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CAS No. : | 626-35-7 | MDL No. : | MFCD00007403 |
Formula : | C4H7NO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FTKASJMIPSSXBP-UHFFFAOYSA-N |
M.W : | 133.10 | Pubchem ID : | 69379 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.75 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 30.73 |
TPSA : | 72.12 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.77 cm/s |
Log Po/w (iLOGP) : | 0.94 |
Log Po/w (XLOGP3) : | 0.48 |
Log Po/w (WLOGP) : | -0.17 |
Log Po/w (MLOGP) : | -0.9 |
Log Po/w (SILICOS-IT) : | -1.55 |
Consensus Log Po/w : | -0.24 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.7 |
Solubility : | 26.3 mg/ml ; 0.198 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.56 |
Solubility : | 3.63 mg/ml ; 0.0273 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.11 |
Solubility : | 102.0 mg/ml ; 0.769 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.13 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P501-P210-P264-P280-P302+P352-P370+P378-P337+P313-P305+P351+P338-P362+P364-P332+P313-P403+P235 | UN#: | N/A |
Hazard Statements: | H315-H319-H227 | 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 |
---|---|---|
81% | With 1,4-diaza-bicyclo[2.2.2]octane In ethanol at 80℃; for 72 h; Ace pressure tube | INTERMEDIATE 4 - PREPARATION OF Ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate.; To a mixture of propargyl alcohol (1.0 ml 16.76 mmol) and ethyl 2-nitroacetate (3.79 ml 33.52 mmol) in ethanol (23.5 ml.) in an Ace pressure tube was added 1 ,4- diazobicyclo[2.2.2]octane (DABCO, 0.194 g; 1.68 mmol). The tube was heated at 800C for 72 h. After cooling, the mixture was evaporated to dryness and the residue was purified by flash chromatography on silica gel (eluent: 0 to 6percent methanol in dichloromethane) to yield 2.32 g (81 percent) of ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate as an oil. ESI/APCI(+): 172 (M+H). |
180 g | With 1,4-diaza-bicyclo[2.2.2]octane In ethanol at 80℃; for 16 h; | Reference Production Example 42 (0684) Ethyl nitroacetate (198 mL, 1.78 mmol), propargyl alcohol (100 g, 1.78 mmol) and 1,4-diazabicyclo[2.2.2]octane (20.0 g, 178.3 mmol) were added to ethanol (1 L), and the mixture was heated at 80°C for 16 hours. Thereafter, the mixture was cooled to room temperature, and the solvent was concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 180 g of ethyl 5-hydroxymethylisoxazole-3-carboxylate represented by the following formula. 1H-NMR (CDCl3, TMS, δ (ppm)) : 6.67 (s, 1H), 4.83(d, 2H), 4.43 (q, 2H), 2.65 (brs, 1H), 1.41 (t, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 1,4-diaza-bicyclo[2.2.2]octane In ethanol at 150℃; for 0.333333 h; Microwave irradiation | INTERMEDIATE 15 - PREPARATION OF Ethyl δ-cyclopropylisoxazole-S-carboxylate.; A solution of ethynylcyclopropane (0.40 ml 4.58 mmol), ethyl 2-nitroacetate (1.30 ml 1 1.46 mmol), and 1 ,4-diazobicyclo[2.2.2]octane (DABCO, 0.053 g; 0.458 mmol) in ethanol(3 ml.) was irradiated in a microwave oven at 150 0C for 20 min and was then evaporated.The residue was dissolved in ethyl acetate and the solution was washed with water. The organic layer was evaporated and the residue was purified by flash chromatography on silica gel (eluent: 20 to 100percent of dichloromethane in heptane) to afford 0.765 g (92 percent) of ethyl 5-cyclopropylisoxazole-3-carboxylate as a yellow oil.ESI/APCI(+): 182 (M+H). |
0.4 g | With 1,4-diaza-bicyclo[2.2.2]octane In ethanol at 150℃; for 0.5 h; Inert atmosphere | A mixture of ethyl 2-nitroacetate (1.0 g, 7.6 mmol, 2.5 eq), ethynylcyclopropane (0.2 g, 3.0 mmol, 1 eq),DABCO (33.9 mg, 303 imol, 0.1 eq) in 2 mL of EtOH was degassed and purged with N2 three times. The mixture was stirred at 150 °C for 30 mm under microwave condition. It was evaporated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02 eluting with petroleum ether:ethyl acetate = 30:1) to give 0.4 g of ethyl 5 -cyclopropylisoxazole-3 -carboxylate as a colorless liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With piperidine; In toluene; at 150℃; for 0.333333h;Microwave irradiation; | General procedure: To a stirred mixture of corresponding salicylilaldehyde oraminobenzaldehyde (5 mmol) and 20 cm3 toluene in a20-cm3 Pyrex microwave vial, equipped with a magneticstir bar, 666 mm3 ethyl 2-nitroacetate (6 mmol, 1.2 equiv)and 100 mm3 piperidine (1 mmol, 0.2 equiv, 20 mol %)were added. The reaction mixture was capped with aTeflon septum, stirred for 10 s and subjected to microwaveheating for 20 min (fixed hold time) at 150 C and subsequently cooled to 50 C. The resulting reactionmixture was cooled down overnight at 0 C, the precipitateseparated by filtration and washed with cold toluenefollowed by excess of cold n-heptane. The resulted productwas dried overnight and used without further purification inthe next synthetic step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With <i>L</i>-proline In ethanol at 20℃; for 4h; | General procedure for the synthesis of 3-nitrocoumarins3 and 5 General procedure: To the solution of salicylaldehyde (1 mmol) and ethylnitroacetate (1 mmol) in 3 cm3 ethanol, L-proline(30 mol %) was added. The reaction mixture was stirredfor an appropriate time. After completion of the reaction(as monitored by TLC), the solvent was evaporated and theproduct so obtained was dissolved in 12 cm3 CHCl3 andwashed with water (3 9 10 cm3). The organic layer waswashed with 10 cm3 brine, dried over anhydrous NaSO4,and evaporated under reduced pressure. The residue wasrecrystallized from ethanol (3, 5a, 5b, and 5h) or purifiedby silica gel column using chloroform/methanol (9:1) aseluent (5c-5g). The combined aqueous layers, containingL-proline, were evaporated, washed with ether, dried at45 C, and reused for next run. |
With 4-methyl-morpholine; titanium tetrachloride Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With <i>L</i>-proline In ethanol at 20℃; for 4h; | General procedure for the synthesis of 3-nitrocoumarins3 and 5 General procedure: To the solution of salicylaldehyde (1 mmol) and ethylnitroacetate (1 mmol) in 3 cm3 ethanol, L-proline(30 mol %) was added. The reaction mixture was stirredfor an appropriate time. After completion of the reaction(as monitored by TLC), the solvent was evaporated and theproduct so obtained was dissolved in 12 cm3 CHCl3 andwashed with water (3 9 10 cm3). The organic layer waswashed with 10 cm3 brine, dried over anhydrous NaSO4,and evaporated under reduced pressure. The residue wasrecrystallized from ethanol (3, 5a, 5b, and 5h) or purifiedby silica gel column using chloroform/methanol (9:1) aseluent (5c-5g). The combined aqueous layers, containingL-proline, were evaporated, washed with ether, dried at45 C, and reused for next run. |
84% | With piperidine In benzene for 8h; Dean-Stark; Reflux; | Synthesis of 3-nitrocoumarin derivatives General procedure: A mixture of 2-hydroxybenzaldehyde (5.0 mmol), ethyl nitroacetate (6.0 mmol, 1.2 equiv), and piperidine (3-4 drops) in benzene was taken in a round bottom flask fitted with Dean-Stark apparatus and a condenser. The reaction mixture was then refluxed for 8 hours. After the completion of the reaction, the mixture was cooled down to room temperature and hexanes (50 mL) was added to precipitate the product. The solid was filtered, washed with excess hexanes, and dried to obtain the desired coumarin derivatives. |
84% | With <i>L</i>-proline In ethanol at 20℃; for 4h; | 4.1.1 3-nitrocoumarin 2 Salicylaldehyde (1mmol) and ethyl nitroacetate (1mmol) were dissolved in 3mL ethanol and l-proline (30mol %) was added. The reaction mixture was stirred for four hours at room temperature and the status of the reaction was monitored by TLC. After completion of the reaction the solvent was evaporated and the crude product was dissolved in 12mL CHCl3 and washed with water (3×10mL). The organic layer was separated and washed with brine (2×10mL), dried over anhydrous NaSO4, and evaporated under reduced pressure. The residue was recrystallized from ethanol. Yield: 84%, mp 142-143°C (lit [36]. 141-142°C); 1H NMR (CDCl3): 8.78 (s, 1H, H-4), 7.76 (m, 2H, H-5 and H-7), 7.46 (m, 2H, H-6 and H-8). |
