* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With potassium hydroxide In tetrahydrofuran; methanolReflux
To a stirred solution of potassium hydroxide (1.34 g, 23.8 mmol) in 6 mL methanol, 4-(Trimethylsilylethynyl)aniline (1.10 g, 0.86 mmol) in tetrahydrofuran (5 mL) was added, and the solution was refluxed overnight. Upon cooling to room temperature, the product was filtered to remove insoluble substance, and the solvent was removed under vacuum. The residue was dissolved in CH2Cl2 (50 mL), filtered, dried over anhydrous MgSO4, and concentrated under reduced pressure providing the product as a yellow solid. Yield: 98percent. 1H NMR (400 MHz; CDCl3; Me4Si): δ (ppm) 7.32 (d, J=2.4 Hz, 2H), 6.61 (d, J=2.4 Hz, 2H), 3.83 (s, 2H), 2.98 (s, 1H). 13C NMR (100 MHz, CDCl3): δ (ppm) 147.0, 133.5, 114.6, 111.3, 84.4, 77.4, 77.1, 76.7, 74.9.
81%
With tetrabutyl ammonium fluoride In tetrahydrofuran at 35℃; for 16 h;
Compound 20g (423 mg, 2.2 mmol) in THF (100 mL) wasstirred with Bu4NF in THF (1.0 M, 6.7 mL) for 16 h at 35°C. Saturated aq. NaHCO3 was added. The mixture was extracted (Et2O,3 ). Drying and chromatography (petroleumether / EtOAc 1:3) gave 21g (230 mg, 81percent) as a pale green powder: mp81-85°C (lit.11 mp 88-90°C): IR nmax 3486, 3388, 2095, 1619, 1513 cm-1;1H NMR (CDCl3) d 2.95 (1 H, s, CCH), 3.79 (2 H, s, NH2), 6.58 (2 H,d, J = 7.6 Hz, 2,6-H2),7.28 (2 H, d, J = 7.7 Hz, 3,5-H2);13C NMR (CDCl3) d 74.79 (ethyne 2-C), 84.32 (ethyne 1-C), 111.34 (4-C), 114.52 (2,6-C2),133.41 (3,5-C2), 146.95 (1-C).
79%
With tetrabutyl ammonium fluoride In tetrahydrofuran at 0 - 20℃; for 0.5 h;
The obtained 4-(trimethylsilyl)ethynylaniline (1.5 g, 7.94 mmol, 1.0 eq.) was dissolved in 10 ml of tetrahydrofuran, after stirring for 10 minutes at 0 °C, was added tetrabutylammonium fluoride (2 g, 23.8 mmol, 3.0 eq.) after half an hour at room temperature, the reaction solution was extracted with ethyl acetate and water to give washing the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then the rotation evaporation concentrated dryness. Concentrated shrink after the product after silica gel column chromatography to give a white solid of p-aminophenylacetylene (0.7 g, yield: 79percent).
77%
With tetrabutyl ammonium fluoride In tetrahydrofuran at 20℃;
To a round bottom flask was added compound 1, followed by 20 ml TBAF (Tetrabutylammoniumfluoride, 1.0 M in THF), and 6 ml THF. The mixture allowed to stirr overnight at room temperature. Solvent removed and residue run down a column of silica in 1:1 ethylacetate:hexanes.1.81 g recovered for a yield of 77percent from theoretical H(at) nmr (CDC13) No.; 7.26 (2 H, d), 6.56 (2 H , d), 4.10 (2 H, d).
1.2 g
With potassium hydroxide In tetrahydrofuran; methanol; water at 20℃; Inert atmosphere
General procedure: In a glovebox were combined aryl bromide, Pd(PPh3)2Cl2 (5 molpercent), triphenylphosphine (10 molpercent), THF (50 mL), and triethylamine (10 mL). After stirring 3 min, CuI (5 molpercent) was added and the solution was stirred another 1 min. TMS-acetylene (1.5 eq.) was then added and the reaction vessel was sealed and heated to 60 °C for 18 h. The reaction mixture was cooled, concentrated, and the residue was purified by silica gel chromatography. The obtained intermediate was then dissolved in THF (50 mL), methanol (25 mL), and a 20 percent KOH solution (aq, 15 mL) in 250 mL round bottom flask and stirred overnight at room temperature. The solution was diluted with ethyl ether (150 mL) and extracted twice with brine (50 mL). The organic layer was collected and concentrated to give a residue that was purified by silica gel chromatography.
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2
[ 937-31-5 ]
[ 14235-81-5 ]
Yield
Reaction Conditions
Operation in experiment
81%
With hydrazine hydrate In ethanol at 80℃; for 1 h; Inert atmosphere
General procedure: Hydrazine hydrate was chosen as the hydrogen donor for the low emission of pollutants. In a typical procedure, hydrazine hydrate (4 equiv) was added into the reactor which containing fresh prepared catalyst as described above. Then the reactor was put into a preheated oil bath with a stirring speed of 500 rpm, and the substrate (1 mmol)dissolved in 1 mL ethanol was added drop-wisely under argon. The reactions were monitored by TLC. After the reaction, the reaction mixture was vacuum filtered through a pad of silica on a glass-fritted funnel and an additional 15 mL of ethyl acetate (5 mL portions) was used to rinse the product from the silica, the filtrate was concentrated in vacuum and analyzed by GC. Products were purified by column chromatography and identified by 1H NMR and 13C NMR.
93 %Chromat.
With carbon monoxide; water In tetrahydrofuran at 125℃; for 24 h; Inert atmosphere; Autoclave
General procedure: Into a reaction glass vial fitted with a magnetic stirring bar anda septum cap penetrated with a syringe needle was added theCo3O4/NGrC-catalyst (2 molpercent, 3 wtpercent Co-phenanthroline oncarbon, 20 mg) followed by the nitro arene (0.5 mmol), theinternal standard (hexadecane, 100 μL), THF (2 mL), and H2O(200 μL). The reaction vial was then placed into a 300 mL autoclave.The autoclave was flushed twice with nitrogen, pressurized with CO at 30 bar pressure. Finally, the autoclave was usedat 60 bar by adding nitrogen and placed into an aluminiumblock, which was preheated at 125 °C. After 24 h the autoclavewas placed into a water bath and cooled to r.t. Finally, theremaining gas was discharged, and the samples were removedfrom the autoclave, diluted with EtOAc and analyzed by GC. Todetermine the yield of isolated products, the general procedurewas scaled up by the factor of two, and no internal standard wasadded. After the reaction was completed, the catalyst was filteredoff, and the filtrate was concentrated and purified by silicagel column chromatography (n-heptane–EtOAc mixtures) togive the corresponding anilines.
93 %Chromat.
With hydrogen In methanol at 100℃; for 4 h; Autoclave
General procedure: The hydrogenation of nitroarenes was carried out in a Teflon-lined stainless steel autoclave equipped with a pressure gauge anda magnetic stirrer. Typically, a mixture of 0.5 mmol nitroarene, 15molpercent Co/C–N–X catalyst, 100 L n-hexadecane and 2 mL solventwas introduced into the reactor at room temperature. Air in theautoclave was purged several times with H2. Then, the reactionbegan by starting the agitation (600 r/min) when hydrogen was reg-ulated to 1 MPa after the reaction temperature was reached. Afterreaction, the solid was isolated from the solution by centrifuga-tion. The products in the solution were quantified and identifiedby GC–MS analysis (Shimadzu GCMS-QP5050A equipped with a0.25 mm × 30 m DB-WAX capillary column).1H NMR and13C NMRdata were obtained on Bruker Avance III 400 spectrometer usingCDCl3or DMSO-d6 as solvent and tetrmethylsilane (TMS) as aninternal standard. The pure product in the scale-up experimentwas obtained by flash column chromatography (petroleum ether and ethyl acetate).
95 %Chromat.
With hydrogen In water at 20℃; for 12 h; Schlenk technique
General procedure: Hydrogen was chosen as hydrogen donor for the hydrogenation of nitroarenes. The hydrogenation reactions were carried out in a Schlenk tube. Typically, the reactant and catalysts were dispersed into the solvent, then the Schlenk tube was purged with H2 four times to replace air. Then the mixture was stirred at room temperature for a desired period. After reaction, the reaction mixture was extracted by ethyl acetate. The product and unreacted reactant were analyzed by GC–MS. The catalysts were separated by centrifugation and washed with ethyl acetate (3 ×15 ml), deionized water (3 ×15 ml) and then used in the next cycle.
90 %Chromat.
With hydrogen In ethanol; water at 110℃; for 18 h; Autoclave
General procedure: In an 8mL glass vial fitted with a magnetic stirring bar and a septum cap, the catalyst (the amount depends on the catalyst) was added followed by the nitroarene (0.5mmol), the internal standard (hexadecane, 20mg) and the solvent (2mL). A needle was inserted in the septum cap, which allows dihydrogen to enter. The vials (up to 7) were placed into a 300mL steel Parr autoclave which was flushed twice with dihydrogen at 20bar and then pressurized to 50bar. Then the autoclave was placed into an aluminum block pre-heated at 110°C. At the end of the reaction, the autoclave was quickly cooled down at room temperature with an ice bath and vented. Finally, the samples were removed from the autoclave, diluted with a suitable solvent, filtered using a Pasteur pipette filled with Celite® (6cm pad) and analyzed by GC using n-hexadecane as an internal standard. Control experiments showed that the position of the vial inside the autoclave is not influential. The same outcome was obtained when the reaction was repeated by moving a vial from a peripheral to a central position.
80 %Chromat.
With carbon monoxide; triethylamine In tetrahydrofuran; water at 125℃; for 24 h; Autoclave
General procedure: An 8 mL glass vial (: 14 mm, height 50 mm) equipped with a Tefloncoated oval magnetic stirring bar (8 5 mm) and a plastic screw cap was charged with the corresponding nitroarene 1 (0.5 mmol, 1.0 equiv), Fe2O3/NGr(at)C catalyst (50 mg, 4.0 molpercent Fe), Et3N (70 μL, 0.5 mmol, 1.0 equiv), THF (2 mL), and deionized H2O (0.2 mL). The silicone septum was punctured with a 26 gauge syringe needle (0.45 12 mm) and the vial was placed in an aluminum plate, which was then transferred into the 300 mL autoclave. Once sealed, the autoclave was placed into an aluminum block and purged 3 times with CO (at 5-10 bar). Then it was pressurized with CO to 30 bar, followed by additional 20 bar of N2. The aluminum block was heated up to 125 °C under thorough stirring (700 rpm). After 24 h, the autoclave was removed from the aluminum block and cooled to r.t. in a water bath. The remaining gases were discharged and the vials containing reaction products were removed from the autoclave. The reaction mixture was filtered through a Celite pad (~1 cm), concentrated, and analyzed by GC and NMR spectroscoopy (Table 2).
