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CAS No. : | 3424-93-9 | MDL No. : | MFCD00007995 |
Formula : | C8H9NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GUCPYIYFQVTFSI-UHFFFAOYSA-N |
M.W : | 151.16 | Pubchem ID : | 76959 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 41.03 |
TPSA : | 52.32 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.61 cm/s |
Log Po/w (iLOGP) : | 1.34 |
Log Po/w (XLOGP3) : | 0.86 |
Log Po/w (WLOGP) : | 0.79 |
Log Po/w (MLOGP) : | 0.91 |
Log Po/w (SILICOS-IT) : | 0.97 |
Consensus Log Po/w : | 0.97 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.59 |
Solubility : | 3.88 mg/ml ; 0.0257 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.54 |
Solubility : | 4.34 mg/ml ; 0.0287 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.1 |
Solubility : | 1.21 mg/ml ; 0.008 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With silica gel; hydrazine In neat (no solvent) at 130℃; for 20 h; Inert atmosphere; Sealed tube | General procedure: These compounds were prepared using the standard procedure at 130°C for 20–24h. For each reaction, the crude product was adsorbed onto silica gel and purified on a 15cm×2.5cm silica gel column eluted with 80percent EtOAc in hexanes. The isolated yields are given in Table 7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.2% | With thionyl chloride; carbonic acid dimethyl ester at 80℃; for 7h; | 1.3; 2.;3 3.3 3) In a 500ml reactor, add 77.2g of p-methoxybenzamide and 231ml of dimethyl carbonate, raise the temperature to 80°C, add 88.8g of thionyl chloride dropwise within 1 hour, and then react at 80°C. After 6 hours, after the completion of the reaction, dimethyl carbonate and thionyl chloride were recovered by vacuum distillation to obtain 67.6 g of white solid anisonitrile with a melting point of 58°C. The purity was 99.8% by liquid phase detection, and the yield was 99.2%. . Based on p-hydroxybenzoic acid, the total yield was 98.1%. |
97% | With trichloromethyl chloroformate In various solvent(s) 0-5 deg C then heated to 60 deg C, 5 min; | |
97% | With ((1,3,5-triazine-2,4,6-triyl)tris(oxy))tris(triphenylphosphonium) chloride at 140 - 150℃; for 2h; |
97% | With 2-methoxyacetonitrile; potassium peroxymonosulfate; TPGS-750-M; palladium diacetate In tetrahydrofuran; water monomer at 45℃; for 3h; Sealed tube; | |
96% | With 1-(4-methoxyphenyl)-1-cyclopropanecarboxylic acid; palladium diacetate; acetonitrile at 20℃; for 18h; | |
95% | With N-succinimide chlorotriphenylphosphonium salt for 0.0833333h; microwave irradiation; | |
95% | With Ph3PCl(1+)*succinimide(1-) for 0.0833333h; microwave-irradiation; | |
95% | With N-methyl-N-trimethylsilyl-2,2,2-trifluoroacetamide; Zinc di(trifluoromethanesulphonate) In tetrahydrofuran at 70℃; for 24h; chemoselective reaction; | |
95% | With 2',4',5',7'-tetrabromofluorescein; carbon tetrabromide; N,N-dimethyl-formamide In acetonitrile at 25℃; for 14h; Irradiation; Inert atmosphere; | |
95% | With oxalyl dichloride; triethylamine In dimethyl sulfoxide; acetonitrile at 20℃; for 0.666667h; | |
94% | With ethyl phosphodichloridite; 1,8-diazabicyclo[5.4.0]undec-7-ene In dichloromethane at 20℃; for 3h; | |
94% | With ferrous(II) chloride tetrahydrate; N-methyl-N-trimethylsilyl-2,2,2-trifluoroacetamide In tetrahydrofuran at 70℃; for 2h; | |
94% | With oxalyl dichloride; Bis-<(p-methoxy)phenyl>cyclopropenon; 1,8-diazabicyclo[5.4.0]undec-7-ene In dichloromethane for 4.5h; Reflux; | |
93% | With N-chloro-succinimide; triphenylphosphine In tetrahydrofuran for 4h; Heating; | |
93% | With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78 - 20℃; | |
93% | With oxalyl dichloride; triethylamine; Triphenylphosphine oxide In acetonitrile at 20℃; for 0.166667h; | |
92% | With dioxouranium(VI) nitrate hexahydrate; N-methyl-N-trimethylsilyl-2,2,2-trifluoroacetamide In 1,2-dimethoxyethane at 100℃; for 24h; | |
91% | With per-rhenic acid In water monomer; 1,3,5-trimethyl-benzene for 24h; Heating; | |
91% | With per-rhenic acid In water monomer; 1,3,5-trimethyl-benzene for 24h; Heating; | |
91% | With diethyl chlorophosphate at 120℃; for 0.0833333h; Neat (no solvent); | |
91% | With Triethoxysilane; [cis-Fe(H)(SPh)(PMe3)4] In tetrahydrofuran at 60℃; for 24h; Inert atmosphere; | 2.2. General procedure for the dehydration of amides to nitriles General procedure: To a 25ml Schlenk tube containing a solution of 1 in 2ml of THF was added amide (1.0 mmol) and (EtO)3SiH (0.50 g, 3.0 mmol). The reaction mixture was stirred at 60 °C until there was no amide left (monitored by TLC and GC-MS). The product was purified according to literature procedures by Beller [27]. |
91% | With triethyl borane; phenylsilane; anhydrous potassium acetate In tetrahydrofuran; tert-butyl methyl ether at 20℃; for 48h; Inert atmosphere; Schlenk technique; Sealed tube; chemoselective reaction; | |
91% | With triethyl borane; phenylsilane; anhydrous potassium acetate In tetrahydrofuran; tert-butyl methyl ether at 20℃; for 48h; Inert atmosphere; Schlenk technique; Glovebox; Sealed tube; | |
90% | With trimethylsilyl methanesulfonate; diphosphorus pentoxide at 70 - 75℃; for 3h; further reagents; | |
90% | With (μ3,η2,η3,η5-acenaphthylene)Ru3(CO)7; 1,1,4,4-tetramethyldisilylethylene In 1,2-dimethoxyethane at 70℃; for 18h; Inert atmosphere; | |
90% | With Triethoxysilane; C43H50FeP4Si; anhydrous zinc bromide In tetrahydrofuran at 40℃; for 30h; Schlenk technique; | |
90% | With lead (II) acetate In dichloromethane for 12h; Reflux; | |
88% | With N,N-dimethyl-formamide; trichlorophosphate at 0 - 5℃; for 2h; | |
87% | With phenylsilane; N,N,N-tributylbutan-1-aminium fluoride In tetrahydrofuran; toluene at 100℃; for 0.5h; Inert atmosphere; | |
87% | With C20H25Cl2CoN3; sodium triethylborohydride In toluene at 60℃; for 18h; Inert atmosphere; | 9 Example 9: Dehydration of p-methoxybenzamide to p-methoxybenzonitrile: Under an inert atmosphere, add the substrate p-methoxybenzamide (133mg, 1mmol), polymethylhydrosiloxane (1.1g, 5mmol), and Co-2 catalyst (4.4mg, 0.01mmol) into the reaction tube. , Sodium triethylborohydride (73.2mg, 0.06mmol) and toluene (2mL),And stir the resulting mixture to homogeneity. Reaction at 60 for 18h in oil bath,The reaction system was cooled to room temperature, diluted and quenched with ethyl acetate, concentrated,The crude product was subjected to flash silica gel column chromatography to obtain the final product as 116 mg of white solid, with a yield of 87%. |
86% | With methyl dimethoxy silane; copper (II) acetate; 1,2-bis-(dicyclohexylphosphino)ethane In tetrahydrofuran at 20℃; for 12h; Sealed tube; | |
86% | With Triethoxysilane; [(2,5-F2C6H2-CH=N-C10H6)Co(III)(H)(PMe3)2] In tetrahydrofuran at 60℃; for 24h; Schlenk technique; | 2.2 General procedure for the dehydration of amides to nitriles General procedure: To a 25 mL Schlenk tube containing a solution of 2 in 2 mL of THF was added amide (1.0 mmol) and (EtO)3SiH (0.50 g, 3.0 mmol). The reaction mixture was stirred at 60 °C until there was no amide left (monitored by TLC and GC-MS). The product was purified according to literature procedures by Beller |
85% | With diphenylsilane; FeH(PMe<SUB>3</SUB>)<SUB>2</SUB>(SiPh(NCH<SUB>2</SUB>PPh<SUB>2</SUB>)<SUB>2</SUB>C<SUB>6</SUB>H<SUB>4</SUB>) In tetrahydrofuran at 70℃; for 24h; Schlenk technique; Inert atmosphere; | |
85% | Stage #1: 4-methoxyphenylacetamide With C39H45N2 In acetonitrile at 20℃; for 0.166667h; Schlenk technique; Glovebox; Inert atmosphere; Stage #2: With phenylsilane In acetonitrile at 20℃; for 16h; Schlenk technique; Inert atmosphere; Sealed tube; | |
84% | With Triethoxysilane; o-Ph<SUB>2</SUB>P(C<SUB>6</SUB>H<SUB>4</SUB>)Si(Me)<SUB>2</SUB>Fe(H)(PMe<SUB>3</SUB>)<SUB>3</SUB> In tetrahydrofuran at 60℃; for 24h; Schlenk technique; | |
83% | With di-2-pyridyl sulfite In toluene for 1h; Heating; | |
83% | With diethoxymethylane; [Et3NH][HFe3(CO)11] In toluene at 100℃; for 20h; Inert atmosphere; | |
83% | With N-methyl-N-trimethylsilyl-2,2,2-trifluoroacetamide; copper chloride (I) In toluene at 100℃; for 24h; | |
82% | With Pd3P0.95 In water monomer; acetonitrile at 20℃; for 4h; | |
81% | Stage #1: 4-methoxyphenylacetamide With N-methylbenzamide; phenylsilane; C28H18ClMnN2O2; potassium-t-butoxide In tetrahydrofuran at 50℃; Inert atmosphere; Glovebox; Sealed tube; Stage #2: With sodium hydroxide In tetrahydrofuran for 2h; Inert atmosphere; Glovebox; Sealed tube; Stage #3: Glovebox; Inert atmosphere; | |
77% | at 315℃; for 1h; | A Nitrile Product Preparation Example A General procedure: Following the amide intermediate Preparation Example A. The reaction vessel is closed (when the amide intermediate has a boiling point at normal pressure equal to or lower than the reaction temperature TB described below) or the reaction vessel is kept open (when the amide intermediate has a boiling point higher than the normal pressure When the reaction temperature is TB), the stirring is continued (600 r/min), the reaction temperature is changed to TB, and after the reaction temperature TB is maintained for TD hours, the reaction is almost complete. Then, the reaction vessel was sealed and connected to a vacuum pump so that the degree of vacuum in the reaction vessel reached 20-50 mbar (according to the type of nitrile product) and the distillate was used as the nitrile product. The yield of the nitrile product was calculated and sampled for nuclear magnetic proteomics and elemental analysis to characterize the nitrile product obtained. Specific reaction conditions and characterization results are shown in Tables A-7, A-8, A-9, A-10 and A-11 below. These characterization results show that the nitrile product obtained has an extremely high purity (above 99%).In these nitrile product preparation examples, 10 g of diphosphorus pentoxide was optionally added to the reaction vessel as a catalyst at the start of the reaction. |
72% | With C36H38Cl6N6Pd3S2 In water monomer; acetonitrile at 80℃; for 6h; | |
65% | With triethylamine; N-(difluoro-λ4-sulfanylidene)-N-ethylethanaminium tetrafluoroborate In ethyl acetate at 20℃; for 1h; Inert atmosphere; | Dehydration of Oximes and Amides to Nitriles; General Procedure General procedure: To a solution of the aldoxime or the amide (1.0 mmol) and Et3N (1.5mmol) in EtOAc (1 mL, 1 M) at r.t. was added XtalFluor-E8 (1.1 mmol)portionwise over ca. 2 min. The resulting solution was stirred at r.t.for 1 h. The reaction mixture was quenched with sat. aq Na2CO3 and extracted with CH2Cl2 (2 × 10 mL). The combined organic layers were washed with H2O and brine, dried (MgSO4), and concentrated under vacuum to afford the crude nitrile, which was purified by flash chromatography, if required. |
61% | With methylcerium dichloride at -78 - 0℃; for 1h; | |
60% | With anhydrous zinc chloride In water monomer; acetonitrile for 0.00833333h; microwave irradiation; | |
51% | With copper (I) iodide; formic acid; anhydrous sodium formate; palladium (II) chloride In water monomer; dimethyl sulfoxide at 100℃; for 36h; | |
With phosphorus(V) chloride at 250 - 255℃; | ||
With phosgene at 90℃; in neutralen Loesungsmitteln im Rohr; | ||
With monoethyl phosphate In chloroform at 80℃; Yield given; | ||
With oxalyl dichloride; dimethyl sulfoxide; triethylamine 1) CH2Cl2, -78 deg C, 15 min, 2) CH2Cl2, -78 deg C to RT; Yield given. Multistep reaction; | ||
97 % Spectr. | With bis(cyclopentadienyl)dimethylzirconium(IV); Hexamethylbenzene; lithium chloride In tetrahydrofuran-d8 for 15h; Heating; | |
With thiophosphorylated amine resin; 1-ethyl-3-methylimidazolium hexafluorophosphate In toluene at 200℃; for 0.25h; microwave irradiation; | ||
Multi-step reaction with 3 steps 1: 54 percent 2: xylene / Heating 3: xylene / Heating | ||
Multi-step reaction with 2 steps 1: Lawessons reagent / tetrahydrofuran / 20 °C / Reflux 2: [7-(dimethylamino)phenothiazin-3-ylidene]dimethylazanium chloride; 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 25 °C / Sealed tube; Irradiation | ||
With sieve-supported lead catalyst at 200℃; for 0.3h; | 19 General procedure: The height of the fixed-bed reactor is L=1500mm, the inner diameter D=100mm; 5000g of catalyst is set inside.The top of the fixed bed reactor is equipped with a pre-heater, and the set temperature of the pre-heater is 150°C,The reaction temperature (bed temperature) in the fixed bed reactor is 200After being heated at the top of the fixed bed reactor, benzamide enters the fixed bed reactor in a liquid form from the top of the fixed bed, and the pressure in the fixed bed reactor is 0.3 MPa.The bed temperature is 200°C, and the feed rate is controlled (about 4.7 g/min) to maintain the benzamide residence time at 0.3 h.(3) The reacted materials are drawn from the bottom of the fixed bed and analyzed by GC, the conversion rate of the raw materials is 97.1%, and the selectivity is 100%.The reacted materials are subjected to vacuum distillation, and the distillate is water and crude benzonitrile in sequence.The bottom liquid is unreacted benzamide, which can be recycled as a raw material into the fixed bed reactor. The purity of the crude benzonitrile was 97.0%. The crude benzonitrile product is further conventionally purified through rectification to obtain the benzonitrile product. The purity of the benzonitrile product is greater than 99.5%,The yield was 95.0%. | |
100 %Chromat. | With phenylsilane-d3; C36H48F6N6NiO5S2 In acetonitrile at 80℃; for 12h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: 4-methoxyphenylacetamide With bis(cyclopentadienyl)dihydrozirconium; 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane at 20℃; Glovebox; Inert atmosphere; Stage #2: With hydrogenchloride In diethyl ether; water for 2h; Glovebox; Inert atmosphere; | 2. Experimental General procedure: In a nitrogen-filled glovebox, to a 15 mL reaction tube equipped with a magnetic stirrer, were added Cp2ZrH2 (0.01mmol, 2.2 mg) as the catalyst, and the appropriate amide (0.2mmol); solvent was added when necessary. HBpin (3 equiv. peramide functional group) was then added, and the reaction tube was taken out from the glovebox and stirred at room temperature for 12-48 h. The resultant crude amines were either isolated using silica gel flash chromatography, or acidified by stirring with HCl in Et2O (2 mL, 1N) for 2 h, after which time precipitation was observed. Then, the reaction solution was transferred to a centrifuge tube and centrifuged three times. The supernatant was removed and the resulting solid was dried inan oven at 80 °C for several hours to obtain the HCl salt of the amine. |
80% | With titanium tetrachloride; magnesium In tetrahydrofuran at 0 - 20℃; Inert atmosphere; | |
60% | With 1,10-Phenanthroline; diethoxymethylane; iron(II) acetate In toluene at 100℃; for 28h; Inert atmosphere; chemoselective reaction; |
42% | With benzo[b]thiophene-2-boronic acid; phenylsilane In toluene at 130℃; for 24h; Inert atmosphere; Schlenk technique; chemoselective reaction; | |
33% | With borane-ammonia complex; boron trifluoride diethyl etherate; tris(pentafluorophenyl)borate In 1,2-dichloro-ethane at 60℃; for 24h; | |
With sulfuric acid at 35 - 40℃; bei elektrolytischen Reduktion an Bleikathode; | ||
Multi-step reaction with 2 steps 1: 1 h / 315 °C 2: hydrogen / ethanol / 1 h / 110 °C / 60006 Torr | ||