82% | With piperidine In benzene at 110℃; for 6h; Dean-Stark; | |
39% | With 2,6-di-tert-butyl-4-methyl-phenol; morpholinium para-toluenesulfonate In toluene at 100℃; for 1h; Molecular sieve; Sealed tube; Inert atmosphere; | |
30% | With sodium acetate In acetic anhydride; acetic acid Heating; | |
With 4-methyl-morpholine; titanium tetrachloride Yield given. Multistep reaction; | ||
With acetic anhydride; sodium hydride at 20℃; for 3h; | ||
With acetic anhydride; sodium hydride at 20℃; for 3h; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With ammonium hydroxide for 72h; | |
75% | With ammonium hydroxide In water at 20℃; for 96h; | A intermediate 1: 2-Chloro-6-cyciopropyi-3 -nitropyridine. Step A: 2-Nitroacetarnide. Ethyl nitroacetate (5.6 mL, 50.5 rnmol) was added to ammoniuni hydroxide (28% in water, 34 mL, 505 mmol) and this was stirred for four days at it The reactionwas cooled to 0 °C and acidified to pH = I with concentrated HCI. This was extracted with EtOAc (x3) and the combined extracts were dried (Na2SO4), filtered, and concentrated in vaeuo to give a white solid (3.95 g, 75%). ‘H NMR (500 MI-k, DM50-cl6) ö 7.84 (s, IH), 7.62 (s, IH), 5.28 (s, |
With ammonia In ethanol at 80℃; for 3h; |
With ammonia; water at 20℃; for 72h; | 1.1 A mixture of ethyl nitroacetate (80.0 g, 601 mmol) in ammonium hydroxide (25% NH3 in water, 400 mL) was stirred at room temperature for 3 days, and then the solution was concentrated by air-drying. The residue was dissolved in water (450 mL). To the solution was added 2,4-pentanedione (73.1 g, 730 mmol), pyridine (16.2 mL, 200 mmol) and acetic acid (11.4 mL, 200 mmol), and the mixture was stirred for an additional 7 days. The resulting precipitates were collected by filtration and dried under reduced pressure to give 35.0 g (35%) of the title compound as yellow solids: 1H-NMR (DMSO-d6) δ 12.44 (1 H, br.s), 6.06 (1 H, s), 2.19 (3H, s), 2.13 (3H, s). | |
35 g | With ammonia In water at 10 - 35℃; for 24h; | 45.A A) 2-nitroacetamide A) 2-nitroacetamide An aqueous solution of nitroethyl acetate (45.0 g) in 28% ammonia (300 mL) was stirred at room temperature for 24 hr, and the solvent was evaporated under reduced pressure. To the residue was added water, the pH of the mixture was adjusted to 3 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (35 g). 1H NMR (400 MHz, DMSO-d6) δ 5.28 (2H, s), 7.64 (1H, s), 7.86 (1H, s). |
With ammonia In methanol at 65℃; for 5h; Sealed tube; | 153 Intermediate 153A: 2-nitroacetamide Ethyl 2-nitroacetate (1 g, 7.51 mmol) was dissolved inNH3 in MeOH (7 M, 16.10 mL, 113 mmol) and heated to 65 °C in a sealed tube at for 5 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to give Intermediate 153A, which was used directly in the subsequent reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With <i>L</i>-proline In ethanol at 20℃; for 5h; | General procedure for the synthesis of 3-nitrocoumarins3 and 5 General procedure: To the solution of salicylaldehyde (1 mmol) and ethylnitroacetate (1 mmol) in 3 cm3 ethanol, L-proline(30 mol %) was added. The reaction mixture was stirredfor an appropriate time. After completion of the reaction(as monitored by TLC), the solvent was evaporated and theproduct so obtained was dissolved in 12 cm3 CHCl3 andwashed with water (3 9 10 cm3). The organic layer waswashed with 10 cm3 brine, dried over anhydrous NaSO4,and evaporated under reduced pressure. The residue wasrecrystallized from ethanol (3, 5a, 5b, and 5h) or purifiedby silica gel column using chloroform/methanol (9:1) aseluent (5c-5g). The combined aqueous layers, containingL-proline, were evaporated, washed with ether, dried at45 C, and reused for next run. |
43% | With piperidine In toluene at 150℃; for 0.333333h; Microwave irradiation; | General procedure for the synthesis of 3-nitrosubstitutedcoumarins and quinolones General procedure: To a stirred mixture of corresponding salicylilaldehyde oraminobenzaldehyde (5 mmol) and 20 cm3 toluene in a20-cm3 Pyrex microwave vial, equipped with a magneticstir bar, 666 mm3 ethyl 2-nitroacetate (6 mmol, 1.2 equiv)and 100 mm3 piperidine (1 mmol, 0.2 equiv, 20 mol %)were added. The reaction mixture was capped with aTeflon septum, stirred for 10 s and subjected to microwaveheating for 20 min (fixed hold time) at 150 C and subsequently cooled to 50 C. The resulting reactionmixture was cooled down overnight at 0 C, the precipitateseparated by filtration and washed with cold toluenefollowed by excess of cold n-heptane. The resulted productwas dried overnight and used without further purification inthe next synthetic step. |
With acetic anhydride; sodium hydride at 20℃; for 3h; Schlenk technique; |
With N,N-dimethylammonium chloride In toluene Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With <i>L</i>-proline In ethanol at 80℃; for 4h; | General procedure for the synthesis of 3-nitrocoumarins3 and 5 General procedure: To the solution of salicylaldehyde (1 mmol) and ethylnitroacetate (1 mmol) in 3 cm3 ethanol, L-proline(30 mol %) was added. The reaction mixture was stirredfor an appropriate time. After completion of the reaction(as monitored by TLC), the solvent was evaporated and theproduct so obtained was dissolved in 12 cm3 CHCl3 andwashed with water (3 9 10 cm3). The organic layer waswashed with 10 cm3 brine, dried over anhydrous NaSO4,and evaporated under reduced pressure. The residue wasrecrystallized from ethanol (3, 5a, 5b, and 5h) or purifiedby silica gel column using chloroform/methanol (9:1) aseluent (5c-5g). The combined aqueous layers, containingL-proline, were evaporated, washed with ether, dried at45 C, and reused for next run. |
79% | With piperidine In benzene at 110℃; for 6h; Dean-Stark; | |
With acetic anhydride; sodium hydride at 20℃; for 3h; |
With N,N-dimethylammonium chloride In toluene Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With <i>L</i>-proline In ethanol at 80℃; for 6h; | General procedure for the synthesis of 3-nitrocoumarins3 and 5 General procedure: To the solution of salicylaldehyde (1 mmol) and ethylnitroacetate (1 mmol) in 3 cm3 ethanol, L-proline(30 mol %) was added. The reaction mixture was stirredfor an appropriate time. After completion of the reaction(as monitored by TLC), the solvent was evaporated and theproduct so obtained was dissolved in 12 cm3 CHCl3 andwashed with water (3 9 10 cm3). The organic layer waswashed with 10 cm3 brine, dried over anhydrous NaSO4,and evaporated under reduced pressure. The residue wasrecrystallized from ethanol (3, 5a, 5b, and 5h) or purifiedby silica gel column using chloroform/methanol (9:1) aseluent (5c-5g). The combined aqueous layers, containingL-proline, were evaporated, washed with ether, dried at45 C, and reused for next run. |
20% | With sodium acetate In acetic anhydride; acetic acid Heating; | |
With N,N-dimethylammonium chloride In toluene Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With phenyl isocyanate; triethylamine In benzene Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With phenyl isocyanate; In toluene; at 20 - 110℃; for 5h;Sealed tube; | A mixture of nitroacetic acid ethyl ester (1.47 g), ethynylbenzene (1.02 g), and phenylisocyanate (2.4 g) in toluene were taken in a sealed tube. This was stirred at room temperature for 1 h followed by at 110 C. for 4 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL) and the solid was filtered off. The filtrate was diluted with ether (250 mL) and washed with 1N sodium hydroxide (50 mL×3). The organic layer was dried over MgSO4, filtered, concentrated in vacuo, and the residue was chromatographed on a silica gel column using hexane/ethyl acetate mixture (8:2) as an eluent to afford 5-phenylisoxazole-3-carboxylic acid ethyl ester (1.1 g, 51% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With piperidine; acetic acid; In butan-1-ol; at 100℃; for 18h; | To a 100 mL flask, 1.93 g (10.0 mmol) of 4-diethylaminosalicyldehyde, 1.05 ml (10.3 mmol) of ethylnitroacetate, 0.2 ml piperidine and 5 ml glacial acetic acid were added in 40 ml of n-BuOH. After heated to 100 C for 18 h, the mixture changed from light orange to dark brown and became clear. Then the orange solids were formed while cooling. The solids were filtered and washed with cold n-BuOH (3 10 ml) and finally dried in vacuum, which afforded an orange solid (2.24 g, yield: 86%). M.p. 169.4-170.7 C. 1HNMR (500 MHz, CDCl3): d = 8.71 (s, 1H, Ar-H), 7.44 (d, J = 9.1 Hz, 1H, Ar-H), 6.70 (dd, J = 7.7, 2.5 Hz, 1H, Ar-H), 6.49 (s, 1H, Ar-H), 3.50 (q, 7.2 Hz, 4H, -CH2-), 1.28 (t, 7.2 Hz, 6H, -CH3). Anal. Calcd for C13H14N2O4: C, 59.54; H, 5.38; N, 10.68%. Found: C, 59.30; H, 5.47; N, 10.72%. |
