* 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 ammonium chloride In ethanol for 0.5 h; Reflux
General procedure: To asolution of hydrazide (0.73 mmol) in 10 mL of anhydrous ethanol, added triethyl orthoester (0.81 mmol) and ammonium chloride (0.219 mmol). The solution was stirred and heated to reflux until it complete (0.5-18 h). The reaction mass was cooled to room temperature and concentrated under vacuum. The crude product was made into slurry in a mixture of hexanes and ether (3:1), filtered,washed with deionized water or purified by column chromatography.
92%
at 100 - 110℃; for 12 h;
To a mixture of 3 (18.0 g, 0.1083 mol) and triethyl orthoformate (80.3 g, 0.541 mol) was heated to 100-110 °C and maintained for 12 h. The reaction completion was monitored by TLC. The reaction mixture was cooled to room temperature and concentrated to syrup. Traces triethyl orthoformate was removed by azeotropic distillation with toluene. The residue was purified by column chromatography on silica gel using eluent 0-5percent ethyl acetate in petroleum ether. The title compound was yielded as pale yellow liquid (Yield: 17.55 g, 92percent).
Reference：
[1] Tetrahedron Letters, 2014, vol. 55, # 50, p. 6776 - 6778
[2] Organic Letters, 2018, vol. 20, # 19, p. 6027 - 6032
[3] Angewandte Chemie - International Edition, 2011, vol. 50, # 48, p. 11511 - 11515
[4] Journal of the American Chemical Society, 2016, vol. 138, # 38, p. 12605 - 12614
[5] European Journal of Medicinal Chemistry, 2013, vol. 65, p. 276 - 283
[6] Tetrahedron Letters, 2008, vol. 49, # 5, p. 879 - 883
[7] Journal of Organic Chemistry, 2009, vol. 74, # 16, p. 6410 - 6413
[8] Chemistry - A European Journal, 2011, vol. 17, # 30, p. 8294 - 8298
[9] Angewandte Chemie - International Edition, 2012, vol. 51, # 19, p. 4666 - 4670
[10] Zhurnal Obshchei Khimii, 1959, vol. 29, p. 2027,2030; engl. Ausg. S. 1996, 1998
[11] Organic Letters, 2010, vol. 12, # 15, p. 3567 - 3569
[12] Tetrahedron, 2012, vol. 68, # 1, p. 300 - 305
[13] Magnetic Resonance in Chemistry, 2011, vol. 49, # 10, p. 648 - 654
[14] European Journal of Organic Chemistry, 2012, # 3, p. 471 - 474
[15] Chemical Communications (Cambridge, United Kingdom), 2012, vol. 48, # 92, p. 11307 - 11309,3
[16] Tetrahedron, 2013, vol. 69, # 9, p. 2220 - 2225
2
[ 3290-99-1 ]
[ 829-35-6 ]
Yield
Reaction Conditions
Operation in experiment
67%
With trifluoroacetic acid In toluene at 130℃; for 12 h;
General procedure: A 25 mL pressure tube was charged with arylhydrazide 1 (0.5 mmol), TFBen (53 mg, 0.25 mmol, white solid, mp 57.2-58.5 °C), TFA (38 μL, 1.0 equiv), and toluene (4 mL). The tube was then heated by stirring the contents at 130 °C for 12 h. Afterwards, the mixture was cooled to r.t., quenched with sat. aq NaHCO3 (3 mL), and extracted with EtOAc (3 4 mL). The combined organic layers were dried (anhyd Na2SO4), filtered, and concentrated under reduced pressure. The pure product 2 was obtained after purification by column chromatography (EtOAc/ pentane 1:3).
With Al3+-K10 montmorillonite clay In neat (no solvent) at 55℃; for 0.25 h; Microwave irradiation
General procedure: A 5 mL microwave vial was charged with acidhydrazide (100 mg, 1 eq), trimethyl orthoester (2 eq) and Al3+-K10 clay (75 mg). The resulting mixture was kept under microwave irradiation maintaining the temperature at 55 °C for 15 min (Microwave irradiations were performed on CEM-discover model No. 908010). The reaction was monitored by TLC. After completion of the reaction, reaction mixture was diluted with ethyl acetate stirred well, filtered, washed well with ethyl acetate. Filtrate was evaporated under reduced pressure to obtain highly pure product. In some cases, products were purified by column chromatography using 60-120 mesh silica with 20-100 percent ethyl acetate in pet ether as eluting solvents. The catalyst recovered by filtration was reused for another 5 more times.