Reference:
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[10] Science, 2013, vol. 342, # 6162, p. 1073 - 1076
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[20] Dalton Transactions, 2017, vol. 46, # 32, p. 10665 - 10672
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[22] Patent: CN107216255, 2017, A, . Location in patent: Paragraph 0014
[23] Journal of Catalysis, 2017, vol. 351, p. 79 - 89
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[27] Synthesis (Germany), 2018, vol. 50, # 22, p. 4369 - 4376
3
[ 1453814-00-0 ]
[ 14235-81-5 ]
Yield
Reaction Conditions
Operation in experiment
50%
With potassium hydroxide In toluene at 110℃; for 10 h; Inert atmosphere; UV-irradiation
General procedure: 1 (100 mg,624 μmol) was dissolved intoluene (10 mL) under nitrogen conditions. KOH powder (700 mg,12.5 mmol) was added and the reaction mixture stirred under reflux (110°C)and irradiation with a UV-lamp (365 nm, 200 μWatt/cm2) for 16 h. Thereaction was quenched by the addition of water. The crude product was extractedwith DCM (3 x 30 mL), dried over MgSO4, filtered off andconcentrated under reduced pressure. The product was purified by flashchromatography to remove the side product 2-nitrosobenzaldehyde. (yield: 45 mg,70percent)
With N,N,N-tributylbutan-1-aminium fluoride In tetrahydrofuran at 20℃; Inert atmosphere; Schlenk technique;
99%
With potassium carbonate In tetrahydrofuran; methanol at 20℃; for 0.5h;
98%
With potassium hydroxide In tetrahydrofuran; methanol Reflux;
To a stirred solution of potassium hydroxide (1.34 g, 23.8 mmol) in 6 mL methanol, 4-(Trimethylsilylethynyl)aniline (1.10 g, 0.86 mmol) in tetrahydrofuran (5 mL) was added, and the solution was refluxed overnight. Upon cooling to room temperature, the product was filtered to remove insoluble substance, and the solvent was removed under vacuum. The residue was dissolved in CH2Cl2 (50 mL), filtered, dried over anhydrous MgSO4, and concentrated under reduced pressure providing the product as a yellow solid. Yield: 98%. 1H NMR (400 MHz; CDCl3; Me4Si): δ (ppm) 7.32 (d, J=2.4 Hz, 2H), 6.61 (d, J=2.4 Hz, 2H), 3.83 (s, 2H), 2.98 (s, 1H). 13C NMR (100 MHz, CDCl3): δ (ppm) 147.0, 133.5, 114.6, 111.3, 84.4, 77.4, 77.1, 76.7, 74.9.
95%
With potassium hydroxide In tetrahydrofuran; methanol at 35℃; for 12h;
95%
With potassium carbonate In methanol at 20℃; for 4h;
94%
With potassium carbonate In tetrahydrofuran; methanol at 20℃; Inert atmosphere;
92%
With methanol; potassium carbonate In tetrahydrofuran at 20℃; for 2h;
88%
With methanol; potassium carbonate In dichloromethane for 3h;
86%
With potassium fluoride In methanol at 20℃; for 40h;
81%
With N,N,N-tributylbutan-1-aminium fluoride In tetrahydrofuran at 35℃; for 16h;
1-Amino-4-ethynylbenzene(21g).
Compound 20g (423 mg, 2.2 mmol) in THF (100 mL) wasstirred with Bu4NF in THF (1.0 M, 6.7 mL) for 16 h at 35°C. Saturated aq. NaHCO3 was added. The mixture was extracted (Et2O,3 ). Drying and chromatography (petroleumether / EtOAc 1:3) gave 21g (230 mg, 81%) as a pale green powder: mp81-85°C (lit.11 mp 88-90°C): IR nmax 3486, 3388, 2095, 1619, 1513 cm-1;1H NMR (CDCl3) d 2.95 (1 H, s, CCH), 3.79 (2 H, s, NH2), 6.58 (2 H,d, J = 7.6 Hz, 2,6-H2),7.28 (2 H, d, J = 7.7 Hz, 3,5-H2);13C NMR (CDCl3) d 74.79 (ethyne 2-C), 84.32 (ethyne 1-C), 111.34 (4-C), 114.52 (2,6-C2),133.41 (3,5-C2), 146.95 (1-C).
79%
With potassium hydroxide In methanol for 1h; Ambient temperature;
79%
With N,N,N-tributylbutan-1-aminium fluoride In tetrahydrofuran at 0 - 20℃; for 0.5h;
26
The obtained 4-(trimethylsilyl)ethynylaniline (1.5 g, 7.94 mmol, 1.0 eq.) was dissolved in 10 ml of tetrahydrofuran, after stirring for 10 minutes at 0 °C, was added tetrabutylammonium fluoride (2 g, 23.8 mmol, 3.0 eq.) after half an hour at room temperature, the reaction solution was extracted with ethyl acetate and water to give washing the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then the rotation evaporation concentrated dryness. Concentrated shrink after the product after silica gel column chromatography to give a white solid of p-aminophenylacetylene (0.7 g, yield: 79%).
77%
With N,N,N-tributylbutan-1-aminium fluoride In tetrahydrofuran at 20℃;
To a round bottom flask was added compound 1, followed by 20 ml TBAF (Tetrabutylammoniumfluoride, 1.0 M in THF), and 6 ml THF. The mixture allowed to stirr overnight at room temperature. Solvent removed and residue run down a column of silica in 1:1 ethylacetate:hexanes.1.81 g recovered for a yield of 77% from theoretical H(at) nmr (CDC13) No.; 7.26 (2 H, d), 6.56 (2 H , d), 4.10 (2 H, d).
74%
With potassium carbonate In methanol at 20℃; for 12h;
73%
With potassium carbonate In methanol at 20℃; for 16h; Inert atmosphere;
Synthesis of 4-ethynylaniline (3)
This compound was prepared according to a reported procedure with some modification.2 Asolution of K2CO3 (0.56 g, 3.67 mmol) in MeOH (5 mL) was slowly added to a solution of 4-trimethylsilylethynylaniline (2) (0.50 g, 2.65 mmol) in CH2Cl2 (5 mL) under nitrogen atmosphere. Thereaction mixture was stirred at room temperature for 16 h, then extracted with CH2Cl2 and deionizedwater. The organic phase was washed with brine, dried over anhydrous Na2SO4, and concentratedunder reduce pressure. The product was purified by a silica gel column chromatography with 20%EtOAc in hexane. A light-yellow solid of 3 was obtained in 0.23 g (73%). 1H-NMR (500 MHz,chloroform-d1) δ ppm 7.30 (d, J = 10 Hz, 2H), 6.58 (d, J = 10 Hz, 2H), 3.83 (s, 1H), 2.99 (s, 1H), 13C-NMR(125 MHz, chloroform-d1) δ ppm 147.2, 133.5, 114.7, 111.2, 84.5, 75.1. These spectra informationagreed with the literature report.
70.5%
With potassium carbonate In methanol; dichloromethane at 20℃; for 12h;
64.4%
With potassium hydroxide In methanol; dichloromethane at 20℃; for 3h;
50%
With potassium hydroxide In tetrahydrofuran; methanol at 20℃; for 5h; Inert atmosphere;
With sodium hydroxide In tetrahydrofuran; ethanol for 0.5h;
With methanol; potassium carbonate at 20℃; for 2h;
With sodium hydroxide
With potassium hydroxide In tetrahydrofuran; methanol at 25℃; for 4h;
3.170 g
With potassium carbonate In methanol for 8h;
With potassium carbonate In tetrahydrofuran; methanol Inert atmosphere;
With potassium carbonate In methanol
With potassium carbonate In methanol; dichloromethane
1.2 g
With potassium hydroxide In tetrahydrofuran; methanol; lithium hydroxide monohydrate at 20℃; Inert atmosphere;
synthesis of aryl ethynylenes.
General procedure: In a glovebox were combined aryl bromide, Pd(PPh3)2Cl2 (5 mol%), triphenylphosphine (10 mol%), THF (50 mL), and triethylamine (10 mL). After stirring 3 min, CuI (5 mol%) was added and the solution was stirred another 1 min. TMS-acetylene (1.5 eq.) was then added and the reaction vessel was sealed and heated to 60 °C for 18 h. The reaction mixture was cooled, concentrated, and the residue was purified by silica gel chromatography. The obtained intermediate was then dissolved in THF (50 mL), methanol (25 mL), and a 20 % KOH solution (aq, 15 mL) in 250 mL round bottom flask and stirred overnight at room temperature. The solution was diluted with ethyl ether (150 mL) and extracted twice with brine (50 mL). The organic layer was collected and concentrated to give a residue that was purified by silica gel chromatography.
With potassium carbonate In tetrahydrofuran; methanol
With C16H20Cl2N2O2Pd; potassium hydroxide In water; acetonitrile at 60℃; for 12h;
31. General procedure for Sonogashira coupling reaction
General procedure: In a 10 mL round bottom flask, the palladium complex (0.010 mmol) was dissolved in acetonitrile (2 mL). Aryl halide (1.0 mmol), alkyne (1.2 mmol), KOH (2.00 mmol) and distilled water (2 mL) were added. The mixture was stirred at room temperature (or 60° C) for the required time. After reaction completion, the product was extracted with ethyl acetate (3x5 mL). The combined organic layers were dried with anhydrous sodium sulfate. The product was analyzed with GC and GC-MS. The product was purified using column chromatography with hexane-ethyl acetate as eluent. The characterization data were in entire agreement with the previously reported literature.32-39
80%
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; diisopropylamine In tetrahydrofuran at 60℃; Inert atmosphere;
55%
With copper(l) iodide; triethylamine at 50℃; for 0.333333h; Heating; 20 min;
15%
With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine at 20℃; Schlenk technique; Ionic liquid;
7%
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine for 0.916667h; Heating;
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine
With C16H20Cl2N2O2Pd; potassium hydroxide; In water; acetonitrile; at 20℃; for 4h;
General procedure: In a 10 mL round bottom flask, the palladium complex (0.010 mmol) was dissolved in acetonitrile (2 mL). Aryl halide (1.0 mmol), alkyne (1.2 mmol), KOH (2.00 mmol) and distilled water (2 mL) were added. The mixture was stirred at room temperature (or 60 C) for the required time. After reaction completion, the product was extracted with ethyl acetate (3x5 mL). The combined organic layers were dried with anhydrous sodium sulfate. The product was analyzed with GC and GC-MS. The product was purified using column chromatography with hexane-ethyl acetate as eluent. The characterization data were in entire agreement with the previously reported literature.32-39
With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); triethylamine; In tetrahydrofuran; at 70℃; for 12h;Inert atmosphere;
Weigh 2.19g of iodoaniline, 0.58g of Pd(PPh3)4,0.095 g of CuI and 1.17 g of p-ethynylaniline were placed in a 100 mL two-necked flask. Under nitrogen protection,To the reaction system were sequentially added 10 mL of triethylamine and 40 mL of tetrahydrofuran.Heat to 70C, stir the reaction for 12 hours, cool to room temperature, and spin dry.Column chromatography using dichloromethane:petroleum ether (1:1) as eluent gave a brown solid.The resulting solid was dried in vacuo at 50 C. The reaction equation is as follows.
Stage #1: 4-Ethynylaniline With dmap; triethylamine In dichloromethane at 20℃; for 0.166667h; Inert atmosphere;
Stage #2: 1,2-bis-(chlorodimethylsilyl)ethane In dichloromethane at 20℃; for 3.28333h; Inert atmosphere;
75%
With triethylamine In dichloromethane at 20℃; for 3h;
With gold(III) bromide; lithium hydroxide monohydrate at 200℃; for 0.333333h; microwave irradiation;
99%
With 5,10,15-tris(pentafluorophenyl)corrole cobalt(III) triphenyl phosphine; sulfuric acid; lithium hydroxide monohydrate In methanol at 80℃; for 12h;
General procedure: A mixture of alkyne 1a (0.5 mmol), F15CCo-PPh3 (0.3 mol%) in CH3OH (0.5 mL), H2SO4 (2 mol%) in CH3OH (0.5 mL) and H2O (4.4 eq.) was heated at 80 °C under air for 12 h in a closed J. Young tube. The progress of the reaction was checked using TLC and GC. After the tube was cooled to R.T., the volatiles were removed under reduced pressure and the pure product 2a as a colorless oil (58 mg, 95% yield) was obtained by flash chromatography of silica gel. acetophenone (2a) Colorless oil (58 mg, 95% yield). 1H NMR (500 MHz, CDCl3) δ 7.96 (d, J = 7.7 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 2.60 (s, 3H). The spectral data were in agreement with literature values.
