromatography (5: 1 hexane / EtOAc ? 20: 1 CH2Cl2 / MeOH) to use the compound 2f was obtained as a brown solid (39.7mg, 82%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With copper(II) sulfate; sodium L-ascorbate; In water; tert-butyl alcohol; at 60℃; for 5h;Inert atmosphere; | General procedure: Azide 13 (300 mumol), alkyne (750 mumol), CuSO4 (9.6 mg, 60 mumol) and sodium ascorbate (60.0 mg, 300 mumol) were dissolved in 1:1 t-BuOH/H2O (3 mL). The mixture was stirred for 2 h at rt. After the completion of the reaction, the mixture was filtered and washed with H2O (70 mL) (solid A). The filtrate was extracted with EtOAc (3 * 70 mL). The combined organic extracts were dried over anhyd MgSO4, filtered, and concentrated by rotary evaporation (residue B). The solid A and residue B were combined and purified by column chromatography to afford 8 or 9. |
71% | With copper(II) sulfate; sodium L-ascorbate; In water; tert-butyl alcohol; at 60℃; for 5h; | Formula 7 of the azide compound (300 mumol), alkynyl (750 mumol), CuSO4 (9.6 mg, 60 mumol) and Na. An ascorbate (60.0 mg, 300 mumol) 1: was dissolved in 1 t-BuOH / H2O (3 mL). The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was filtered of and washed using H2O (70 mL) (solid A). The filtrate was extracted with EtOAc (3 × 70 mL). The combined organic extracts were then dried using anhydrous MgSO4, filtered and concentrated by rotaryevaporation (residue B). It was combined and the solid residue A and B, was purified by column chromatography to give the compound of formula 2 and 3. Following the general method for the general formula 2, 1: 1 t-BuOH / H2O (1 mL) Compound 7g (31.2 mg, 100 mumol), in a 1-Ethynyl -3,5-dimethoxy-benzene (40.5 mg, 250 mumol), CuSO4 (3.2 mg, 20 mumol) and Na. Using ascorbate (20.0 mg, 100mumol) was prepared the desired compound. After stirring at 60 the reaction mixture for 5 hours, was purified by column chromatography (5: 1 hexane / EtOAc ? 20: 1 CH2Cl2 / MeOH) using afford 2g as a brown solid (33,6mg, 71% ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃; for 2h;Inert atmosphere; | 5-(Benzenesulfonyl)-2-[2-(3,5-dimethoxyphenyl)ethynyl]-5H-pyrrolo[2,3-b]pyrazine 5-(Benzenesulfonyl)-2-bromo-5H-pyrrolo[2,3-b]pyrazine (3.50 g, 10.35 mmol), copper(1+) iodide (197.1 mg, 1.03 mmol) and palladium tetrakis triphenylphospine (597.7 mg, 0.52 mmol) were dissolved in MeCN (40 ml). Reaction mixture was degassed with nitrogen for 5 mins. <strong>[171290-52-1]1-ethynyl-3,5-dimethoxybenzene</strong> (2.52 g, 15.52 mmol) and DIPEA (8.96 ml, 51.75 mmol) were added and reaction heated to 80C, under a nitrogen atmosphere, for 2 h. Reaction mixture was allowed to cool to RT, then to 0C and left to stand overnight. The beige precipitate formed after this time was filtered off, dissolved in EtOAc, washed with water and concentrated. Crude material was re-crystallised from EtOAc to give the title compound as a yellow solid (3.16 g, 73%). 1H NMR (500 MHz, Chloroform-d) delta 8.55 (s, 1H), 8.24 - 8.13 (m, 2H), 8.04 (d, J = 3.7 Hz, 1H), 7.66 - 7.60 (m, 1H), 7.52 (t, J = 7.9 Hz, 2H), 6.82 (s, 1H), 6.77 (d, J = 2.2 Hz, 2H), 6.51 (t, J = 2.2 Hz, 1H), 3.80 (s, 6H). M/Z: 419.09, M+1: 419.95, tR= 1.59 min (System 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃; for 1.5h;Inert atmosphere; Sealed tube; | 1-(Benzenesulfonyl)-5-[2-(3,5-dimethoxyphenyl)ethynyl]-1H-pyrrolo[2,3-b]pyridine 1-(Benzenesulfonyl)-5-bromo-1H-pyrrolo[2,3-b]pyridine (639.0 mg, 1.90 mmol), 1-ethynyl-3,5-dimethoxybenzene (461.0 mg, 2.84 mmol), copper(1+) iodide (36.1 mg, 0.19 mmol) and DIPEA (1.62 ml, 9.48 mmol) were dissolved in MeCN (10 ml). Reaction mixture was degassed with nitrogen for 5 mins. Palladium tetrakis triphenylphospine (109.5 mg, 0.09 mmol) was added and reaction heated to 80C in a sealed tube for 90 mins. Reaction mixture was cooled to RT, partitioned between saturated aq. NaHCO3 solution and EtOAc and organics separated. Organics were washed with brine, dried, filtered and concentrated. Crude material was purified by FCC on Biotage (0 - 50% EtOAc / Heptane) to give the title compound as a yellow solid (867.0 mg, 100%). 1H NMR (500 MHz, Chloroform-d) delta 8.59 (d, J = 1.9 Hz, 1H), 8.27 - 8.12 (m, 2H), 8.00 (d, J = 1.9 Hz, 1H), 7.78 (d, J = 4.0 Hz, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.52 (t, J = 7.8 Hz, 2H), 6.71 (d, J = 2.3 Hz, 2H), 6.62 (d, J = 4.0 Hz, 1H), 6.50 (t, J = 2.3 Hz, 1H), 3.83 (s, 6H). M/Z: 418.10, M+1: 418.90, tR= 1.63 min (System 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In acetonitrile at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With copper(II) sulfate; sodium L-ascorbate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; water; at 65 - 70℃;Inert atmosphere; | General procedure: The azido derivative of N,-C terminal protected L-serine (1.0equiv) was taken in a 5:1 dry THF and water mixture solvent anddegassed it for 5 min with nitrogen gas. Then, terminal alkyne(1.1 equiv) was added with continuing stirring and degassing forthe next 5 min. Then 6 mol% sodium ascorbate and 1 mol% powderCuSO4 were added. The reaction mixture was degassed and allowed to proceed 18-20 h about 65-70 C. After total consumptionof the starting azide, the reaction mixture evaporatedcompletely and work up done by EtOAc and NH4Cl solution. Theorganic layer was washed with brine, dried over Na2SO4. Thesynthesized trizolyl amino acids were separated by column chromatography(si-gel, PE/EA = 1:1) and characterized. The averageyields were 50-85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With copper(l) iodide; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran;Reflux; | General