Reference：
[1] Tetrahedron Letters, 2014, vol. 55, # 27, p. 3678 - 3682
[2] Journal of Medicinal Chemistry, 2001, vol. 44, # 8, p. 1268 - 1285
[3] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 11, p. 2909 - 2914
Reference：
[1] Journal of Organic Chemistry, 2016, vol. 81, # 15, p. 6820 - 6825
6
[ 292638-84-7 ]
[ 3290-99-1 ]
[ 829-35-6 ]
Reference：
[1] Journal of Organic Chemistry, 2016, vol. 81, # 15, p. 6820 - 6825
7
[ 121-98-2 ]
[ 829-35-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 2001, vol. 44, # 8, p. 1268 - 1285
[2] Magnetic Resonance in Chemistry, 2011, vol. 49, # 10, p. 648 - 654
[3] Angewandte Chemie - International Edition, 2012, vol. 51, # 19, p. 4666 - 4670
[4] Chemical Communications (Cambridge, United Kingdom), 2012, vol. 48, # 92, p. 11307 - 11309,3
8
[ 100-09-4 ]
[ 829-35-6 ]
Reference：
[1] Angewandte Chemie - International Edition, 2012, vol. 51, # 19, p. 4666 - 4670
[2] Chemical Communications (Cambridge, United Kingdom), 2012, vol. 48, # 92, p. 11307 - 11309,3
[3] European Journal of Medicinal Chemistry, 2013, vol. 65, p. 276 - 283
9
[ 94-30-4 ]
[ 829-35-6 ]
Reference：
[1] Chemistry - A European Journal, 2011, vol. 17, # 30, p. 8294 - 8298
[2] European Journal of Medicinal Chemistry, 2013, vol. 65, p. 276 - 283
10
[ 121-98-2 ]
[ 149-73-5 ]
[ 829-35-6 ]
Reference：
[1] Magnetic Resonance in Chemistry, 2003, vol. 41, # 9, p. 689 - 692
11
[ 74-83-9 ]
[ 829-35-6 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1966, p. 376 - 381
2-[5-amino-2-(4-fluoro-phenyl)-6-oxo-6<i>H</i>-pyrimidin-1-yl]-<i>N</i>-{1-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazole-2-carbonyl]-2-methyl-propyl}-acetamide[ No CAS ]
{2-(4-Fluoro-phenyl)-1-[((S)-1-{hydroxy-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-methyl}-2-methyl-propylcarbamoyl)-methyl]-6-oxo-1,6-dihydro-pyrimidin-5-yl}-carbamic acid benzyl ester[ No CAS ]
With bis-triphenylphosphine-palladium(II) chloride; copper(I) bromide; sodium t-butanolate; In toluene; at 100℃; for 10h;Inert atmosphere;
Under the nitrogen atmosphere, an over-dried Schlenk tube with a magnetic stirring bar was charged with 2-(gem-dibromovinyl)phenol or 2-(gem-dibromovinyl)aniline (0.50 mmol), azole (0.50 mmol), CuBr (0.05 mmol), Pd(PPh3)2Cl2 (0.025 mmol), LiOtBu (2.0 mmol), and toluene (2.0 mL). The reaction vessel was placed in an oil bath at 100 C and the mixture was stirred for 10 h, then it was cooled to room temperature. The solvent was filtered and concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel (eluant: hexane/ethyl acetate) to give the corresponding benzofuranyl or indolyl azole product.