89%
With trifluorormethanesulfonic acid; lithium hydroxide monohydrate In 2,2,2-trifluoroethanol at 25 - 70℃; for 45h; Sealed tube; regioselective reaction;
85%
With ethyl 2-hydroxypropionate; lithium hydroxide monohydrate at 110℃; Green chemistry;
3.3. General process for alkyne hydration to form compounds 2
General procedure: Alkynes (2mmol) were added to a stirred 35mL solution of EL:H2O(1:3). The reaction mixture was stirred at 110 °C for a suitable time.After successful conversion, the resultant solution was cooled to roomtemperature and extracted with ethyl acetate (4-6 mL). The combinedorganic phaseswere dehydrated over anhydrous sodium sulfate and filtered.The filtered solution was concentrated under reduced pressureand purified by column chromatography on silica gel (hexane:EtOAcas the eluent) to provide the pure desired product
78%
With C20H14AuN2O2(1+)*Cl(1-); lithium hydroxide monohydrate; trifluoroacetic acid In methanol at 80℃; for 5h; Sealed tube;
2.3 Typical procedure for the hydration of alkynes
General procedure: Alkyne (0.5 mmol), catalyst (2.0 mol%), H2O (4.0 equiv., 0.04 mL) and CF3COOH (2.0 mol%) were dissolvedin MeOH (0.4 mL) and the homogeneous solution was stirred in a sealed tube at 80°C for 5 h. After the completion of the reaction, the mixture was cooled to room temperature, and then CH2Cl2 and H2O were added to it. The organic layer was separated and washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified over silica gel by column chromatography (25% EtOAc in hexane).
78%
With 4-methyl-morpholine; iodine In dimethyl sulfoxide at 120℃; for 16h;
Synthesis of acetophenone derivatives (2a-q)
General procedure: A 10 mL reaction flask was charged with terminal alkynes 1a-q (1.0 mmol), I2 (0.3 mmol) and N-methyl morpholine (1.0 mmol) in DMSO (2.0 mL) and then the reaction mixture was heated at 120 °C for 16 h. After completion of the reaction (progress was monitored by TLC; SiO2, hexane/EtOAc = 9:1), the recation mixture was quenched with saturated sodium thiosulphate solution, diluted with water (20 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layer was dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and the remaining residue was purified over silica gel column chromatography using hexane/EtOAc = 4:1 as an eluent to obtain the desired products 2a-q in high yields.
72%
With lithium hydroxide monohydrate In Cyclooctan at 100℃; for 0.3h;
70%
With hydrogenchloride; tetrakis-(triphenylphosphine)-palladium In tetrahydrofuran; lithium hydroxide monohydrate at 45℃; for 0.5h; Inert atmosphere; Schlenk technique; chemoselective reaction;
67%
With 3,4,5-trihydroxybenzoic acid; lithium hydroxide monohydrate at 60℃; for 6h; Sealed tube; Green chemistry;
With hydrogenchloride; lithium hydroxide monohydrate; N-hexadecyl-N,N,N-trimethylammonium bromide In isopropanol at 140℃; for 1h;
General procedure for the Sonogashira coupling reaction
General procedure: A 10 mL round-bottom flask was charged with iodobenzene (4a, 1 mmol, 1 eq.), phenylacetylene (7a, 1.5mmol, 1.5 eq.), triethylamine (3 mmol, 3 eq.), H2O (2 mL), and Pd catalyst (0.01 mmol). The flask was stirred at 80°C in air. The reaction was monitored by TLC and GC. After the reaction was complete, the reaction mixture was cooled to room temperature and ethyl acetate (5mL) was added to the flask. Afterward, the catalyst was filtered and washed with water (10 mL) and ethyl acetate (10 mL). The aqueous phase was extracted three times with 30 mL EtOAc. The organic phases were collected together, dried over MgSO4, and filtered. The solvent was then evaporated under reduced pressure. The pure product was obtained via silica gel column chromatography with an eluent of EtOAc and hexane. The resulting product was analyzed by 1H NMR spectroscopy.
92%
With triethylamine In N,N-dimethyl-formamide at 120℃; for 16h;
86%
With Pd/SiO2; triethylamine In diethyl ether; water at 20℃; for 10h;
5-[(4-aminophenyl)ethynyl]pyrimidin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With N,N,N',N'-tetramethylguanidine;copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); In DMF (N,N-dimethyl-formamide); at 60℃; for 2.5h;
A mixture of <strong>[1445-39-2]2-amino-5-iodopyrimidine</strong> (1.10 g), 4-ethynylaniline (0.82 g), 1,1, 3,3- tetramethylguanidine (0.81 g), and copper (I) iodide (9.5 mg) in dry DMF (3.0 mL) was stirred and degassed with nitrogen. Tetrakis (triphenylphosphine) palladium (0) (115 mg) was added and the mixture heated at 60 C for 2.5 hours. The solvent was evaporated and the residue was triturated with DCM. The solid formed was filtered off and washed with water then dissolved in 1: 1 DCM/MeOH, filtered then evaporated. The solid obtained was triturated with ether and dried to give the title compound (0.67 g, 63%) ; 'HNMR (DMSO-d6) 5.50 (s, 2H), 6.55 (d, 2H), 6.95 (s, 2H), 7.15 (d, 2H), 8.35 (s, 2H) ; MS m/e MH+ 211.
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1h; Inert atmosphere; Cooling with ice;
96%
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1h; Cooling with ice; Inert atmosphere;
Synthesis of methyl 2-((4-ethynylphenyl)amino)-2-oxoacetate (Core 1).
To an ice-cold solution of 4-ethynylphenylamine (4.0 g, 34.14 mmol) and N,N-diisopropyl ethylamine (11.82 mL, 68.29 mmol) in 100 mL of anhydrous CH2Cl2 was added methyl chlorooxoacetate (3.46 mL, 37.56 mmol) drop-wise under N2 atmosphere. The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was washed with 100 mL of DI water and 100 mL of brine. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuo. The product was then purified by column chromatography on silica gel using a mixture of ethylacetate-hexanes as eluent. White powder; (6.2 g, 96% yield). 1H NMR (DMSO-d6, 500 MHz) δ 10.94 (s, 1H), δ 7.77 (d, J=9.0 Hz, 2H) δ 7.45 (d, J=9.0 Hz, 2H), δ 4.11 (s, 1H), δ 3.84 (s, 3H); 13C NMR (DMSO-d6, 125 MHz) δ 161.3, 155.7, 138.5, 132.8, 120.8, 118.2, 83.7, 80.9, 53.7. Mass spectra (ESI): m/e 202 (M-H)-. HRMS (ESI-TOF, [M-H]-) m/z calcd for C11H9NO3 202.0504, found 202.0510.
R.396 Methyl 2-(4-ethynylanilino)-2-oxoacetate:
REFERENTIAL EXAMPLE 396 Methyl 2-(4-ethynylanilino)-2-oxoacetate: The title compound was obtained from 4-ethynylaniline and methyl chlorooxoacetate in a similar manner to the process described in Referential Example 242. 1H-NMR (CDCl3) δ: 3.09(1H,s), 3.98(3H,s), 7.50(2H,d,J=8.4 Hz), 7.62(2H,d,J=8.4 Hz), 8.89(1H,br.s).
With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In tetrahydrofuran; at 20℃;
A solution of 4-ethynylaniline (820 mg, 7 mmol), <strong>[811842-30-5]2-bromo-1-fluoro-4-iodobenzene</strong> (2.1 g, 7 mmol), copper(I) iodide (8 mg, 0.04 mmol) and bis(triphenylphosphine)palladium(II) dichloride (30 mg, 0.04 mmol) in a 2:1 mixture of tetrahydrofuran and triethylamine (18 mL) was stirred at room temperature under an atmosphere of argon overnight. The reaction mixture was concentrated in vacuo and the residue partitioned between dichloromethane (100 mL) and water (75 mL). The organic phase was separated and the aqueous phase extracted with dichloromethane. The combined organics were concentrated and purified by column chromatography, using 0-30% ethyl acetate in heptane as the eluent.Recrystallization from diethyl ether/heptane gave 1.42 g (70% yield) of the title compound: 1H NMR (DMSO-d6) 7.80 (dd, J=6.8, 2.0 Hz, 1H), 7.52-7.48 (m, 1H), 7.38 (t, J=8.8 Hz, 1H), 7.22-7.18 (m, 2H), 6.58-6.54 (m, 2H), 5.60 (br s, 2H); MS (ES) m/z 290, 292 [M+H]+.
With hydrogen In 1,4-dioxane at 20℃; for 24h; chemoselective reaction;
24 %Chromat.
With hydrogen In 1,4-dioxane at 85℃; for 14h; chemoselective reaction;
With carbon monoxide; hydrogen In tetrahydrofuran at 70℃; for 6h; Autoclave;
2.3. General experimental procedure for synthesis of alkenes viasemi-hydrogenation of alkynes
General procedure: To a 100 mL high-pressure reactor, phenylacetylene (1 mmol),Pd (0.96 mol%) in a 10 mL THF were transferred under an inertatmosphere. The reactor was flushed three times with nitrogen then pressurized with desired 150 psi of syngas, then heated at70C with constant stirring (400 rpm) for 6 h. After the comple-tion of reaction, the reactor cooled down to room temperature andthe remaining syngas was carefully depressurized. The resultantreaction mixture filtered off by simple filtration. The filtrate was then collected in sample vial and the product was extracted for fur-ther analysis such as GC, GC-MS,1H &13C NMR and matched with those of authentic data. Selective experiments were performed in triplicate and it was observed that results showed variation of ±2%.
With C16H20Cl2N2O2Pd; potassium hydroxide In water; acetonitrile at 20℃; for 3h;
31. General procedure for Sonogashira coupling reaction
General procedure: In a 10 mL round bottom flask, the palladium complex (0.010 mmol) was dissolved in acetonitrile (2 mL). Aryl halide (1.0 mmol), alkyne (1.2 mmol), KOH (2.00 mmol) and distilled water (2 mL) were added. The mixture was stirred at room temperature (or 60° C) for the required time. After reaction completion, the product was extracted with ethyl acetate (3x5 mL). The combined organic layers were dried with anhydrous sodium sulfate. The product was analyzed with GC and GC-MS. The product was purified using column chromatography with hexane-ethyl acetate as eluent. The characterization data were in entire agreement with the previously reported literature.32-39
95%
With dichlorido[2,2'-(4-methylbenzene-1,2-diyl)bis(4,4-dimethyl-4,5-dihydro-1,3-oxazole)-N,N']palladium(II); potassium hydroxide In water; acetonitrile at 20℃; for 3h;
General procedure: Appropriate palladium complex was dissolved in acetonitrile. Aryl halide, alkyne, KOH and distilled water were added. The mixture was stirred at room temperature (or 60°C) for the required time.