procedure: The azido-sugar 2(1 equiv) was dissolved in dry THF (45 mL/mmol) and the required alkyne derivative (5.4 equiv), diisopropylethylamine(1.9 equiv), CuI (0.57 equiv) and DMEDA (5.2 equiv) were added. The reaction mixture was heated to reflux until TLC indicated complete consumption of 2, then the solvent was removed.The residue was dissolved in EtOAc and washed with H2O twice and once with an aqueous solution of EDTA (1%,m/v). The organic layer was dried over MgSO4, filtered and the solvent removed. Purification of the crude material on column chromatography on silica gel (CH2Cl2/EtOAc) afforded the desired product |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 2h;Sealed tube; | Cul (0.053g, 0.2mmol) was added to the degassed solution of 5-Iodo-N-(2-methyl-6- nitrophenyl)pyrimidin-2-amine (lg, 2.8mmol) and l-ethynyl-3,5-dimethoxybenzene (0.5g, 3.0mmol) in DMF (5mL) followed by the addition of tetrakis (0.32g, 0.2mmol) in a sealed tube. Stirred the reaction mass for 10 min and added DIPEA (0.75mL, 4.2mmol) and heated the resultant reaction mass to 80 C for 2h. Reaction mass was filtered through celite and washed the celite bed with ethyl acetate. The organic layer washed with water followed by brine, dried over Na2S04, filtered and concentrated. The residue was purified by 60-120 silica gel column chromatography to afford desired title compound (0.7g, 66%). LCMS: m/z = 391.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With potassium tert-butylate; In toluene; at 20℃;Inert atmosphere; | General procedure: To a solution of an alkyne 2 (1.2 equiv) in anhydrous toluene (3 mL) under an argon atmosphere, KOtBu (1.0 equiv) was added, and the mixture was stirred for 10-15 min. Then, an N-protected isatin 1 (1.0 equiv) was added to the reaction mixture, which was stirred for 30 min to 3 h until all the isatin was consumed (confirmed by TLC). The reaction was finally quenched with a few drops of 1 N HCl and the resulting mixture was extracted with CH2Cl2 (2 × 15 mL). The combined organic phases were washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was then purified by column chromatography on silica gel (EtOAc-hexane,10:90 to 30:70) to give compounds 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With tellurium; sodium tetrahydroborate; at 90℃; for 5h;Inert atmosphere; | General procedure: In a two-necked round bottomed flask under nitrogen atmosphere, sodium telluride was generated by reaction of elemental tellurium (Te0, 0.5 mmol) with sodium tetrahydroborate (0.8 mmol, 0.030 g) and NaOH (0.55 mmol, 0.022 g) in PEG-400 (3.0 mL) at 60 C. After 30 min, a violet solution was obtained and the corresponding alkyne was added (1.0 mmol). After stirring for 5 h at 60 or 90 C, the reaction mixture was quenched with water (10.0 mL) and extracted with ethyl acetate (3 × 15.0 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography over silica gel eluting with hexanes to yield the products. All compounds were properly characterized by MS, 1H-NMR, and 13C-NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With N-chloro-succinimide; silver nitrate; In acetonitrile; at 40℃; for 8h; | A solution of 3,5-dimethoxyphenylacetylene in 0.5 mmol (80 mg)N-chlorosuccinimide 1 mmol (133 mg),Silver nitrite 1 mmol (154 mg) and acetonitrile 4 ml were successively added to a 25 ml volume sealed pressure vessel.The mixture was reacted at 40 C for 8 hours.After completion of the TLC reaction, the reaction solution was diluted with methylene chloride and filtered to give a clear solution which was separated by column chromatography (eluent ratio: petroleum ether to ethyl acetate volume ratio of 10: 1) The eluent was evaporated to remove the solvent to give 1,3-dimethoxy-5- (nitroalkynylbenzene) (66% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | General procedure: 2-Iodo-N-phenyl-N-(trimethylsilylethynyl)benzenesulfonamide 18 (100 mg, 0.22 mmol), CuI (4.2 mg, 0.022 mmol), and PdCl2(PPh3)2 (7.7 mg, 0.011 mmol) were placed successively in a two-necked 100 mL flask containing a bar magnet and capped by a three-way stopcock. The reactor was purged of air (three vacuum-nitrogen cycles) before 5 mL of dry and degassed triethylamine and 3 mL of dry and degassed THF were added. 0.5 h later, the desired alkyne 19 (0.24 mmol) was added. The resulting mixture was stirred at room temperature and the reaction was followed by thin layer chromatography. When the reaction was complete, the solvents were removed under reduced pressure and the crude product was purified by column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With iodine; dimethyl sulfoxide; at 20 - 100℃; for 5h; | General procedure: To a stirred solution of phenylacetylene2a(165mL, 1.49 mmol)in DMSO (5 mL) were added molecular iodine (0.157 g, 0.62 mmol)and1a(0.2 g, 1.25 mmol) at room temperature and the reaction wasallowed to continue for 4 h at 100C. Thereafter, the reaction wasquenched by adding aqueous Na2S2O3(10% w/v, 10 mL) and theresulting mixture was extracted with EtOAc (3 20 mL). Theorganic fractions were pooled, dried over anhydrous Na2SO4andevaporated under vacuum. The crude product thus obtained waspurified by chromatography over a column of silica gel using hexanes/EtOAc (8.0:2.0, v/v) as eluent to afford the desired product3aa(0.285 g, 84%) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With piperidine; iodine; In water; at 100℃; for 12h; | General procedure: A 10 mL reaction vial was charged with a terminal acetylenes 1a-p (1.0 mmol), piperidine (3.0 mmol), H2O (1 mL) and 30 mol% molecular iodine. The reaction vial was then heated at 100 C for 12 h. After completion of the reaction (progress was monitored by TLC; SiO2, Hexane/EtOAc = 9.5:0.5), the mixture was diluted with ethyl acetate (15 mL) and water (20 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layer was washed with brine (3 × 10 mL) and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and the remaining residue was purified by column chromatography over silica gel using hexane / ethyl acetate (9.5:0.5) as an eluent to obtain the desired products 2a-p in high yields. |