With 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane In neat (no solvent) at 120℃; for 24h; Inert atmosphere; Sealed tube; chemoselective reaction; | General procedure for hydroboration of primary amides General procedure: Benzamide (0.0606 g, 0.5 mmol) was placed in a culture tube (11 mL) at 25 °C, sealed with septum, the air in culture tube was replaced with argon gas (Tables 1 and 2). After adding pinacolborane (0.36 ml, 2.5 mmol 5 equiv), the screw cap was closed, stirred at 120 °C for 24 h. After this time, it was cooled to room temperature, excess HBpin was quenched by adding water (0.5 ml). The mixture was diluted with ethyl acetate (5 ml), 1 M HCl in ether (2 ml) and stir for 1 h. The generated amine salt was filtered using ethyl acetate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With ammonia; In water; at 20℃; for 1h; | Into a 100-mL round-bottom flask, was placed concentrated ammonia in water (30 mL). This was followed by the addition of 4-methoxybenzoyl chloride (3 g, 17.59 mmol, 1.00 equiv) dropwise with stirring. The resulting solution was stirred for 1 h at room temperature. The solids were collected by filtration. This resulted in 2.1 g (79%) of 4-methoxybenzamide as a white solid. |
50% | With ammonia; In 1,4-dioxane; at 20℃; for 12h; | To a solution of 4-methoxybenzoyl chloride (0.5 g,2.93 mmol) in 1,4-dioxane (5 mL) wasadded ammonia in 1,4-Dioxane (3 mL) at room temperature.The reaction mixturewas stirred for 12 h at room temperature. The reaction mixture wasconcentrated, and the crude residue was purified by Combiflash purifier using 7%EtOAc in n-Hexane to afford the title compound as off-white crystalline solid(0.22 g, 50 %). 1H NMR (DMSO-d6,400 MHz) delta 3.78 ( s, 3H), 6.95 (d, J = 8.8 Hz, 2H), 7.11 (bs, 1H),7.77(bs, 1H), 7.82 (d, J = 8.8 Hz,2H); MS (ESI) m/z 152.1 (M+H)+;HPLC Purity 254 nm, 99.95%. |
With ammonia; In tetrahydrofuran; water; at 0℃; | To a stirred solution of 4-methoxybenzoyl-chloride (1.0 g, 0.8 mL, 5.862 mmol, Sigma-Aldrich A8,847-6) in THF (10 mL), 25 % aqueous ammonia solution (25 mL) was added dropwise at 0 C, and then stirred for a further 30 min. The aqueous layer was separated and extracted with THF (20 ml) and EtOAc (2 × 20 mL). The combined organic layer was dried (Na2SO4), and then concentrated under reduced pressure. Mp: 166-168 C (reference: 164-167 C, Catalog of Sigma Aldrich 2009-2010 pp. 1785.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With C18H57O3P6Ru2(1+)*C6H5O(1-)*C6H6O; water; In 1,4-dioxane; for 6h;Sealed tube; Inert atmosphere; Schlenk technique; | General procedure: Complex 3 (18.3 mg, 0.0204 mmol), 1,4-dioxane (1.0 ml),benzonitrile (103.7 mg, 1.18 mmol), water (100 mul, 5.53 mmol)were added in a screw-cap tube. The reaction mixture was heatedat 100 C for 12 h. After cooling the reaction mixture to room temperature,dibenzyl and methanol (1 ml) were added to give ahomogeneous solution and the products were analyzed by GLC. |
99% | With C12H24O16Ru3*2H2O; In water; at 110℃; for 13h;Schlenk technique; Inert atmosphere;Catalytic behavior; | General procedure: Hydration reactions were carried out in Schlenk tube under N2atmosphere. The reaction mixture was prepared dissolving 5 mg(6.5 lmol) of catalyst 2 in 3 mL of H2O. The mixture was degassedand 1.5 mmol of corresponding acetonitrile substrate was addedwith micropipette to stirred solution. The reaction was allowedfor heating at 110 C using oil bath or microwave-assisted heating.The isomerization reactions of allylic alcohols were conductedSchlenk tube under N2 atmosphere. The reaction mixture wasprepared dissolving 3 mg (3.9 lmol) of catalyst 2 in 2 mL ofappropriate solvent (DMF, EtOH or H2O). The mixture wasdegassed and 1 mmol of corresponding allylic alcohol substratewas added with micropipette to stirred solution. The reactionwas allowed for heating using oil bath.The reaction solutions were analyzed by regular sampling usingGC/FID (Hewlett Packard) equipped with Beta DEX 120(30 m 0.25 mm 0.25 lm) 30 m long column. The degrees ofconversion were calculated on the basis of the ratio of areas ofthe substrate material and the products determined from correspondingchromatograms. The optimization of chromatographicmethods and the calibration procedures for detection of productsas well as substrates were realized by injection of authenticcommercial samples. |
94% | With [{Au(IPr)}2(mu-OH)][BF4]; water; In tetrahydrofuran; at 140℃; under 5250.53 Torr; for 2h;Sealed tube; Microwave irradiation; | In a typical reaction, [Au(IPr)(NTf2)] (13 mg, 20 mumol, 2 mol %) or [{Au(IPr)}2(mu-OH)]BF4 (17 mg, 10 mumol, 1 mol %) was added to THF (0.5 mL) in a 2 mL microwave vial in air. Benzonitrile (103 mg, 1 mmol) was added, followed by distilled H2O (500 muL). The vial was sealed and heated in the microwave for 2 h at 140 C. (7 bar). The conversion was determined by gas chromatography |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With silver(I) trifluoromethoxide; In ethyl acetate; at 50℃; for 4h;Darkness; | General procedure: A mixture of bromo-ketone (0.6 g,2.9 mmol), amide (0.55 g, 3.6 mmol, 1.25 equiv), and silver triflate (0.9 g,3.6 mmol, 1.25 equiv) in ethyl acetate (4 mL) was heated to 50-70 C. After thereaction was deemed complete by HPLC analysis, the mixture was cooled to 20 C and diluted with ethyl acetate (3 mL). A solution of sat?d NaCl (3-4 mL)was added and the mixture stirred at 20 C for at least 4 h. The silver salts (AgBr and AgCl) are removed by filtration and the resulting biphasic solution transferred to a separatory funnel and the layers separated. The organic layer isthen washed with water (4 mL), 5% NaHCO3 (4 mL), 1 N HCl (4 mL), and water(4 mL). The organic layer is concentrated to dryness and the residue purified by flash column chromatography (5% EtOAc/hexanes) to obtain pure oxazole product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With tetraphosphorus decasulfide In 1,4-dioxane at 50 - 68℃; for 3h; | 1.S3; 2.S3; 3.S3 S3, Synthesis of 4-methoxybenzenecarbothioamide Add 9.5 g of 4-methoxybenzamide to 100 mL of 1,4-dioxane in a 200 mL reaction flask, heat to 50°C, add 4.2 g of phosphorus pentasulfide, and react at 68°C for 3 hours. TLC analysis the raw material reaction is complete, add 200mL water, stir for 1h, a solid precipitated, filtered, dissolved in 100 mL ethyl acetate, washed with brine, drying with anhydrous sodium sulfate, filtering and concentrating to obtain 11.6 g of 4-methoxybenzenecarbothioamide, the yield is calculated according to 100%, and proceed directly to the next step. |
88% | With pyridin-1-ium-1-yl[pyridin-1-ium-1-yl(sulfido)phosphinothioyl]sulfanyl-sulfido-thioxo-phosphane In acetonitrile for 0.5h; Reflux; | |
80% | With Lawessons reagent In tetrahydrofuran at 20℃; Reflux; |
68% | With tetraphosphorus decasulfide In dichloromethane for 2.5h; Inert atmosphere; Reflux; | |
67% | With P<SUB>2</SUB>S<SUB>5</SUB>/alumina In tetrahydrofuran at 60℃; for 0.333333h; Microwave irradiation; | |
30% | With Lawessons reagent In tetrahydrofuran at 20℃; for 12h; | |
With phosphorus pentoxide In benzene for 3h; Heating; | ||
With Lawessons reagent In benzene Heating; | ||
With tetraphosphorus decasulfide In diethyl ether at 0 - 20℃; | ||
Multi-step reaction with 2 steps 1: water / 90 °C / Green chemistry 2: water / 90 °C / Green chemistry | ||
With Lawessons reagent In tetrahydrofuran for 4h; Reflux; | General synthetic procedure forintermediates 13a-u General procedure: To a solution of benzamide 11a-u (1 equiv) in THF (30mL) was added Lawesson’s reagent (0.6 equiv), and the mixture was heated to reflux for 4 hrs. The reaction mixture was concentrated invacuo,then diluted with ethyl acetate (30 ml), and washed with 1N NaHCO3 (3× 20 mL) and brine (2 × 20 mL). The organic layer was dried over anhydrous sodium sulfate,filtered and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using a mixture of dichloromethane/methanol(100:1, v/v) as eluent to afford a yellow solid product.A solution of the obtained solid 12a-u (1 equiv) and ethyl 2-chloroacetoacetate (1.2 equiv) in ethanol (25 ml) was heated to reflux for 6 h, then the mixture was allowed to stand at 0 °C for 10 hrs, and a white needle crystal was precipitate out.The reaction mixture was filtered and the filter cake was washed with 10 mL of ethanol, dried in vacuum to give the desired product. | |
With tetraphosphorus decasulfide | General procedure for the preparation of compounds 3 General procedure: Benzamides 2 (6 mmol) was dissolved in dry THF (20 mL) andthereto was added P2S5 (6 mmol) and heated at 65 C for 3 h, afterwhich the reaction mixture was cooled, poured in NaHCO3 (10%,100 mL), stirred for half an hour, then the resulting solid wasfiltered, dried and recrystallized from ethyl acetate to get compounds3. | |
With Lawessons reagent In tetrahydrofuran for 4h; | 1 Ethyl 2-(4-methoxyphenyl)-4-methylthiazole-5-carboxylate(T2): Add 4-methoxybenzamide (152.2 mg, 1 mmol) to a 25 mL round bottom flask.Lawson's reagent (485.4 mg, 1.2 mmol) and THF (20 mL).The Lawson reagent and the solvent are removed after reacting for 4 hours under normal temperature conditions.The intermediate thiobenzamide is obtained by column chromatography and purification.Then, ethyl 3-bromo-2-oxobutanoate (209 mg, 1 mmol) was refluxed in ethanol (10 mL) as a solvent at 70 ° C for 4 h. After the reaction was completed, the solvent was removed.The compound T2 was obtained by separation and purification by column chromatography. Yield 92%,White solid, unrolled system PE/EA 10:1 (Rf=0.5, PE/EA=3:1) | |
With Lawessons reagent In toluene at 115℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With 1,3-diadamantane-4,5-dihydroimidazole chloride; potassium tert-butylate; bis(pinacol)diborane; copper(l) chloride; In toluene; at 25℃; for 4h;Schlenk technique; Inert atmosphere; | General procedure: To a 10 mL Schlenk tube, B2pin2 (2.0 mmol, 2.0 equiv) was added to a toluene (2.0 mL) solution of CuCl (0.1 mmol, 10 mol%), IAmd·HCl (0.1 mmol, 10 mol%) andKOtBu (1.0 mmol, 1.0 equiv) at 25 C under argon atmosphere. The reaction mixturewas stirred at 25 C for 30 min. Then azide (1.0 mmol, 1.0 equiv) was added andevolution of gas was observed immediately. The resulting mixture was stirred for acertain time at 25 C until disappearance of the starting azide monitored by TLC. Thereaction was quenched by adding 25 mL H2O and 1M HCl aqueous solution to adjustPH = 4, and then the aqueous phase was basified to PH = 8 with Na2CO3. Theaqueous phase was extracted with ethyl acetate (30 mL×2). The organic phase wascombined and dried with Na2SO4 and evaporated to dryness to afford the amine whichwas in a few cases finally purified by silica column chromatography (DCM/MeOH).Analogous results were obtained by dissolving the azide into the toluene solution ofCuCl, IAmd·HCl and KOtBu, followed by adding B2pin2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With hydroxylamine; C33H28F3N5O3Ru(1+)*Cl(1-) In water at 60℃; for 0.5h; Sonication; | A typical procedure for the one-pot conversion of aldehydes to amides General procedure: A mixture of aldehyde (1.0 mmol) and hydroxylamine (1.0 mmol) in water (5.0mL) was prepared. The ensuing mixture and 0.1 mol% of Ru-complexes (5 or 9) were taken in a reaction vessel and sonicated at 60 oC for the appropriate time. Theprogress of the reaction was monitored by TLC analysis. After completion of thereaction, the reaction was cooled to room temperature and the solvent wasevaporated. The residue was suspended in ethyl acetate, filtered to remove thecatalyst and the solvent evaporated to obtain the desired product. The identity ofthe obtained amides was assessed by comparison of their NMR spectroscopic datawith those reported in the literature. |
97% | Stage #1: 4-methoxy-benzaldehyde With hydroxylamine hydrochloride; caesium carbonate In water; dimethyl sulfoxide at 100℃; Stage #2: With palladium diacetate In water; dimethyl sulfoxide at 125℃; chemoselective reaction; | |
97% | With copper(ll) sulfate pentahydrate; hydroxylamine hydrochloride; sodium acetate at 110℃; for 2h; Neat (no solvent); | Typical procedure for synthesis of primary amide 1a from aldehyde 1: General procedure: To an intimate mixture of neat piperonal 1 (150 mg, 1 mmol), NH2OH.HCl (69 mg, 1 mmol) and NaOAc (90 mg, 1.1 mmol) taken in a dried round bottomed flask was added CuSO4.5H2O (13 mg, 5 mol %) and the mixture was heated at 110 °C on an oil bath with thorough stirring for 2 h (TLC monitoring). After cooling the reaction mixture, water (2 mL) was added to it to quench the reaction followed by extraction with EtOAc (3 × 6 mL). The combined extract was washed with brine (2 × 3 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude product so obtained was filtered through a short pad of silica gel (60-120 mesh, Spectrochem, India) using EtOAc-n-hexane (1:1) as eluent to afford 3,4-methylenedioxybenzamide 1a as a white crystalline solid (161 mg, 98%), mp 166-168 °C (lit 169 °C).10 |
97% | With hydroxylamine hydrochloride; caesium carbonate In water at 100℃; Green chemistry; | |
96% | With C49H54Cl2N2O6Rh2; hydroxylamine hydrochloride; sodium hydrogencarbonate In toluene at 110℃; for 12h; Inert atmosphere; Schlenk technique; | General procedure for the catalytic transformation of aldehydes to amides General procedure: The complexes (1-3) (0.002mmol), the aldehyde (1mmol), NH2OH·HCl (1mmol) and NaHCO3 (1mmol) were introduced in a dried schlenk tube and purged with N2. Then, to the mixture, dried and degassed toluene (2mL) was added, and the solution was refluxed for 12h. The mixture was cooled to room temperature and the products were extracted with methanol and dichloromethane before being filtered through Celite to remove the remaining complex. The amide was purified using column chromatography, and dried under vacuum. Characterization details for each amide are given in the Supporting information. |
95% | Stage #1: 4-methoxy-benzaldehyde With ammonia; iodine In tetrahydrofuran; water at 20℃; for 1h; Stage #2: With dihydrogen peroxide In tetrahydrofuran; water at 20℃; for 4h; Further stages.; | |
93% | With 1-n-butyl-3-methylimidazolium azide; sulfuric acid; acetic acid at 58℃; | |
92% | With hydroxylamine hydrochloride In acetonitrile for 0.0611111h; Microwave irradiation; | |
92% | With hydroxylamine hydrochloride; sodium carbonate In water at 80℃; for 48h; | |
91% | With tert.-butylhydroperoxide; ammonium hydroxide In water at 80℃; for 12h; | |
91% | With hydroxylamine hydrochloride; sodium carbonate In water at 80℃; for 24h; Green chemistry; | |
91% | With tert.-butylhydroperoxide; titanium superoxide; saccharin In 1,4-dioxane; hexane at 90℃; for 1h; Green chemistry; | |
91% | With hydroxylamine hydrochloride; potassium carbonate In water at 80℃; for 20h; Schlenk technique; | 2.5. General procedure for the synthesis of amide bond General procedure: The mixture of benzaldehyde (1 mmol), NH2OHHCl (1.2 mmol),K2CO3 (1.1 mmol), DI-H2O (2 mL) were added to 10 mol % ofCuONRs/g-C3N4-NS catalyst in a Schlenk tube. Then, the reactionmixture was stirred at 80 C for 20 h. After completing the reaction,the catalyst was separated by centrifugation and organic phasepurified by column chromatography on silica to obtain the amideproduct 3. Finally, all primary amides were identified by 1H and13C NMR spectroscopy |
90% | Stage #1: 4-methoxy-benzaldehyde With hydroxylamine hydrochloride In dimethyl sulfoxide at 100℃; Stage #2: With water; dihydrogen peroxide; sodium hydroxide In dimethyl sulfoxide | |
90% | With hydroxylamine hydrochloride at 120℃; for 5h; neat (no solvent); | |
90% | With hydroxylamine hydrochloride In water at 120℃; for 7h; Reflux; | |
90% | With triacetonitrile 4′-(4-chlorophenyl)-2,2′:6′,2″-terpyridine ruthenium(II) nitrate; hydroxylamine hydrochloride; sodium acetate In water at 100℃; for 12h; Inert atmosphere; | |
89% | With hydroxylamine hydrochloride; sodium carbonate; scandium tris(trifluoromethanesulfonate) In water at 135℃; for 0.25h; Microwave irradiation; Sealed vial; | General MW procedure: A mixture of Sc(OTf)3 (10 mol %, 49 mg), aldehyde (1 mmol), NH2OH·HCl (1 mmol, 69 mg) and Na2CO3 (1 mmol) was placed in a safe pressure regulation 10 mL pressurized vial containing H2O (1 mL). The vial was sealed with a ‘snap-on’ cap and irradiated in a single-mode CEM Discover Bench Mate microwave reactor at 300 W and 135 °C for 15-35 min. After the reaction was complete (periodic TLC monitoring), the mixture was allowed to cool to room temperature and was extracted with EtOAc (3 × 10 mL). The combined organic phase was dried over Na2SO4, filtered and the solvent was removed under vacuum. The leftover residue was purified by column chromatography on silica gel (EtOAc/hexane 3:7 as eluent) and then characterized based on their physical and spectral data. |