83% | With piperidine; In benzene; for 8h;Dean-Stark; Reflux; | General procedure: A mixture of 2-hydroxybenzaldehyde (5.0 mmol), ethyl nitroacetate (6.0 mmol, 1.2 equiv), and piperidine (3-4 drops) in benzene was taken in a round bottom flask fitted with Dean-Stark apparatus and a condenser. The reaction mixture was then refluxed for 8 hours. After the completion of the reaction, the mixture was cooled down to room temperature and hexanes (50 mL) was added to precipitate the product. The solid was filtered, washed with excess hexanes, and dried to obtain the desired coumarin derivatives. |
77% | With piperidine; acetic acid; In butan-1-ol; for 12h;Reflux; | In a 100 mL round bottom flask, add 10 mmol4-diethylamino salicylaldehydeAnd 30 mL of n-butanol, 11 mmol of ethyl nitroacetate was added with stirring at room temperature, then 0.15 mL of piperidine and 0.3 mL of glacial acetic acid were added dropwise. The reaction system was heated to reflux for 12 hours and then cooled to room temperature. The reaction mixture was filtered under reduced pressure and the filtrate was recrystallized from ethanol to give the product, named as 3-nitro-7-diethylaminocoumarin, 77%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With potassium carbonate; triphenylphosphine In tetrahydrofuran at 40℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In water at 20℃; for 72h; | |
90% | In water at 20℃; for 72h; | |
90% | In water at 20℃; for 72h; |
84% | In water at 20℃; for 48h; Schlenk technique; Sealed tube; | |
66% | Stage #1: nitroacetic acid ethyl ester; methylamine In methanol at 20℃; for 18h; Stage #2: With hydrogenchloride In water | 6 Synthesis of 1-methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid (5-tert-butyl-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-amide Ethyl nitroacetate (1.64 g, 12.3 mmol) was added to a solution of methylamine (33% in methanol, 7.7 mL, 61.6 mmol) and the solution was stirred at room temperature for 18 h. The solvent was concentrated in vacuo and the residue was dissolved in aqueous 1.0 M HCl. The aqueous layer was washed with diethyl ether and the organic washings were discarded. The aqueous layer was then extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to provide N-methyl-2-nitro-acetamide (961 mg, 66%) as a pale yellow solid. To a solution of 2-tert-butyl-malonaldehyde (385 mg, 3.00 mmol) and the above amide (355 mg, 3.00 mmol) dissolved in ethanol (6.0 mL) was added pyrrolidine (63 microL, 0.750 mmol). The mixture was heated at reflux for 18 h and concentrated in vacuo. Purification by silica-gel chromatography (75% ethyl acetate in hexanes) provided 5-tert-butyl-1-methyl-3-nitro-1H-pyridin-2-one (186 mg, 30%) as an orange solid. The above nitro pyridine (186 mg, 0.886 mmol) was dissolved in methanol/ethyl acetate (2:1, 3 mL) and placed in a Parr hydrogenation vessel. Pd (10% on carbon, 20 mg) was added and the reaction was placed under a hydrogen atmosphere (50 psi) and shaken at room temperature for 1 h. The solution was then filtered through diatomaceous earth and concentrated in vacuo. The residue was redissolved in diethyl ether and extracted (3×) with 1.0 M HCl. The pH of the combined aqueous layers was adjusted to 10 with NaHCO3 and extracted with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to provide 3-amino-5-tert-butyl-1-methyl-1H-pyridin-2-one (110 mg, 69%) as a blue solid: 1ESI MS m/z 180 [C10H16N2O3+H]+. 1-Methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid (125 mg, 0.466 mmol) and the above aminopyridinone (84 mg, 0.466 mmol) were dissolved in pyridine (1.5 mL) at room temperature. Phosphorus oxychloride (48 micro L, 0.513 mmol) was added dropwise to the solution and the reaction mixture was stirred at room temperature for 0.5 h. The solvent was concentrated in vacuo and the residue was partitioned between saturated aqueous NaHCO3 and methylene chloride. The aqueous layer was extracted with methylene chloride and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica-gel chromatography (50% ethyl acetate in methylene chloride) provided 1-methyl-7-(pyridine-4-yloxy)-1H-indole-2-carboxylic acid (5-tert-butyl-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-amide (65 mg, 33%) as a pale pink solid: mp: 74-76° C. (dec.); ESI MS m/z 431 [C25H26N4O3+H]+; HPLC>97%, tR=15.69 min. |
In water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With 1,4-diaza-bicyclo[2.2.2]octane; In ethanol; at 80℃; for 72h;Ace pressure tube; | INTERMEDIATE 4 - PREPARATION OF Ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate.; To a mixture of propargyl alcohol (1.0 ml 16.76 mmol) and ethyl 2-nitroacetate (3.79 ml 33.52 mmol) in ethanol (23.5 ml.) in an Ace pressure tube was added 1 ,4- diazobicyclo[2.2.2]octane (DABCO, 0.194 g; 1.68 mmol). The tube was heated at 800C for 72 h. After cooling, the mixture was evaporated to dryness and the residue was purified by flash chromatography on silica gel (eluent: 0 to 6% methanol in dichloromethane) to yield 2.32 g (81 %) of ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate as an oil. ESI/APCI(+): 172 (M+H). |
180 g | With 1,4-diaza-bicyclo[2.2.2]octane; In ethanol; at 80℃; for 16h; | Reference Production Example 42 (0684) Ethyl nitroacetate (198 mL, 1.78 mmol), propargyl alcohol (100 g, 1.78 mmol) and 1,4-diazabicyclo[2.2.2]octane (20.0 g, 178.3 mmol) were added to ethanol (1 L), and the mixture was heated at 80C for 16 hours. Thereafter, the mixture was cooled to room temperature, and the solvent was concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 180 g of ethyl 5-hydroxymethylisoxazole-3-carboxylate represented by the following formula. 1H-NMR (CDCl3, TMS, delta (ppm)) : 6.67 (s, 1H), 4.83(d, 2H), 4.43 (q, 2H), 2.65 (brs, 1H), 1.41 (t, 3H) |
400 mg | With 1,4-diaza-bicyclo[2.2.2]octane; In ethanol; at 80℃; for 72h;Microwave irradiation; | To a solution of prop-2-yn-1 -ol (500 mg, 0.52 ml, 8.92 mmol) and ethyl 2-nitroacetate (2.26 g, 1 .88 ml, 16.95 mmol) in EtOH (15 ml) was added DABCO (1 .0 g, 8.92 mmol). The mixture was stirred at 80 C for 72 hours under microwave irradiation. The mixture was concentrated and purified directly by flash chromatography with heptane:ethyl acetate = 1 :0 to 0:1 to give ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate (400 mg). |
400 mg | With 1,4-diaza-bicyclo[2.2.2]octane; In ethanol; at 80℃; for 72h; | To a solution of prop-2-yn-1-ol (500 mg, 0.52 ml, 8.92 mmol) and ethyl 2-nitroacetate (2.26 g, 1.88 ml, 16.95 mmol) in EtOH (15 ml) was added DABCO (1.0 g, 8.92 mmol). The mixture was stirred at 80 C for 72 hours under microwave irradiation. The mixture was concentrated and purified directlyby flash chromatography with heptane:ethyl acetate = 1:0 to 0:1 to give ethyl 5- (hydroxymethyl)isoxazole-3-carboxylate (400 mg). |
400 mg | With 1,4-diaza-bicyclo[2.2.2]octane; In ethanol; at 80℃; for 72h;Microwave irradiation; | To a solution of 373 prop-2-yn-1-ol (500 mg, 0.52 ml, 8.92 mmol) and 374 ethyl 2-nitroacetate (2.26 g, 1.88 ml, 16.95 mmol) in 25 EtOH (15 ml) was added 375 DABCO (1.0 g, 8.92 mmol). The mixture was stirred at 80 C. for 72 hours under microwave irradiation. The mixture was concentrated and purified directly by flash chromatography with heptane:ethyl acetate=1:0 to 0:1 to give 376 ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate (400 mg). |