66% | With N,N,N,N,-tetramethylethylenediamine; copper; In 1,4-dioxane; chloroform; at 50℃;Schlenk technique; Inert atmosphere; | General procedure: Following a modified literature procedure[11] in a flame dried 100 mL-Schlenk tube copper powder (6.4 mg, 0.1 mmol, 5 mol%), TMEDA (47 mg, 0.4 mmol, 20 mol%) and terminal alkyne S3a-d, S4-8, S10 (2.0 mmol, 1.0 equiv.) are suspended in chloroform (1.0 mL) and 1,4-dioxane (0.3 mL). The mixture is stirred at 50 C overnight. After cooling the mixture is diluted with dichloromethane (4 mL) and filtered through a plug of silica (1 cm) and concentrated under reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With oxygen; palladium diacetate; triethylamine; triphenylphosphine; In N,N-dimethyl-formamide; at 120℃; for 4h;Schlenk technique; | To a clean Schlenk reaction tube was added 0.8 mmol of phenylhydrazine hydrochloride, palladium acetate (5 mol%), triphenylphosphine (10 mol%) and a stirrer, then plugged with a soft plug to the tube, and the branch was charged with carbon monoxide And oxygen (CO / O2 = 1/1), and the Schlenk reaction tube was ventilated three times. Finally, 2 ml of a solution containing 3,5-dimethoxyphenylacetylene (0.2 mmol) and triethylamine (0.8 mmol ) In DMF solvent at 120 C for 4 hours. After the reaction was finished, the reaction solution was extracted with water and extracted three times with ethyl acetate. The organic layer was concentrated and separated by column chromatography to give 3-(3,5-dimethoxyphenyl)-1,5-diphenyl-1H-pyrazole as a pale yellow solid in 58% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With copper(II) sulfate; sodium L-ascorbate; In water; N,N-dimethyl-formamide; at 70℃; for 0.166667h;Sealed tube; Microwave irradiation; | General procedure: To a solution of the azide intermediate (0.1 mmol) in 0.2 mL of DMFin a microwave tube, CuSO4 (0.05 mmol) diluted in 50.0 muL of water,sodium ascorbate (0.025 mmol) and the alkyne (0.2 mmol) were added.The tube was sealed and the solution was irradiated (70 C, 150 W) for10 min and, then, TLC analysis showed the complete consumption ofthe starting material. The reaction was diluted with 15 mL of brine,extracted with ethyl acetate (3×10 mL), dried by anhydrous Na2SO4and concentrated under reduced pressure. The resulting crude productwas purified by column chromatography on silica gel [hexane: ethylacetate, 60:40% (v/v)] yielding the expected product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With copper(II) sulfate; sodium L-ascorbate; In water; N,N-dimethyl-formamide; at 70℃; for 0.166667h;Sealed tube; Microwave irradiation; | General procedure: To a solution of the azide intermediate (0.1 mmol) in 0.2 mL of DMFin a microwave tube, CuSO4 (0.05 mmol) diluted in 50.0 muL of water,sodium ascorbate (0.025 mmol) and the alkyne (0.2 mmol) were added.The tube was sealed and the solution was irradiated (70 C, 150 W) for10 min and, then, TLC analysis showed the complete consumption ofthe starting material. The reaction was diluted with 15 mL of brine,extracted with ethyl acetate (3×10 mL), dried by anhydrous Na2SO4and concentrated under reduced pressure. The resulting crude productwas purified by column chromatography on silica gel [hexane: ethylacetate, 60:40% (v/v)] yielding the expected product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With copper(II) sulfate; sodium L-ascorbate; In water; N,N-dimethyl-formamide; at 70℃; for 0.166667h;Sealed tube; Microwave irradiation; | General procedure: To a solution of the azide intermediate (0.1 mmol) in 0.2 mL of DMFin a microwave tube, CuSO4 (0.05 mmol) diluted in 50.0 muL of water,sodium ascorbate (0.025 mmol) and the alkyne (0.2 mmol) were added.The tube was sealed and the solution was irradiated (70 C, 150 W) for10 min and, then, TLC analysis showed the complete consumption ofthe starting material. The reaction was diluted with 15 mL of brine,extracted with ethyl acetate (3×10 mL), dried by anhydrous Na2SO4and concentrated under reduced pressure. The resulting crude productwas purified by column chromatography on silica gel [hexane: ethylacetate, 60:40% (v/v)] yielding the expected product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With copper(II) sulfate; sodium L-ascorbate; In water; N,N-dimethyl-formamide; at 70℃; for 0.166667h;Sealed tube; Microwave irradiation; | General procedure: To a solution of the azide intermediate (0.1 mmol) in 0.2 mL of DMFin a microwave tube, CuSO4 (0.05 mmol) diluted in 50.0 muL of water,sodium ascorbate (0.025 mmol) and the alkyne (0.2 mmol) were added.The tube was sealed and the solution was irradiated (70 C, 150 W) for10 min and, then, TLC analysis showed the complete consumption ofthe starting material. The reaction was diluted with 15 mL of brine,extracted with ethyl acetate (3×10 mL), dried by anhydrous Na2SO4and concentrated under reduced pressure. The resulting crude productwas purified by column chromatography on silica gel [hexane: ethylacetate, 60:40% (v/v)] yielding the expected product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With