93%
With triethylamine In ethanol; water at 80℃; for 36h; Schlenk technique; Inert atmosphere; Green chemistry;
85%
With iron(III) chloride; potassium phosphate; triphenylphosphine In toluene at 135℃; for 48h; Inert atmosphere;
78%
With caesium carbonate In methanol at 65℃; for 24h;
Stage #1: 3,4-di-chloro-5-methyl-1H-pyrrole-2-carboxylic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 0℃; for 0.5h;
Stage #2: 4-Ethynylaniline In N,N-dimethyl-formamide at 20℃; for 72h;
3,4-Dichloro-5-methyl-lH-pyrrole-2-carboxylic acid (Intermediate 42; 2 g, 10.3 mmol) and HATU (4.3 g, 11.3 mmol, 1.1 eq.) were dissolved in dry DMF (100 ml) and DIEA (3.98 g, 30.9 mmol, 3 eq.). The reaction mixture was stirred at 0°C for 30 minutes. The solution was warmed to room temperature and (4-ethynylphenyl)amine (1.2 g, 10.3 mmol, 1 eq.) was added in a single portion. The reaction was stirred for 3 days while monitoring by LC/MS. The reaction mixture was concentrated to 1A the volume via rotary evaporation, diluted with EtOAc and washed with H2O (3 x 50 ml) and brine. The organic phase was dried over Na2SO4, filtered and concentrated. The crude reaction mixture was purified by flash column chromatography (20% EtOAc / hexanes). Isolation gave 1.4 g of the title compound in a 46% yield. M/z 293, 295; NMR: 2.23 (s, 3H), 4.11 (s, IH), 7.45 (d, 2H), 7.67 (d, 2H), 9.6 (s, IH), 12.2 (s, IH).
Stage #1: 4-Ethynylaniline; 4-ethynylbenzoic acid methyl ester With pyridine In methanol for 0.25h;
Stage #2: With copper diacetate In methanol for 3h;
1 Synthesis of methyl 4-((4-aminophenyl) buta- 1 ,3-diyn- 1-yl)benzoate (2)
4-ethynylaniline (5 g, 0.0426 mol) and methyl 4-ethynylbenzoate (13.6 g, 0.085 mol) were taken in methanol : pyridine (100 ml: 20 ml) mixture and stirred for 15 mm. Copper acetate (25.5 g, 0.128 mol) was added in one portion and stirred the reaction mass for 3 h. After completion of the reaction, reaction mixture was concentrated, obtained crude was taken in 1.5N HC1 (2 x 100 mL) and extracted with ethyl acetate. The separated organic layer was dried over anhydrous Na2504 and concentrated. The obtained crude was purified by flash chromatography over 230-400 mesh column silica gel with gradient elution of 2-6% ethyl acetate in pet ether to get 2 as light yellow solid (5.6 g). Yield: 47.8%. LC-MS and ‘H NIVIR confirm the required product. LCMS Calculated for C,8H,3N02: 275. 31, Observed 276.3
35%
With pyridine; copper diacetate In methanol at 20℃; for 48h;
Copper (II) acetate (1.13 g, 6.2 mmol, 2 equiv) was added to a stirred solution of 4 (0.50 g, 3.1 mmol) and 4-ethynylbenzenamine (2.64 g, 15.5 mmol, 5 equiv) in anhydrous pyridine (5 mL) and MeOH (5 mL), and the mixture was stirred at room temperature for 48 h. The resulting blue solution was concentrated to dryness under reduced pressure. The residue was treated with water (50 mL), and extracted with EtOAc (3×70 mL). The combined extracts were washed with water (50 mL), brine (50 mL) and dried. The crude product was purified by CombiFlash (eluting with 20-30% EtOAc in hexane) to afford methyl 4-[(4'-aminophenyl)buta-1,3-diyn-1-yl]benzoate 5 (0.30 g, 35% yield) as yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 3.83 (s, 3H), 5.85 (s, 2H), 6.54 (d, J=8.1 Hz, 2H), 7.25 (d, J=8.1 Hz, 2H), 7.64 (d, J=8.1 Hz, 2H), 7.92 (d, J=8.1 Hz, 2H); 13C NMR (75 MHz, DMSO-d6): δ 53.03, 71.77, 78.28, 80.49, 86.98, 105.73, 114.28, 126.74, 130.06, 130.31, 132.98, 134.75, 151.63, 166.18; MS (ESI, positive): m/z 276 [M+H]+.
35%
With pyridine In methanol at 20℃; for 24h; Inert atmosphere;
1
5: Copper (II) acetate (1 .13 g, 6.2 mmol, 2 equiv) is added at room temperature and under stream of argon to a stirred solution of 3 (0.50 g, 3.1 mmol) and 4-ethynylbenzenamin (2.64 g, 15.5 mmol, 5 equiv) dissolved in anhydrous pyridine (5 mL), and MeOH (5 mL), and the mixture are stirred at room temperature for 24h. The resulting blue solution is condensed to dryness with a rotavapor, and the residue is treated with water (50 mL), extracted with EtOAc (3x70 mL), and dried over anhydrous Na2SO . The crude products are purified by flash chromatography (eluting with20-30% EtOAc in hexane) to afford 5 (0.30 g, 35% yield) as yellow solid.1 H NMR (300 MHz, DMSO-d6) 53.83 (s, 3H), 5.85 (s, 2H), 6.54 (d, J=8.1 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.1 Hz, 2H), 7.92 (d, J=8.1 Hz, 2H); 13C NMR (75 Hz, DMSO-de) 553.04, 71 .77, 78.29, 80.49, 86.98, 105.73, 1 14.28, 126.74, 130.06, 130.32, 132.98, 134.76, 151 .64, 166.19; LC/MS m/s [M+H]+ 276.1 .
With silver trifluoromethanesulfonate; aniline In tetrahydrofuran; 1,2-dichloro-ethane at 80℃; for 3h;
A typical procedure for the AgOTf-catalyzed one-pot synthesis of 2-quinolines from the reactions of Alkynes with 2-aminobenzaldehydes
General procedure: A solution of 2-aminobenzaldehyde (1a) (61 mg, 0.5 mmol) in DCE (2 ml) was added Phenylacetylene (2a) (0.083 ML, 0.75 mmol), aniline (0.091ML, 1.0 mmol) and AgOTf (3.2 mg, 5 mol %, 0.05 M in THF), and the resulted reaction mixture was stirred at 80 oC for 3 h under air. After cooling to room temperature, the solvent was evaporated under vacuo and the residue was purified by chromatography on silica gel(eluent: petroleum ether/ethyl acetate=10:1). A yellow solid of product (84%) 3a was obtained.
90 %Chromat.
With C46H44Ag2Fe2N6O2; aniline In 1,2-dichloro-ethane for 8h; Inert atmosphere; Schlenk technique; Sealed tube; Heating; regioselective reaction;
Stage #1: (S)-2-methoxy-2-phenylacetic acid With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; HATU In dichloromethane for 0.166667h;
Stage #2: 4-Ethynylaniline In dichloromethane for 24h;
83%
Stage #1: (S)-2-methoxy-2-phenylacetic acid With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine; HATU In dichloromethane for 0.166667h;
Stage #2: 4-Ethynylaniline In dichloromethane for 24h;
83%
Stage #1: (S)-2-methoxy-2-phenylacetic acid With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 20℃; for 0.166667h;
Stage #2: 4-Ethynylaniline In dichloromethane at 20℃; for 24h;
81%
Stage #1: (S)-2-methoxy-2-phenylacetic acid With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane for 0.166667h;
Stage #2: 4-Ethynylaniline In dichloromethane
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; at 50℃; for 16h;Inert atmosphere;
The respective halogenated oligofluorobenzene (2.0 mmol) and the corresponding terminal ethynyl compound (2.2 mmol) were dissolved in degassed triethylamine (20 ml). To this solution, the catalyst, being composed of bis(triphenylphosphane)palladium(II) chloride (22 mg, 0.03 mmol) and copper(I) iodide (5.6 mg, 0.03 mmol), was added and the mixture was stirred at 50 C under argon for 16 h. The mixture was filtered through Celite, the filtration residue washed with diethyl ether and the combined organic layers evaporated. Column chromatography (SiO2, eluent :hexane-ethyl acetate) yielded the pure compounds.
With pyridine;copper diacetate; In methanol; at 20.0℃; for 20.0h;Inert atmosphere;
Sodium 5-[4'-(4'-aminophenyl)buta-1 ',3'-diyn-1 -yl]pyridine-2-carboxylate (144): Copper (II) acetate (1 .36 g, 7.46 mmol, 2.0 equiv) is added at room temperature under stream of argon to a stirred solution of 142 (0.60 g, 3.73 mmol) and 4- ethylnylbenzenamine (2.18 g 18.63 mmol, 5.0 equiv) dissolved in anhydrous pyridine (10 mL) and MeOH (10 mL). The reaction mixture is stirred at room temperature for 20 h. The resulting suspension is filtered, and the solid is washed with EtOAc (3^50 mL). The solid is dried under high vacuum for 12 h to afford as an orange powder, and then used for next step directly. 4N NaOH (10 mL) is added to a stirred solution of the crude methyl ester (600 mg) in MeOH (50 mL) at room temperature. Then reaction solution is heated to reflux for 40 min under argon. The reaction mixture turned clear. After all the starting material has been consumed monitored by TLC,the reaction mixture is cooled to room temperature, and the solvents are removed by evaporation under reduced pressure. The yellow solid is washed by water (3^50 mL), EtOAc (3x50 mL) to give a yellow solid (320 mg, 31 % yield, for two steps ), which is used for next step without future purification. 1 H NMR (300 MHz, CD3OD) 56.62 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.7 Hz, 2H), 7.59 (d, J=9.0 Hz, 1 H), 8.27 (d, J=10.2 Hz, 1 H), 9.01 (s, 1 H); 13C NMR (75 MHz, CD3OD) 570.50, 75.996, 78.48, 85.59, 107.59, 1 14.17, 127.44, 133.09, 134.06, 137.62, 142.94, 150.69, 170.58; MS (ESI, positive): m/z 263 [M+H+].
With hydrogen In toluene at 20℃; for 12h; Autoclave; chemoselective reaction;
90%
With hydrogen; 3-azapentane-1,5-diamine In methanol at 25℃; for 6h;
76%
With Au0998Ag0002; hydrogen; diethylamine at 90℃; for 24h; chemoselective reaction;
98 %Chromat.
With palladium on silica; hydrogen; dimethyl sulfoxide In hexane at 30℃; for 2h;
90.3 %Chromat.
With hydrogen In methanol; dimethyl sulfoxide at 25℃; for 4h; chemoselective reaction;
With water; potassium hydroxide In 1,4-dioxane; ethanol at 20℃; Electrochemical reaction;
With hydrogen In methanol at 25℃; for 0.5h;
2.4 Catalysts test
General procedure: The selective hydrogenations of the substrate reactions were conducted in round-bottom flask under H2 (1atm). The progress of the catalysts test was as follows: substrate (1.5mmol), catalysts (5mg) and solvent (15mL) were mixed in the round-bottom flask and the reaction was continued for 0.5h under vigorous stirring at temperature of 25°C and hydrogen pressure of 1atm. Subsequently, the product was collected, filtered, extracted and further analyzed by GC-MS (Agilent 6, 890N/5, 937N). The activity of the catalysts were calculated as follows: conversion (%)=100×([C0]-[C1]/[C0]), selection (%)=100×([C]-[C])/[C], TOF=(C0-C1)×V/(MPd), The substrate concentration at the beginning and end of the reaction was represented by [C0] and [C1], respectively. Similarly, [C] and [C] were the concentrations of the product and target product at the end of the reaction, respectively. And MPd was mole number of Pd in catalyst.