400 mg | With 1,4-diaza-bicyclo[2.2.2]octane; In ethanol; at 80℃; for 72h;Microwave irradiation; | To a solution of prop-2-yn-l-ol (500 mg, 0.52 ml, 8.92 mmol) and ethyl 2-nitroacetate (2.26 g, 1.88 ml, 16.95 mmol) in EtOH (15 ml) was added DABCO (1.0 g, 8.92 mmol). The mixture was stirred at 80 C for 72 hours under microwave irradiation. The mixture was concentrated and purified directly by flash chromatography with heptane:ethyl acetate = 1:0 to 0:1 to give ethyl 5- (hydroxymethyl)isoxazole-3-carboxylate (400 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With 1,4-diaza-bicyclo[2.2.2]octane In ethanol at 80℃; for 36h; | |
95% | With N-methylcyclohexylamine; copper In chloroform at 60℃; for 16h; sealed tube; | |
93% | With 1,4-diaza-bicyclo[2.2.2]octane In ethanol at 80℃; for 48h; Ace pressure tube; | 25 INTERMEDIATE 25 - PREPARATION OF Ethyl 5-(hydroxymethyl)-4,5-dihydroisoxazole- 3-carboxylate.; To a mixture of allylic alcohol (0.650 ml 9.35 mmol) and ethyl 2-nitroacetate (2.65 ml 23.37 mmol) in ethanol (12 mL) in an Ace pressure tube was added 1 ,4- diazobicyclo[2.2.2]octane (DABCO, 0.189g; 1.64 mmol). The tube was heated at 800C for 48 h. The mixture was evaporated. The flash chromatography on silica gel (eluent: 0 to6% of methanol in dichloromethane ) of the residue provided 1.51 g (93%) of ethyl 5-(hydroxymethyl)-4,5-dihydroisoxazole-3-carboxylate as an oil.ESI/APCI(+): 174 (M+H), 196 (M+Na). |
83 %Spectr. | With triethylamine In water at 60℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With phenyl isocyanate; triethylamine; In 1,4-dioxane; for 5.0h; | A solution of ethyl nitroacetate (133 g, 1.0 mol) in dry dioxane (3 L) was treated with phenylisocyanate (130 g, 1.1 mol). Acetylene was bubbled through a solution, and triethylamine (111 g, 1.1 mol) was added dropwise for 5 h. The mixture was filtered, and the precipitate was washed with dioxane. The filtrate was evaporated, and the residue was distilled, providing the fraction with a boiling point of 110-112 C at 12 mmHg as the product isoxazole ester (89 g, 63%). This material was diluted into toluene (1 L), and this solution then added dropwise to a solution of diisobutyl aluminum hydride (630 mL, 0.63 mol, 1M toluene) at-75 C with stirring. The reaction mixture was stirred for 30 min, and 10% aqueous ammonium chloride (excess) was added. The organic partition was separated, washed with water (100 mL) and evaporated. The residue was distilled to provide the fraction with a boiling point of 85-90 C at 12 MMHG as the title compound (42 g, 43%). |
63% | With phenyl isocyanate; triethylamine; In 1,4-dioxane; for 5.0h; | A solution of ethyl nitroacetate (133 g, 1.0 mol) in dry dioxane (3 L) was treated with phenylisocyanate (130 g, 1. 1 mol). Acetylene was bubbled through a solution, and triethylamine (111 g, 1.1 mol) was added dropwise for 5 h. The mixture was filtered, and the precipitate was washed with dioxane. The filtrate was evaporated, and the residue was distilled, providing the fraction with a boiling point of 110-112 C at 12 MMHG as the product isoxazole ester (89 g, 63%). This material was diluted into toluene (1 L), and this solution then added dropwise to a solution of diisobutyl aluminum hydride (630 ML, 0.63 mol, 1M toluene) at-75 C with stirring. The reaction mixture was stirred for 30 min, and 10% aqueous ammonium chloride (excess) was added. The organic partition was separated, washed with water (100 ML) and evaporated. The residue was distilled to provide the fraction with a boiling point of 85-90 C at 12 MMHG as the title compound (42 g, 43%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With piperidine In benzene for 8h; Dean-Stark; Reflux; | Synthesis of 3-nitrocoumarin derivatives General procedure: A mixture of 2-hydroxybenzaldehyde (5.0 mmol), ethyl nitroacetate (6.0 mmol, 1.2 equiv), and piperidine (3-4 drops) in benzene was taken in a round bottom flask fitted with Dean-Stark apparatus and a condenser. The reaction mixture was then refluxed for 8 hours. After the completion of the reaction, the mixture was cooled down to room temperature and hexanes (50 mL) was added to precipitate the product. The solid was filtered, washed with excess hexanes, and dried to obtain the desired coumarin derivatives. |
85% | With piperidine In benzene at 110℃; for 6h; Dean-Stark; | |
60% | With piperidine In toluene at 150℃; for 0.333333h; Microwave irradiation; | General procedure for the synthesis of 3-nitrosubstitutedcoumarins and quinolones General procedure: To a stirred mixture of corresponding salicylilaldehyde oraminobenzaldehyde (5 mmol) and 20 cm3 toluene in a20-cm3 Pyrex microwave vial, equipped with a magneticstir bar, 666 mm3 ethyl 2-nitroacetate (6 mmol, 1.2 equiv)and 100 mm3 piperidine (1 mmol, 0.2 equiv, 20 mol %)were added. The reaction mixture was capped with aTeflon septum, stirred for 10 s and subjected to microwaveheating for 20 min (fixed hold time) at 150 C and subsequently cooled to 50 C. The resulting reactionmixture was cooled down overnight at 0 C, the precipitateseparated by filtration and washed with cold toluenefollowed by excess of cold n-heptane. The resulted productwas dried overnight and used without further purification inthe next synthetic step. |
33% | With N-propylamine hydrochloride In toluene for 20h; Heating / reflux; | |
With acetic anhydride; sodium hydride at 20℃; for 3h; | ||
With acetic anhydride; sodium hydride at 20℃; for 3h; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In dichloromethane | XI.B Step B Step B 3,3-Bis-(4'-methoxyphenyl)-2-nitropropionic acid ethyl ester To a stirred (0° C.) solution of bis-(4-methoxyphenyl)methanol (2.5 g, 10.2 mmol) and ethyl nitroacetate (2.26 ml, 20.4 mmol) in CH2 Cl2 (50 ml) under argon was added AlCl3 (1.36 g, 10.2 mmol) in one portion. After 1 h, the reaction mixture was allowed to warm to approximately 10° C. and poured into a mixture of ice and 2M HCl. The resulting mixture was stirred for 45 min, and the aqueous layer extracted with CH2 Cl2. The combined organic layers were washed with 10% Na2 CO3, dried over MgSO4, treated with activated carbon, and concentrated to give a reddish oil that was chromatographed (CHCl3 elution) to afford the title compound as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 5,5-dimethyl-1,3-cyclohexadiene | XIII Compound 31 (2E/Z,4E)-N-Isobutyl 3-methyl-12-(3-nitro-2-quinolinyloxy) dodeca-2,4-dienamide Starting from 2-hydroxy-3-nitroquinoline (prepared by analogy with Compound 30, from 2-aminobenzaldehyde reacted with ethyl nitroacetate (ex. Aldrich) in xylene in the presence of piperidine). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In water in air; suspended in water at 80°C, stirred for 24 h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With 9-amino-9-deoxyepicinchonine In 5,5-dimethyl-1,3-cyclohexadiene at 20℃; for 24h; optical yield given as %de; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With 9-amino-9-deoxyepicinchonine In 5,5-dimethyl-1,3-cyclohexadiene at 20℃; for 24h; optical yield given as %de; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With 1,4-diaza-bicyclo[2.2.2]octane In water at 80℃; for 24h; Sonication; | 4.2.2. General procedure for the synthesis of isoxazoles (4h, 4j, 4l and 4m) 1,4-Diazabicyclo[2.2.2]octane (DABCO) (20 mol %) was added to a mixture of aldehyde (1.0 mmol, 1.0 eq.) and ethyl nitroacetate (1.68 mmol, 2.0 eq.) at 0 C dissolved in water (2 mL). The reaction mixture was stirred for 5 min at 0 C and then ultrasonicated for 24 h at 80 C. After the completion of the reaction as indicated byTLC, the reaction was quenched with ethyl acetate (3 x 6 mL). The combined organic extract was washed with water (2 x 5 mL) and 5 % HCl (1 x 3 mL), dried over anhydrous MgSO4 and concentrated in vacuo. The residue was loaded on to a silica gel column and eluted with hexane: ethyl acetate to afford isoxazoles 4h, 4j, 4l, and 4m. |