N-Bromosuccinimide; silver(I) nitrite; In 1,2-dichloro-ethane; at 20℃; for 8h;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 (52% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 90℃; for 6h;Inert atmosphere; | Compound e (500 mg, 1 eq), f (530 mg, 1.3 eq), CuI (40 mg, 0.08 eq), Triethylamine (79 muL, 2 eq), Bis(triphenylphosphine)palladium(II) chloride (90 mg, 0.05 eq) was placed in the reaction flask. Add 20 mL of dry N,N-dimethylformamide, Replace the air three times with nitrogen, Reaction at 90 C for 6 h, After the reaction is completed, Add 200mL of water, Extracted with ethyl acetate three times, The organic layer was dried over anhydrous sodium sulfate and concentrated. The title compound g (496 mg, yield: 71%) was obtained by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With copper(II) sulfate; sodium L-ascorbate; In water; tert-butyl alcohol; at 20℃; | General procedure: To a solution of the unprotected pyrrolidineazidein tBuOH:H2O 2:1 (25-30 mM), the corresponding alkyne(1.2 eq), sodium ascorbate (0.11-0.22 eq) and CuSO4 (0.034-0.068 eq) were added and the solution was stirred at r.t. for 15-24 h. The solventwas evaporated, and the resulting residue was purified by chromatographycolumn on silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With copper(II) sulfate; sodium L-ascorbate; In water; tert-butyl alcohol; at 20℃; | General procedure: To a solution of the unprotected pyrrolidineazidein tBuOH:H2O 2:1 (25-30 mM), the corresponding alkyne(1.2 eq), sodium ascorbate (0.11-0.22 eq) and CuSO4 (0.034-0.068 eq) were added and the solution was stirred at r.t. for 15-24 h. The solventwas evaporated, and the resulting residue was purified by chromatographycolumn on silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 80℃; for 5h;Inert atmosphere; | To a solution of 69 benzyl-3-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)azetidine-1-carboxylate 2e (0.123 g, 0.31 mmol), 43 <strong>[171290-52-1]1-ethynyl-3,5-dimethoxybenzene</strong> (0.740 g, 3.10 mmol) and 44 triethylamine (0.310 g, 3.10 mmol) in 32 N,N-dimethylformamide (5 mL), under nitrogen protection, were added 45 cuprous iodide (12 mg, 0.06 mmol) and 46 1,1?-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (22 mg, 0.03 mmol). The mixture was heat to 80 C. and stirred for 5 h. The mixture was cooled to room temperature, quenched with saturated ammonium chloride solution (10 mL) and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with brine (20 mL×2), dried over anhydrous sodium sulfate and filtered. The residue was purified by preparative-TLC (19:1 dichloromethane/methanol) to provide 71 benzyl-3-(8-amino-1-((3,5-dimethoxyphenyl)ethynyl)imidazo [1,5-a]pyrazin-3-yl)azetidine-1-carboxylate2f (52.5 mg, 0.11 mmol, grey solid), yield: 35%.MS m/z (ESI): 484 [M+1]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With copper(ll) sulfate pentahydrate; sodium L-ascorbate; In water; tert-butyl alcohol; at 20℃; for 24h;Darkness; | General procedure: Azide 9 (300 mg, 7.6 mmol) and an appropriate ethynylbenzene 10a-10j (7.6 mmol) were dissolved in a 1:1 mixture of water with t-butyl alcohol (15 mL). Sodium ascorbate (225 mg, 15 mol%, 1.14 mmol) was added followed by copper (II) sulfate pentahydrate (95 mg, 5 mol %, 0.38 mmol). The mixture was stirred vigorously in darkness for 24 h. After completion of reaction tert-butyl alcohol was evaporated in vacuum, and the aqueous phase was extracted with ethyl acetate (3×30 mL). The combined organic phases were was hed with water and dried over Na2SO4. The crude product was purified by column chromatography (ethyl acetate-hexane, 1 : 1) to obtain the corresponding pure compound 11a-11j. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With copper(ll) sulfate pentahydrate; potassium ascorbate; In water; butan-1-ol; at 70℃; for 13h; | General procedure: Compound 9 (500 mg, 9.67 mmol) and an ethynylbenzene 10a-10j(9.67 mmol) were mixed in n-BuOH-H2O (1 : 1,10 mL) in a sealed tube in presence of CuSO4·5H2O (24 mg, 0.096 mmol) and potassium ascorbate (207 mg, 0.967 mmol). The reaction mixture was stirred at 70C for 13 h. Upon cooling down, the reaction mixture was poured into H2O (16 mL) at 0C,and the precipitate was filtered off and washed withH2O. The crude product was purified by column chromatography with ethyl acetate-hexane (3 : 7) to afford the corresponding pure compound 11a-11j. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With Selectfluor; In acetonitrile; at 0 - 20℃; | The mixture <strong>[171290-52-1]1-ethynyl-3,5-dimethoxybenzene</strong> 1e (2 g, 12.3 mmol) was dissolved in acetonitrile (15 mL), and cooled down to 0 C., then a salt of 1-chloromethyl-4-fluoro-1,4-diazonium dicyclo 2.2.2 octane bis(tetrafluoroborate) (6.6 g, 18.5 mmol) was added in portions, then stirred at room temperature overnight, the reaction solution was poured into water (50 mL), and extracted with dichloromethane (30 mL*3), and the organic phases were combined and dried over anhydrous sodium sulfate, the desiccant was removed by filtering, next the system was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30/1), so as to obtain the title product 1-ethynyl-2-fluoro-3,5-dimethoxybenzene 17a (800 mg, yellow solid), and the yield was 36%. 1H NMR (400 MHz, CDCl3) delta 6.46 (dd, J=6.9, 2.9 Hz, 1H), 6.41 (dd, J=4.5, 3.0 Hz, 1H), 3.78 (s, 3H), 3.69 (s, 3H), 3.22 (s, 1H). |