With 5% Pd-CaCO3; hydrogen In tetrahydrofuran at 25℃;
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;
Step 2. Synthesis of N-(4-Ethynylphenyl)-5,7-dimethylpyrazolo[l,5-a]pyrimidine-3- carboxamide (13); [0079] 5,7-Dimethylpyrazolo[l,5-a]pyrimidine-3-carboxylic acid (722 mg, 3.78 mmol), 4- ethynylaniline (442 mg, 3.78 mmol), and HATU (1436 mg, 3.78 mmol) were taken up in DMF (10 ml) and then treated with diisopropylethylamine (1.979 ml, 11.33 mmol). The contents stirred at room temperature overnight. The product had precipitated from reaction mixture. The reaction was diluted with water, filtered through a Biichner funnel under house vacuum. The residue was washed with water (X2), then CH2CI2, diethyl ether, and air dried to obtain N-(4-ethynylphenyl)-5,7-dimethylpyrazolo[l,5-a]pyrimidine-3-carboxamide (500 mg, 1.72 mmol, 46 % yield). LC-MS: rt (min) = 3.65. 1H NMR (400 MHz, DMSO-d6) delta ppm 2.71 (s, 3 H), 2.77 (s, 3 H), 4.11 (s, 1 H), 7.21 (s, 1 H), 7.49 (d, 7=8.6 Hz, 2 H), 7.77 (d, 7=8.6 Hz, 2 H), 8.65 (s, 1 H), 10.31 (s, 1 H).
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; at 100℃; for 2h;
General procedure: In a dry Schlenk tube, the dihalopyridine, CuI (6 mol %), and PdCl2(PPh3)2 (3 mol %) were added in Et3N (2 mL per mmol of pyridine). After stirring for 10 min, the (hetero)arylacetylene (1.0 or 1.1 equiv) was added, and the solution was heated to 100 C in a silicone bath for 2 h. The reactions were monitored by TLC, following the disappearance of the starting materials. After completion, the mixture was allowed to cool to room temperature. Then ethyl acetate and water were added and the organic phase was separated, dried (MgSO4), and filtered. Removal of the solvent under reduced pressure gave either oils, which were submitted to column chromatography or pure products corresponding to the expected (hetero)arylethynylpyridines.
With palladium 10% on activated carbon; hydrogen In methanol at 75℃; Flow reactor;
4.2 Typical procedure for the palladium-catalyzed hydrogenation under the flow conditions (Tables 2 and 3)
General procedure: A solution of the substrates possessing reducible functional groups (1mmol) within the molecule in MeOH (20mL) was flowed at 1mL/min into the catalyst-packed cartridge (10% Pd/C, 10% Pd/HP20, 0.5% Pd/MS3A, or 0.3% Pd/BN; 30mm long-cartridge, ca. 0.3mL volume) under 1, 50, or 80bar hydrogen gas at 25, 50, 75, or 100°C using H-Cube (ThalesNano Nanotechnology Inc.). Catalyst cartridges were filled with 10% Pd/C (99.4mg), 10% Pd/HP20 (101.4mg), 0.5% Pd/MS3A (99.6mg), and 0.3% Pd/BN (99.7mg). The reaction mixture was passed through the catalyst cartridge once and MeOH (the carrier solvent) was concentrated in vacuo to give an analytically pure product. The obtained product was identified by 1H NMR measurement.
96%
With copper(ll) sulfate pentahydrate; 2.9-dimethyl-1,10-phenanthroline; hydrazine hydrate In ethanol at 78℃; for 20h;
94%
With hydrogen In methanol at 20℃; for 5h; chemoselective reaction;
4.3. Typical procedure for the chemoselective hydrogenation
General procedure: The mixture of the substrate (0.250 mmol), 0.5% Pd/MS3A or 0.5% Pd/MS5A (10 wt % of the substrate) and MeOH (1 mL) was stirred under H2 atmosphere (balloon) at room temperature. After a given period, the reaction mixture was filtered through a membrane filter (Millipore, Millex-LH, 0.45 mm), and the filtrate was concentrated in vacuo to produce the corresponding reduced product.
50%
With iron(II)β-diketiminate complex; 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane In benzene-d6 at 20℃; for 0.5h; Sealed tube; Inert atmosphere; Schlenk technique; Glovebox;
Triphenylphosphine (30 mg, 115 pmol), [Pd(PPh3)2]C12 (20 mg, 285 pmol) and copper(l)iodide (16 mg, 84 pmol) were placed in a 100 ml three-necked flask and suspended in 30 ml methanol., or alternatively triphenylphosphine (30 mg, 115 pmol), [Pd(PPh3)2]C12 (20 mg, 285 pmol) and copper(l)iodide (16 mg, 84 pmol) were suspended in 30 ml methanol in a nitrogen flushed 100 ml three-necked flask. The trifluoroacetyl-5/6- aminochlorophenanthroline 4 (205 mg, 466 pmol) was transferred into the flask dissolved in20 ml methanol, in other words the educt trifluoroacetyl-5/6-aminochlorophenanthroline 4 (205 mg, 466 pmol) was transferred into the flask with 20 ml methanol. The reaction mixture was tempered or heated up to 40 00, or alternatively the reaction mixture was tempered or heated up to 4000, and nitrogen was fed into. Ethinylaniline (200 mg, 1.7 mmol) was dissolved in a few millilitres of methanol and added to the reaction mixture. Then, DIPEA(N,N-diisopropylethylamine, 2 ml) was added, and the reaction mixture was stirred overnight. After this, the reaction mixture was extracted three times with 50 ml chloroform, respectively. The chloroform phase was washed with a diluted sodium bicarbonate solution, diluted hydrochloric acid and again with a sodium bicarbonate solution. Then, the chloroform phase was dried over Na2SO4 and purified on an aluminium oxide column (eluent:chloroform).
Example 1: Syntheis of the amino-reactive phosphorescent dye of the invention Nitration of <strong>[7089-68-1]2-chloro-1,10-phenanthroline</strong> 150 ml concentrated sulphuric acid was placed in a 500 ml three-necked flask and <strong>[7089-68-1]2-Chloro-1,10-phenanthroline</strong> 1 (CAS-Nr. 7089-68-1)(30g) was added while cooled with ice and stirred. The solution was heated in an oil bath to 180 °C. At 80 °C, the solution boiled and a strong smoke emission could be observed. At 160 °C, nitric acid (65 percent, 80 ml) was added dropwise while maintaining a temperature of 170 °C. The bath temperature was increased to 215 °C, and the adding was performed in such a way that the temperature was below or equal to 160 °C. After complete addition of the nitric acid, the solution was heated under reflux for 1 h to 165 to 170 °C. Following this, the reaction mixture was cooled in a ice bath, added to approximately 1 kg ice and diluted with 1 l water. A sodium hydroxide solution (50 percent w/v) was added dropwise until the pH value of the reaction mixture was in a neutral/weak alkaline range. This was accompanied by formation of a slightly yellow precipitate. The precipitate was separated and washed with water. The crude product of the reaction was dried over night at 110 °C, extracted with chloroform via Soxleth extraction and reduced to a dry powder in rotary evaporator. Reduction of 2-chloro-5/6-nitro-1,10-phenanthroline 2-Chloro-5/6-nitro-1,10-phenanthroline 2 (1 eq.) was dissolved in methanol and hydrogenated under stirring in the presence of the catalyst (palladium/coal 10percent, 10molpercent) in a hydrogenation plant until no further hydrogen consumption could be observed. The catalyst was filtered off and the filtrate was reduced to dryness under reduced pressure (complete conversion). Introduction of a trifluoro acetyl group to 5/6-amino-<strong>[7089-68-1]2-chloro-1,10-phenanthroline</strong> 5/6-Aminochlorophenanthroline 3 (230 mg, 1 mmol) was suspended in 20 ml water-free THF and tempered to 0 °C. Then, trifluoroacetic acid was added (275 mul, 3mmol). The initially formed precipitate dissolved after 30 min. The reaction was performed until completion under stirring for 24 hours at room temperature. The reaction mixture was reduced to a dry powder in rotary evaporator. Then, 20 ml water was added the dry substance, and the pH-value of the solution was adjusted with ammonia (25percent) to 8. The aqueous phase was extracted 3 times with 50 ml chloroform, respectively. The organic phase was dried over Na2SO4, reduced to a dry powder in a rotary evaporator. The crude product was purified with silica gel 60 (m=33 g) and chloroform/methanol (9/1; v/v) as eluent. Fractions containing pure product (examined by thin layer chromatography) were unified and reduced to a dry powder in a rotary evaporator (m=205 mg, 63percent yield). Coupling of TFA-protected 2-chloroaminophenanthroline and ethinylaniline Triphenylphosphine (30 mg, 115 mumol), [Pd(PPh3)2]Cl2 (20 mg, 285 mumol) and copper(I)iodide (16 mg, 84 mumol) were placed in a 100 ml three-necked flask and suspended in 30 ml methanol. The educt trifluoroacetyl-5/6-aminochlorophenanthroline 4 (205 mg, 466 mumol) was transferred into the flask with 20 ml methanol. The reaction mixture was tempered to 40 °C, and nitrogen was fed into. Ethinylaniline (200 mg, 1.7 mmol) was solved in a few millilitres methanol and added to the reaction mixture. Then, DIPEA (N,N-diisopropylethylamine, 2 ml) was added, and the reaction mixture was stirred over night. After this, mixture was extracted three times with 50 ml chloroform, respectively. The chloroform phase was washed with diluted sodium bicarbonate solution, diluted hydrochloric acid and again with sodium bicarbonate solution. Then, the chloroform phase was dried over Na2SO4 and purified with an aluminium oxide column and chloroform.
[2-[(4?-Aminophenylen)ethynylen]-l ,1 0-phenanthrolin-5/6-yl]amine 5 (1 eq.), DTPAdianhydride and triethylamine (5 eq.) were stirred in DMF under argon for 2 h at 80°C. The solvents were removed under reduced pressure. The residue was purified by RP-HPLC(water/MeCN).A potential problem regards the coupling of the antenna (compound 5) with the chelator (DTPA-anhydride) as the used DTPA- anhydride has two activated acid groups, but only the monosubstituted product is desired. The formation of a disubstituted product was reduced by applying the suitable excess of DTPA as described above and by a reaction design thatkeeps the concentration of compound 5 as small as possible.