77% | With triethylamine In acetonitrile at 60℃; for 36h; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With 1,4-diaza-bicyclo[2.2.2]octane In water at 80℃; for 24h; Sonication; | 4.2.2. General procedure for the synthesis of isoxazoles (4h, 4j, 4l and 4m) 1,4-Diazabicyclo[2.2.2]octane (DABCO) (20 mol %) was added to a mixture of aldehyde (1.0 mmol, 1.0 eq.) and ethyl nitroacetate (1.68 mmol, 2.0 eq.) at 0 C dissolved in water (2 mL). The reaction mixture was stirred for 5 min at 0 C and then ultrasonicated for 24 h at 80 C. After the completion of the reaction as indicated byTLC, the reaction was quenched with ethyl acetate (3 x 6 mL). The combined organic extract was washed with water (2 x 5 mL) and 5 % HCl (1 x 3 mL), dried over anhydrous MgSO4 and concentrated in vacuo. The residue was loaded on to a silica gel column and eluted with hexane: ethyl acetate to afford isoxazoles 4h, 4j, 4l, and 4m. |
60% | With triethylamine In acetonitrile at 60℃; for 14h; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 1,4-diaza-bicyclo[2.2.2]octane In ethanol at 150℃; for 0.333333h; Microwave irradiation; | 15 INTERMEDIATE 15 - PREPARATION OF Ethyl δ-cyclopropylisoxazole-S-carboxylate.; A solution of ethynylcyclopropane (0.40 ml 4.58 mmol), ethyl 2-nitroacetate (1.30 ml 1 1.46 mmol), and 1 ,4-diazobicyclo[2.2.2]octane (DABCO, 0.053 g; 0.458 mmol) in ethanol(3 ml.) was irradiated in a microwave oven at 150 0C for 20 min and was then evaporated.The residue was dissolved in ethyl acetate and the solution was washed with water. The organic layer was evaporated and the residue was purified by flash chromatography on silica gel (eluent: 20 to 100% of dichloromethane in heptane) to afford 0.765 g (92 %) of ethyl 5-cyclopropylisoxazole-3-carboxylate as a yellow oil.ESI/APCI(+): 182 (M+H). |
90% | With N-methylcyclohexylamine; copper diacetate In chloroform at 60℃; for 24h; Sealed tube; | |
0.4 g | With 1,4-diaza-bicyclo[2.2.2]octane In ethanol at 150℃; for 0.5h; Inert atmosphere; | 60 General procedure for preparation of ethyl 5-cyclopropylisoxazole-3-carboxylate A mixture of ethyl 2-nitroacetate (1.0 g, 7.6 mmol, 2.5 eq), ethynylcyclopropane (0.2 g, 3.0 mmol, 1 eq),DABCO (33.9 mg, 303 imol, 0.1 eq) in 2 mL of EtOH was degassed and purged with N2 three times. The mixture was stirred at 150 °C for 30 mm under microwave condition. It was evaporated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02 eluting with petroleum ether:ethyl acetate = 30:1) to give 0.4 g of ethyl 5 -cyclopropylisoxazole-3 -carboxylate as a colorless liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With 1,4-diaza-bicyclo[2.2.2]octane In ethanol at 80℃; for 60h; Ace pressure tube; | 28 INTERMEDIATE 28 - PREPARATION OF Ethyl 5-benzyl-4,5-dihydroisoxazole-3- carboxylate.; To a mixture of allylbenzene (0.73ml 5.39 mmol) and ethyl 2-nitroacetate (1.53 ml 13.48 mmol) in ethanol (12 ml_) in an Ace pressure tube was added 1 ,4- diazobicyclo[2.2.2]octane (DABCO, 0.106g; 0.92 mmol). The tube was heated at 800C for60 h. The mixture was evaporated. The flash chromatography on silica gel (eluent: 15 to 100% of dichloromethane in heptane) of the residue provided 1.06 g (85%) of ethyl 5- benzyl-4,5-dihydroisoxazole-3-carboxylate as an oil. ESI/APCI(+):234 (M+H), 256 (M+Na). |
62% | With sodium hydroxide In water at 60℃; for 72h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Stage #1: nitroacetic acid ethyl ester; 1-(4-tolylsulfonyl)indole-3-carboxaldehyde With titanium tetrachloride In tetrahydrofuran at 0℃; for 0.25h; Inert atmosphere; Stage #2: With 4-methyl-morpholine In tetrahydrofuran at 0℃; Inert atmosphere; | 4.1.1. Ethyl (E)- and (Z)-3-[1-(4-toluenesulfonyl)-indole-3-yl]-2-nitroacrylate 24 General procedure: Anhydrous tetrahydrofuran (20 mL), placed in a three-necked round bottomed flask equipped with a dropping funnel, was stirred and cooled to 0 °C. Titanium(IV) chloride (2.95 mL, 26.0 mmol) was added dropwise via syringe and a bright yellow precipitate formed immediately. A mixture of 1-(4-toluenesulfonyl)-indole-3-carboxaldehyde 23 (4.00 g, 13.0 mmol; mp 148-150 °C [lit.refPreviewPlaceHolder [17] and refPreviewPlaceHolder[38] mp 148-150 °C]) and ethyl nitroacetate (1.48 mL, 13.0 mmol) in tetrahydrofuran (10 mL) was then added slowly from the dropping funnel. The now brown solution was stirred for 0.25 h at the same temperature before 4-methylmorpholine (5.89 mL, 52.0 mmol) was added during 0.5 h. The resulting mixture was then stirred overnight without the addition of any more coolant and finally quenched by the addition of water (50 mL). Ether (20 mL) was added and the resulting two layers separated. The aqueous layer was extracted with ether (2×50 mL) and the combined organic solutions dried, filtered and evaporated. The resulting solid was crystallised from ethyl acetate/hexanes to give the nitroacrylate24 (3.70 g, 67%) as an orange solid in a ratio of (E)- and (Z)-isomers of 1.5:1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium carbonate at 20℃; for 1.33333h; Sonication; Neat (no solvent); | |
97% | With potassium carbonate In N,N-dimethyl-formamide at 140℃; for 0.333333h; Sealed tube; Microwave irradiation; | Synthesis of indoles 7a-i (General method). General procedure: Nitroalkene 5 (94 mg, 0.50 mmol), K2CO3 (83 mg, 0.60 mmol),DMF (0.5 ml), and the respective Michael donor (2.5 mmolfor MeNO2, EtNO2, and acetone, or 0.55 mmol for the remain-ing compounds) were charged in a G10 vial. The vial wassealed, heated in the microwave apparatus at 140° for 20 min(for compound 7g - at 70° for 3 h), whereupon the vial wasopened and the reaction mixture poured into H2O (30 ml).The resulting mixture was extracted with EtOAc (3×50 ml),the combined organics washed with H2O (2×20 ml), andconcentrated under reduced pressure. The crude product wasdissolved in benzene (20 ml), and the resulting solutionfiltered through a plug of silica gel (2-3 cm), followed bywashing with an additional amount of benzene (20 ml). Thetarget compound was obtained by evaporating the filtrate todryness. The crystalline compounds could be additionallypurified by recrystallization from the given solvent. Spectralcharacteristics of compounds 7b-h match literature data.8 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With iodine; copper(II) oxide In dimethyl sulfoxide at 70℃; for 16h; Inert atmosphere; regioselective reaction; | 4.4.12. Diethyl 4-(benzofuran-2-carbonyl)isoxazole-3,5-dicarboxylate (4la) General procedure: Methyl ketone 1 (1.0 mmol), α-nitro carbonyl compound 3 (2.0 mmol), CuO (2.0 mmol), and iodine (2.0 mmol) were placed in an oven-dried and argon filled Schlenk tube. After addition of anhydrous DMSO (5 mL), the mixture was stirred at 70°C for 16 h. After the reaction completed (monitored by TLC), the reaction mixture was cooled to room temperature, then filtered through a layer of silica gel and eluted with EtOAc. The filtrate was diluted with water and treated with Na2S2O3 (5% w/w, aq.) until the color turned to pale yellow. The mixture was then extracted with additional EtOAc (2 × 30 mL), the combined organic layers were washed with brine and dried over Na2SO4. After evaporation, the crude product was purified by column chromatography on silica gel (eluent: petroleum ether/EtOAc) to afford the pure product 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With acetic acid; In ethanol; at 70℃; for 92.0h;Sealed tube; | [00395] Intermediate 35A. Ethyl 3-((3-chloro-2,6-difluorophenyl)amino)-2- nitroacrylate: A sealed, high pressure vial containing a clear, colorless solution of ethyl nitroacetate (0.170 ml, 1.529 mmol), triethylorthoformate (0.255 ml, 1.529 mmol), 3- chloro-2,6-difluoroaniline (0.250 g, 1.529 mmol), acetic acid (0.026 ml, 0.459 mmol), and EtOH (1.529 ml) was heated to 70 C. After 92 h, the clear, dark yellow solution was concentrated to give an orange oil. Purification by normal phase chromatography gave Intermediate 35A (0.0721 g, 15%) as a yellow solid. MS(ESI) m/z: 307.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 93 % ee 2: 93 % ee | With ortho-nitrobenzoic acid; C21H31N3 In dichloromethane at 25℃; for 24h; Overall yield = 87 %; enantioselective reaction; | General procedure for the catalytic Michael addition Reactions were performed with enone 3 (0.2 mmol) and 2 (44uL, 0.4 mmol, 2eq.) in the presence of catalyst 1f (0.02 mmol, 10 mol%) and acid additive 2-nitro benzoic acid (0.02 mmol, 10 mol%) in dichloromethane (0.5 mL) under aerobic atmosphere, taking no precaution to exclude moisture. After 24 to 40 h of stirring at room temperature (about 25 oC), the reaction mixture was quenched with 1mL 1 M aqueous HCl solution, extracted with EtOAc for three times. The combined organic layer was dried over Na2SO4, filtered, and concentrated to afford the corresponding Michael adduct 4 after purified by column chromatography on silica gel, eluting with petroleum ether and ethyl acetate |