With copper(l) iodide; lithium tert-butoxide; N,N`-dimethylethylenediamine; In dimethyl sulfoxide; at 70℃; for 3h;Inert atmosphere;
General procedure: In a 10 mL round bottom flask under nitrogen atmosphere, CuI (9 mg, 0.05 mmol), DMEDA (4.5 mg, 0.05 mmol), LiO-t-Bu (80 mg, 1.0 mmol), 2-aryl-1,3,4-oxadiazole (0.50 mmol), and trans-beta-iodostyrene (0.50 mmol) in DMSO (2.0 mL) were taken. The reaction mixture was stirred at 70 C for 3 h. The progress of the reaction was monitored by TLC. After the consumption of the starting materials, the reaction mixture was allowed to cool, and subsequently extracted with EtOAc (2×10 mL). The combined organic extracts were dried over anhydrous Na2SO4. Concentration in vacuo followed by column chromatography (EtOAc/hexane: 5:95 to 10:90) gave pure compound 3 in 85-93% yield.
With copper(l) iodide; lithium tert-butoxide; N,N`-dimethylethylenediamine; In dimethyl sulfoxide; at 70℃; for 3h;Inert atmosphere;
General procedure: In a 10 mL round bottom flask under nitrogen atmosphere, CuI (9 mg, 0.05 mmol), DMEDA (4.5 mg, 0.05 mmol), LiO-t-Bu (80 mg, 1.0 mmol), 2-aryl-1,3,4-oxadiazole (0.50 mmol), and trans-beta-iodostyrene (0.50 mmol) in DMSO (2.0 mL) were taken. The reaction mixture was stirred at 70 C for 3 h. The progress of the reaction was monitored by TLC. After the consumption of the starting materials, the reaction mixture was allowed to cool, and subsequently extracted with EtOAc (2×10 mL). The combined organic extracts were dried over anhydrous Na2SO4. Concentration in vacuo followed by column chromatography (EtOAc/hexane: 5:95 to 10:90) gave pure compound 3 in 85-93% yield.
With copper(l) iodide; lithium tert-butoxide; N,N`-dimethylethylenediamine; In dimethyl sulfoxide; at 70℃; for 3h;Inert atmosphere;
General procedure: In a 10 mL round bottom flask under nitrogen atmosphere, CuI (9 mg, 0.05 mmol), DMEDA (4.5 mg, 0.05 mmol), LiO-t-Bu (80 mg, 1.0 mmol), 2-aryl-1,3,4-oxadiazole (0.50 mmol), and trans-beta-iodostyrene (0.50 mmol) in DMSO (2.0 mL) were taken. The reaction mixture was stirred at 70 C for 3 h. The progress of the reaction was monitored by TLC. After the consumption of the starting materials, the reaction mixture was allowed to cool, and subsequently extracted with EtOAc (2×10 mL). The combined organic extracts were dried over anhydrous Na2SO4. Concentration in vacuo followed by column chromatography (EtOAc/hexane: 5:95 to 10:90) gave pure compound 3 in 85-93% yield.
General procedure: Under nitrogen atmosphere, a sealable reaction tube equipped with a magnetic stirrer bar was charged with azole (0.50 mmol), sodium arylsulfinate (1.0 mmol), Pd(OAc)2 (0.025 mmol), Cu(OAc)2 (1.0 mmol), CF3COOH (0.50 mmol), and dimethylglycol (2.0 mL). The rubber septum was then replaced by a Teflon-coated screw cap, and the reaction vessel placed in an oil bath at 120 C for 24 h. After the reaction was completed, it was cooled to room temperature and the mixture was treated with K2CO3 solution (1.0 mol/L, 3.0 mL), then extracted with ethyl acetate. The resulting solution was dried by Na2SO4 then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluant: petroleum ether/ethyl acetate=12:1, v/v) to give the desired product.
With potassium fluoride; copper diacetate; palladium diacetate; silver nitrate; In N,N-dimethyl-formamide; at 100℃; for 12h;
General procedure: In a 10 mL round bottom flask Pd(OAc)2 (5 mol %, 11.3 mg), Cu(OAc)2 (2 equiv, 404 mg), KF (3.0 equiv, 174 mg), AgNO3 (1.5 equiv, 255 mg), 2-aryl 1,3,4-oxadiazole (1 mmol), and benzothiazole (1.3 mmol) were taken in dry DMF (2.5 mL). The reaction mixture was stirred for 10 min at room temperature then heated at 100 C for 12 h. The progress of the reaction was monitored by TLC. After consumption of starting material the reaction mixture was allowed to cool and subsequently extracted with EtOAc. The combined organic extracts were dried over anhydrous Na2SO4. Concentration in vacuo followed by column chromatography (EtOAc/hexane: 5:95 to 10:90) gave pure compound 3 in 85-94% yield.