89% | With choline chloride * 2ZnCl2; hydroxylamine hydrochloride at 100℃; for 17h; Green chemistry; | |
89% | With hydroxylamine hydrochloride; C21H27ClIrNO; sodium hydrogencarbonate In water at 50℃; for 6h; | |
88% | With iron(III) chloride; hydroxylamine hydrochloride; caesium carbonate In water at 100℃; for 22h; chemoselective reaction; | |
88% | With hydroxylamine hydrochloride; C27H27ClIrNO; sodium hydrogencarbonate In dimethyl sulfoxide at 50℃; for 6h; | |
87% | With alumina sulfuric acid; hydroxylamine hydrochloride at 150℃; for 3h; | |
87% | With C31H28ClNORu; hydroxylamine hydrochloride; sodium hydrogencarbonate In toluene for 18h; Inert atmosphere; Reflux; | 4.5. General procedure for the conversion of aldehyde to amide General procedure: Under a nitrogen atmosphere, the reaction vessel was chargedwith aldehyde (1 mmol), NaHCO3 (1 mmol), NH2OH.HCl (1 mmol)and ruthenium catalyst (0.01 mmol) and the mixture was refluxedin toluene for 18 h. The reaction mixture was cooled to roomtemperature. On completion of the reaction, 2mL of methanol wasadded to the mixture, followed by filtration through celite toremove the NaHCO3 and ruthenium catalyst. The crude product was then purified by column chromatography (CH2Cl2/MeOH, 1:1 ratio) over silica gel using as solid phase, providing the amide in good yield. The identity of the resulting amides was assessed by comparison of their 1H NMR spectroscopic data with those reported in the literature [52]. |
86% | With [Ru(L1)Cl(CO)(PPh3)2]; hydroxylamine hydrochloride; sodium hydrogencarbonate In toluene for 12h; Inert atmosphere; Reflux; | 2.4 Representative procedure for the rearrangement of aldehydes to amides General procedure: Conversion of aldehydes to amides was carried out using the procedure described in the literature [34]. Under nitrogen atmosphere, the corresponding aldehyde (1mmol), NH2OH·HCl (1mmol), NaHCO3 (1mmol), toluene (3mL) and ruthenium(II) catalyst 1 (0.01mmol) were introduced into a RB flask, and the reaction mixture was stirred at 120°C in an oil bath for 12h. After the completion of reaction, 2-3mL of MeOH was added to the reaction mixture. The catalyst and NaHCO3 which settled down the flask was removed by filtration through Celite. The filtrate has been dried and the crude product was purified by the use of column chromatography (MeOH/CH2Cl2). Finally, the isolated amide was characterized by the aid of 1H NMR. |
85% | With hydroxylamine hydrochloride; potassium carbonate In dimethyl sulfoxide at 120℃; for 48h; Green chemistry; | 4.4. General procedure for synthesis of primary amides from aldehyde General procedure: In a typical method, benzaldehyde (1.0 mmol), hydroxylaminehydrochloride (1.5 mmol), potassium carbonate (2.5 mmol) and0.5 mL of as-prepared SEF127-Pd(nanoparticle)/GO in DMSO were added to reaction media in the presence of 1.5 mL DMSO. The reac-tion was allowed to stir at 120C. Upon reaction completion, thecatalyst was separated by centrifuge and the organic residue was extracted with dichloromethane and evaporated under reducedpressure. The organic residue was purified by column chromatography. All yields were reported based on isolated amount. All productsare known and identified by 1H-NMR,13C-NMR spectrum and physical properties. |
84% | With 3C2H3O2(1-)*Cu(2+)*C8H15N2(1+); hydroxylamine hydrochloride; sodium carbonate In water at 109.84℃; for 48h; Autoclave; | |
84% | With hydroxylamine hydrochloride; C59H50ClN2OP2Ru; sodium hydrogencarbonate In acetonitrile for 5h; Inert atmosphere; Reflux; | 2.4. General procedure for the conversion of aldehyde to amide General procedure: The reaction vessel was equipped with magnetic stirring bar, complex catalyst(1 mol%), aldehyde (1 mmol), NH2OHHCl(1 mmol) and NaHCO3 (1 mmol) was taken and the mixture was placed under an atmosphere of N2. Dry and degassed acetonitrile(3 mL) was added and the reaction mixture was refluxed for 5 h.The reaction mixture was then cooled to room temperature and the solvent was evaporated. The residue was dissolved in CH2Cl2,filtered and the solvent was removed. The amide was then purified using column chromatography, which gives the amide in high isolated yield. The products were confirmed by1H NMR spectra. |
83% | Stage #1: 4-methoxy-benzaldehyde With 9-aminofluorene In toluene at 20℃; for 0.5h; Stage #2: With oxygen; triethylamine In toluene for 1.5h; Reflux; | |
79% | With hydroxylamine hydrochloride; caesium carbonate In water; dimethyl sulfoxide at 125℃; for 48h; | General procedure for conversion of aldehydes to primary amides General procedure: Aldehyde (0.5mmol), NH2OH·HCl (0.6mmol) and Cs2CO3 (0.6mmol) were stirred at 125°C for 48h in a 3:1 mixture of DMSO-H2O (2mL) under air. The progress of the reaction was monitored by TLC using ethyl acetate and hexane as eluent. After completion, the reaction mixture was cooled to room temperature and treated with water (1mL). The resulting mixture was extracted with ethyl acetate (3×5mL). Drying (Na2SO4) and evaporation of the solvent gave a residue that was purified on silica gel column chromatography using ethyl acetate and hexane. The purified products were identified by 1H NMR spectra and the melting points comparison with the literature data. |
79% | With hydroxylamine hydrochloride; caesium carbonate In tetrahydrofuran; water at 0 - 250℃; for 0.0833333h; | |
78% | With hydroxylamine; copper diacetate In water at 110℃; for 48h; | 4.2. General procedure for the synthesis of amides General procedure: To a solution of copper(II) acetate (0.04 mmol) in water (1 mL) were added the corresponding aldehyde (3, 2 mmol) and the hydroxylamine (4, 2 mmol). After 2 days stirring at 110 °C the mixture was quenched with a saturated solution of ammonium chloride (10 mL), or added ether (2 mL) for the recycling process. The mixture was extracted with AcOEt (3×10 mL) and washed with brine (10 mL), after drying with anhydrous MgSO4, the organic layer was filtered on Celite and the solvents were removed under low pressure (15-18 Torr). The product was purified recrystallization from chloroform/hexane mixtures to give the corresponding product 2. Amides 2a,262b,272c, 272d,172e,282f,292g,272h,172j,302k,172l30 and 2m17 are commercially available and were characterized by comparison of their physical and spectroscopic data with those of pure examples. Yields are included in Table 4 (Fig. 1 for recycling processes). Physical and spectroscopic data, as well as literature data for known compounds, follow. |
76% | With hydroxylamine In water at 110℃; for 12h; | 2.4. General procedure for the synthesis of amides from aldehydes General procedure: Aldehyde (1 mmol), hydroxylamine (1 mmol), polymer supported-Cu (II) catalyst (30 mg-10 mg) and solvent (2 m/L) were added in a 10 mL round bottom flask and the reaction mixture was stirred at 110 °C. The progress of the reaction was by TLC. The crude product obtained was purified by column chromatography with ethyl acetate:hexane as 1:5 eluent system. |
76% | With hydroxylamine In water at 110℃; for 12h; | 2.4. General procedure for the synthesis of amides from aldehydes General procedure: Aldehyde (1 mmol), hydroxyl amine (1 mmol), polymer supported-Cu (II) catalyst (30 mg-10 mg) and solvent (2 m/L) were added in a 10 mL round bottom flask and the reaction mixture was stirred at110 °C. The progress of the reaction was by TLC. The crude product obtained was purified by column chromatography with ethyl acetate:hexane as 1:5 eluent system. |
76% | With C29H29ClN2ORu; hydroxylamine hydrochloride; sodium hydrogencarbonate In acetonitrile at 78℃; for 5h; Inert atmosphere; | 4.3. Typical procedure for the one-pot conversion of aldehydes toamides General procedure: To an oven-dried round-bottom flask equipped with magneticstirring bar was added complex (1) (1 mol%), the aldehyde(1 mmol), NH2OHHCl (1 mmol) and NaHCO3 (1 mmol) and themixture was placed under an atmosphere of N2. Dry and degassedMeCN (2 mL) was added and the reaction mixture was refluxed forthe time specified under an N2 atmosphere. The reaction wascooled to room temperature and the solvent evaporated. The residuewas dissolved in CH2Cl2, filtered and the solvent removed. Thecrude product was then purified using silica gel chromatography(CHCl3/MeOH) giving the amides in high isolated yields. Characterizationdetails for each amide are given in the supporting informationS16-S20. |
76% | With nitromethane; trifluoromethylsulfonic anhydride; acetic acid In formic acid at 80 - 120℃; | 52 Example 52 p-Methoxybenzamide Take a reaction tube, add 60-100mg (1.2mmol) of nitromethane, 30-50mg (0.3mmol) of p-methoxybenzaldehyde, 0.5mL of acetic acid,Trifluoromethanesulfonic anhydride 150-200mg (0.6mmol),Formic acid 30-60mg (0.75mmol),Stir at 80-120°C for 1-72 hours. After the reaction was completed, 10 mL of sodium hydroxide solution was added to quench the reaction, extracted with ethyl acetate 3 times, the organic phase was washed with 5 mL of brine, and the organic phases were combined and separated by column chromatography to obtain 34.5 mg of p-methoxybenzamide, with a yield of 76 %. |
76% | With formic acid; nitromethane; trifluoromethylsulfonic anhydride In acetic acid at 100℃; for 12h; | |
75% | With C29H23ClN3O2PRuS; hydroxylamine hydrochloride; sodium hydrogencarbonate In toluene at 20℃; for 12.25h; Inert atmosphere; Reflux; | |
75% | With tert.-butylhydroperoxide; sodium carbonate; ammonium chloride In acetonitrile at 50℃; for 0.666667h; Inert atmosphere; Green chemistry; | |
75% | Stage #1: 4-methoxy-benzaldehyde With hydroxylamine hydrochloride; sodium hydrogencarbonate In water Stage #2: In water at 100℃; for 10h; | |
74% | With hydroxylamine hydrochloride; C30H30ClNO2Ru; sodium hydrogencarbonate In acetonitrile for 7h; Reflux; Inert atmosphere; | 4.3. Typical procedure for the one-pot conversion of aldehydes toamides General procedure: The reaction mixture containing complex catalyst 2 (1 mol%),the aldehyde (1 mmol), NH2OHHCl (1 mmol) and NaHCO3(1 mmol) in 5 mL of acetonitrile was refluxed for the time specifiedunder an N2 atmosphere. Then, the resulting was cooled to roomtemperature and the solvent was evaporated. The residue obtainedwas dissolved in CH2Cl2 and the solvent was removed. The crudeproduct was then purified using silica gel chromatography usingCHCl3/MeOH as an eluent. |
73% | With C21H22N2O5RuS2; hydroxylamine hydrochloride; sodium hydrogencarbonate In toluene for 18h; Inert atmosphere; Reflux; | Catalytic conversion of aldehydes to amides General procedure: Catalytic conversion of aldehydes into their correspondingamides were carried out using ruthenium(II) complexes as catalystin the following general procedure. The reaction vessel wascharged with aldehyde (2 mmol), NH2OH.HCl (2 mmol), NaHCO3(2 mmol) and ruthenium catalyst (0.01 mmol) and the mixturewas placed under an atmosphere of nitrogen. About 4 ml of dryand degassed toluene was added and the mixture was stirred for15 min at room temperature followed by reflux for 18 h. On completionof the reaction, 2-3 ml methanol was added to the mixturefollowed by filtration through Celite to remove the catalyst andNaHCO3. The crude product was then purified by column chromatography(MeOH/CH2Cl2) and the formation of pure amide wasconfirmed using 1H NMR spectral analyses. The catalytic efficiencyin various solvents was also studied. |
72% | With tert.-butylhydroperoxide; tetraethylammonium iodide; ammonium bicarbonate In 1,2-dichloro-ethane at 70℃; for 22h; | |
68% | With tert.-butylhydroperoxide; copper nanoparticles on black carbon; sodium carbonate; ammonium chloride In acetonitrile at 60℃; for 6h; Inert atmosphere; | General procedure for the synthesis of compounds (2a-v) General procedure: To a mixture of catalyst (20 mg, 3.68 mol %), amine hydrochloride salt (2 mmol) and Na2CO3 (212 mg, 2 mmol) in acetonitrile (1 mL) was added aldehyde (1 mmol) and TBHP (1.5 equiv) under an argon atmosphere at room temperature. The reaction vessel was capped and stirred at 60 °C for 6 h. The progress of the reaction was monitored by thin-layer chromatography. After completion, the reaction mixture was allowed to cool to room temperature, then diluted with ethyl acetate and the catalyst separated from the reaction mixture by filtration. The combined organic layers were concentrated under vacuum and the resulting residue was purified by column chromatography. |
65% | With tert.-butylhydroperoxide; sodium carbonate; ammonium chloride In acetonitrile at 20 - 60℃; for 6h; Inert atmosphere; Green chemistry; | |
60% | With copper(I) oxide; potassium carbonate; ammonium chloride In water; acetonitrile at 80℃; for 4h; Inert atmosphere; | |
60% | With trimethylsilylazide; tetrabutylammomium bromide; iron(II) bromide In neat (no solvent) at 40℃; for 6h; Irradiation; | |
44% | With pylyphosphoric acid; hydroxylamine hydrochloride at 110 - 135℃; for 1.25h; | |
138 mg | With hydroxylamine hydrochloride In toluene at 111℃; for 16h; | |
Multi-step reaction with 2 steps 1: 27 percent / pyridine; hydroxylamine hydrochloride / methanol / 24 h / 20 °C 2: 93 percent / aq. p-toluenesulfonic acid; dppe / carbonyl(dihydro)tris(triphenylphosphine)ruthenium(II) / toluene / Heating | ||
97 %Chromat. | With ammonia; water; oxygen In 1,4-dioxane at 130℃; for 3h; Autoclave; | |
Multi-step reaction with 2 steps 1: hydroxylamine hydrochloride; pyridine / methanol / 24 h / 20 °C 2: [RuCl2(η2-C6H6){P(NMe2)3}]; water / 5 h / 100 °C / Inert atmosphere; Sealed tube | ||
97 %Chromat. | With ammonium hydroxide; cryptomelane; oxygen In 1,4-dioxane at 130℃; for 3h; Autoclave; Green chemistry; | |
78 %Chromat. | With C33H28ClN2O2PRu; hydroxylamine hydrochloride; sodium hydrogencarbonate In toluene at 20℃; for 10h; Inert atmosphere; Reflux; | Catalytic conversion of aldehydes to amides General procedure: Catalytic conversion of aldehydes into their corresponding amides was carried out by ruthenium(II) carbonyl complexes as catalyst in the following general procedure. The reaction vessel was charged with aldehyde (2mmol), NH2OH·HCl (2mmol), NaHCO3 (2mmol) and ruthenium catalyst (0.01mmol) and the mixture was placed under an atmosphere of nitrogen. About 4mL of dry and degassed toluene was added and the mixture was stirred for 15min at room temperature followed by reflux for 10h. On completion of the reaction, 2-3mL methanol was added to the mixture followed by filtration through Celite to remove catalyst and NaHCO3. The filtrate was subjected to GC analysis and the product was identified and determined with authentic samples. |
Multi-step reaction with 2 steps 1: hydroxylamine hydrochloride; triethylamine / ethanol / 3 h / 80 °C 2: mercury dichloride; C82H80N4O6 / water; tetrahydrofuran; toluene / 5 h / 20 °C | ||
Multi-step reaction with 2 steps 1: sodium hydroxide; hydroxylamine hydrochloride / ethanol / 20 °C 2: copper diacetate / o-xylene / 2.5 h / 160 °C / Dean-Stark; Inert atmosphere | ||
With hydroxylamine hydrochloride; sodium carbonate; copper(ll) bromide | ||
Multi-step reaction with 2 steps 1: toluene / 1 h / 20 °C / Molecular sieve 2: triethylamine; oxygen / toluene / Reflux | ||