Example 1: Syntheis of the amino-reactive phosphorescent dye of the invention Nitration of <strong>[7089-68-1]2-chloro-1,10-phenanthroline</strong> 150 ml concentrated sulphuric acid was placed in a 500 ml three-necked flask and <strong>[7089-68-1]2-Chloro-1,10-phenanthroline</strong> 1 (CAS-Nr. 7089-68-1)(30g) was added while cooled with ice and stirred. The solution was heated in an oil bath to 180 °C. At 80 °C, the solution boiled and a strong smoke emission could be observed. At 160 °C, nitric acid (65 percent, 80 ml) was added dropwise while maintaining a temperature of 170 °C. The bath temperature was increased to 215 °C, and the adding was performed in such a way that the temperature was below or equal to 160 °C. After complete addition of the nitric acid, the solution was heated under reflux for 1 h to 165 to 170 °C. Following this, the reaction mixture was cooled in a ice bath, added to approximately 1 kg ice and diluted with 1 l water. A sodium hydroxide solution (50 percent w/v) was added dropwise until the pH value of the reaction mixture was in a neutral/weak alkaline range. This was accompanied by formation of a slightly yellow precipitate. The precipitate was separated and washed with water. The crude product of the reaction was dried over night at 110 °C, extracted with chloroform via Soxleth extraction and reduced to a dry powder in rotary evaporator. Reduction of 2-chloro-5/6-nitro-1,10-phenanthroline 2-Chloro-5/6-nitro-1,10-phenanthroline 2 (1 eq.) was dissolved in methanol and hydrogenated under stirring in the presence of the catalyst (palladium/coal 10percent, 10molpercent) in a hydrogenation plant until no further hydrogen consumption could be observed. The catalyst was filtered off and the filtrate was reduced to dryness under reduced pressure (complete conversion). Introduction of a Boc group to 5/6-amino-<strong>[7089-68-1]2-chloro-1,10-phenanthroline</strong> Alternatively, the amine group of <strong>[7089-68-1]2-chloro-1,10-phenanthroline</strong> 3 may be protected with a Boc group. To do this, 5/6-amino-<strong>[7089-68-1]2-chloro-1,10-phenanthroline</strong> (1 eq.) was dissolved in dry DMF and triethylamine (5 eq.). Then, DMAP (1.1 eq.) and di-t-butyldicarbonate (2 eq.) were added The solution was stirred at room temperature for 20 h. Then, water was added and the aqueous phase was extracted three times with diethylether. The combined organic phases were dried over Na2SO4 and concentrated to dryness. The crude product was purified with silica gel (CH2Cl2). (63percent yield). Coupling of the Boc-protected 2-chloro-5/6-amino-1,10-phenanthroline and 4-ethinylaniline Triphenylphosphine (30 molpercent), [Pd(PPh3)2]Cl2 (3molpercent), the protected 2-chloro-5/6-amino-1,10-phenanthroline 4 (1 eq.) and copper(I)iodide (2molpercent) were placed in a three-necked flask and suspended in 30 ml methanol. The 4-ethinylaniline (1.2 eq.) was added dissolved in 20 ml methanol. The reaction mixture was refluxed for 10 h. The mixture was extracted three times with dichloromethan, respectively. The combined organic phases were washed with water and brine before being concentrated to dryness. Purification by flash-chromatography yielded compound 5 as a brown solid. Coupling of the 19 Boc-protected [2-[(4'-aminophenylen)ethynylen]-1,10-phenanthrolin-5/6-yl]amine and DTPA-anhydride [2-[(4'-Aminophenylen)ethynylen]-1,10-phenanthrolin-5/6-yl]amine 5 (1 eq.), DTPA-dianhydride and triethylamine (5 eq.) were stirred in DMF under argon for 2 h at 80°C. The sovents were removed under reduced pressure. The residue was purified by RP-HPLC (water/MeCN).
Triphenylphosphine (30 molpercent), [Pd(PPh3)2]012 (3molpercent), the protected 2-chloro-5/6-amino- 1,10-phenanthroline 4 (1 eq.) and copper(l)iodide (2molpercent) were placed in a three-neckedflask and suspended in 30 ml methanol. The 4-ethinylaniline (1.2 eq.) was added dissolved in20 ml methanol. The reaction mixture was refluxed for 10 h. The mixture was extracted three times with dichloromethane, respectively. The combined organic phases were washed with water and brine before being concentrated to dryness. Purification by flash-chromatography yielded compound 5 as a brown solid.Compound 4 was converted in a Sonogashira cross coupling reaction to the antennacomponent (compound 5). For this reaction, chloride was chosen as leaving group, because the starting material of the synthesis, <strong>[7089-68-1]2-chloro-1,10-phenanthroline</strong>, is readily available at amuch lower price or easier obtainable than corresponding bromide or iodine compoundsusually used. Due to the spatial proximity of the chloride in position 2 and the nitrogen atomin position 1 of the phenanthroline ring, the palladium catalyst is coordinated in more favorable position by intramolecular interactions, whereby the Sonogashira cross coupling reaction can take place with a good yield, and the undesired Glaser reaction is restrained.This could also be achieved by keeping the concentration of the 4-ethinylalanine small as possible. Further, the isolation of the antenna compound (compound 5) is complex due to itsrigid molecular structure, its very poor solubility and the similar polarity of side products and degradation products of the catalyst, but is possible by applying a very shallow slope of the gradient from pure dichloromethane to a mixture of dichloromethane and methanol (10:5) in a flash chromatography.
Example 1: Syntheis of the amino-reactive phosphorescent dye of the invention Nitration of <strong>[7089-68-1]2-chloro-1,10-phenanthroline</strong> 150 ml concentrated sulphuric acid was placed in a 500 ml three-necked flask and <strong>[7089-68-1]2-Chloro-1,10-phenanthroline</strong> 1 (CAS-Nr. 7089-68-1)(30g) was added while cooled with ice and stirred. The solution was heated in an oil bath to 180 °C. At 80 °C, the solution boiled and a strong smoke emission could be observed. At 160 °C, nitric acid (65 percent, 80 ml) was added dropwise while maintaining a temperature of 170 °C. The bath temperature was increased to 215 °C, and the adding was performed in such a way that the temperature was below or equal to 160 °C. After complete addition of the nitric acid, the solution was heated under reflux for 1 h to 165 to 170 °C. Following this, the reaction mixture was cooled in a ice bath, added to approximately 1 kg ice and diluted with 1 l water. A sodium hydroxide solution (50 percent w/v) was added dropwise until the pH value of the reaction mixture was in a neutral/weak alkaline range. This was accompanied by formation of a slightly yellow precipitate. The precipitate was separated and washed with water. The crude product of the reaction was dried over night at 110 °C, extracted with chloroform via Soxleth extraction and reduced to a dry powder in rotary evaporator. Reduction of 2-chloro-5/6-nitro-1,10-phenanthroline 2-Chloro-5/6-nitro-1,10-phenanthroline 2 (1 eq.) was dissolved in methanol and hydrogenated under stirring in the presence of the catalyst (palladium/coal 10percent, 10molpercent) in a hydrogenation plant until no further hydrogen consumption could be observed. The catalyst was filtered off and the filtrate was reduced to dryness under reduced pressure (complete conversion). Introduction of a Boc group to 5/6-amino-<strong>[7089-68-1]2-chloro-1,10-phenanthroline</strong> Alternatively, the amine group of <strong>[7089-68-1]2-chloro-1,10-phenanthroline</strong> 3 may be protected with a Boc group. To do this, 5/6-amino-<strong>[7089-68-1]2-chloro-1,10-phenanthroline</strong> (1 eq.) was dissolved in dry DMF and triethylamine (5 eq.). Then, DMAP (1.1 eq.) and di-t-butyldicarbonate (2 eq.) were added The solution was stirred at room temperature for 20 h. Then, water was added and the aqueous phase was extracted three times with diethylether. The combined organic phases were dried over Na2SO4 and concentrated to dryness. The crude product was purified with silica gel (CH2Cl2). (63percent yield). Coupling of the Boc-protected 2-chloro-5/6-amino-1,10-phenanthroline and 4-ethinylaniline Triphenylphosphine (30 molpercent), [Pd(PPh3)2]Cl2 (3molpercent), the protected 2-chloro-5/6-amino-1,10-phenanthroline 4 (1 eq.) and copper(I)iodide (2molpercent) were placed in a three-necked flask and suspended in 30 ml methanol. The 4-ethinylaniline (1.2 eq.) was added dissolved in 20 ml methanol. The reaction mixture was refluxed for 10 h. The mixture was extracted three times with dichloromethan, respectively. The combined organic phases were washed with water and brine before being concentrated to dryness. Purification by flash-chromatography yielded compound 5 as a brown solid.
2-(4-Aminophenylethynyl)-3-cyanopyridine (28f). N,N-Diisopropylamine (10 mL) was added to copper(l) iodide (36 mg, 0.02 mmol) and bis(triphenylphosphine)- palladium(ll) dichloride (66.5 mg, 0.01 mmol) under argon and the mixture was stirred until a green suspension formed. 2-Bromo-3-cyanopyridine 2790 (350 mg, 1.9 mmol) in tetrahydrofuran (10 mL) was added and the mixture was stirred for 30 min. 4-Amino- phenylethyne (445 mg, 3.8 mmol) was added and the mixture was stirred at 40C for 12 h. Evaporation and chromatography (petroleum ether / ethyl acetate 5:1? 1 :3) gave 2-(4-aminophenylethynyl)-3-cyanopyridine 28f (362 mg, 87%) as a dark green powder: mp 128-130C; H NMR (CDCI3) delta 3.96 (2 H, br, NH2), 6.64 (2 H, d, J = 9.1 Hz, Ph 3,5-H2), 7.30 (1 H, dd, J = 8.5, 1.8 Hz, 5-H), 7.49 (2 H, d, J = 6.6 Hz, Ph 2,6-H2), 7.92 (1 H, dd, J = 7.9, 1.7 Hz, 4-H), 8.73 (1 H, dd, J = 4.9, 1.7 Hz, 6-H); 13C NMR (CDCI3) (HSQC / HMBC) delta 82.87 (ethyne 2-C), 98.10 (ethyne 1-C), 106.48 (Ph 1-C), 1 13.68 (Ph 3,5-C2), 1 16.51 (5-C), 121.94 (C?N), 133.58 (Ph 2,6-C2), 140.65 (3-C), 145.43 (4-C), 150.12 (6-C), 151.16 (Ph 4-C), 153.27 (2-C); MS m/z 242.0693 (M + Na)+ (C14H9N3Na requires 242.0694), 220.0876 (M + H)+ (C14H10N3 requires 220.0875).
87%
General procedure: Compound 24 (150 mg, 0.80 mmol) in THF (5 mL) was stirredwith CuI (15.2 mg, 80 lmol) and (Ph3P)2PdCl2 (28 mg, 40 lmol)in Pri2NH (5 mL) under Ar at 45 C for 30 min. Phenylethyne 21a(163 mg, 1.6 mmol) was added. The mixture was stirred at 40 Cfor 5 d. Evaporation and chromatography (petroleum ether/EtOAc3:1) gave 25a (80 mg, 50%) as a pale buff powder.
With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); N-ethyl-N,N-diisopropylamine; In water; at 75℃;
General procedure: A general procedure for the synthesis of diarylacetylenes 2 involved the addition of 2.0 mmol of arylacetylene to a mixture of 2.1 mmol of an aryliodide, 3.0 mmol of diisoproprylethylamine, 0.02 mmol of Pd(PPh3)4, and 0.02 mmol of CuI in water (7 mL). The mixture was stirred for 1-2 h at 75 C. After cooling, the product was collected by filtration or extracted using dichloromethane and purified by recrystallization and/or chromatography.
65%
With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); N-ethyl-N,N-diisopropylamine; In water; at 75℃;
General procedure: A general procedure for the synthesis of diarylacetylenes 2 involved the addition of 2.0 mmol of arylacetylene to a mixture of 2.1 mmol of an aryliodide, 3.0 mmol of diisoproprylethylamine, 0.02 mmol of Pd(PPh3)4,and 0.02 mmol of CuI in water (7 mL). The mixture was stirred for 1-2 h at 75C. After cooling, the product was collected by filtration or extracted using dichloromethane and purified by recrystallization and/or chromatography.