To a 500 mL four necked flask was charged tetrahydrofuran (170 mL) and 4 (17.0 g, 0.096 mol). The reaction mass was cooled to 65 to 70 C under nitrogen atmosphere with stirring and added n-butyllithium (50.3 mL, 2.3 M in n-hexane, 0.1157 mol) over a period of 1 h, further reaction mass was stirred at same temperature for 1.0 h. Bromine (9.2 g, 0.1157 mol) was added slowly to reaction mass by maintaining the reaction temperature 65 to 70 C. Further stirred the reaction mass for 1.0 h. Reaction completion was monitored by TLC. Reaction mass was warmed to around 10 C and quenched with 1.0 N HCl solution (100 mL). Reaction mass was warmed to room temperature and the compound was extracted with ethyl acetate (2 Chi 100 mL). Combined organic layer was washed with water (1 Chi 100 mL) followed by brine (100 mL), dried over anhydrous sodium sulphate and concentrated to one volume stage. Compound was crystallized using petroleum ether to yield the title compound as white solid.
With sodium t-butanolate; In N,N-dimethyl-formamide; at 20℃; for 4h;
General procedure: A mixture of 2-substituted-1,3,4-oxadiazole (0.5 mmol), t-BuONa (0.5 mmol) and DMF or DMSO (1 mL) was stirred at room temperaturefor an appropriate time. When the reaction completed, EtOAc (5 mL) and petroleum ether (5 mL) were added, and the mixture was washed by water (3 × 10 mL) to remove DMF or DMSO. The organic layer was collected and filtered through a bed of silica gel layered over Celite.The volatiles were removed under reduced pressure to afford the final product. In a few cases, further column chromatography on silica gel was needed to afford the pure desired product.
With copper(II) oxide; potassium carbonate; triphenylphosphine; In diethylene glycol dimethyl ether; for 18h;Reflux; Green chemistry;
General procedure: A 10 mL round-bottomed flask was charged with the appropriate 2-aryl-1,3,4-oxadiazole 1 (0.25 mmol), aryl halide 2 (0.50 mmol), nanoparticulate CuO (10 mol%) , Ph3P (30 mol%), K2CO3 (2 equiv), and diglyme (3.0 mL). The mixture was stirred under reflux until the starting materials were consumed (TLC). The mixture was then allowed to cool and extracted with EtOAc (2 × 10 mL). The organic extracts were combined, dried (Na2SO4), and concentration in vacuo. The residue was purified by column chromatography (silica gel).
With copper(II) oxide; potassium carbonate; triphenylphosphine; In diethylene glycol dimethyl ether; for 20h;Reflux; Green chemistry;
General procedure: A 10 mL round-bottomed flask was charged with the appropriate 2-aryl-1,3,4-oxadiazole 1 (0.25 mmol), aryl halide 2 (0.50 mmol), nanoparticulate CuO (10 mol%) , Ph3P (30 mol%), K2CO3 (2 equiv), and diglyme (3.0 mL). The mixture was stirred under reflux until the starting materials were consumed (TLC). The mixture was then allowed to cool and extracted with EtOAc (2 × 10 mL). The organic extracts were combined, dried (Na2SO4), and concentration in vacuo. The residue was purified by column chromatography (silica gel).