With benzoic acid In chloroform at 30℃; for 4h; Overall yield = 85 %; Optical yield = > 99 %ee; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ortho-nitrobenzoic acid; C21H31N3; In dichloromethane; at 25℃; for 24h; | Reactions were performed with enone 3 (0.2 mmol) and 2 (44uL, 0.4 mmol, 2eq.) in the presence of catalyst 1f (0.02 mmol, 10 mol%) and acid additive 2-nitro benzoic acid (0.02 mmol, 10 mol%) in dichloromethane (0.5 mL) under aerobic atmosphere, taking no precaution to exclude moisture. After 24 to 40 h of stirring at room temperature (about 25 oC), the reaction mixture was quenched with 1mL 1 M aqueous HCl solution, extracted with EtOAc for three times. The combined organic layer was dried over Na2SO4, filtered, and concentrated to afford the corresponding Michael adduct 4 after purified by column chromatography on silica gel, eluting with petroleum ether and ethyl acetate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: 4-bromo-2-(ethylamino)-3-methyl-benzoic acid With bis(trichloromethyl) carbonate In tetrahydrofuran at 20℃; for 3h; Inert atmosphere; Stage #2: nitroacetic acid ethyl ester With triethylamine In tetrahydrofuran at 60℃; Inert atmosphere; | 2.d (d) 7-bromo- 1 -ethyl-4-hydroxy-8-methyl-3-nitro-qui nol in-2-one To a solution of 4-bromo-2-(ethylamino)-3-methyl-benzoic acid (1.74g, 6.74 mmol) in dry THF (20 mL) at room temperature under N2 atmosphere was added triphosgene (1.2 g, 4.03 mmol) in one portion. This was allowed to stir at room temperature for 3 h, after which time the solvent was carefully removed in vacuo (rotary evaporator was prohibited from reaching > 40°C. vacuum was set at 1 mbar, and reached between 1-10 mbar) to give a thick red oil which was diluted with dry THF (10 mL) under a N2 atmosphere. To the resulting solution Et3N (7.5 mL, 53.93 mmol) was added dropwise, followed by the addition of ethyl nitroacetate (1.12 mL, 10.11 mmol) in one portion. The reaction mixture was heated to 60°C overnight, after which time the solvent was removed in vacuo (maintaining bath 67temperature <4000). The residue was then partitioned between EtOAc (20 mL) and brine (20 mL). 2M aqueous HCI was then added to adjust the pH to around 3. The organic phase was separated, dried over Na2SO4, filtered and the solvent removed in vacuo to give 7- bromo-1-ethyl-4-hydroxy-8-methyl-3-nitro-quinolin-2-one as an orange solid in quantitative yield, which was used in the next step without further purification.LC-MS (Method A) 327.3/329.3 [M] RT 2.08 mm |
100% | Stage #1: 4-bromo-2-(ethylamino)-3-methyl-benzoic acid With bis(trichloromethyl) carbonate In tetrahydrofuran at 20℃; for 3h; Inert atmosphere; Stage #2: nitroacetic acid ethyl ester With triethylamine In tetrahydrofuran at 60℃; Inert atmosphere; | 2.d (d) 7-bromo-1-ethyl-4-hydroxy-8-methyl-3-nitro-quinolin-2-one To a solution of 4-bromo-2-(ethylamino)-3-methyl-benzoic acid (1.74 g, 6.74 mmol) in dry THF (20 mL) at room temperature under N2 atmosphere was added triphosgene (1.2 g, 4.03 mmol) in one portion. This was allowed to stir at room temperature for 3 h, after which time the solvent was carefully removed in vacuo (rotary evaporator was prohibited from reaching > 40°C. vacuum was set at 1 mbar, and reached between 1-10 mbar) to give a thick red oil which was diluted with dry THF (10 mL) under a N2 atmosphere. To the resulting solution EtzN (7.5 mL, 53.93 mmol) was added dropwise, followed by the addition of ethyl nitroacetate (1.12 mL, 10.11 mmol) in one portion. The reaction mixture was heated to 60°C overnight, after which time the solvent was removed in vacuo (maintaining bath temperature < 40°C). The residue was then partitioned between EtOAc (20 mL) and brine (20 mL). 2 M aqueous HCI was then added to adjust the pH to around 3. The organic phase was separated, dried over Na2S04, filtered and the solvent removed in vacuo to give 7-bromo-1-ethyl-4-hydroxy-8-methyl-3-nitro-quinolin-2-one as an orange solid in quantitative yield, which was used in the next step without further purification. LC-MS (Method A) 327.3/329.3 [M]+; RT 2.08 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.67 g | With 1,4-diaza-bicyclo[2.2.2]octane In ethanol at 80℃; for 48h; | 119 Reference Production Example 119 Reference Production Example 119 (0761) Ethyl nitroacetate (8.60 g, 72.3 mmol), 7-octyn-1-ol (7.63 g, 57.8 mmol) and 1,4-diazabicyclo[2.2.2]octane (1.30 g, 11.6 mmol) were added to ethanol (25 ml). The mixture was heated at 80°C for 48 hours and cooled to room temperature, and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 9.67 g of 5-(6-hydroxyhexyl)isoxazole-3-carboxylate represented by the following formula. 1H-NMR (CDCl3, TMS, δ (ppm)) :1.37-1.41(7H, t), 1.54-1.59 (2H, m), 1.70-1.76(2H, m), 2.79(2H, t), 3.61(2H, t), 4.41(2H, q), 6.39 (1H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.33 g | N Nitro ethyl acetate (2.0 g), N-dimethylformamide dimethyl acetal (3.6 g) was added, the reaction mixture was 1.5 hours heating and stirring at 0.89 C. After stirring for 1 hour at room temperature.The reaction mixture and the solvent was evaporated under reduced pressure after cooling to room temperature.The residue in ethanol (40 mL), the Pibaruamijin hydrochloride (2.3 g) and triethylamine (2.4 mL) was added at room temperature, the reaction mixture was heated for 8 hours stirring at 0.89 C..The reaction mixture was evaporated after cooling to room temperature, the residue was purified by silica gel column chromatography (solvent; chloroform / methanol = 100 / 0-90 / 10) to give the title compound (1.33 g).MS (ESI) M / Z; 198 [M Tasu H]Tasu |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With aluminum (III) chloride; sodium azide In dimethyl sulfoxide at 80℃; for 12h; | 15 Example 15: Synthesis of 5-(2,4-dichloro-phenyl) - 4-acetyl acetic acid ethoxycarbonyl -2H-1, 2, 3-triazole Specific steps: To a 50mL round bottom flask, add 0.33mmol 2,4-dichlorobenzaldehyde, 0.50mmol ethyl nitroacetate, 0.39mmol sodium azide, 0.03mmol AlCl3, 2mL DMSO. At 80 deg.C under magnetic stirring, react for 12 hours. after the reaction solution was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a crude product, the crude product from ethyl acetate / petroleum ether = 1: 5 (V / V) as the eluent was subjected to column separation and purification to obtain the desired product, the product as a white solid, a yield of 85%. |
85% | With aluminum (III) chloride; sodium azide In dimethyl sulfoxide at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With aluminum (III) chloride; sodium azide In dimethyl sulfoxide at 80℃; for 12h; | 17 Example 17: Synthesis of 5-o-chlorophenyl-4-acetyl acetic acid ethoxycarbonyl -2H-1, 2, 3-triazole Specific steps: To a 50mL round bottom flask was added 0.33mmol benzaldehyde, 0.50mmol ethyl nitroacetate, 0.39mmol sodium azide, 0.03mmol AlCl3, 2mL DMSO. At 80 deg.C under magnetic stirring, react for 12 hours. with The reaction solution was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a crude product, the crude product from ethyl acetate / petroleum ether = 1: 5 (V / V) for the separation and purification by column eluent to obtain the desired product, the product as a white solid, a yield of 85%. |