With C33H27ClN3OPRu; hydroxylamine hydrochloride; sodium hydrogencarbonate In toluene at 20 - 110℃; for 8.25h; Inert atmosphere; Schlenk technique; | 2.7 Representative procedure for ruthenium-catalyzedaldehydes to amides conversion General procedure: The reaction vessel was charged with aldehyde (1mmol), NH2OH·HCl (1 mmol), NaHCO3 (1 mmol),[Ru-NHC] catalyst (0.5 mol %) and the mixture wasplaced under an atmosphere of N2. About 2 mL of dryand degassed toluene was added and the mixture wasstirred for 15 min at room temperature followed byreflux for 8 h. On completion of the reaction, 2-3 mLmethanol was added to the mixture followed by filtrationthrough Celite to remove the catalyst and NaHCO3.The crude product was then purified by column chromatography(MeOH/CH2Cl2, 1:1) using silica (200-400 mesh) as solid phase provided the amide in goodyield. The resultant amide solution was subjected to GCanalysis and the product was identified in comparisonwith authentic samples | |
Multi-step reaction with 2 steps 1: hydroxylamine hydrochloride; zinc(II) oxide / 80 °C 2: Cu(II) complex on SiO2-coated Fe3O4 nanoparticles / 2 h / 80 °C / Green chemistry | ||
76 %Chromat. | With C23H27Cl2N3Rh(1+)*C24H20B(1-); hydroxylamine hydrochloride; sodium hydrogencarbonate In toluene at 110℃; for 2h; Inert atmosphere; Schlenk technique; | 4.3. General procedure for the catalytic transformation of aldehydeto amide General procedure: Compound 3 (0.002 mmol), the aldehyde (1 mmol), NH2OHHCl(1 mmol) and NaHCO3 (1 mmol) were introduced in a dried schlenktube and purged with N2. Then, to the mixture, dried and degassedtoluene (2 ml) was added and the mixture was stirred for about10 min at room temperature, before the solution was refluxed understirring for 2 h. The mixture was cooled and the products wereextracted with methanol and dichloromethane before beingfiltered through celite to remove the remaining catalyst andNaHCO3. The crude amide was purified using column chromatography,and dried under vacuum. |
Multi-step reaction with 2 steps 1: hydroxylamine hydrochloride; zinc(II) oxide / 80 °C 2: Cu(II)–metformin immobilized ongraphene oxide / water / 1 h / 100 °C / Green chemistry | ||
89 %Chromat. | With hydroxylamine hydrochloride; C27H26Cl2NORh; sodium hydrogencarbonate In water at 39.84℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: 4-methoxybenzoic acid With 1,3,5-trichloro-2,4,6-triazine; potassium carbonate In tetrahydrofuran for 0.0166667h; Milling; Stage #2: With ammonium thiocyanate In tetrahydrofuran for 0.0833333h; Milling; | 2.General procedure for solvent-free reduction of carboxylic acid Unless otherwise specified, carboxylic acid (0.542 mmol), TCT (0.0400 g, 0.216 mmol) and K2CO3 (0.2247 g, 1.626 mmol) were mixed together and hand ground for one minute using porcelain mortar and pestle. After addition of ammonium thiocyanate (0.0495 g, 0.650 mmol), the mixture was ground manually for further five minute. During the grinding, THF (calculated to be less than 1 L/mg of solids) was added to aid homogeneous mixing. The crude material was then purified by short column chromatography (column diameter 1.5 cm, packed with 3-4 g silica gel ) using 40-50% ethyl acetate/hexane as an eluent. |
90% | With pyridine; urea for 0.00833333h; microwave irradiation; | |
84% | Stage #1: 4-methoxybenzoic acid With thionyl chloride In tetrahydrofuran at 50℃; for 1h; Stage #2: With ammonium hydroxide In tetrahydrofuran at 0℃; for 0.0833333h; |
81% | With 1H-imidazole; urea for 0.1h; microwave irradiation; | |
80% | With ammonia hydrochloride; triethylamine; 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride In methanol at 20℃; for 4h; | |
78% | With CAN; urea for 0.05h; microwave irradiation; | |
78% | With ammonium cerium (IV) nitrate; urea for 0.05h; Microwave irradiation; Green chemistry; | |
70% | With ammonium hydrogen carbonate; formamide for 0.133333h; Irradiation; | |
70.1% | With ammonia; tungstic acid; zinc oxide In toluene at 120℃; for 8h; | 17 Example 17 In the reactor, add 15.2g, 0.1mol 4-methoxybenzoic acid, add 10ml ammonia, 0.8g, 10mmol zinc oxide, 1.25g, 5mmol tungstic acid, 200ml of toluene, heat up to 120 degrees, stir and react 8 hour. Filtration with suction, and rotary evaporation under reduced pressure to remove the solvent to obtain 16.7 g of a pale yellow crude product of 4-methoxybenzamide. The crude product was recrystallized by heating and refluxing with 30 ml of acetic acid to obtain 10.6 g of white crystals with a yield of 70.1%. |
70% | With tris(2-phenylpyridinato-N,C2′)iridium(III); Potassium phosphate, dibasic; borane-ammonia complex; di-<i>tert</i>-butyl dicarbonate; magnesium(II) chloride In acetonitrile at 20℃; for 36h; Schlenk technique; Irradiation; Green chemistry; | |
61% | With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h; | |
52% | Stage #1: 4-methoxybenzoic acid With phosphorus(V) chloride Heating; Stage #2: With ammonium hydroxide In water monomer Cooling; | |
50% | With ammonia hydrochloride; triethylamine at 20℃; for 0.0166667h; | |
43% | With ammonium bicarbonate; copper(II) nitrate In dimethyl sulfoxide at 140℃; for 30h; Autoclave; | Representative Procedure for Conversion of Various Arylethenesto Aromatic Nitriles General procedure: To a stainless steel autoclave lined with Teflon, 0.5 mmol substrate,0.075 mmol Cu(NO3)2, 1 mmol (NH4)2CO3, and 2 mLDMSO were added. Then the reactor was filled with 2 MPaoxygen and was heated under magnetic stirring at 140 °C for 30h or 40 h (Caution: the use of the high-pressure oxygen ispotentially hazardous. Thus, experiments using the high-pressureoxygen must only be carried out under rigorous safety precautions,and it is required to use the appropriate high-pressurereactor to avoid the potential leakage or explosion of the gas).Once the reaction time was reached, the mixture was cooled toroom temperature, diluted with 30 mL diethyl ether, and filteredvia a Celite pad. The organic mixture was washed withwater (3 × 5 mL), dried with anhydrous sodium sulfate, and concentratedin vacuum. GC analysis provided the GC yields of theproduct with an internal standard. In addition, the combinedcrude product from another 1-5 parallel experiments was purifiedby column chromatography and identified by 1H NMR and13C NMR spectroscopy. All the products are the known compounds,and the analytical data of several typical compoundsare as follows: |
25% | Stage #1: 4-methoxybenzoic acid With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at 0℃; for 0.5h; Stage #2: With ammonia hydrochloride In tetrahydrofuran; water monomer at 0℃; for 0.5h; | 4.2.8 4.2. Typical procedure for the primary amidation of 3-phenylpropanoic acid 1a with NH4Cl General procedure: To a colorless solution of 75mg (0.50mmol) of 3-phenylpropanoic acid 1a in 10mL of THF were added at 0°C 67μL (0.70mmol, 1.4equiv) of ClCO2Et and 209μL (1.5mmol, 3.0equiv) of Et3N. After stirring for 30min at 0°C, 0.75 ml of a 1.0M aqueous solution of NH4Cl (0.75mmol, 1.5equiv) was added at 0°C to the colorless suspension. The mixture was stirred for 30min at 0°C and 5mL of H2O was added to the resulted mixture. The colorless clear solution was extracted with 30mL of EtOAc and the aqueous layer was extracted with 20mL of EtOAc. The organic layers were combined, washed with 5mL of brine, and dried over anhydrous MgSO4. The crude product was chromatographed on silica gel with EtOAc to afford 72mg (96% yield) of 3-phenylpropanamide 2a. 4.2.8 4-Metoxybenzamide 2h 19 mg (25%); coloress solid; mp: 139-142 °C; 1H NMR (400 MHz, MeOD-d4): δ 3.86 (s, 3H, CH3), 6.97, 7.84 (d, d, J = 9.0, 9.0 Hz, 2H, 2H, C6H4); 13C NMR (100 MHz, MeOD-d4): δ 56.0, 114.7, 127.0, 130.7, 164.2, 172.1; IR (KBr, vmax/cm-1): 3392 (CONH), 3168 (CONH), 1646 (CON), 1618 (CON); HRMS (ESI-TOF): Calcd for C9H9NO3Na (M+Na)+: 202.0475, found: 202.0496. |
With monoethyl phosphate; ammonia In chloroform 1.) 0 - 5 deg C, 30 min, 2.) room temp., 1.5h; | ||
Multi-step reaction with 2 steps 1: 2 h / 80 °C / Ionic liquid 2: ammonium acetate; triethylamine / 3 h / 80 °C / Ionic liquid | ||
Multi-step reaction with 2 steps 1: thionyl chloride / 2 h / Reflux 2: ammonium hydroxide / 0.03 h / 0 °C | ||
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 0.5 h / 0 °C 2: ammonia hydrochloride / tetrahydrofuran; water monomer / 0.5 h / 0 °C | ||
Stage #1: 4-methoxybenzoic acid With ammonia In methanol; water monomer at 20℃; Stage #2: With N-Tosylimidazole In N,N-dimethyl-formamide at 100℃; for 1h; Stage #3: With triethylamine In N,N-dimethyl-formamide at 100℃; for 3.5h; | Synthesis of aminium carboxylates; general procedure; Synthesis of amides from aminium carboxylates using TsIm; general procedure General procedure: The carboxylic acid (1 equiv.) was added to a solution of the amine (1 equiv.) in a minimum amount of H2O-MeOH (70:30). The reactionmixture was stirred at room temperature and the reaction was complete when pH paper indicated that the solution was neutral. The solution was then evaporated under vacuum and the crude product was dried ina vacuum oven for 24 h at 50 °C. The aminium carboxylates were then stored in a desiccator. A mixture of the appropriate aminium carboxylate (0.01 mol) and TsIm (0.012 mol) was added in DMF (15 mL) to a round bottom flask (50 mL) and the reaction mixture was heated at 100 °C for 1 h. Then, Et3N (0.012 mol) was added and the heating of the reaction mixture was continued at 100 °C until TLC monitoring indicated no further progress in the conversion (2-6 h, see Table 2). After completion of the reaction, the solvent was evaporated in vacuo (Note). The remaining foam was then dissolved in CHCl3 (100 mL) and subsequently washed with water (2 × 100 mL). Then, the organic layer was dried over anhydrous sodium sulfate and evaporated. The crude productwas purified by column chromatography on silica gel eluting withn-hexane : EtOAc. (Note: DMF (b.p. 153 °C) can be evaporated in a rotary evaporator if the vacuum system is capable of sufficiently low pressure. For instance, DMF can be boiled below 80 °C if the vacuum is reduced to 5 torr or less. However, if an efficient vacuum pump is not available,then an alternative procedure can be employed in which the reaction mixture is diluted in water (100 mL). Then, CHCl3 (100 mL) is addedand the organic phase is separated. The separated CHCl3 is washed subsequently with water (4 × 100 mL). The CHCl3 is evaporated toobtain the crude product.) | |
Multi-step reaction with 2 steps 1: thionyl chloride / 0.5 h / 85 °C / Reflux 2: ammonium hydroxide / dichloromethane / 0.5 h / Cooling with ice | ||
9.938 g | With ammonium hydroxide In dichloromethane at 5℃; for 1h; | 25 Synthesis of 1,4-methoxybenzamide In 100mL volumetric flask 40mL25% ammonia water, ice water bath to 5 ° C, added dropwise with stirring a solution of the theoretical amount of CH2C12 66.lmmol4- methoxybenzoyl chloride, the addition was complete stirring was continued for LH, precipitated The solid, concentrated under reduced pressure, the product was washed with water by filtration, a white solid 9. 752g, the filtrate was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give a white solid of 0.186 g of ethyl acetate, the total was 9. 938g, |
79 %Chromat. | With ammonia hydrochloride; triethylamine; 2,2-dichloro-1,3-diisopropylimidazolidine-4,5-dione In dichloromethane at 20℃; for 3h; Inert atmosphere; chemoselective reaction; | General procedure for the synthesis of amides General procedure: Carboxylic acid (1 mmol), amine or ammonium chloride (1 mmol) and triethylamine (3 or 4 mmol) were introduced to the solution of DCDD (1.05 mmol) and stirred at r.t. for 3 h. After reaction, the mixture was distilled under evacuation to remove CH2Cl2. Then, 15 mL of H2O was added to the residues and a solution pH value of 8.0 was set with potassium carbonate. Next, the mixture was extracted with ethyl acetate (25 mL × 3), and the organic layer was isolated and combined. The organic layer was washed with brine and dried over anhydrous MgSO4. Finally, the solvent was removed, and the residue was chromatographed on silica gel using hexane/ethyl acetate as eluent to give the corresponding pure product. |
With ammonia at 200℃; for 0.5h; | A Amide Intermediate Preparation Example A General procedure: Into a 1L open reactor was added 500g of carboxylic acid raw material (chemically pure) and stirring was turned on (600 r/min) from the reactorThe bottom is continuously fed with ammonia gas (chemical purity, water content of 5.1% by weight, flow rate of 100 g/min) to the carboxylic acid feed. After the reaction was allowed to proceed for TC hours at the reaction temperature TA, ammonia gas flow was stopped. The contents of the reactor were sampled and subjected to nuclear magnetic proton and elemental analysis to characterize the amide intermediate. Specific reaction conditions and characterization results are shown in Table A-1, Table A-2, Table A-3, Table A-4, Table A-5 and Table A-6. These characterization results show that the amide intermediates obtained have an extremely high purity (above 99%).In this embodiment, the ammonia gas can be directly replaced with waste ammonia gas (from Yangzi Petrochemical Plant, containing approximately50wt% of ammonia gas, the rest were toluene, oxygen, nitrogen, steam, carbon monoxide, and carbon dioxide, and the flow rate of this waste ammonia was 130g/min). | |
Multi-step reaction with 2 steps 1: 1,3,5-trichloro-2,4,6-triazine; 1-pyrrolidinecarboxaldehyde 2: ammonium hydroxide / water monomer / 20 h / 0 - 20 °C / Alkaline conditions | ||
Multi-step reaction with 2 steps 1: phosphorus(V) chloride 2: ammonium hydroxide | ||
Multi-step reaction with 2 steps 1: thionyl chloride / 12 h / Reflux 2: ammonia / 1 h / -10 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: 4-methoxyphenylacetamide; sodium methylate In methanol at 20℃; for 0.25h; Stage #2: With bis(1,3-dimethyl-2-imidazolidinone) hydrotribromide In methanol for 4h; Reflux; | 4.5 Typical procedure for the Hofmann rearrangement with 3a General procedure: To a mixture of benzamide (14c, 244mg, 2.01mmol) in methanol (2mL), was added NaOMe (498mg, 9.21mmol) in methanol (6mL) and the mixture was stirred at 20°C for 15min. Complex 3a (1.18g, 2.52mmol) and methanol (2mL) were added to the mixture and stirred at reflux for 4h. The reaction mixture was then cooled to room temperature, diluted with diethyl ether (20mL) and quenched with a saturated NH4Cl aqueous solution (40mL). After separation of the organic layer, the aqueous layer was further extracted with diethyl ether (15mL×3). The combined organic layers were washed with water (20mL×2), dried over Na2SO4, and concentrated in vacuo. The resulting crude residue was purified using silica gel column chromatography (eluent: hexane/chloroform=1:1) to afford methyl phenylcarbamate (15c, 279mg, 92%) [26] as a white crystalline solid |
87% | With N-Bromosuccinimide In methanol for 0.166667h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | at -78 - 0℃; for 2h; 5.0 equival. MeCeCl2; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With tribromo-isocyanuric acid; potassium hydroxide; at 60℃; for 0.0833333h;Microwave irradiation; | General procedure: A 10mL borosilicate tube was charged with the Benzamide (0,5mmol), methanol (4mL), TBCA (2eq- 0,4mmol) and KOH (2eq -1 mmol). After the irradiation and cooling of the reaction media, it was filtered and the solid washed with copious amount of acetone. The clean methanolic-acetone solution was evaporated and the products purified through column chromatography. |