65%
With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); N-ethyl-N,N-diisopropylamine; In water; at 75℃;
General procedure: A general procedure for the synthesis of diarylacetylenes 2 involved the addition of 2.0 mmol of arylacetylene to a mixture of 2.1 mmol of an aryliodide, 3.0 mmol of diisoproprylethylamine, 0.02 mmol of Pd(PPh3)4, and 0.02 mmol of CuI in water (7 mL). The mixture was stirred for 1-2 h at 75 C. After cooling, the product was collected by filtration or extracted using dichloromethane and purified by recrystallization and/or chromatography. Purified by chromatography on silica gel using 1:2ethyl acetate-hexane (R0.43). Yield 65%, mp 104-105 C. 1H NMR (DMSO-d6): delta 7.46-7.39 (m, 1H), 7.22 (d, 2H, J=8.8 Hz), 7.20-7.16 (m, 2H), 6.58 (d, 2H, J=8.8 Hz), 5.69 (s, 2H, NH2). 13C NMR (DMSO-d6):delta 161.72 (dd, J1=248.9 Hz, J2=5.3 Hz, two C), 150.21, 132.77 (two C), 129.89 (t, J=9.9 Hz), 113.60 (two C), 111.68 (dd, J1=18.2 Hz, J2=6.1 Hz, two C), 106.96, 101.96 (t, J=19.8 Hz), 102.28 (d, J=2.7 Hz), 73.11. HRMS (ESI) calcd for C14H9F2N [MH+]: 230.07758. Found: 230.07660. Anal. Calcd for C14H9F2N: C, 73.36; H, 3.96. Found: C, 73.10; H, 4.03.
4-(4-aminophenylethynyl)-3-cyanopyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
35%
General procedure: 4-Bromo-3-cyanopyridine 27 (92 mg, 0.5 mmol) in THF (5 mL)was added to CuI (9.6 mg, 50 lmol), (Ph3P)4Pd (29 mg, 25 lmol)and Na ascorbate (9.9 mg, 50 lmol) in Et3N (5 mL) under Ar. Themixture was stirred at 40 C for 30 min. Phenylethyne 21a(76.5 mg, 0.75 mmol) was added and the mixture was stirred at40 C for 10 h. Evaporation and chromatography (petroleumether/EtOAc 3:1) gave 28a (80 mg, 78%) as an off-white powder.
1-(3-ethynylphenyl)-N-(4-ethynylphenyl)methanimine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
In methanol; at 20℃; for 3h;
General procedure: Dimers D1, D2, D3, D4, and D5 (see below) were prepared by reaction of respective ethynyl(s)benzaldehyde (2mmol) with respective ethynylaniline (2mmol). Reactions were started by mixing reactant solutions (solutions were prepared by dissolving the reactants in minimum amounts of methanol, 3-ethynylaniline, which is liquid, and used undiluted). The first crystals of the product appeared in the reaction mixture within a 5-30 min interval. After 3 h, a yellowish microcrystalline precipitate was separated by filtration, washed with cold methanol to remove non-reacted starting compounds, and dried in a vacuum at room temperature to a constant weight.
4-(4-(N,N-di(3-methylbenzyl)amino)phenyl)-1-(3-methylbenzyl)-1H-1,2,3-triazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With sodium azide; copper; In methanol; at 20℃; for 24h;
General procedure: Sodium azide(0.3 mmol), benzyl halides (0.9 mmol), and aminophenylacetylene (0.25 mmol) were added into a suspension of 0.025 mmol of Cu NPs in MeOH (1 mL). The reaction mixture was stirred at room temperature for completion monitored by TLC. Then the solution was filtered by suction and the solvent was evaporated under reduced pressure. The residue was passed through flash column chromatography (EtOAc/ hexane=1/10) on silica gel to give the pure products.
5-chloro-3-(4-aminophenylethynyl)pyrazolo[1,5-a]pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82.4%
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In tetrahydrofuran; at 20℃;Inert atmosphere;
[00340] To a mixture of <strong>[923595-58-8]5-chloro-3-iodopyrazolo[1,5-a]pyrimidine</strong> (2.5 g, 8.95 mmol) in THF (70 mL) were added 4-ethynylaniline (2.62 g, 22.4 mmol), Et3N (40 mL), PdC12(PPh3)2 (650 mg, 0.9 mmol) and CuT (350 mg, 1.8 mmol) with stirring in turn. After the addition, the reation mixture was stirred at rt under a N2 atmosphere. After the reaction monitored by TLC was completed, the resulting mixture was filtered through a Celite pad, and the filter cake was washed with a little THF. The combined filtrates were concentrated in vacuo and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 3/2) to give the title compound as a claybank solid (1.98 g, 82.4%). The compound was characterized by the following spectroscopic data: MS-ESI: (ESI, pos.ion) m/z: 269.0 [M+1].
82.4%
With copper(l) iodide; trans-bis(triphenylphosphine)palladium dichloride; triethylamine; In tetrahydrofuran; at 20℃;Inert atmosphere;
<strong>[923595-58-8]5-chloro-3-iodopyrazolo[1,5-a]pyrimidine</strong> (2.5 g, 8.95 mmol) was dissolved in 70 mL of tetrahydrofuran p-aminophenylacetylene (2.62 g, 22.4 mmol), 40 mL of Et3N, Pd(PPh3)2Cl2 (650 mg, 0.9 mmol) and CuI (350 mg, 1.8 mmol) were added with stirring and the mixture was stirred at rt under N2 for overnight. TLC monitoring reaction is basically complete, diatomaceous earth filter, the filter cake was washed with a small amount of tetrahydrofuran, the combined filtrate, concentrated. The residue was chromatographed on silica gel. Column chromatography (V (petroleum ether) / V (ethyl acetate) = 3/2) gave 1.98 g of a tan solid with a yield of 82.4%.
5-((4-aminophenyl)ethynyl)-2-chlorophenol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49.2%
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In tetrahydrofuran; at 40℃; for 24h;Inert atmosphere;
[00381] To a 250 mL three-neck flask were added <strong>[289039-26-5]2-chloro-5-iodophenol</strong> (2.54 g, 10.0 mmol), 4-ethynylaniline (2.34 g, 20.0 mmol), bi s(triphenylphosphine)palladium(II) chloride (700 mg,1.0 mmol) and CuT (190 mg, 1.0 mmol). THF (60 mL) and triethylamine (6 mL) were added to the mixture via syringe under a N2 atmosphere and the mixture was stirred at 40 C for 24 hours. The reaction mixture was poured into water (200 mL), and the resulting mixture was extracted with dichloromethane (500 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (CH2C12/MeOH (v/v) = 10/1) to give the title compound as a brown solid (1.2 g, 49.2%). The compound was characterized by the following spectroscopic data: MS-ESI: (ESI, pos.ion) m/z: 244.2 [M+1].
49.2%
With copper(l) iodide; trans-bis(triphenylphosphine)palladium dichloride; triethylamine; In tetrahydrofuran; at 40℃; for 24h;Inert atmosphere;
<strong>[289039-26-5]2-chloro-5-iodophenol</strong> (2.54g, 10.0mmol), p-aminophenylacetylene (2.34g, 20.0mmol), bis(triphenylphosphine)palladium(II) chloride (700 mg, 1.0 mmol) and CuI (190 mg, 1, 0 mmol) were placed in a 250 mL three-necked flask and the system was replaced with N2. Tetrahydrofuran (60 mL) and triethylamine (6 mL) were added by syringe and reacted at 40 C for 24 h. The reaction mixture was poured into water (200 mL), extracted with dichloromethane (500 mL), dried over anhydrous sodium sulfate, filtered, concentrated. Column chromatography (V (methanol) / V (methylene chloride) = 1/10) gave 1.2 g of a brown solid in a yield of 49.2%.
N-(4-ethynylphenyl)-2-oxo-2H-pyran-5-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
With 1-hydroxybenzotriazol-hydrate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 72h;
General procedure: To a solution of carboxylic acids (2 mmol) in methylene chloride (10 mL), solid 1-hydroxybenzotriazole monohydrate (0.27 g, 2 mmol) and N-ethyl-N?-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.38 g, 2 mmol) were added. The mixture solutions were reacted with various anilines (4 mmol) and then stirred at room temperature for 3 days in parallel synthesis reactor. The reaction mixture was evaporated to dryness under reduced pressure and the residue was extraction with ethyl acetate, washed with 10% NaHCO3, and H2O. The organic phasewas separated and dried with anhydrous MgSO4, and dried in vacuo. The crude product was washed and purified by crystallization from hot ethanol and methylene chloride to obtain title compounds.
(E)-4-(3-(4-ethynylphenyl)triaz-1-enyl)benzimidamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25%
General procedure: The synthesis of DMZ analogues followed previously reported procedure [19a], see Scheme 2. <strong>[2498-50-2]4-Aminobenzamidine dihydrochloride</strong> (212mg, 1.0mmol) was added to a stirred solution of 12N HCl (0.27mL) and water (1.5mL) in a 10mL flask at 0C and stirring was continued for 15min. To the mixture was added (dropwise) cold (?0C) NaNO2 solution (76mg in 0.27mL water, 1.1 eq.) and stirring was continued for 15min before cold (?0C) NaOAc solution (328mg in 1.5mL water, 4.0 eq.) was added dropwise over 15min to adjust the pH to 6.0. Cold (?0C) aromatic amine solution (1.0mmol in 1.0mL methanol) was added dropwise to the above solution and stirring was continued for another 1-12hat 0C. After the reaction was completed, the solvent was removed under reduced pressure. Water (100mL) was added to the residue and the aqueous mixture was washed with dichloromethane (2×15mL). The aqueous layer was then basified with 2.5% NaOH solution to make the pH>10.0. The desired compound was then extracted from the aqueous layer with ethyl acetate (2×100mL). The organic layer was washed with brine and dried with sodium sulfate. Finally, the solvent was removed under reduced pressure and the final product was obtained with purity >95%.
(2-(2-(4-aminophenyl)ethynyl)-5-bromophenyl)methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; triphenylphosphine; at 20 - 80℃; for 24h;Inert atmosphere;
Solution of compound 3 (5.00g, 0.04mol) dissolved in dry triethylamine (100mL) was added dropwise to a suspension of compound 2 (12.52g, 0.04mol), Pd(PPh3)2Cl2 (0.63g, 0.9mmol), triphenylphosphine (0.89g, 3.4mmol), and copper(I) iodide (0.29g, 1.7mmol) in dry triethylamine (200mL) at room temperature under nitrogen. The mixture was stirred at near 80C for 24h. The mixture was cooled to room temperature and filtered to remove the insoluble salt (triethylamine hydrobromide) formed during the reaction. The filtrate was washed with ether. After concentrated, the product was purified by column chromatography [silica gel, petroleum ether: ethyl acetate (v:v)=2:1] to give 6.3g of a yellowish solid. Yield:55%; 1H NMR (600MHz, DMSO-d6): delta=7.62 (s, 1H), 7.41 (dd, J=8.2, 1.9Hz, 1H), 7.32 (d, J=8.2Hz, 1H), 7.19 (d, J=8.4Hz, 1H), 6.55 (d, J=8.5Hz, 1H), 5.58 (s, 1H), 5.42 (t, J=5.7Hz, 1H), 4.65(d, J=5.6Hz, 1H)ppm (Fig.S3). HRMS(EI,DIP); m/z calcd. for C15H12BrNO [M+H]+: 301.01, found 301 (Fig.S4).