36% | With Selectfluor; In acetonitrile; at 0 - 20℃; | The mixture <strong>[171290-52-1]1-ethynyl-3,5-dimethoxybenzene</strong> 1e (2g, 12.3mmol) was dissolved in acetonitrile (15mL), cooled to 0 C, and 1-chloromethyl-4-fluoro-1,4-diazobicyclo 2.2.2 octane bis (tetrafluoroborate) was added in portions. ) Salt (6.6 g, 18.5 mmol), then stirred at room temperature overnight.The reaction solution was poured into water (50 mL) and extracted with dichloromethane (30 mL × 3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography ( Petroleum ether / ethyl acetate = 30/1), the target product 1-ethynyl-2-fluoro-3,5-dimethoxybenzene 17a (800 mg, yellow solid) was obtained, yield: 36%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; copper(l) iodide; triethylamine; In N,N-dimethyl-d6-formamide; at 90℃; for 12h;Inert atmosphere; | (S)-3-(3-bromo-4-cyano-5-(methylamino)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 21a (1.85 g, 5.0 mmol), triethylamine (20 mL), 1,1'-bisdiphenylphosphinoferrocene palladium dichloride (816 mg, 1 mmol), cuprous iodide (190 mg, 1 mmol) and N,N-dimethylmethyl Mix the amide (20 mL) were mixed together, deoxygenated, and then heated to 90 C. under an argon atmosphere, then a solution of <strong>[171290-52-1]1-ethynyl-3,5-dimethoxybenzene</strong> (4.86 g, 30 mmol) in N,N-dimethylformamide (10 mL) was added dropwise, stirring continued for 12 hours, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=50/1 to 0/1), so as to obtain the title product (S)-3-(4-cyano-3-((3,5-dimethoxyphenyl)ethynyl)-5-(methylamino)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 21b (2.1 g, brown solid), and the yield was 80%. MS m/z (ESI): 496[M+H-56] |
80% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 90℃; for 12h;Inert atmosphere; | (S) -3- (3- Bromo-4-cyano-5- (methylamino) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester 21a (1.85g, 5.0mmol), triethylamine (20mL) , 1,1'-bisdiphenylphosphine-ferrocene palladium dichloride (816mg, 1mmol), cuprous iodide (190mg, 1mmol) and N, N-dimethylformamide (20mL) were mixed, except Oxygen, heated to 90 C under an argon atmosphere, and then <strong>[171290-52-1]1-ethynyl-3,5-dimethoxybenzene</strong> (4.86 g, 30 mmol) of N, N-dimethylformamide (10 mL) was added dropwise. ) Solution and continue stirring for 12 hours.Desolvate under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50/1 to 0/1) to give the target product (S) -3- (4-cyano-3-((3, 5-Dimethoxyphenyl) ethynyl) -5- (methylamino) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl 21b (2.1g, brown solid), produced Rate: 80%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 80℃; for 12h; | A mixture of (S)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-iodo-1H-pyrazole-4-ethyl formate 1 h (1 g, 2.25 mmol), 1-acetylene-3,5-dimethoxybenzene 1e (0.75 g, 4.5 mmol), bis(triphenylphosphine) palladium chloride (175 mg, 0.25 mmol), cuprous iodide (95 mg, 0.5 mmol), triethyl the amine (12.5 ml), and N,N-dimethylformamide (12.5 mL) was heated to 80 C. and stirred for 12 hours, the reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=2/1), so as to obtain the title product (S)-1-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazole-4-ethyl formate (0.95 g, yellow oily substance), and the yield was 90%. MS m/z (ESI): 414 [M+1-56] |
90% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 80℃; for 12h; | (S) -1- (1- (third-butoxycarbonyl) pyrrolidin-3-yl) -3-iodine -1H-pyrazole-4-carboxylic acid ethyl ester 1h (1g, 2.25mmol), <strong>[171290-52-1]1-ethynyl-3,5-dimethoxybenzene</strong> 1e (0.75g, 4.5mmol), bis (triphenylphosphine) chloride A mixture of palladium (175mg, 0.25mmol), cuprous iodide (95mg, 0.5mmol), triethylamine (12.5ml) and N, N-dimethylformamide (12.5mL) was heated to 80 C, Stir for 12 hours.The reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2/1) to obtain the target product (S) -1- (1- ( Tributoxycarbonyl) pyrrolidin-3-yl) -3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazole-4-carboxylic acid ethyl ester 1i (0.95 g, yellow oil Material), yield: 90%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With bis-triphenylphosphine-palladium(II) chloride; triethylamine; In tetrahydrofuran; at 20℃; for 15h;Inert atmosphere; | The compounds of 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide 2c (2.7 g, 7.3 mmol), <strong>[171290-52-1]1-ethynyl-3,5-dimethoxybenzene</strong> (1.78 g, 11 mmol), triethylamine (2.2 g, 21.9 mmol), bis(triphenylphosphine)palladium chloride (512 mg, 0.73 mmol), and anhydrous tetrahydrofuran (70 mL) were mixed, and then subjected to deoxygenation, and stirred at room temperature for 15 hours under an argon atmosphere, the solvent was then removed under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether=10/1 to 2/1), so as to obtain the title product 3-((3,5-dimethoxyphenyl)ethynyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxamide 2d (1.5 g, yellow solid), and the yield was 51%. MS m/z (ESI): 402[M+1] |