94% | With dibromamine-T; 1,8-diazabicyclo[5.4.0]undec-7-ene; for 0.333333h;Reflux; | General procedure: To a solution of amide (1 mmol) in methanol (10 mL) was added DBU (0.5 mL). To this solution TsNBr2 (1 mmol) was added. The reaction mixture was heated under reflux condition for a period of 10-20 min (TLC). After completion of the reaction (TLC) methanol was evaporated under reduced pressure. The crude mixture was then dissolved in EtOAc. This solution was washed with 5% HCl and then with saturated Na2CO3 solution. The organic extracts were separated and dried over anhydrous Na2SO4. The crude product was purified by flash column chromatography using petroleum ether and ethyl acetate (4:1) as eluent to get the pure carbamate product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With ammonium hydroxide; 1,3,5,7-tetramethyl-2,4,8-trioxa-6-phenyl-6-phosphaadamantane; palladium diacetate; In toluene; at 130℃; under 5171.62 Torr;Autoclave; | General procedure: To a 45 mL glass-lined autoclave, 1 (0.5 mmol), Pd(OAc)2 (0.01mmol), CYTOP292 (0.02mmol), aqueous ammonia (0.2 mL) and toluene (10 mL) were sequentially added. After sealing, the autoclave was purged three times with carbon monoxide and pressurized with 100 psi of CO. The resulting mixture was then heated at 100 C for 20 h. The autoclave was removed from the oil bath and cooled to room temperature prior to the release of excess carbon monoxide. The reaction mixture was concentrated by rotary evaporator, and purified by flash chromatography on silica gel with a mixture of hexanes and ethyl acetate (2:1to 1:2) as the eluent to afford the products. |
93% | With 1,4-diaza-bicyclo[2.2.2]octane; N-methoxylamine hydrochloride; sodium iodide; palladium dichloride; In acetonitrile; at 90℃; under 3800.26 Torr; for 8h;Autoclave; Inert atmosphere; | General procedure: To an autoclave (100 mL capacity), were added an arylhalide (1 mmol), methoxylamine hydrochloride (1.2 equiv),DABCO (2 equiv), PdCl2 (10 mol%), NaI (0.2 mmol) and MeCN (15 mL), under an inert atm. The autoclave was flushed three times with CO and then pressurized to 5 atm of CO. The mixture was stirred with a mechanical stirrer (550rpm) at 90 C for 8 h. The reactor was cooled to r.t., degassed carefully, opened and the reaction mixture removed. The reactor vessel was washed with EtOAc (2 × 5 mL) to remove residual product. The mixture was filtered and the filtrate washed with brine (2 × 4 mL), dried over Na2SO4, filtered and the solvent evaporated under vacuum. Purification of the residue was carried out by column chromatography (silicagel, 100-200 mesh, PE-EtOAc) to afford the corresponding product in good to excellent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With silver tetrafluoroborate; chloro(1,3-bis(2,6-di-i-propylphenyl)imidazol-2-ylidene)gold(I) at 100℃; for 20h; Sealed tube; Neat (no solvent); | |
94% | With C55H45ClN5P2Ru(1+)*Cl(1-) In water at 110℃; for 12h; Sealed tube; | |
93% | With C82H80N4O6; mercury dichloride In tetrahydrofuran; water; toluene at 20℃; for 5h; |
92% | Stage #1: p-methoxyl benzaldoxime With N,N-dimethyl-formamide; trichlorophosphate at 0 - 5℃; for 1.5h; Stage #2: With sodium hydroxide In water for 0.0166667h; Heating; | |
91% | With copper diacetate In o-xylene at 160℃; for 2.5h; Dean-Stark; Inert atmosphere; | |
91% | With Cu(II) on nano silica functionalized triazine dendrimer In water at 20℃; for 0.65h; Green chemistry; | |
90% | With Cu(II)-metformin immobilized ongraphene oxide In water at 100℃; for 1h; Green chemistry; | |
89% | With zinc(II) chloride In n-heptane for 18h; Reflux; | |
88% | With chloro(η4-1,5-cyclooctadiene)(1,3-dimesitylimidazol-2-ylidene)rhodium(I); toluene-4-sulfonic acid; 4-methoxybenzonitrile In toluene at 80℃; for 6h; | |
84% | With [PdCl2{κ2-(P,N)-2-Ph2PC6H4CH=NOH}] In water at 100℃; for 24h; Inert atmosphere; Sealed tube; | |
82% | With [(eta.(5)-pentamethylcyclopentadienyl)Ir(H2O)3](OTf)2 In water at 110℃; for 12h; Schlenk technique; | |
82% | With [(eta.(5)-pentamethylcyclopentadienyl)Ir(H2O)3](OTf)2 In water at 120℃; for 12h; Schlenk technique; | 5 Example 5: 4-Methoxybenzamide To a solution of 4-methoxybenzoic acid (75.6 mg, 0.5 mmol), [Cp * Ir (H20) 3] [0Tf] 2 (5.1 mg, 0.0075 mmol, 1.5 mol%) and Water (1 ml) was added sequentially to a 25 ml Schlenk reaction flask. The reaction mixture was allowed to react at 120 ° C for 12 hours and then cooled to room temperature. The water was removed by rotary evaporation, and the product was isolated by column chromatography. Yield: 82%. (M, 3 H, ArH and N H), 7. 19 (br s, 1 H, N, H), 6. 97 (d , J = 8.3 Hz ζ, 2., ArH), 3.80 (s, 3,, 0 CH3); C NMR (125 MHz, DMSO-d) δ 167.4, 161.5, 129.3, 126.5, 113.3, 55.3. |
80% | With [Ru(κ(3)-tpy)(κ(1)-P-PPh2Py)Cl2] In toluene for 10h; Reflux; | 2.4. Catalytic activity General procedure: Mixture of the oxime (2.0 mmol) and the catalyst [Ru(κ3-tpy)(κ1-P-PPh2Py)Cl2)] (3) (13.3 mg, 0.02 mmol) was refluxed in toluene (1 mL) for appropriate time (refPreviewPlaceHolderTable 1). After completion of the reaction CH2Cl2 was added to reaction mixture and resulting solution was filtered through celite. The crude product was purified by column chromatography (silica gel, MeOH/CH2Cl2). After work-up amides were obtained in good yield (Table 1). |
79% | With [Ru(OTf){η6:κ1(P)-PPh2-binaphthyl}{PPh2(OH)}][OTf] In water at 100℃; for 6h; Inert atmosphere; Sealed tube; | |
75% | With cis,cis,trans-[RuCl2{κ2-(P,N)-2-Ph2PC6H4CH=NOH}2] In water at 100℃; for 9h; Sealed tube; Inert atmosphere; | |
72% | With [RuCl2(η2-C6H6){P(NMe2)3}]; water at 100℃; for 5h; Inert atmosphere; Sealed tube; | |
70% | With 2-nitro-1-naphthol; cobalt(II) diacetate tetrahydrate In water; acetonitrile at 80℃; for 24h; | 2.3. Typical procedures for the synthesis of amides from aldoximes General procedure: Aldoxime (0.25 mmol), cobalt acetate(II) tetrahydrate (6.2 mg, 0.025 mmol), 2-nitro-1-naphthol (9.5 mg, 0.05 mmol) and acetonitrile/H2O (0.01 + 0.24 mL, 4 v/v% of acetonitrile in water) were added to an oven-dried vial. The mixture was vigorously stirred at 80 °C for24 h and then diluted with ethyl acetate. Solvent was removed in vacuo, and the desired product was purified and isolated by silica gel column chromatography (ethyl acetate/n-hexane). |
70% | With Cu(II) complex on SiO2-coated Fe3O4 nanoparticles at 80℃; for 2h; Green chemistry; | |
63% | With copper diacetate; acetonitrile In ethanol at 78℃; for 3h; | Preparation of amides from aldoximes; general procedures General procedure: To a 25 mL round-bottom flask equipped with a magnetic stirrer were added aldoximes (5 mmol), copper(II) acetate (45 mg, 0.25 mmol),acetonitrile (10 mg, 0.25 mmol) and EtOH (15 mL). The mixture was stirred for 4-8 h at 78 °C or for 12 h at room temperature. After removal of the solvent, the residue was purified by column chromatography to afford the desired product. |
With Cu(II) catalyst In toluene |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With silver(I) trifluoromethoxide In ethyl acetate at 50℃; for 24h; Darkness; | General procedure for oxazole cyclization: General procedure: A mixture of bromo-ketone (0.6 g,2.9 mmol), amide (0.55 g, 3.6 mmol, 1.25 equiv), and silver triflate (0.9 g,3.6 mmol, 1.25 equiv) in ethyl acetate (4 mL) was heated to 50-70 °C. After thereaction was deemed complete by HPLC analysis, the mixture was cooled to 20 °C and diluted with ethyl acetate (3 mL). A solution of sat’d NaCl (3-4 mL)was added and the mixture stirred at 20 °C for at least 4 h. The silver salts (AgBr and AgCl) are removed by filtration and the resulting biphasic solution transferred to a separatory funnel and the layers separated. The organic layer isthen washed with water (4 mL), 5% NaHCO3 (4 mL), 1 N HCl (4 mL), and water(4 mL). The organic layer is concentrated to dryness and the residue purified by flash column chromatography (5% EtOAc/hexanes) to obtain pure oxazole product. |
42% | at 115℃; for 15h; | A mixture of 3-Chloro-2-butanone (2.1g, 10.0 mmol) and 4-methoxybenzamide (0.30 g, 1.0 mmol) was heated at 1150C for 15 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified over silica gel (230-400 M, 20% EtOAc-Hexane) to get the desired product (0.17 g, 42%) as a white solid. The corresponding chloro derivative was also prepared by the same general method. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 110℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 10.0h;Inert atmosphere; Sealed tube; | General procedure: A flame-dried resealable Schlenk tube was charged with Pd(OAc)2 (7.5 mg, 0.05 mmol, 5 mol%), Xantphos (29 mg, 0.05 mmol, 5 mol%), the solid reactant(s) (1.0 mmol of the bromoquinolin-2(1H)-one 6, 1.5 mmol of appropriate amine or amide) and Cs2CO3 (651 mg, 2 mmol). The Schlenk tube was capped with a rubber septum, evacuated and backfilled with argon; this evacuation/backfill sequence was repeated one additional time. The liquid reactant(s) and 1,4-dioxane (2 mL) were added through the septum. The septum was replaced with a teflon screwcap. The Schlenk tube was sealed, and the mixture was stirred at 100 C for 10 h. The resulting suspension was cooled to room temperature and filtred through celite eluting with ethyl acetate, and the inorganic salts were removed. The filtrate was concentrated and purification of the residue through a silica gel column chromatography gave the expected product 7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With dihydrogen peroxide; at 80℃; for 10h;Inert atmosphere; | General procedure: Benzylamine (0.214 g, 2.00 mmol), [VO(PS-BBMA]SO4 (80 mg, 0.08 mmol) and H2O2 (4 mmol) was heated at 80 C for 10 h in a round bottom flask under nitrogen atmosphere. The reaction was monitored by TLC, and after complete consumption of benzylamine, the reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate: hexane=1:8) to afford benzamide. The product was analyzed by 1H NMR spectroscopy. |
92% | With tert.-butylhydroperoxide; caesium carbonate; In water; acetonitrile; for 4h;Reflux; | General procedure: To a solution of 4-methoxybenzyl amine (1.0 mmol) and cesium carbonate (1.0 mmol) in 3 mL of CH3CN was added a solution of 70% aqueous TBHP (3.0 mmol) and the mixture was refluxed for 4 h. The mixture was then dried to vacuum and extracted three times with ethyl acetate followed by washing with brine,and dried over anhydrous Na2SO4. Evaporation of the solvent under vacuum afforded the crude product, which was furthur purified by column chromatography using hexane/ethyl acetate mixture and then analyzed by spectroscopy. |
With manganese(IV) oxide; oxygen; In dichloromethane; at 180℃; under 15001.5 Torr; for 24h; | Add 300mg of manganese dioxide, 60mg of 4-methoxybenzylamine in 6g of dichloromethane (the mass in the mixture is thick)Degree: 1.0%), uniformly mixed; charged with 2MPa oxygen, reacted at 180 C for 24 hours, 4-methoxybenzylamine conversion rate 95.5%, correspondingThe selectivity to 4-methoxybenzamide was 99.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In xylene for 48h; Heating / reflux; | 1 Example 1; 1- [2- (4- {2- [ (E)-2- (4-Methoxy-phenyl)-vinyl]-oxazol-4-ylmethoxy}-phenyl)- oxazol-4-ylmethyl]-1 H- [1,2, 3] triazole; 15.12 g (100.0 mmol) 4-Methoxy-benzamide, 15.24 g (100 mmol) 1,3- dichloroacetone and 150 ml xylene were kept at reflux temperature for 24 h with continuous removal of water by use of a Dean-Stark trap. Another 15 g of 1,3- dichloroacetone were added and heating continued for additional 24 h. After removal of solvents in vacuo, the residue was triturated with isopropanol/water 1: 1 and the crystals isolated and dried. Yield: 21.29 g (95%) 4-chloromethyl-2- (4- methoxy-phenyl) -oxazole as tan solid, melting at 80-82°C. lH-NMR (400MHz, D-DMSO) : 8= 3.83 (s, 3H, OCH3), 4.72 (s, 2H, C1CH2), 7.08 (d, 2H, Ar-H), 7.91 (d, 2H, Ar-H), 8.19 (s, 1H, oxazole). |
87% | In neat (no solvent) at 130℃; for 4h; | |
83% | In toluene at 120℃; for 1h; | To a solution of 1 ,3 dichloroacetone (0.504 g, 3.90 mmol) in toluene (5 ml) was added 4-methoxy benzamide (0.30 g, 1.90 mmol). The reaction mixture was heated at 12O0C for 1 h. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified over silica gel (230-400 M, 15% EtOAc-Hexane) to get the desired product (0.37 g, 83%). |
78% | In toluene at 100℃; for 4h; | 107 4-(Chloromethyl)-2-(4-methoxyphenyl)oxazole This compound was synthesized from 4-methoxybenzamide and 1,3-dichloroacetone as described in example 74 step 1 (2.3 g, yield 78%) as a yellow solid. 1H NMR (400MHz, CDCl3) δ 7.98 - 7.96 (d, J = 8.3 Hz, 2H), 7.65 (s, 1 H), 6.97 - 6.95 (d, J = 8.3 Hz, 2H), 4.56 (s, 2H), 3.86 (s, 3H). MS (ESI) m/z: Calculated for C11H10ClNO2: 223.04; found: 223.8 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With toluene-4-sulfonic acid In neat (no solvent) at 60℃; for 0.5h; Sonication; | General procedure for the synthesis of 3 and 5 General procedure: To a well ground mixture of cyclohex-2-enone (2.0 mmol) and benzamide (1.0 mmol)containing 1 mol % p-TsOH·H2O was placed in a glass rod, and the resultingmixture was irradiated in the water bath of an ultrasonic processor at 60°C for 30 min. The temperature of the water bath wascontrolled by the addition or removal of water from the bath. Upon completionof reaction (as indicated by TLC), the mixture was purified on a shortsilica-gel column using ethyl acetate/petroleum ether (1:3, v/v) as the eluent. |
95% | With toluene-4-sulfonic acid In neat (no solvent) at 60℃; for 0.5h; Irradiation; Green chemistry; | General procedure for the synthesis of 3 and 5 General procedure: To a well ground mixture ofcyclohex-2-enone (2.0 mmol) and benzamide (1.0 mmol) containing 1 mol %p-TsOH·H2O was placed in a glass rod, and the resulting mixturewas irradiated in the water bath of an ultrasonic processor at 60°C for 30 min. The temperature of the water bath wascontrolled by the addition or removal of water from the bath. Upon completionof reaction (as indicated by TLC), the mixture was purified on a shortsilica-gel column using ethyl acetate/petroleum ether (1:3, v/v) asthe eluent. |
80% | With toluene-4-sulfonic acid In acetonitrile at 20℃; for 55h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With copper(I) oxide; potassium phosphate; tetra-n-propylammonium bromide; In water; at 130℃; for 24h; | The N-nucleophile (2.21 mmol), Cu2O (Sigma-Aldrich, 99.99% purity, 0.147-0.294 mmol), K3PO4(2.94 mmol), the aryl halide (1.47 mmol), phase transfer catalyst (0.147-0.294 mmol) and water(0.40 mL) were added to a reaction vial and a screw cap was fitted to it. The reaction mixture wasstirred under air in a closed system at 130C for 24 h, then the heterogeneous mixture was cooledto RT and diluted with dichloromethane. The resulting solution was directly filtered through apad of Celite. The combined organic extracts were dried with anhydrous Na2SO4 and the solventwas removed under reduced pressure. The crude product was purified by silica-gel columnchromatography to afford the N-arylated product. The identity and purity of all products wasconfirmed by 1H and 13C NMR spectroscopic analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With iodobenzene; oxone; water In acetonitrile at 20℃; | |