1-(4-ethynylphenyl)-3-{2-[2-(2-hydroxyethoxy)ethoxy]ethyl}urea[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
4-Ethynylaniline (170.4 mg, 1.5 mmol) was added to a solution of 4-nitrophenyl chloroformate (289.3 mg, 1.4mmol) in tetrahydrofuran (6.8 mL), stirred at room temperature for 3 hours, and then the solvent was distilled away undera reduced pressure. To a solution of the resulting crude product in dichloromethane (4 mL), a solution of 2-[2-(2-aminoethoxy)ethoxy]ethanol (239 mg, 1.6 mmol) in dichloromethane (4 mL) and triethylamine (303 mL, 2.2 mmol) wereadded, stirred at room temperature overnight, and then the solvent was distilled away under a reduced pressure. Theresidue was purified by silica gel column chromatography (ethyl acetate/methanol (v/v) = 100/0 ? 90/10) to obtain thetitle compound (325.4 mg, 77%) as a pale yellow oily matter.1H NMR (400 MHz, CDCl3) delta 8.30 (1H, br s), 7.32 (4H, m), 6.22 (1H, br t, J = 4.4 Hz), 4.37 (1H, br s), 3.72 (2H, br t, J= 4.4 Hz), 3.55-3.53 (6H, m), 3.49 (2H, t, J = 4.4 Hz), 3.36-3.34 (2H, m), 3.05 (1H, s)
N-(5-ethynylpyridine-2-yl)-2,5,8,11-tetraoxatridecane-13-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;
44 Production of N-(5-ethynylpyridine-2-yl)-2,5,8,11-tetraoxatridecane-13-amide
1-Ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (526.1 mg, 2.7 mmol), 4-dimethylaminopyridine(664.6 mg, 5.4 mmol), dichloromethane (5 mL) and 5-ethynylpyridine-2-amine (239.6 mg, 2.0 mmol) were added to3,6,9,12-tetraoxatridecanoic acid (320.1 mg, 1.4 mmol), and stirred at room temperature overnight. The reaction solutionwas diluted with ethyl acetate, washed with a 10% citric acid aqueous solution, dried with anhydrous sodium sulfate,and then the solvent was distilled away under a reduced pressure. The residue was purified by silica gel column chromatography(hexane/ethyl acetate (v/v) = 1/4) to obtain the title compound (199.4 mg, 43%) as a brown oily matter.1H NMR (400 MHz, CDCl3) δ 9.24 (1H, br, s), 8.42 (1H, br d, J = 2.4 Hz), 8.23 (1H, d, J = 8.8 Hz), 7.79 (1H, dd, J = 8.8,2.4 Hz), 4.16 (2H, s), 3.79-3.77 (2H, m), 3.74-3.72 (6H, m), 3.66-3.63 (2H, m), 3.55-3.52 (2H, m), 3.37 (3H, s), 3.16 (1H, s)
N-(p-ethynyl)phenyl-pentafluorobenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 23℃; for 24h;
1
Will be 1 .Ommol P-aminophenylacetylene, 1.3 mmol Of pentafluorobenzoic acid and 0.2 mmol Of N, N-dimethyl-4-aminopyridine was dissolved 5 ml of anhydrous CH2C12, Then add 1.5 mml of dimethylaminopropyl ethylcarbamide hydrochloride (EDC-HC1) and stir at 23 ° C for 24 h. The reaction was carried out with CH2C12 as solvent, The reaction system was washed with water, The organic layer was separated and the aqueous layer was extracted three times with CH2C12. The resulting organic layers were combined and washed with brine, The organic layer was separated and dried over anhydrous Na? S04 and then filtered. The filtrate was concentrated by distillation under reduced pressure. The crude product was purified by silica gel column chromatography on ethyl acetate as eluant to give the target product, (P-ethynyl) -phenyl-2-X-tetrafluorobenzamide (pale yellow crystals, 92% yield).
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In dichloromethane; at 25℃; for 2h;
To a stirred mixture of 4-ethynylaniline (2.0 g, 17.0 mmol) and <strong>[68-95-1](S)-1-acetylpyrrolidine-2-carboxylic acid</strong> (2.68g, 17.0 mmol) in anhydrous dichloromethane (50 mL) was added EEDQ (4.23 g, 17.0 mmol) in one portion. The mixturewas stirred for 2 h at 25 C before it was poured into 1N HCl. The organic phase was separated, dried with Na2SO4,filtered and concentrated down to volume to afford Example D55, step a as an orange solid after filtration (3.4 g). 1HNMR (300 MHz, DMSO-d6) delta 10.32 and 10.12 (2s, 1H), 7.64-7.59 (m, 2H), 7.44-7.40 (m, 2H), 4.53-4.49 and 4.41-4.37(2m, 1H), 4.08 and 4.06 (2s, 1H), 3.65-3.35 (2m, 2H), 2.38-1.78 (series of m, 4H), 1.99 (s, 3H); Rt = 1.00 min (Cond.-MSW1);90%; LCMS: Anal. Calc. for [M+H]+ C15H17N2O2: 257.13; found: 257.16.
4-((4-chloropyridin-2-yl)ethynyl)aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; N-ethyl-N,N-diisopropylamine; triphenylphosphine; In tetrahydrofuran; at 50℃; for 12h;Inert atmosphere;
To a mixture of <strong>[22918-01-0]2-bromo-4-chloropyridine</strong> (6e, 3.84 g, 20 mmol, 1.0 equivalent), 4- ethynylaniline (2.57 g, 22 mmol, 1 .1 equivalenl). Pd(PPh3)2Cl2 (702 nig, 1.0 mmol, 5 mol%). PPh3(524 mg. 2.0 mmol, 10 ml%) and Cul (382 mg. 2.0 mmol, 10 mol%) in a 100 mL round- bottom flask was added 50 mL 'Pr2NH/THF (9:1) under nitrogen. The reaction mixture was stirred at 50 C overnight, and then concentrated. The residue was purified by column chromatography with ISCO system to afford the desired compound 4-((4-chloropyridin-2- yl)ethynyl)aniline as a light yellow solid (4.1 g, 90%).?H NMR (CD3OD, 400 MHz): 8.45 (d, J = 4.0 Hz, 1H), 7.80 (dd, J= 8.0 Hz, J2 = 4.0 Hz, 1H), 7.48 (d, J= 8.0 Hz, 1H), 7.28 (d, .7 = 8.0 Hz, 2H), 8.64 (d, .7= 8.0 Hz, 2H).
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In tetrahydrofuran; at 70℃; for 6h;Inert atmosphere;
General procedure: To a solution of 3 (117mg, 1.0mmol), methyl 4-iodobenzoate (288mg, 1.1mmol), Pd(PPh3)2Cl2 (21mg, 0.03mmol), and CuI (5mg, 0.03mmol) in the mixture of THF (20mL) and triethylamine (20mL) was added under a nitrogen atmosphere. After being stirred at 70°C for 6h, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography with dichloromethane/petroleum ether (1:2, v/v) as the eluent to afford the pure product 5a (221mg, 0.88mmol) as a light brown powder in 88percent yield.
2-((4-aminophenyl)ethynyl)-4-nitroaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In tetrahydrofuran; at 20℃; for 3h;Inert atmosphere;
Part A To a suspension of <strong>[6293-83-0]2-iodo-4-nitroaniline</strong> (10) (500 mg, 1.9 mol), bis(triphenylphosphine)palladium(II) dichloride (66.5 mg, 0.095 mmol), and copper (I) iodide (18 mg, 0.095 mmol) in THF (3.5 mL, previously degassed 5-10 min) was added in succession triethylamine (792 muL, 5.68 mmol) and 4-ethynylaniline (266 mg, 2.3 mmol). The mixture was stirred for 3 h at room temperature under argon at which point LCMS indicated the reaction was complete. The crude reaction mixture was diluted with EtOAc (90 mL) and washed successively with water and brine (30 mL each). The organic layer was dried over MgSO4 and concentrated under vacuum. The crude product was purified on silica gel (Hexane:EtOAc, 0-100% B) to give 2-((4-aminophenyl)ethynyl)-4-nitroaniline (11) as an orange solid (454 mg, 95% yield). 1H NMR (DMSO-d6): delta 8.01 (1H, d, J=3.0 Hz), 7.95-7.89 (1H, m), 7.32 (2H, d, J=8.4 Hz), 6.83 (2H, brs), 6.76 (1H, d, J=9.2 Hz), 6.55 (2H, d, J=8.2 Hz), 5.59 (2H, s). ESI-MS: C14H12N3O2 (M+H) 254.1; found 254.0.
tris(4-(2-(4-aminophenyl)ethynyl)phenyl)amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper(l) iodide; dichlorobis(tri-O-tolylphosphine)palladium; triphenylphosphine; In N,N-dimethyl-formamide; at 80 - 90℃; for 12h;Inert atmosphere;
Tris (4-iodobenzene) amine, 4-ethynylaniline, triphenylphosphine, bis (triphenylphosphine) palladium dichloride, cuprous iodide,Now steamed N, N- dimethylformamide,Now steamed triethylamine was added to a reaction vessel equipped with a thermometer and reflux condenser,The reaction was heated to 80 ° C for 12 hours under mechanical stirring and nitrogen protection, the temperature was raised to 90 ° C to distill off most of the triethylamine,After cooling to room temperature in the deionized water and washed with deionized water 3 to 4 times until the filtrate was colorless,After drying in vacuo at 80 ° C for 6 to 12 hours, dichloromethane was used as a developing solvent to give a pale yellow solid by column chromatography.(4- (2- (4-aminophenyl) ethynyl) phenyl) amine; tris (4-iodophenyl) amine, 4ethynylaniline, triphenylphosphine,Bis (triphenylphosphine) palladium dichloride, cuprous iodide, N, N-dimethylformamide,Triethylamine in a molar ratio of 1: 3.45: 0.15: 0.01: 0.040: 55: 66. (Where the maximum molar ratio of 1:3.45 to 3.50: 0.10 to 0.20: 0.01 to 0.03: 0.040 to 0.050: 53 to 56: 65 to 68).The monomer obtained in this example
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 15℃; for 12h;
To a solution of compound 3 (105.10 mg, 512.17 umol, 1.2 eq) in DCM (2 mL) was added DIPEA (165.49 mg, 1.28 mmol, 223.03 uL, 3 eq) and HATU (243.43 mg, 640.22 umol, 1.5 eq) compound 3A (50 mg, 426.81 umol, 1 eq). The mixture was stirred at 15C for 12 hrs. LCMS showed it was finished. It was washed with 1 mL sat. NH4Cl, the organic layer was separated and concentrated. Compound 4 (80 mg, 262.86 umol, 61.59% yield) as a yellow solid was used into the next step without further purification. LCMS: RT = 1.165 min, MS cal.: 304.3, [M/2+H] + = 305.2
methyl 4-((4’-ethynylphenyl)carbamoyl)cubane-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
Stage #1: 4-(methoxycarbonyl)-1-cubanecarboxylic acid With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere;
Stage #2: 4-Ethynylaniline In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere;
N-(4-ethynylphenyl)-2-(4-hydroxyphenyl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55.3%
With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 20℃; for 8h;
4.2.2. N-(3,5-dimethylphenyl)-4-hydroxybenzamide (12b)
General procedure: To a stirring solution of 4-hydroxybenzoic acid 11b (0.73 g, 6 mmol), EDCl (1.44 g,7.5 mmol) and HOBT (0.81 g, 6 mmol) in dry DCM (20 mL) at room temperature was added3,5-dimethylaniline 10a (0.73 g, 6 mmol) for 8 h. Upon completion, the mixture was washedwith water (3 20 mL) and dried over anhydrous sodium sulfate before concentrationin vacuo. The crude product was purified with silica gel column chromatography usingpetroleum ether (PE)/ethyl acetate (EA) (5:1 to 3:1) as eluent to afford 12b as a white solid(0.53 g, 44%).