51% | With bis-triphenylphosphine-palladium(II) chloride; triethylamine; In tetrahydrofuran; at 20℃; for 15h;Inert atmosphere; | Compound 3-iodo-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole 4-formamidine 2c (2.7 g, 7.3 mmol), <strong>[171290-52-1]1-ethynyl-3,5-dimethoxybenzene</strong> (1.78 g, 11 mmol), triethylamine (2.2 g, 21.9 mmol), bis (triphenylphosphonium) palladium chloride (512 mg, 0.73 mmol) and anhydrous tetrahydrofuran (70 mL) were mixed, deoxygenated, and stirred at room temperature under an argon atmosphere for 15 hours.The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 10/1 to 2/1) to give the target product 3-((3,5-dimethoxyphenyl) acetylene Yl) -1-((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazole-4-carboxamide 2d (1.5 g, yellow solid), yield: 51%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 80℃; for 2h;Inert atmosphere; | A mixture of (S)-3-(5-amino-3-bromo-4-cyano-1H-pyrazol-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 7c (5 g, 14.1 mmol), cuprous iodide (0.6 g, 2.8 mmol), triethylamine (9 mL), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (2 g, 2.8 mmol) and N,N-dimethylformamide (150 mL) was heated to 80 C. under argon, and then <strong>[171290-52-1]1-ethynyl-3,5-dimethoxybenzene</strong> (14 g, 84.5 mmol) was added in portions, next stirred for 2 hours, and then cooled to room temperature, poured the reaction solution into water, extracted with ethyl acetate (200 mL*3); next the organic phases were combined and dried over anhydrous sodium sulfate, the desiccant was removed by filtering, and the reaction system was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5/1), so as to obtain the title product (S)-3-(5-amino-4-cyano-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 7d (5 g, brown oil), and the yield was 81%. MS m/z (ESI): 382[M+1-56] |
81% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 80℃; for 2h;Inert atmosphere; | (S) -3- (5-amino-3-bromo-4-cyano-1H -Pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester 7c (5g, 14.1mmol), cuprous iodide (0.6g, 2.8mmol), triethylamine (9mL), [1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride (2g, 2.8mmol) And N, N-dimethylformamide (150mL) were heated to 80 C under the protection of argon, and <strong>[171290-52-1]1-ethynyl-3,5-dimethoxybenzene</strong> (14g, 84.5mmol) was added in portions. And stir for 2 hours.After cooling to room temperature, the reaction solution was poured into water and extracted with ethyl acetate (200 mL × 3).The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5/1) to obtain the target product (S) -3- ( 5-amino-4-cyano-3-((3,5-dimethoxyphenyl) ethynyl) -1H-pyrazol-1-yl) pyrrolidine-1-carboxylic acid third butyl ester 7d (5 g, brown oil), yield: 81%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; copper(l) iodide; triethylamine; In 1,4-dioxane; at 60℃; for 6.0h;Inert atmosphere; | Methyl 5-bromo-2-chloro isonicotinate (30 g, 120 mmol) was dissolved in 1,4-dioxane (300 mL), and 3,5-dimethoxyphenylacetylene (20.4 g, 120 mmol), CuI (2.28 g, 12 mmol), Pd(dppf)Cl2 (4.2 g, 6 mmol) and Et3N (12.0 g, 120 mmol) were added, and the mixture was heated to 60 C. under N2, for 6 h. The reaction was complete, and the mixture was filtered and concentrated. The crude product was separated by silica gel column chromatography (DCM:PE=20:1) to obtain compound methyl 2-chloro-5-((3,5-dimethoxyphenyl)ethynyl)isonicotinate (22 g, yield: 55%). MS (ESI): m/z 332.1 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With copper(l) iodide; In tetrahydrofuran; at 20℃; for 16h; | General procedure: A solution of azide 11 (500 mg, 9.5 mmol) and 1-ethynylbenzene (12a) (0.64 mL, 9.5 mmol) in anhydrous THF (15 mL) was mixed with CuI (90 mg, 5 mol%, 4.75 mmol). The mixture was stirred vigorously at room temperature for 16 h. After completion of the process (THF) the solvent was evaporated in vacuum and the crude product was dissolved in ethyl acetate (3*30 mL). The organic phase was washed with water and dried over Na2SO4. After evaporation of the solvent in vacuum the crude product was purified by column chromatography (ethyl acetate-hexane 7 : 3) to obtain compound 13a. Yield 52%, mp 257-259C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 50℃; for 1h;Inert atmosphere; | 5-bromo-2-chloroisonicotinaldehyde (2.5 g, 11.3 mmol), <strong>[171290-52-1]1-ethynyl-3,5-dimethoxybenzene</strong> (1.93 g, 11.9 mmol), DIPEA (3.66 g, 28.4=lop, CuI (108 mg, 0.6 mmol), and Pd(PPh3)2Cl2 (398 mg, 0.6 mmol) were added to 1,4-dioxane (50 mL) under N2, the mixture was heated to 50 C. for 1 h. After the reaction was completed, the mixture was diluted with EtOAc (300 mL), washed successively with water (50 mL*3) and saturated brine (100 mL), concentrated and separated by column chromatography (Eluent: PE/EtOAc 9:1) to obtain compound 2-chloro-5-((3,5-dimethoxyphenyl)ethynyl)isonicotinaldehyde (3.0 g, yield: 75%). MS m/z (ESI): 302.2, 3042 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; triphenylphosphine; In tetrahydrofuran; at 90℃;Inert atmosphere; | Methyl 5-bromo-2-(methylthio)pyrimidine-4-carboxylate (2631 mg, 10.0 mmol) and 1-ethynyl-3,5-dimethoxybenzene (1622 mg, 10.0 mmol) were dissolved in dried THF (50 mL). The gas was exchanged with N2, Et3N (2:8 mL, 20.0 mmol), Pd(PPh3)2Cl2 (702 mg, 1.0 mmol), PPh3 (525 mg, 2.0 mmol) and CuI (190 mg, 1.0 mmol) were added successively under N2, the mixture was heated to 90 C. and stirred overnight. After the reaction was completed, the mixture was cooled to room temperature, added with a saturated aqueous solution of NaHCO3 (100 mL), extracted twice with EtOAc (100 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtrated, concentrated, and separated by silica gel column chromatography (PE:EA 4:1) to obtain compound methyl 5-((3,5-dimethoxyphenyl)ethynyl)-2-(methylthio)pyrimidine-4-carboxylate (2.5 g, yield: 73%). MS m/z (ESI): 345.