75% | With sodium hydrogen sulfate; [bis(acetoxy)iodo]benzene In water; acetonitrile at 20℃; for 0.666667h; | GENERAL PROCEDURE. General procedure for synthesis of benzoquinone derivatives. General procedure: (Diacetoxyiodo) benzene (5 mmol, 1.61g) and NaHSO4.H2O (1mmol, 0.138g) were stirred for 10-15 min, at room temperature in aqueous solution of acetonitrile (5 ml water and 5 mlacetonitrile). In this reaction mixture benzamide (1mmol) was added and stirring was continuing till reaction goes to completion (TLC). After completion of reaction, the reaction mixture was quenched with water and further extracted with chloroform (3×10 ml). The combined chloroform layers were washed with water (3×20ml) dried over Na2SO4, and concentrated on rota-evaporator to get the crude residue. The residue was further purified by column chromatography on silica gel using ethyl acetate: hexane (1:9) as an eluent to afford pure benzoquinone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 100℃; for 16h; Inert atmosphere; | Typical procedure for Pd-catalyzed amidation of 2-chloropyrimidines. A screw-cap vial was charged with benzamide (121 mg, 1.00 mmol), Cs2CO3 (456 mg, 1.40 mmol), Xantphos (87 mg, 0.15 mmol), Pd2(dba)3 (46 mg, 0.050 mmol), 2-chloropyrimidine (137 mg, 1.20 mmol), and 1,4-dioxane (2 mL). The mixture was sparged with nitrogen for 3 min, stirred for 16 h at 100 °C, and cooled to room temperature. The residue was diluted with dichloromethane, filtered through celite, and concentrated. The crude product was purified by silica gel flash chromatography (40-100% ethylacetate/hexanes) to provide N-(pyrimidin-2-yl)benzamide (188 mg, 0.85 mmol, 94% yield) as an amorphous solid (Table 1, entry 8). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With di-tert-butyl peroxide; acetic acid; cobalt(II) bromide In 1,1,2-trichloroethane at 120℃; for 28h; | 4.2. General procedure for amination of benzylic hydrocarbons General procedure: Ethylbenzene (1 mL), or a solution of diphenylmethane (1 mmol) in trichloroethane (1 mL), was added to a mixture of amide (0.5 mmol), CoBr2 (0.1 mmol) and AcOH (0.05 mmol) at room temperature, and DTBP (1 mmol) was then added. The resulting mixture was stirred at 120 °C for 28 h under air. After cooling to room temperature, the mixture was diluted with ethyl acetate (50 mL) and washed with water. The organic phase was dried over MgSO4 and removed under reduced vacuum. The residue was purified by column chromatography eluting with ethyl acetate and hexane to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With di-tert-butyl peroxide; acetic acid; cobalt(II) bromide; In 1,1,2-trichloroethane; at 120℃; for 28h; | General procedure: Ethylbenzene (1 mL), or a solution of diphenylmethane (1 mmol) in trichloroethane (1 mL), was added to a mixture of amide (0.5 mmol), CoBr2 (0.1 mmol) and AcOH (0.05 mmol) at room temperature, and DTBP (1 mmol) was then added. The resulting mixture was stirred at 120 C for 28 h under air. After cooling to room temperature, the mixture was diluted with ethyl acetate (50 mL) and washed with water. The organic phase was dried over MgSO4 and removed under reduced vacuum. The residue was purified by column chromatography eluting with ethyl acetate and hexane to afford the desired product. |
80% | With 2,3-dicyano-5,6-dichloro-p-benzoquinone; In 1,2-dichloro-ethane; at 100℃; for 24h;Schlenk technique; Molecular sieve; Inert atmosphere; | General procedure: A 20 mL Schlenk tube equipped with a stir-bar was charged with substituted diphenylmethanes (0.5 mmol), TsNH2 (1.0 mmol), DDQ (0.6 mmol) and 200.0 mg 3 A molecular sieve. The reaction tube was purged with nitrogen. 4 mL 1,2-dichloroethane (DCE) was then added to the reaction tube via a syringe. The Schlenk tube was placed in an oil-bath and heated to 100C for 24 h. The reaction mixture was then cooled to room temperature and filtered with ethyl acetate (2×10 mL) to remove the solid residue. The combined solution was concentrated by the rotary evaporator, and then purified by column chromatography on silica gel using petroleum ether/ethyl acetate as eluent to give the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; caesium carbonate; In toluene; at 140℃; for 12h; | 4- methoxybenzonitrile (133mg, 1mmol), [(IPr) AuNTf] (17mg, 0.02mmol, 2mol%),tetrahydrofuran (0.5ml), H 2O (0.5ml) were successively added to the reaction flask25mlSchlenk. After the mixture was reacted at 140C at 12 hours, cooled to roomtemperature, the solvent was removed in vacuo under reduced pressure. The [Cp * IrCl 2]2After (8mg, 0.01mmol, 1mol%), benzyl alcohol (130mg, 1.2mmol), cesium carbonate (65mg,0.2equiv.) And toluene (1ml) was added to the reaction flask and the reaction mixturewas continued at 130C at 12 h cooled to room temperature. The solvent was removedrotary evaporation, then purified by column chromatography (developing solvent: ethylacetate / petroleum ether) to give pure title compound Yield: 84%. |
75% | With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; In neat (no solvent); at 160℃; for 3h;Microwave irradiation; | General procedure: N-Alkylation of Amides with Alcohols; General ProcedureThe amide (100 mg, 1 equiv), alcohol (3 equiv) and (Cp*IrCl2)2 (2.5mol%) were added to a microwave reactor tube. The reaction mixturewas subjected to microwave irradiation at 160 C for 3 h. The mixture was allowed to cool to r.t. and H2O (10 mL) was added. Themixture was extracted with EtOAc (3 × 10 mL). The combined organiclayers were dried (Na2SO4) and filtered. The solvent was removedunder reduced pressure and the residue was purified usingflash silica gel chromatography with CH2Cl2-MeOH (95:5) to furnishthe N-alkylamide (Tables 2 and 3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With Fe3+ exchanged montmorillonite K-10 In neat (no solvent) at 140℃; for 30h; Inert atmosphere; | General procedure: A typical procedure for transamidation of benzamide with n-octylamineis as follows. Fe-mont (121.4mg, 1.0 mol% Fe-mont with respect to benzamide) was added to the mixture of benzamide (1.0 mmol), n-octylamine (1.1 mmol) in a reaction vessel equipped with a condenser under N2. The resulting mixture was vigorously stirred at 140 °C. The reaction mixture was analyzed by GC.Conversion and yield of the products were determined based on benzamide and n-octyl benzamide using dodecane as an internal standard. After completion of the reaction, acetone (2 g) was added to the mixture, and then the Fe-mont catalyst was separated by centrifugation. The crude product was isolated by column chromatography and the resulting product was identified by GCMS, 1H-NMR and 13C-NMR analyses. |
72 %Chromat. | With cerium(IV) oxide at 160℃; for 24h; Neat (no solvent); Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With caesium carbonate In 1,4-dioxane at 90℃; for 18h; Inert atmosphere; | 9 According to route (E), 4-methoxybenzamide (4.53 g, 30 mmoles, 1 eq.), 1-bromo-4-nitrobenzene (6.67 g, 33 mmoles, 1.1 eq.), Pd(OAc)2 (67.3 mg, 0.3 mmoles, 1 mol%), XantPhos (260.4 mg, 0.45 mmoles, 1.5 mol%) and Cs2CO3 (15.9 g, 45 mmoles, 1.5 eq.) were placed in dioxane (30 mL). The reaction mixture was heated at 90 °C and stirred for 18 hours under an inert atmosphere of argon. The reaction mixture was then filtered on Celite, washed with CH2Cl2 and acetone and the filtrate was concentrated under reduced pressure. The resulting solid was recristallized from ethanol and filtered to afford 4-methoxy-N-(4-nitrophenyl)benzamide (4.82 g, 60%). 1H NMR (300 MHz, CDCl3) δ 8.27 (d, J = 9.3 Hz, 2H), 8.01 (s, 1H), 7.85 (t, J = 9.3 Hz, 4H), 7.02 (d, J = 9.3 Hz, 2H), 3.90 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With MCM-41 mesoporous silica In ethanol; water at 80 - 90℃; for 11h; Green chemistry; | General synthetic procedure for preparation of thioamide (4): General procedure: In a typical reaction a solution of amide (1 mmol), rhodanine (1.2 mmol) and Morpholine (1.2 mmol) in EtOH/water (2 + 2 ml) were refluxed at 80-90 °C till completion using 40 mg of MCM-41 catalyst. The completion of the reaction was indicated by the disappearance of the starting material in thin layer chromatography. After completion of the reaction the solvent was evaporated in a rotary evaporator and the crude product was taken in dichloromethane and filtered to separate the products as filtrate from the catalyst (residue). Then the crude product was purified by silica gel column chromatography where the compound (5) came out from the column with 25%EtOAc/75% petroleum ether, but thioamide (4) came out with 65%EtOAc/35% petroleum ether making their separation easy. The thioamides (4) were characterized by IR, 1H NMR, 13C NMR, CHN and X-ray single crystal analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sulfated tungstate In toluene for 12h; Reflux; Green chemistry; | |
85% | With trifluoroacetic acid In toluene at 130℃; for 18h; Sealed tube; | |
72% | With nanosized zeolite beta In neat (no solvent) at 135℃; for 24h; |
60% | With Ce(III) immobilised on an aminated epichlorohydrin-activated agarose matrix at 140℃; for 8h; Green chemistry; | General procedure for transamidation of benzamide with benzylamine using CAEA and recovery of CAEA General procedure: CAEA (0.01 g) was added to a mixture of benzamide (1 mmol, 0.121 g) and benzylamine (1.1 mmol, 0.117 g) in a round-bottom flask equipped with a condenser under solvent-free conditions. The reaction mixture was stirred (250 min-1) at 140 °C. The progress of the reaction was monitored by TLC. Following the reaction, the reaction mixture was cooled and the resultant mixture was submitted to silica gel preparative TLC using ethyl acetate/hexane (1/1) as eluent. N-Benzylbenzamide was obtained with a 95 % yield (0.198 g). The spectral data of the compounds are given in Tables 1 and 2. The reaction mixture was centrifuged (1000 min-1,10 min) and washed several times with ethyl acetate and acetone to remove all the organic compounds then the precipitate was dried at ambient temperature. |
54 mg | With benzoic acid In toluene at 130℃; for 30h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With dibromamine-T; potassium carbonate In ethyl acetate at 20℃; for 6h; Inert atmosphere; | General procedure for the synthesis of N-acyl-N''-arylureas 4: General procedure: To a solution ofcarboxamide 1 (1 mmol) and 2 (1 mmol) in EtOAc (12 mL), N,N-dibromo-ptoluenesulfonamide3 (1 mmol) and K2CO3 (3 mmol) were added and themixture was stirred under nitrogen at room temperature for 5-6 h (Table 2).After completion of reaction (monitored by TLC), water (10 mL) was added, andthe mixture was extracted with EtOAc (3 5 mL). The combined organic phasewas dried over anhyd Na2SO4, filtered, and evaporated under reduced pressure.The resulting crude product was purified by silica gel column chromatographyusing a mixture of EtOAc-n-hexane (1:9) as eluent to afford an analytically pureproduct. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With bismuth(lll) trifluoromethanesulfonate In nitromethane at 80℃; for 24h; regioselective reaction; | Typical Procedure for the Synthesis of amidomethylarenes General procedure: A 10 mL screw cap vial was charged with Bi(OTf)3 (5 mol%), amide (1.0 equiv), formaldehyde (1.2 equiv),(hetero)arene (3-4 equiv.) and nitromethane and closed with a Teflon lined screw cap. The reaction mixture was stirred at 25-100 °C for the specified time. After cooling to room temperature the reaction mixture was diluted with EtOAc and filtered over a short plug of celite and silica gel. The plug was rinsed with additional EtOAc.The combined filtrates were concentrated under reduced pressure. Purification of the crude residue by columnchromatography (hexane:EtOAc) afforded the analytically pure product. |
65% | With bismuth(lll) trifluoromethanesulfonate In nitromethane at 80℃; for 24h; Sealed tube; | |
With water at 100℃; for 10h; Sealed tube; Green chemistry; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With iron(III) perchlorate hydrate; In nitromethane; at 80℃; for 24h; | General procedure: A 10 mL screw cap vial was charged with the respective iron salt (1-5 mol%) or Bi(OTf)3 (1-5 mol%), the appropriate amide (1.0 equiv), and MeNO2 (4.0 mL/mmol amide) (or DCE wherever applicable). Ethyl glyoxalate (1.2 equiv) and the appropriate aromatic compound (3.0 equiv) were added under vigorous stirring. Ethyl glyoxalate was used as a 50 wt% solution in toluene (technical form) and used as received for the reactions with iron(III) salts. For the reaction with Bi(OTf)3 toluene was removed in vacuo (1 mbar, 3 h) in order to avoid side reactions. The resulting oil was redissolved in MeNO2. The reaction mixture was heated to 40-100 C and stirred at this temperature. After cooling to r.t., the reaction mixture was diluted with EtOAc and filtered through a short plug of Celite and silica gel. The plug was rinsed with additional EtOAc. The combined filtrates were concentrated under reduced pressure. Purification of the crude residue by column chromatography (cyclohexane/EtOAc, then n-hexane/EtOAc) afforded the analytically pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With boron trifluoride diethyl etherate In acetone at 20℃; for 2h; Inert atmosphere; | General procedure 1 for thepreparation of bisamide in acetone General procedure: Acetone (5.0 mL) was added to the mixture of amide (2.0 mmol) and aldehyde (1.0mmol), followed by the addition of BF3 etherate (12.6 μL, 0.1 mmol).Then the mixture was stirred at room temperature until the full consumption ofstarting material detected by TLC analysis. Then the product was collected assolid by filtration and washed with a small portion of diethyl ether. After drying under vacuum, the purity was checked by 1HNMR: only desired peaks were observed except minor solvent residue in only afew cases. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With boron trifluoride diethyl etherate In acetone at 20℃; for 0.416667h; Inert atmosphere; | General procedure 1 for thepreparation of bisamide in acetone General procedure: Acetone (5.0 mL) was added to the mixture of amide (2.0 mmol) and aldehyde (1.0mmol), followed by the addition of BF3 etherate (12.6 μL, 0.1 mmol).Then the mixture was stirred at room temperature until the full consumption ofstarting material detected by TLC analysis. Then the product was collected assolid by filtration and washed with a small portion of diethyl ether. After drying under vacuum, the purity was checked by 1HNMR: only desired peaks were observed except minor solvent residue in only afew cases. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With dmap; ammonia; palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 90℃; for 0.333333h; Sealed tube; Microwave irradiation; | General Procedure for the preparation of benzamides. General procedure: To a dry microwave vial, aryl halide (Br, I) (1 eqv.) and amine (2eqv.) were taken in dry 1,4-dioxane. 5 mol% of Pd(OAc)2, 5 mol% ofXantphos and DMAP (2 eqv.) were added followed by (0.25 or 0.3) equivalents ofCo2(CO)8 and the vial was sealed immediately andmicrowave irradiated for 20 min. The reactionmixture was concentrated under reduced pressure, diluted with ethyl acetate andwater, the ethyl acetate layer separated, dried over sodium sulphate, andconcentrated. Thecrude products obtained were subjected to purification by flash chromatographyon silica gel coloumn eluting with petroleum ether and ethyl acetate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With ammonium hydroxide; oxygen In neat (no solvent) at 120℃; for 6h; Sealed tube; | General Procedure for preparation of amides catalyzed by Fe3O4*SiO2-SMTU-Cu General procedure: A sealed pressure vessel was charged with phenylacetic acids (68.0 mg, 0.5 mmol), Fe3O4*SiO2-SMTU-Cu catalyst (20 mg), and aqueous ammonia solution (28 wt% in H2O; 1.5 mL). The resulting solution was stirred at 120 °C under O2 (monitored by TLC and GC) for 6 hours. Upon completion of the reaction, the catalyst was separated using magnetic stirring bar and ethyl acetate (20 mL) was added, the organic layer was washed with saturate NaHCO3 (20 mL) solution twice, brine (20 mL) once, the combined aqueous layers was extracted with EtOAc (20 mL) twice. The combine organic layers were dried over anhydrous Na2SO4. The solvents were removed via rotary evaporator and the residue was purified with flash chromatography (silica gel, ethyl acetate: petroleum ether=2:1) to give amide products. |
80% | With copper oxide (I); ammonium hydroxide; oxygen In lithium hydroxide monohydrate at 130℃; for 32h; | |
6 %Chromat. | With oxygen; potassium hexacyanoferrate(II) |