84% | Stage #1: nitroacetic acid ethyl ester; 2-chloro-benzaldehyde With sodium azide In dimethyl sulfoxide Stage #2: With aluminum (III) chloride In dimethyl sulfoxide at 80℃; | 2 Example 2 Synthesis of 4- (2-chloro-phenyl) -5-ethylacetate-2H-1,2,3-triazole To a 100 mL round bottom flask was added 500 mg (3.57 mmol) of o-chlorobenzaldehyde,The benzaldehyde solution was diluted with 20 mL of DMSO,To this was added dropwise 570 mg (4.29 mmol) of ethyl nitroacetate;439 mg (5.36 mmol) of NaN3 was weighed,Into the flask; agitating the mixed liquid,71 mg (0.53 mmol) of AlCl3 powder was added.The mixed solution was placed in an oil bath at 80 ° C,The reaction was monitored by TLC. After completion of the reaction, the mixed solution was poured into water, washed with ethyl acetate /Water was extracted three times; the organic layers were combined and washed once with saturated brine; the ethyl acetate layer was dried over anhydrous sodium sulfate,The ethyl acetate was removed by steaming and then separated by ethyl acetate / petroleum ether (v / v = 1: 3) eluent to give the product as a pale yellowSolid 4- (2-chlorophenyl) -5-ethylacetate-2H-1,2,3-triazole 752 mg, yield 84%. |
81% | With aluminum (III) chloride; sodium azide In dimethyl sulfoxide at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With aluminum (III) chloride; sodium azide In dimethyl sulfoxide at 80℃; for 12h; | 14 Example 14: Synthesis of 5-phenyl-4-acetyl-2H-1,2,3-triazolylacetic acid ethyl ester Specific steps: To a 50mL round bottom flask was added 0.33mmol benzaldehyde, 0.50mmol ethyl ntiroacetate, 0.39mmol sodium azide, 0.03mmol AlCl3, 2mL DMSO. At 80 deg.C under magnetic stirring, react for 12 hours. with ethyl ester reaction solution was extracted, the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a crude product, the crude product from ethyl acetate / petroleum ether = 1: 5 (V / V) as the leaching column wash separation and purification to obtain the desired product, the product as a white solid, a yield of 85%. |
85% | With aluminum (III) chloride; sodium azide In dimethyl sulfoxide at 70℃; | |
85% | Stage #1: nitroacetic acid ethyl ester; benzaldehyde With sodium azide In dimethyl sulfoxide Stage #2: With aluminum (III) chloride In dimethyl sulfoxide at 80℃; | 1 Example 1:Synthesis of 4-phenyl-5-ethylacetate-2H-1,2,3-triazole To a 100 mL round bottom flask was added 500 mg (4.72 mmol) of benzaldehyde,The benzaldehyde solution was diluted with 20 mL of DMSO,To this was added 753 mg (5.67 mmol) of ethyl nitroacetate;43 ml of NaN3 (7.08 mmol)Into the flask;Stirring the mixed liquid,94 mg (0.7 mmol) of AlCl3 powder was added.The above mixed solution was placed in an 80 ° C oil bath,Constant temperature reflux reaction, with TLC to monitor the reaction process. After the reaction,The mixed solution was poured into water and extracted three times with ethyl acetate / water; the organic layers were combined,Washed once with saturated brine; the ethyl acetate layer was dried over anhydrous sodium sulfate,The ethyl acetate was removed by steaming and the column was separated by ethyl acetate / petroleum ether (v / v = 1: 3)To give the product as a pale yellow solid 4-phenyl-5-ethylhexyl-2H-1,2,3-triazole 871 mg in 85% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With aluminum (III) chloride; sodium azide In dimethyl sulfoxide at 80℃; for 12h; | 7 Example 7 Specific steps: to 50mL round bottom flask 0.33mmol2- pyridinecarboxaldehyde, 0.50mmolNitro-ethyl acetate, 0.39mmol sodium azide, 0.04mmolAlCl3,2mLDMSO, after magnetic stirring at 80 deg.] C for 12 hours, the reaction solution was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, evaporated under reduced pressure the solvent to obtain a crude product, the crude product with ethyl acetate / petroleum ether = 1: 3 (V / V) was subjected to column separation and purification to obtain the desired product as a white solid product as the eluent, the yield was 85%. |
75% | With aluminum (III) chloride; sodium azide In dimethyl sulfoxide at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With <i>L</i>-proline In ethanol at 80℃; for 5h; | General procedure for the synthesis of 3-nitrocoumarins3 and 5 General procedure: To the solution of salicylaldehyde (1 mmol) and ethylnitroacetate (1 mmol) in 3 cm3 ethanol, L-proline(30 mol %) was added. The reaction mixture was stirredfor an appropriate time. After completion of the reaction(as monitored by TLC), the solvent was evaporated and theproduct so obtained was dissolved in 12 cm3 CHCl3 andwashed with water (3 9 10 cm3). The organic layer waswashed with 10 cm3 brine, dried over anhydrous NaSO4,and evaporated under reduced pressure. The residue wasrecrystallized from ethanol (3, 5a, 5b, and 5h) or purifiedby silica gel column using chloroform/methanol (9:1) aseluent (5c-5g). The combined aqueous layers, containingL-proline, were evaporated, washed with ether, dried at45 C, and reused for next run. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With <i>L</i>-proline In ethanol at 20℃; for 1.5h; | General procedure for the synthesis of 3-nitrocoumarins3 and 5 General procedure: To the solution of salicylaldehyde (1 mmol) and ethylnitroacetate (1 mmol) in 3 cm3 ethanol, L-proline(30 mol %) was added. The reaction mixture was stirredfor an appropriate time. After completion of the reaction(as monitored by TLC), the solvent was evaporated and theproduct so obtained was dissolved in 12 cm3 CHCl3 andwashed with water (3 9 10 cm3). The organic layer waswashed with 10 cm3 brine, dried over anhydrous NaSO4,and evaporated under reduced pressure. The residue wasrecrystallized from ethanol (3, 5a, 5b, and 5h) or purifiedby silica gel column using chloroform/methanol (9:1) aseluent (5c-5g). The combined aqueous layers, containingL-proline, were evaporated, washed with ether, dried at45 C, and reused for next run. |
80% | With piperidine In benzene at 110℃; for 6h; Dean-Stark; | |
79% | With piperidine In toluene at 150℃; for 0.333333h; Microwave irradiation; | General procedure for the synthesis of 3-nitrosubstitutedcoumarins and quinolones General procedure: To a stirred mixture of corresponding salicylilaldehyde oraminobenzaldehyde (5 mmol) and 20 cm3 toluene in a20-cm3 Pyrex microwave vial, equipped with a magneticstir bar, 666 mm3 ethyl 2-nitroacetate (6 mmol, 1.2 equiv)and 100 mm3 piperidine (1 mmol, 0.2 equiv, 20 mol %)were added. The reaction mixture was capped with aTeflon septum, stirred for 10 s and subjected to microwaveheating for 20 min (fixed hold time) at 150 C and subsequently cooled to 50 C. The resulting reactionmixture was cooled down overnight at 0 C, the precipitateseparated by filtration and washed with cold toluenefollowed by excess of cold n-heptane. The resulted productwas dried overnight and used without further purification inthe next synthetic step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With potassium phenolate; palladium diacetate; potassium carbonate; dimethyl cis-but-2-ene-1,4-dioate; triphenylphosphine In N,N-dimethyl-formamide at 120℃; for 24h; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With potassium phenolate; palladium diacetate; potassium carbonate; dimethyl cis-but-2-ene-1,4-dioate; triphenylphosphine In N,N-dimethyl-formamide at 120℃; for 24h; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
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86% | With 1,4-diaza-bicyclo[2.2.2]octane; In water; at 40℃; for 24h;Sonication; | General procedure: 1,4-Diazabicyclo[2.2.2]octane (DABCO) (20 mol %) was added toa mixture of aldehyde (1.0 mmol, 1.0 eq.) and ethyl nitroacetate (1.68 mmol, 2.0 eq.) at 0 C dissolved in water (2 mL). The reaction mixture was stirred for 5 min at 0 C and then ultrasonicated for 24 h at 40 C. After the completion of the reaction as indicated by TLC, the reaction was quenched with ethyl acetate (3 x 6 mL). The combined organic extract was washed with water (2 x 5 mL) and 5 % HCl (1 x 3 mL), dried over anhydrous MgSO4 and concentrated in vacuo. The residue was loaded on to a silica gel column and eluted with hexane: ethyl acetate to afford isoxazoline N-oxides 2a-z, and dihydroisoxazoles 3u-w. |
Yield | Reaction Conditions | Operation in experiment |