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With 1,10-Phenanthroline; copper diacetate; potassium carbonate; In toluene; at 100℃; for 12h; | In a 25 ml round bottom flask, 9 mg of copper acetate,18mg 1,10-phenanthroline, 276mg potassium carbonate, 325mgN-allyl-N- (6-chlorohexynyl) p-toluenesulfonamide, 486mg of 3,5-dimethoxyphenylacetylene, 5mL of toluene,Then heated to 100 C for 12h, and then filtered to obtain 6-allyl-7-((3,5-dimethoxyphenyl) ethynyl) -1-p-toluenesulfonyl-2,3,4 Crude product of 5,5-tetrahydro-1H-azepineThe crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1).Get6-allyl-7-((3,5-dimethoxyphenyl) ethynyl) -1-p-toluenesulfonyl-2,3,4,5-tetrahydro-1H-azepine Pure302 mg, yield 67%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; triphenylphosphine; In water; N,N-dimethyl-formamide; at 70℃; for 2h;Inert atmosphere; | General procedure: A mixture of 2 (0.50 g, 1.40 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.05 g, 0.07 mmol), copper(I) iodide (0.03 g,0.14 mmol), triphenylphosphine (0.02 g, 0.08 mmol) and triethylamine(0.17 g, 1.68 mmol) in 4:1 DMF-water (v/v, 20 mL) was placed in a two necked round-bottomed flask equipped with a stirrer bar, condenser and a rubber septum. The mixture was flushed with argon gas for30 min and a solution of phenylacetylene derivative (1.2 equiv.) in DMF(2 mL) was introduced via a rubber septum by means of a syringe. A balloon filled with argon was connected to the top of the condenser andthe mixture was left to stir at 70 C for 2 h. The mixture was allowed to cool and then poured into crushed ice. The product was extracted into chloroform and the combined organic phases were washed with water and dried over anhydrous MgSO4. The salt was filtered off and the solvent was evaporated under reduced pressure on a rotary evaporator.The residue was purified by column chromatography on using silica gelusing 9:1 toluene-ethyl acetate mixture (v/v) as an eluent. The following compounds were prepared in this fashion. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With copper(l) iodide; In tetrahydrofuran; at 20℃; for 16h; | General procedure: Azide 12 (200 mg, 4.9 mmol) and 1-ethynylbenzene (13a) (0.33 mL, 4.9 mmol) were dissolved in anhydrous THF (20 mL), and CuI (466 mg, 5 mol %, 2.45 mmol) was added to it. The mixture was stirred vigorously at room temperature for 16 h. Upon completion of the process (THF), the solvent was evaporated in vacuum, and the crude product was re-dissolved in ethyl acetate (3×30 mL). The organic phase was washed with water and dried over with Na2SO4. After removal of the solvent in vacuum, the crude product was purified by column chromatography with ethyl acetate-hexane (6 : 4) to obtained pure compound 14a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With tetrakis(triphenylphosphine) palladium(0); triethylamine; In N,N-dimethyl-formamide; at 120℃;Inert atmosphere; | To a solution of 35a (900 mg, 1.4 mmol) in DMF (18 mL) wereadded Pd(PPh3)4 (315 mg, 0.27 mmol), <strong>[171290-52-1]1-ethynyl-3,5-dimethoxybenzene</strong>(0.22 g, 1.4 mmol), and Et3N (951 muL, 6.8 mmol) under anargon atmosphere. After stirring at 120 C for 0.5 h, additional <strong>[171290-52-1]1-ethynyl-3,5-dimethoxybenzene</strong> (2.0 g, 12 mmol) in DMF (18 mL) wasadded dropwise to the mixture over 4 h. After stirring at 120 C for 2 h,the mixture was diluted with EtOAc and passed through a Celite pad.The filtrate was concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (CHCl3/MeOH = 100:0 to 80:20)and then purified by column chromatography on amino functionalizedsilica gel (EtOAc/MeOH = 100:0 to 80:20). The residue was dilutedwith EtOAc and stirred under reflux conditions. After cooling to roomtemperature, the resulting precipitate was filtered and dried to give theproduct (771 mg, 76%) as a pale yellow solid. 1H NMR (DMSO-d6): delta0.95 (3H, t, J = 7.2 Hz), 1.46-1.60 (2H, m), 1.75-1.85 (2H, m), 2.14(3H, s), 2.20-2.56 (11H, m), 2.83-2.94 (2H, m), 3.26-3.38 (2H, m),3.62 (3H, s), 3.77 (6H, s), 6.53 (1H, dd, J = 2.4, 2.4 Hz), 6.77-6.86(3H, m), 7.16-7.30 (3H, m), 7.57 (1H, t, J = 7.4 Hz), 7.82 (1H, dd,J = 8.0, 1.6 Hz), 7.93-8.02 (1H, m), 8.40 (1H, s), 8.55-8.75 (1H, m),9.52 (2H, br s); MS (ESI) m/z [M+H]+ 741; Anal. Calcd forC39H48N8O5S. 0.3EtOAc.0.04CHCl3: C, 62.59; H, 6.58; N, 14.51; S,4.15; Cl, 0.55. Found: C, 62.64; H, 6.61; N, 14.51; S, 4.08; Cl, 0.50. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; triphenylphosphine; In water; N,N-dimethyl-formamide; at 70℃; for 3h;Sealed tube; Inert atmosphere; | General procedure: A mixture of 3 (0.10g, 0.22mmol), PdCl2(PPh3)2 (0.016g, 0.02mmol), CuI (0.008g, 0.04mmol), Et3N (0.03g, 0.33mmol), and triphenyl phosphine (0.006g, 0.02mmol) in 9:1 DMF-water (v/v, 20mL) was placed in a two necked round-bottom flask equipped with a condenser, and rubber septum. The mixture was purged with nitrogen gas for 30min and a balloon filled with nitrogen gas was connected to the top of the condenser. A solution of phenylacetylene (0.03g, 0.30mmol) in DMF (1mL) was added through the rubber septum by means of a syringe. The mixture was then stirred at 70C for 3h under an inert atmosphere. The mixture was poured into an ice-cold water and the product was extracted with chloroform. The combined organic extracts were washed with brine and then dried over anhydrous magnesium sulphate. The salt was filtered off and the solvent was evaporated under reduced pressure on a rotary evaporator. The residue was purified by silica gel column chromatography using a 9:1 toluene-ethyl acetate mixture (v/v) as an eluent. Compounds 4a-h were prepared in this fashion. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With copper(ll) sulfate pentahydrate; sodium L-ascorbate; In water; tert-butyl alcohol; at 20℃; for 24h;Darkness; | General procedure: To a mixture of compound 8 (8.8 mmol) with substituted 1-ethynylbenzene (9a-9j) (8.8 mmol) dissolved in a 1 : 1 mixture of water and tert-butyl alcohol (15 mL) were added sodium ascorbate (15 mol %, 1.32 mmol) and CuSO4*5H2O (5 mol %, 0.44 mmol). The reaction mixture was stirred vigorously in darkness for 24 h. After completion of the reaction, tert-butyl alcohol was evaporated in vacuum, and the aqueous phase was extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with water and dried over Na2SO4. After evaporation of the solvent in vacuum the crude product was purified by column chromatography using ethyl acetate/hexane as an eluent giving the corresponding target compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With manganese; nickel(II) bromide diethylene glycol dimethyl ether; 4,4'-Dimethoxy-2,2'-bipyridin; lithium bromide; In N,N-dimethyl acetamide; at 20℃; for 24h;Inert atmosphere; Sealed tube; | General procedure: In a N2-filledglovebox, to an oven-dried 5 mL vial equipped with a magnetic stir bar was addedalkyne substrate (1.0 equiv., 0.1 mmol), alkynyl bromide (1.2 equiv., 0.12 mmol), NHPI ester (2.5 equiv., 0.25 mmol), NiBr2•diglyme (10 mmol%), Ligand 1 (12 mol%),Mn powder (2.5 equiv., 0.25 mmol) and LiBr (0.5 equiv., 0.05 mmol) (unlessotherwise noted). The mixture was then dissolved in 0.3 mL dry DMA (unlessotherwise noted). The vial was tightly capped and removed from the glovebox. Themixture was allowed to vigorously stir at room temperature for 24 h. After thereaction was complete, the mixture was directly subjected to flash silica gel columnchromatography to afford the pure product. (*Note: for alkynyl bromide scope, 1.0equiv. of LiBr and DMSO were used instead for the preparation of 4y, 4z, 4aa; forpreparation of 4ab, 4ag, 4ap, 4aq, 4as, 3.0 equiv. of alkyne and 1.0 equiv. of alkynylbromide were used; for preparation of 4at, 1.5 equiv. of alkynyl bromide and 1.7 equiv.of C4F9I were used; for preparation of 4au, 1.5 equiv. of alkynyl bromide and 2.0equiv. of C4F9I were used; for preparation of 4av, 3 equiv. of alkyne and 1.0 equiv. ofalkyne bromide and 2.0 equiv. of C4F9I were used with Ligand 7) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine / N,N-dimethyl-formamide / 0.08 h / Inert atmosphere 1.2: 15 h / Inert atmosphere 2.1: boron tribromide / dichloromethane / 3 h / -78 - 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With silver hexafluoroantimonate; dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; silver(l) oxide; Trimethylacetic acid In m-xylene at 105℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Stage #1: N,N-diisopropyl benzamide With bis(triphenylphosphine)carbonyliridium(I) chloride; H2SiEt2 In toluene at 20℃; for 0.166667h; Schlenk technique; Glovebox; Stage #2: 1-Ethynyl-3,5-dimethoxy-benzene With copper(l) iodide; (R)-BTFM-Garphos; triethylamine In toluene at 20℃; for 1h; Schlenk technique; Glovebox; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: triethylamine; copper(l) iodide; triphenylphosphine; bis-triphenylphosphine-palladium(II) chloride / toluene / 18 h / 75 °C / Inert atmosphere 1.2: 2 h / 60 °C 2.1: potassium phosphate / water / 3 h / 10 °C 2.2: 3 h / 20 - 30 °C | ||
Multi-step reaction with 2 steps 1.1: triethylamine; copper(l) iodide; triphenylphosphine; bis-triphenylphosphine-palladium(II) chloride / toluene / 18 h / 75 °C / Inert atmosphere 1.2: 2 h / 60 °C 2.1: potassium phosphate / water; acetonitrile / 1 h / Cooling with ice | ||
Multi-step reaction with 2 steps 1.1: triethylamine; copper(l) iodide; triphenylphosphine; bis-triphenylphosphine-palladium(II) chloride / toluene / 18 h / 75 °C / Inert atmosphere 1.2: 2 h / 60 °C 2.1: sodium hydroxide / water; acetonitrile / 4.67 h / 30 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: triethylamine; copper(l) iodide; triphenylphosphine; bis-triphenylphosphine-palladium(II) chloride / toluene / 18 h / 75 °C / Inert atmosphere 1.2: 2 h / 60 °C 2.1: potassium phosphate / water; acetonitrile / 0.5 h / 20 - 30 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61 % | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In N,N-dimethyl-formamide at 15 - 25℃; Inert atmosphere; | 1.2; 2.2 Step 2: futibatinib Synthesis Intermediate under nitrogen atmosphere (S)-1-(3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)- 2-propen-1-one (19.2g, 0.05mol),1-ethynyl-3,5-dimethoxybenzene (12.2g, 0.075mol),Add bistriphenylphosphine palladium dichloride (7.0g, 0.01mol), CuI (1.9g, 0.01mol) and triethylamine (10.1g, 0.10mol) into 150ml DMF, and react at 15-25°C for 3-4h , filter, add 300ml of dichloromethane and 200ml of water, stir and separate the liquid, wash the organic phase with 150ml of saturated sodium chloride solution, add 300ml of 0.2mol/L dilute hydrochloric acid solution to the organic phase, stir and separate the liquid, add 200ml of dichloromethane to the aqueous phase, add Adjust the pH to 7-8 with saturated sodium bicarbonate solution, separate the layers, wash the organic phase with water (200ml×2), dry over anhydrous sodium sulfate (15g) for 2h, filter, evaporate the filtrate to dryness under reduced pressure, and use ethanol-water to remove the residue Recrystallization gave the title compound futibatinib (12.8 g, yield 61%, chemical purity 99.7%, optical purity 100%), |
Tags: 171290-52-1 synthesis path| 171290-52-1 SDS| 171290-52-1 COA| 171290-52-1 purity| 171290-52-1 application| 171290-52-1 NMR| 171290-52-1 COA| 171290-52-1 structure
[ 126829-31-0 ]
2-Ethynyl-1,3-dimethoxybenzene
Similarity: 0.86
[ 126829-31-0 ]
2-Ethynyl-1,3-dimethoxybenzene
Similarity: 0.86
[ 126829-31-0 ]
2-Ethynyl-1,3-dimethoxybenzene
Similarity: 0.86
[ 89414-50-6 ]
(2-Ethynyl-5-methoxyphenyl)methanol
Similarity: 0.84
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H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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