Multi-step reaction with 2 steps 1: potassium hexacyanoferrate(II); oxygen; copper (II) bromide / N,N-dimethyl-formamide / 40 h / 120 °C / 11251.1 Torr / Autoclave 2: copper(II) oxide; potassium hexacyanoferrate(II); oxygen |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With silver(I) trifluoromethoxide; In ethyl acetate; at 50℃; | General procedure: A mixture of bromo-ketone (0.6 g,2.9 mmol), amide (0.55 g, 3.6 mmol, 1.25 equiv), and silver triflate (0.9 g,3.6 mmol, 1.25 equiv) in ethyl acetate (4 mL) was heated to 50-70 C. After thereaction was deemed complete by HPLC analysis, the mixture was cooled to 20 C and diluted with ethyl acetate (3 mL). A solution of sat?d NaCl (3-4 mL)was added and the mixture stirred at 20 C for at least 4 h. The silver salts (AgBr and AgCl) are removed by filtration and the resulting biphasic solution transferred to a separatory funnel and the layers separated. The organic layer isthen washed with water (4 mL), 5% NaHCO3 (4 mL), 1 N HCl (4 mL), and water(4 mL). The organic layer is concentrated to dryness and the residue purified by flash column chromatography (5% EtOAc/hexanes) to obtain pure oxazole product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With silver(I) trifluoromethoxide In ethyl acetate at 50℃; for 4h; Darkness; | General procedure for oxazole cyclization: General procedure: A mixture of bromo-ketone (0.6 g,2.9 mmol), amide (0.55 g, 3.6 mmol, 1.25 equiv), and silver triflate (0.9 g,3.6 mmol, 1.25 equiv) in ethyl acetate (4 mL) was heated to 50-70 °C. After thereaction was deemed complete by HPLC analysis, the mixture was cooled to 20 °C and diluted with ethyl acetate (3 mL). A solution of sat’d NaCl (3-4 mL)was added and the mixture stirred at 20 °C for at least 4 h. The silver salts (AgBr and AgCl) are removed by filtration and the resulting biphasic solution transferred to a separatory funnel and the layers separated. The organic layer isthen washed with water (4 mL), 5% NaHCO3 (4 mL), 1 N HCl (4 mL), and water(4 mL). The organic layer is concentrated to dryness and the residue purified by flash column chromatography (5% EtOAc/hexanes) to obtain pure oxazole product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With silver(I) trifluoromethoxide In ethyl acetate at 70℃; for 17h; Darkness; | General procedure for oxazole cyclization: General procedure: A mixture of bromo-ketone (0.6 g,2.9 mmol), amide (0.55 g, 3.6 mmol, 1.25 equiv), and silver triflate (0.9 g,3.6 mmol, 1.25 equiv) in ethyl acetate (4 mL) was heated to 50-70 °C. After thereaction was deemed complete by HPLC analysis, the mixture was cooled to 20 °C and diluted with ethyl acetate (3 mL). A solution of sat’d NaCl (3-4 mL)was added and the mixture stirred at 20 °C for at least 4 h. The silver salts (AgBr and AgCl) are removed by filtration and the resulting biphasic solution transferred to a separatory funnel and the layers separated. The organic layer isthen washed with water (4 mL), 5% NaHCO3 (4 mL), 1 N HCl (4 mL), and water(4 mL). The organic layer is concentrated to dryness and the residue purified by flash column chromatography (5% EtOAc/hexanes) to obtain pure oxazole product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With N-iodo-succinimide; [bis(trifluoromethanesulfonyl)imidate](triphenylphosphine)gold(I) In 1,2-dichloro-ethane; toluene at 85℃; for 14h; | General Procedure: General procedure: To a stirred solution of the substrate (1 mmol) in CH2Cl2 or (CH2Cl)2 (0.1 M) were added Ph3PAuNTf2 (0.025 mmol, 19 mg; complex Ph3PAuNTf2 toluene, 2:1) followed by N-iodosuccinimide (1.1 mmol, 248 mg). The resulting solution was stirred at r.t. or under reflux until complete conversion of the starting material. After removal of the solvent under reduced pressure, the crude material was purified by flash column chromatography using different gradients of hexanes and EtOAc to obtain the pure desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With bis[chloro(1,2,3-trihapto-allylbenzene)palladium(II)]; potassium hydroxide; tert-butyl XPhos In ethanol at 50℃; for 6h; | |
93% | With bis[chloro(1,2,3-trihapto-allylbenzene)palladium(II)]; TPGS-750-M; sodium t-butanolate; tert-butyl XPhos In water at 50℃; for 16h; Inert atmosphere; Green chemistry; | |
89% | With bis(η3-allyl-μ-chloropalladium(II)); sodium t-butanolate; tert-butyl XPhos In water at 50℃; for 0.5h; Inert atmosphere; | 1.4.3 1.4 Preparation of 4-methoxy-N-(m-tolyl)benzamide General procedure: An amine (1.2 eq), an aryl bromide (1.0 eq), [(7i-allyl)PdCl]2 catalyst (0.005 eq), a phosphine ligand (0.020 eq) and a base (1.50 eq) were added under an Argon atmosphere into a 5.0 mL microwave vial containing a magnetic stir bar and Teflon- lined septum. HPMC in water solution (40-60 cps, 3 ml of 2 wt % in degassed Millipore water) was added under a positive flow of argon (however, any liquid components were always added after the solvent). The reaction mixture was stirred at 1200 rpm for the indicated time at the indicated temperature. To the reaction mixture were added ethyl acetate and saturated aqueous sodium sulfate solution. The organic phase was separated from the solid. The solid was washed three times with ethyl acetate. The combined ethyl acetate phases were dried in vacuo and the residue was further purified by flash chromatography on silica gel (0-30% ethyl acetate/heptane).; According to the general procedure II, 4-methoxybenzamide (181 mg, 1.20 mmol), 3 -bromo -toluene (171 mg, 0.98 mmol), [(7i-allyl)PdCl]2 catalyst (5.6mg, 0.011 mmol), di-tert-butyl(2',4',6'-triisopropyl-[l,l '-biphenyl]-2-yl)phosphine (tBuXPhos) ligand (18.3 mg, 0.043 mmol), NaO-t-Bu (141 mg, 1.50 mmol) and a HPMC-solution (4-6 cps, 2 wt % in 0.35 ml degassed Millipore water) were stirred at 1200 rpm for 30 min at 50°C. To the reaction mixture were added 20 ml of ethyl acetate and 3 ml of saturated aqueous sodium sulfate solution. The organic phase was separated from the solid. The solid was washed three times with ethyl acetate. The combined ethyl acetate phases were dried in vacuo and the residue was further purified by flash chromatography on silica gel (0-100% ethyl acetate/cyclohexane). The desired product was obtained as an off- white solid (221 mg, 89% yield, 95% purity). ESI-MS: m/z (%): 242.20 (100, [M+H]+).1H NMR (600MHz, |
With D-glucose; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; copper(ll) bromide; sodium t-butanolate In water at 25℃; for 20h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With diphenyl hydrogen phosphate In diethyl ether; toluene at 20℃; for 18h; | General Procedure for the Synthesis of the Carboniolamide General procedure: To a reaction vial charged with amide (1.0mmol), glyoxylate (1.0 mmol), and diphenyl hydrogen phosphate (25.0 mg, 0.1 mmol) was added Et2O (4 mL). Then the sealed reaction mixture was stirred at r.t. for the specified time. The obtained slurry was then filtered, and the precipitate was washed with a minimum amount of cold Et2O to give the compound as a white powder. |
84% | With diphenyl hydrogen phosphate In diethyl ether; toluene at 20℃; for 18h; Sealed tube; | General Procedure for the Synthesis of the Carboniolamide: General procedure: To a reaction vial charged with amide (1.0mmol), glyoxylate (1.0 mmol), and diphenyl hydrogenphosphate (25.0 mg, 0.1 mmol) was added Et2O (4 mL).Then the sealed reaction mixture was stirred at r.t. for the specified time. The obtained slurry was then filtered, and the precipitate was washed with a minimum amount of cold Et2O to give the compound as a white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With dmap; ammonia; palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 90℃; for 0.333333h; Microwave irradiation; | General Procedure for the preparation ofbenzamides General procedure: To a dry microwave vial, aryl halide (Br, I) (1 eqv.) and amine (2 eqv.)were taken in dry 1,4-dioxane. 5 mol% of Pd(OAc)2, 5 mol% ofXantphos and DMAP (2 eqv.) were added followed by (0.25 or 0.3) equivalents ofCo2(CO)8 and the vial was sealed immediately andmicrowave irradiated for 20 min. The reaction mixture was concentrated under reducedpressure, diluted with ethyl acetate and water, the ethyl acetate layerseparated, dried over sodium sulphate, and concentrated. The crude products obtained were subjected topurification by flash chromatography on silica gel coloumn eluting withpetroleum ether and ethyl acetate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With tert.-butylhydroperoxide; ammonia; iodine; In water; at 100℃; for 3h;Sealed tube; Green chemistry; | General procedure: A sealed tube equipped with a magnetic stirring bar was charged with ethylarene (1, 1.0 mmol), aq NH3 (2, 25% aq solution,10.0 mmol), I2 (1.1 mmol), and TBHP (6.0 mmol, 70% aq solution) at r.t. The resulting mixture was heated to 100 C for 3.0 h. After completion of the reaction (monitored by TLC), sat.Na2S2O3 solution (10 mL) was added to the reaction mixture,and it was extracted with EtOAc (2 × 20 mL). The organic layer was washed with brine solution (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on 100-200 mesh silica gel using EtOAc-n-hexane (1:2) as the eluent to obtain the corresponding benzamide 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: 4-methoxyphenylacetamide; methyl 4-((4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl)benzoate hydrochloride With acetic acid; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 0.166667h; Stage #2: With sodium cyanoborohydride In dichloromethane at 20℃; for 8h; | 40.1 Step 1: Synthesis of methyl4-((4-(4-(4-methoxybenzyl)piperazin- I -yl)- IH-pyrrolo[23-blpyridin- 1-yl)methyl)benz oate (compound 9-3) The compound of formula 8-1 (0.06 g, 0.16 mmol) and DIPEA (0.02 g, 0.19 mmol) were dissolved in methylene chloride (4 mL) at room temperature. To the solution, 4-methoxybenzamide (0.04 g, 0.31 mmol) and acetic acid (0.02 g, 0.31 mmol) were added, followed by stirring for 10 minutes. NaCNBH3 (0.01 g, 0.19 mmol) was added to the stirred solution, followed by stirring at the same temperature for 8 hours. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (Si02, 4 g cartridge; ethyl acetate / hexane = from 30% to 60%) to afford the desired compound of formula 9-3 (0.07 g, 89%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With silica gel; hydrazine In neat (no solvent) at 130℃; for 20h; Inert atmosphere; Sealed tube; | 3 Conversion of benzamides to benzhydrazides General procedure: These compounds were prepared using the standard procedure at 130°C for 20-24h. For each reaction, the crude product was adsorbed onto silica gel and purified on a 15cm×2.5cm silica gel column eluted with 80% EtOAc in hexanes. The isolated yields are given in Table 7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With ammonium peroxodisulphate In 1,4-dioxane at 100℃; for 4h; Green chemistry; | |
85% | With oxalyl dichloride In toluene at 0℃; for 2.5h; Reflux; | 4.2. General experimental procedures General procedure: General Procedure for syntheses of methylenebisamides from aimdes and DMSO in Toluene with a substoichiometric amount of (COCl) 2 . To a solution of DMSO (10 mmol, 2 equivalents) in toluene (5 mL) was added dropwise a solution of oxalyl chloride (1.65 mmol, 0.33 equivalents) in toluene (5 mL) at 0 °C. Then a solution of amide (1) (5 mmol, 1 equivalent) in toluene (10 mL) was added subsequently. After addition, the reaction mixture was heated to reflux in an oil bath and monitored by TLC or GC-MS. For the reactions of substrates 1a-cc and all the reactions with DMSO-d6 , the reaction mixture was poured into 120 mL petroleum ether after completion. The precipitated product (2a-2cc and all the deuterated products) was filtered and dried at 45 C in a vac- uum oven for 1 h. The products (2dd and 2ee) were obtained by removing toluene under reduced pressure without further purifi- caiton. The pure products (2ffand 2 gg) were obtained by purifi- cation on flash column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: 4-methoxyphenylacetamide With sodium hydride In dimethyl sulfoxide; paraffin oil for 0.5h; Stage #2: acridine With potassium hexacyanoferrate(III) In dimethyl sulfoxide; paraffin oil at 20℃; for 8h; | Synthesis of N-(acridin-9-yl)acylamides 2-10 (Generalmethod). General procedure: The reaction was performed in a vessel protectedfrom air moisture. Sodium hydride (60% suspension in oil,120 mg, 3 mmol) was added with stirring to a solution ofthe appropriate amide (3 mmol) in anhydrous DMSO(4 ml). After the evolution of hydrogen ceased (~0.5 h), thereaction mixture was treated with acridine (1) (89.5 mg,0.5 mmol), K3Fe(CN)6 (1 g, 3 mmol) and vigorously stirredat room temperature for the duration indicated in Table 1.Then the mixture was poured into cold water (50 ml) andacidified with dilute HCl solution to pH ~7. The precipitatewas filtered off, washed with water, dried (when isolatingthe amide 5, the precipitate on filter was washed at firstwith 100 ml of hot water (~90°C) to remove the exess of 4-nitrobenzamide). The products were further purified byrecrystallization from the appropriate solvents. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With dmap In neat (no solvent) for 4h; Milling; chemoselective reaction; | General procedure for N-tert-butoxycarbonylation of amides General procedure: To a stainless steel milling jar (50 mL) equipped with stainless steel milling balls (7.0-10.0 mm in diameter) were added amide (1 or 3, 1.0 mmol, 1.0 equiv.), Boc2O (1.2-4.0 mmol, 1.2-4.0 equiv.) and DMAP (6.1-36.6 mg, 0.05-0.30 mmol). The milling jar was clamped into planetary ball mill and milled at 30 Hz for given time. The operation cycle was 60 min on, 10 min off to take sample for TLC. After the elapsed time, the reaction mixture was transferred from the milling jar into a flask with aid of CH2Cl2 (3 x 5 mL)and then was concentrated by rotavapor to afford the crude product, which was purified by flash column chromatography on silica gel using a gradient of ethyl acetate in petroleum ether. |
90% | With dmap In acetonitrile at 20℃; for 15h; Inert atmosphere; Sealed tube; | |
86% | With dmap In acetonitrile at 20℃; for 15h; |
62% | With dmap In dichloromethane at 0 - 20℃; Inert atmosphere; | |
40% | With dmap In dichloromethane at 0 - 23℃; Inert atmosphere; | |
40% | With dmap In dichloromethane at 0 - 20℃; Inert atmosphere; | |
With dmap In dichloromethane at 0 - 20℃; Inert atmosphere; | General procedure for N,N-Boc2-amide synthesis. General procedure: A previously published procedure was followed. An oven-dried round-bottomed flask (100 mL) equipped with a stir bar was charged with the primary amide (8.26 mmol, 1.0 equiv.), 4-dimethylaminopyridine (DMAP) (typically, 0.10 equiv.),and dichloromethane (typically, 25 mL), placed under a positive pressure of nitrogen, and subjected to three evacuation/backfilling cycles under high vacuum.84 Di-tert-butyl dicarbonate (typically, 2.0 equiv.) was added portion-wise to the reaction mixture with vigorous stirring at 0 °C, and the reaction mixture was stirred overnight at room temperature. After the indicated time, the reaction mixture was concentrated and unless stated otherwise, purified directly by chromatography on silica gel (hexanes/ethyl acetate) to give analytically pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With toluene-4-sulfonic acid; In toluene; for 1h;Reflux; Dean-Stark; Microwave irradiation; | General procedure: A mixture of amide (1.29 mmol, 1 equiv), phenyl pyruvic acid (323 mg, 1.93 mmol, 1.5 equiv) and pTsOH (250 mg, 1.29 mmol, 1 equiv) in anhydrous toluene (the volume required to obtain a concentration of 0.3M respect to the amide) was refluxed under microwave heating (150 watts, 60 min) using a Dean-Stark trap. The reaction was cooled to room temperature and purified by flash column chromatography on silica gel (8:2 hexanes/EtOAc) to provide the desired product as a yellow powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | General procedure: A mixture of the amide (1.29 mmol, 1 equiv), <strong>[156-06-9]phenylpyruvic acid</strong> (323 mg, 1.93 mmol, 1.5 equiv) and pTsOH acid (250 mg, 1.29 mmol, 1 equiv) in anhydrous toluene (the volume required to obtain a concentration of 0.3M respect to the amide) was refluxed under microwave heating (150 watts, 60 min) using a Dean-Stark trap. Then, the reaction was cooled to 0 oC in an ice-water bath and triethylamine (0.3 mL, 1.94 mmol, 1.5 equiv) and sec-butylamine (0.4 mL, 2.58 mmol, 2 equiv) were added sequentially via syringe and the stirring continued for two hours at room temperature. The mixture reaction cooled down to 0 oC, followed by the dropwise addition of POCl3 (0.61 mL, 6.45 mmol, 5 equiv). The resultant mixture was refluxed (90 watts, 20 min), cooled down to 0 oC and quenched with saturated aqueous NaHCO3 (pH = 9). The two phases were separated and the aqueous layer was extracted with EtOAc (5 mL x 5). The organic extracts were combined, washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide a viscous oil. The crude product was subjected to purification by flash column chromatography on silica gel (98:02 hexanes/EtOAc) to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With copper(l) iodide; 1,10-Phenanthroline In benzene at 60℃; for 11h; Inert atmosphere; | |