With 1,3-bis-(diphenylphosphino)propane; palladium dichloride; silver(l) oxide; In toluene; at 80℃; for 10h;
General procedure: To a 10-mL round-bottom flask PdCl2 (6.7 mg, 10 mol%), dppp (24.7mg, 20 mol%), Ag2O (208.6 mg, 0.9 mmol), and alpha,beta-ynoic acid 2(0.45 mmol) and toluene (3 mL) were added under air. To this mixture 1,3,4-oxadiazole 1 (0.5 mmol) was added and the entire mixture was refluxed at 80 C for 10 h (TLC monitoring). After completion of the reaction, the mixture was allowed to cool, quenched by the addition of H2O, and subsequently extracted with EtOAc (2 × 10 mL). The combined organic extracts were dried (anhyd Na2SO4). Concentration of the organic layer in vacuo followed by column chromatography (silica gel) afforded oxadiazole derivatives 3.
With 1,3-bis-(diphenylphosphino)propane; palladium dichloride; silver(l) oxide; In toluene; at 80℃; for 10h;
General procedure: To a 10-mL round-bottom flask PdCl2 (6.7 mg, 10 mol%), dppp (24.7mg, 20 mol%), Ag2O (208.6 mg, 0.9 mmol), and alpha,beta-ynoic acid 2(0.45 mmol) and toluene (3 mL) were added under air. To this mixture 1,3,4-oxadiazole 1 (0.5 mmol) was added and the entire mixture was refluxed at 80 C for 10 h (TLC monitoring). After completion of the reaction, the mixture was allowed to cool, quenched by the addition of H2O, and subsequently extracted with EtOAc (2 × 10 mL). The combined organic extracts were dried (anhyd Na2SO4). Concentration of the organic layer in vacuo followed by column chromatography (silica gel) afforded oxadiazole derivatives 3.
With 1,3-bis-(diphenylphosphino)propane; palladium dichloride; silver(l) oxide; In toluene; at 80℃; for 10h;
General procedure: To a 10-mL round-bottom flask PdCl2 (6.7 mg, 10 mol%), dppp (24.7mg, 20 mol%), Ag2O (208.6 mg, 0.9 mmol), and alpha,beta-ynoic acid 2(0.45 mmol) and toluene (3 mL) were added under air. To this mixture 1,3,4-oxadiazole 1 (0.5 mmol) was added and the entire mixture was refluxed at 80 C for 10 h (TLC monitoring). After completion of the reaction, the mixture was allowed to cool, quenched by the addition of H2O, and subsequently extracted with EtOAc (2 × 10 mL). The combined organic extracts were dried (anhyd Na2SO4). Concentration of the organic layer in vacuo followed by column chromatography (silica gel) afforded oxadiazole derivatives 3.
With 1,3-bis-(diphenylphosphino)propane; palladium dichloride; silver(l) oxide; In toluene; at 80℃; for 10h;
General procedure: To a 10-mL round-bottom flask PdCl2 (6.7 mg, 10 mol%), dppp (24.7mg, 20 mol%), Ag2O (208.6 mg, 0.9 mmol), and alpha,beta-ynoic acid 2(0.45 mmol) and toluene (3 mL) were added under air. To this mixture 1,3,4-oxadiazole 1 (0.5 mmol) was added and the entire mixture was refluxed at 80 C for 10 h (TLC monitoring). After completion of the reaction, the mixture was allowed to cool, quenched by the addition of H2O, and subsequently extracted with EtOAc (2 × 10 mL). The combined organic extracts were dried (anhyd Na2SO4). Concentration of the organic layer in vacuo followed by column chromatography (silica gel) afforded oxadiazole derivatives 3.
With 1,10-Phenanthroline; palladium(II) trifluoroacetate; silver trifluoroacetate; In toluene; at 120℃; for 24h;Inert atmosphere;
General procedure: A 10 mL round-bottomed flask was charged with the appropriate1,3,4-oxadiazole 1 (0.5 mmol), styrene 2 (1.5 mmol),Pd(TFA)2 (10 mol%), 1,10-phen (10 mol%), AgTFA (2.0 equiv),and toluene (3 mL), and the mixture was stirred at 120 C underN2 for 24 h until the starting materials were consumed (TLC).The mixture was then allowed to cool and extracted with EtOAc(2 × 10 mL). The organic extracts were combined, dried (Na2SO4),filtered, and concentrated in vacuo. The residue was purified byflash chromatography (silica gel, 60 × 120 mesh, EtOAc-hexane10:90).
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