99% | With copper(l) iodide; 1,10-Phenanthroline In benzene at 60℃; for 11h; Inert atmosphere; | 1 General procedure for the Cu-catalyzed mono-N-alkylation of primary amides using acyclic alkylsilyl peroxides (Tables 1-3) General procedure: To a suspension of primary amide (0.2 mmol, 1.0 equiv), CuI (1.9 mg, 5 mol%) and 1,10-phenanthroline (1.8 mg, 5 mol%) in benzene (0.5 mL) was added alkylsilyl peroxide 1 (0.3 mmol, 1.5 equiv) under argon atmosphere. The reaction mixture was stirred at 60°C for 2h. After cooling to room temperature, the reaction mixture was concentrated and analyzed by 1H NMR for the determination of NMR yield using DMF as an internal standard. The residue was purified by flash column chromatography on silica gel (eluting with ethyl acetate/hexane=2/3) to afford a corresponding product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With potassium hydroxide In dimethyl sulfoxide at 20℃; for 16h; | 3.5 4.2. Typical procedure for the synthesis of 2aa General procedure: A mixture of 2-fluorobenzamide (1a, 69.5 mg, 0.5 mmol), MeOH (ca. 32.0 mg, 1.0 mmol), KOH (56.0 mg, 1.0 mmol) and DMSO (2.0 mL) in a 25 mL screw-capped thick-walled Pyrex tube was stirred at room temperature for 16 h, and then water (10 mL) was added to the reaction mixture with stirring, and the mixture was extracted with ethyl acetate three times (3 * 10 mL). The combined organic phases were dried over Na2SO4 overnight. The filtered solution was concentrated under reduced pressure, and the crude residue was purified by column chromatography on silica gel with the use of petroleum ether/ethyl acetate/trimethylamine (gradient mixture ratio from 6:1:0.05 to 2:1:0.05 in volume) to afford 2aa as a white solid in 80% yield (60.7 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium hydride; dimethyl sulfoxide; In paraffin oil; at 20℃; for 1.0h; | General procedure: A solution of the appropriate amide (0.75 mmol) in anhydrous DMSO (4 ml) was stirred at room temperature and treated by adding NaH suspension in paraffin oil (30 mg, 0.75 mmol NaH) and 6- or <strong>[613-51-4]7-nitroquinoline</strong> (87 mg, 0.5 mmol, compounds 7 or 10,respectively). The mixture was vigorously stirred at room temperature for the duration indicated in Table 2. The reaction mixture was then poured onto ground ice (50 g) and after warming to room temperature was acidified with dilute HCl solution to pH ~7. The precipitate that formed was filtered off, washed with water, and dried. The product was recrystallized from a suitable solvent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19%; 52% | With sodium hydride; dimethyl sulfoxide; In paraffin oil; at 20℃; for 1.5h; | General procedure: A solution of the appropriate amide (1 mmol) in anhydrous DMSO (4 ml) was treated at room temperature by adding a suspension of NaH in paraffin oil (40 mg, 1 mmol of NaH) and <strong>[607-34-1]5-nitroquinoline</strong> (1) (87 mg, 0.5 mmol). The mixture was vigorously stirred at room temperature for the duration indicated in Table 1. The reaction mixture was then poured onto ice (50 g) and after warming to room temperature was acidified with dilute HCl solution to pH ~7. The precipitate that formed was filtered off, washed with water, and dried. The obtained mixture was separated into fractions by the dry silica gel flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With N-chloro-succinimide; palladium diacetate; trifluoroacetic acid In 1,2-dichloro-ethane at 90℃; for 24h; Sealed tube; regioselective reaction; | 2.1. General procedure for palladium(II)-catalyzed ortho-halogenation of benzamides General procedure: To a clean oven-dried 15 mL sealed tube equipped with magnetic stir bar, benzamide (0.25 mmol, 1.0 equiv), Pd(OAc)2 (5.0 mol%, 2.8 mg), and NXS (0.3 mmol, 1.2 equiv.) were added sequentially. DCE (2.0 mL) was then added to the reaction mixture followed by trifluoroacetic acid (475 μL). The tube was tightly closed and placed in a preheated oil bath of 60 °C and stirred for 24 h. In each case, the reaction was monitored by TLC, and after completion, the reaction mixture was cooled to room temperature. The solvent was evaporated under reduced pressure and then diluted with ethyl acetate followed by neutralization with a saturated solution of sodium bicarbonate. After extraction with ethyl acetate (15 mL×3), the organic layer was washed with brine solution and dried over sodium sulphate. After evaporation of the solvent, the crude mixture was purified by column chromatography silica gel using ethyl acetate/hexanes as the eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With n-butyllithium; cyclopentyl methyl ether; In hexane; at 115℃; for 24h;Inert atmosphere; | General procedure: To a solution of the amide derivative (1: 0.20 mmol) in CPME (1.0 mL) wassequentially added trialkyl phosphate (0.60 mmol, 3.0 equiv.) and n-BuLi (0.14 mL,0.37 mmol, 2.65 mol/L in n-hexane, 1.8 equiv.). After stirring at 115 C under argon for24 h, the mixture was quenched with brine (2 mL) and extracted with EtOAc (50 mL ×3). The combined organic layers were dried over Na2SO4 and concentrated in vacuo.The residue was purified by silica-gel column chromatography to give the N-mono alkylamide product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With chlorine[2-(4,5-dihydro-1H-imidazol-2-yl)-6-methoxypyridine](pentamethylcyclopentadienyl)iridium(III) chloride; potassium-t-butoxide In 1,4-dioxane at 80℃; for 10h; Schlenk technique; | Quinazolines 3 from 1 and 2; General Procedure General procedure: In a 10.0 mL Schlenk tube, a mixture of 1 (1.0 mmol), 2 (1.1 mmol), t-BuOK (1.1 mmol), 1,4-dioxane (2.0 mL), and TC-6 (0.1 mol%) was reactedat 80 °C in the air. After completion of the reaction, the mixturewas extracted with EtOAc (3 × 10 mL). The combined EtOAc layerswere then dried (MgSO4) and concentrated in vacuum. The resultingcrude product was purified by silica gel chromatography using a mixtureof EtOAc/PE (1:20-1:50). |
70% | With manganese(I) pentacarbonyl bromide; N,N,N',N'',N'''-pentamethyldiethylenetriamine; potassium-t-butoxide In toluene at 130℃; for 36h; Sealed tube; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With copper dichloride In dimethyl sulfoxide at 120℃; for 11h; | General procedure for CuCl2-promoted oxidative C-N bond cleavage of N-benzoyl aminoacids for primary aryl amides 2. General procedure: A mixture of benzoyl amino acid 1 (0.5 mmol), CuCl2 (85 mg,0.5 mmol), and DMSO (0.5 mL) was placed in a 25 mL flask under air. The tube was heated at120 for 11 h. The reaction mixture was cooled, diluted with ethyl acetate (10 mL), filtered through Celite, and concentrated in vacuo. The residue was purified by silica gel columnchromatography with ethyl acetate/ petroleum ether (ethyl acetate/ petroleum ether = 1:3) toafford the desired product 2. |
93% | With copper dichloride In dimethyl sulfoxide at 120℃; for 11h; | General procedure for CuCl2-promoted oxidative C-N bond cleavage of N-benzoyl amino acids for primary aryl amides 2. General procedure: A mixture of benzoyl amino acid 1 (0.5 mmol), CuCl2 (85 mg, 0.5 mmol), and DMSO (0.5 mL) was placed in a 25 mL flask under air. The tube was heated at 120 for 11 h. The reaction mixture was cooled, diluted with ethyl acetate (10 mL), filtered through Celite, and concentrated in vacuo. The residue was purified by silica gel column chromatography with ethyl acetate/ petroleum ether (ethyl acetate/ petroleum ether = 1:3) to afford the desired product 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With [bis(acetoxy)iodo]benzene; ammonia In methanol at 0 - 20℃; for 2h; Inert atmosphere; | N-Substituted Ureas; General Procedure A General procedure: (Diacetoxyiodo)benzene (1.0 mmol, 2.0 equiv) was added in one portion to a stirred solution of the amide (0.5 mmol, 1.0 equiv) in NH3/MeOH (7 M, 1.25 mL, 17.5 equiv) at 0 °C under argon. After 30 min at 0 °C, the reaction mixture was allowed to reach room temperature and was left to stir for 90 min. After completion (monitored by TLC and 1H NMR), the reaction mixture was concentrated under reduced pressure and the crude product was purified by flash chromatography on silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; | 3.5. General Procedure for the Preparation of Compounds (2), (5-25) General procedure: To a solution of the appropriate carboxamide compound (1.06 mmol, 1.5 equiv.) in dry DMF (3mL) at 0 °C under N2, 60% sodium hydride in oil (25.5 mg, 1.06 mmol, 1.5 equiv) were added portionwise. The resulting mixture were added dropwise to a solution of 4-chloro-2-(trichloromethyl)quinazoline (4) (200 mg, 0.71 mmol, 1.0 equiv.) in dry DMF (2 mL) at 0 °C under N2.The reaction was stirred overnight at rt. Then, the excess of NaH was hydrolyzed with ice. Thereaction mixture was extracted with EtOAc and washed three times with brine. The organic layerwas dried with Na2SO4, filtered, and evaporated. The crude product was purified by silica gel columnchromatography and recrystallized from appropriate solvent to give the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Stage #1: 4-methoxyphenylacetamide With bis(cyclopentadienyl)dihydrozirconium; 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane at 20℃; for 24h; Inert atmosphere; Stage #2: With hydrogenchloride In diethyl ether Inert atmosphere; | 67 The bis(cyclopentadiene) zirconium dihydride (denoted as Cp2ZrH2, 0.01mmol, 2.23mg), 4-methoxybenzamide (denoted as 5c, 0.2mmol, 30.2mg) and pinacol borane (denoted as Is HBpin, 0.6mmol, 87μL), stirred at room temperature under nitrogen (1atm) atmosphere for 24h, treated with hydrogen chloride in ether solution to obtain the hydrochloride compound of formula 6c (white solid,(4-Methoxyphenyl) methylamine hydrochloride). The isolated yield was 83%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With calcium hydroxide In neat (no solvent) at 80℃; for 2.3h; Sealed tube; | General Methylation Procedure B (Neat Conditions) General procedure: A 10-mL glass reaction tube fitted with a resealable Teflon valve wascharged with the heteroatom nucleophile substrate (1.0 mmol, 1.0equiv), Ca(OH)2 (100 mg, 1.35 mmol, 1.35 equiv), and TMP (0.20 mL,1.7 mmol, 1.7 equiv). The flask was sealed and heated at 80 °C withoutstirring until TLC indicated complete conversion. The reactionwas then worked up as described below. Workup Procedure AAfter complete conversion, 1 N HCl (5 mL) was added and the mixturewas extracted with CH2Cl2 (10 mL). The organic phase was separated,washed with H2O (20 mL), dried over Na2SO4, filtered, and then concentratedin vacuo. The resulting residue was purified by silica gelcolumn chromatography to afford the desired methylated product.Workup Procedure BAfter complete conversion, petroleum ether (5 mL) was added, andthe solid was smashed into fine particles using a spatula and sonicatedfor 5 min. The resulting residue was then directly subjected to silicagel column chromatography to afford the desired methylated product.Workup Procedure CAfter complete conversion, CH2Cl2 (5 mL) was added, and the mixturewas filtered through a pad of Celite, washed with H2O (10 mL), andextracted with EtOAc (5 × 20 mL). The organic phase was separated,dried over Na2SO4, filtered, and concentrated in vacuo. The resultingresidue was purified by silica gel column chromatography to affordthe desired methylated product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With ammonium bicarbonate; copper(II) nitrate In dimethyl sulfoxide at 140℃; for 30h; Autoclave; | Representative Procedure for Conversion of Various Arylethenesto Aromatic Nitriles General procedure: To a stainless steel autoclave lined with Teflon, 0.5 mmol substrate,0.075 mmol Cu(NO3)2, 1 mmol (NH4)2CO3, and 2 mLDMSO were added. Then the reactor was filled with 2 MPaoxygen and was heated under magnetic stirring at 140 °C for 30h or 40 h (Caution: the use of the high-pressure oxygen ispotentially hazardous. Thus, experiments using the high-pressureoxygen must only be carried out under rigorous safety precautions,and it is required to use the appropriate high-pressurereactor to avoid the potential leakage or explosion of the gas).Once the reaction time was reached, the mixture was cooled toroom temperature, diluted with 30 mL diethyl ether, and filteredvia a Celite pad. The organic mixture was washed withwater (3 × 5 mL), dried with anhydrous sodium sulfate, and concentratedin vacuum. GC analysis provided the GC yields of theproduct with an internal standard. In addition, the combinedcrude product from another 1-5 parallel experiments was purifiedby column chromatography and identified by 1H NMR and13C NMR spectroscopy. All the products are the known compounds,and the analytical data of several typical compoundsare as follows: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With chlorine[2-(4,5-dihydro-1H-imidazol-2-yl)-6-methoxypyridine](pentamethylcyclopentadienyl)iridium(III) chloride; potassium-t-butoxide In 1,4-dioxane at 80℃; for 15h; Schlenk technique; | Quinazolines 3 from 1 and 2; General Procedure General procedure: In a 10.0 mL Schlenk tube, a mixture of 1 (1.0 mmol), 2 (1.1 mmol), t-BuOK (1.1 mmol), 1,4-dioxane (2.0 mL), and TC-6 (0.1 mol%) was reactedat 80 °C in the air. After completion of the reaction, the mixturewas extracted with EtOAc (3 × 10 mL). The combined EtOAc layerswere then dried (MgSO4) and concentrated in vacuum. The resultingcrude product was purified by silica gel chromatography using a mixtureof EtOAc/PE (1:20-1:50). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With oxalyl dichloride In toluene at 0℃; for 2.5h; Reflux; | 4.2. General experimental procedures General procedure: General Procedure for syntheses of methylenebisamides from aimdes and DMSO in Toluene with a substoichiometric amount of (COCl) 2 . To a solution of DMSO (10 mmol, 2 equivalents) in toluene (5 mL) was added dropwise a solution of oxalyl chloride (1.65 mmol, 0.33 equivalents) in toluene (5 mL) at 0 °C. Then a solution of amide (1) (5 mmol, 1 equivalent) in toluene (10 mL) was added subsequently. After addition, the reaction mixture was heated to reflux in an oil bath and monitored by TLC or GC-MS. For the reactions of substrates 1a-cc and all the reactions with DMSO-d6 , the reaction mixture was poured into 120 mL petroleum ether after completion. The precipitated product (2a-2cc and all the deuterated products) was filtered and dried at 45 C in a vac- uum oven for 1 h. The products (2dd and 2ee) were obtained by removing toluene under reduced pressure without further purifi- caiton. The pure products (2ffand 2 gg) were obtained by purifi- cation on flash column chromatography. |
Tags: 3424-93-9 synthesis path| 3424-93-9 SDS| 3424-93-9 COA| 3424-93-9 purity| 3424-93-9 application| 3424-93-9 NMR| 3424-93-9 COA| 3424-93-9 structure
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P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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