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43% | With piperidine; In toluene; at 150℃; for 0.333333h;Microwave irradiation; | General procedure: To a stirred mixture of corresponding salicylilaldehyde oraminobenzaldehyde (5 mmol) and 20 cm3 toluene in a20-cm3 Pyrex microwave vial, equipped with a magneticstir bar, 666 mm3 ethyl 2-nitroacetate (6 mmol, 1.2 equiv)and 100 mm3 piperidine (1 mmol, 0.2 equiv, 20 mol %)were added. The reaction mixture was capped with aTeflon septum, stirred for 10 s and subjected to microwaveheating for 20 min (fixed hold time) at 150 C and subsequently cooled to 50 C. The resulting reactionmixture was cooled down overnight at 0 C, the precipitateseparated by filtration and washed with cold toluenefollowed by excess of cold n-heptane. The resulted productwas dried overnight and used without further purification inthe next synthetic step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With Aspergillus niger glucoamylase In acetonitrile at 40℃; for 48h; Green chemistry; Enzymatic reaction; | 3.1 General Procedure for the AnGA-Catalyzed Bis-Michael Addition General procedure: A mixture of (1E,4E)-1,5-diarylpenta-1,4-dien-3-one (1)(1.00 mmol), active methylene compound (2) (0.25 mmol)and AnGA (40 mg, 4.8 kU) in MeCN (2.0 mL) was stirredat 40 °C for the specified reaction time and monitored byTLC. The reaction was terminated by filtering out theenzyme (with 40 mm Buchner funnel and qualitative filterpaper), and the filter cake was washed with ethyl acetate(3 × 10 mL). The solvents were removed under reducedpressure. The crude products were purified by columnchromatography on a silica gel (petroleum ether/EtOAc:20/1-4/1) and gave the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With piperidine; In benzene;Dean-Stark; Reflux; | The commercially available compound represented by formula (10), i.e., <strong>[14382-91-3]o-hydroxy-2,4-dimethoxybenzaldehyde</strong>, and ethyl nitroacetate are performed with piperidine catalyzed condensation reaction in a Dean-Stark separator to acquire a compound represented by formula (11), i. e., 6,7-dimethoxy-3-nitrocoumarin, a yield of which is 93 wt. %, in which, the reaction condition includes addition of piperidine and benzene, and the reaction time is overnight. The compound represented by formula (11) and the compound represented by formula (7) are placed in a sealed tube for coupling reaction, in which, the reaction condition includes: addition of xylene, a reaction temperature of 160 C., and a reaction time of 16 hrs, to acquire lamellarin D trimethyl ether represented by formula (12), a yield of which is 40 wt. %, and a recovery rate of the compound represented by formula (7) is 26 wt. %. The compound represented by formula (12) is demethylated under a low temperature of approximately -78 C. by an overdose of a boron tribromide/dichloromethane solution with a reaction time of approximately 16 hrs, so that lamellarin H represented by formula (13) is acquired, and a yield thereof is 83 wt. %. |
85% | With piperidine; In benzene; for 8h;Dean-Stark; Reflux; | General procedure: A mixture of 2-hydroxybenzaldehyde (5.0 mmol), ethyl nitroacetate (6.0 mmol, 1.2 equiv), and piperidine (3-4 drops) in benzene was taken in a round bottom flask fitted with Dean-Stark apparatus and a condenser. The reaction mixture was then refluxed for 8 hours. After the completion of the reaction, the mixture was cooled down to room temperature and hexanes (50 mL) was added to precipitate the product. The solid was filtered, washed with excess hexanes, and dried to obtain the desired coumarin derivatives. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With (S)-2-((2-(hydroxydiphenylmethyl)pyrrolidin-1-yl)methyl)-6-(trifluoromethyl)phenol; copper(II) acetate monohydrate; triethylamine In toluene at 0℃; for 24h; enantioselective reaction; | 1.2 General procedures of Michael reaction General procedure: A mixture of Ligand (L2a, 10 mol%), Cu(OAc)2.H2O (10 %, 4.0 mg) and Et3N (10 %, 2.78 μL) in corresponding solvent (5.0 mL) was stirred for 1h at ambient atmosphere, corresponding 2-enoyl-pyridine N-oxides (0.2 mmol)were then added. The resulting mixture was cooled to 0 °C. After 30 min, corresponding nitro esters (0.4 mmol) was added slowly by syringe. After reaction was finished (monitored by TLC), the solvent was removed under vacuum. The crude product was charged to column chromatography on silica gel to give the pure product 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With (S)-2-((2-(hydroxydiphenylmethyl)pyrrolidin-1-yl)methyl)-6-(trifluoromethyl)phenol; copper(II) acetate monohydrate; triethylamine In toluene at 0℃; for 24h; enantioselective reaction; | 1.2 General procedures of Michael reaction General procedure: A mixture of Ligand (L2a, 10 mol%), Cu(OAc)2.H2O (10 %, 4.0 mg) and Et3N (10 %, 2.78 μL) in corresponding solvent (5.0 mL) was stirred for 1h at ambient atmosphere, corresponding 2-enoyl-pyridine N-oxides (0.2 mmol)were then added. The resulting mixture was cooled to 0 °C. After 30 min, corresponding nitro esters (0.4 mmol) was added slowly by syringe. After reaction was finished (monitored by TLC), the solvent was removed under vacuum. The crude product was charged to column chromatography on silica gel to give the pure product 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With (S)-2-((2-(hydroxydiphenylmethyl)pyrrolidin-1-yl)methyl)-6-(trifluoromethyl)phenol; copper(II) acetate monohydrate; triethylamine In toluene at 0℃; for 24h; enantioselective reaction; | 1.2 General procedures of Michael reaction General procedure: A mixture of Ligand (L2a, 10 mol%), Cu(OAc)2.H2O (10 %, 4.0 mg) and Et3N (10 %, 2.78 μL) in corresponding solvent (5.0 mL) was stirred for 1h at ambient atmosphere, corresponding 2-enoyl-pyridine N-oxides (0.2 mmol)were then added. The resulting mixture was cooled to 0 °C. After 30 min, corresponding nitro esters (0.4 mmol) was added slowly by syringe. After reaction was finished (monitored by TLC), the solvent was removed under vacuum. The crude product was charged to column chromatography on silica gel to give the pure product 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With (S)-2-((2-(hydroxydiphenylmethyl)pyrrolidin-1-yl)methyl)-6-(trifluoromethyl)phenol; copper(II) acetate monohydrate; triethylamine In toluene at 0℃; for 24h; enantioselective reaction; | 1.2 General procedures of Michael reaction General procedure: A mixture of Ligand (L2a, 10 mol%), Cu(OAc)2.H2O (10 %, 4.0 mg) and Et3N (10 %, 2.78 μL) in corresponding solvent (5.0 mL) was stirred for 1h at ambient atmosphere, corresponding 2-enoyl-pyridine N-oxides (0.2 mmol)were then added. The resulting mixture was cooled to 0 °C. After 30 min, corresponding nitro esters (0.4 mmol) was added slowly by syringe. After reaction was finished (monitored by TLC), the solvent was removed under vacuum. The crude product was charged to column chromatography on silica gel to give the pure product 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With (S)-2-((2-(hydroxydiphenylmethyl)pyrrolidin-1-yl)methyl)-6-(trifluoromethyl)phenol; copper(II) acetate monohydrate; triethylamine In toluene at 0℃; for 24h; enantioselective reaction; | 1.2 General procedures of Michael reaction General procedure: A mixture of Ligand (L2a, 10 mol%), Cu(OAc)2.H2O (10 %, 4.0 mg) and Et3N (10 %, 2.78 μL) in corresponding solvent (5.0 mL) was stirred for 1h at ambient atmosphere, corresponding 2-enoyl-pyridine N-oxides (0.2 mmol)were then added. The resulting mixture was cooled to 0 °C. After 30 min, corresponding nitro esters (0.4 mmol) was added slowly by syringe. After reaction was finished (monitored by TLC), the solvent was removed under vacuum. The crude product was charged to column chromatography on silica gel to give the pure product 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27%Spectr. | With sodium hydride; In dimethyl sulfoxide; mineral oil; at 50℃; | General procedure: Sodium hydride (60% in mineral oil) (600 mg, 15 mmol) was suspended in DMSO (50 mL), and the compound11 (4.7 mmol) was added upon vigorous stirring. Theresulting mixture was stirred for additional 10 min, and<strong>[27221-49-4]2,3-bis(chloromethyl)pyridine hydrochloride</strong> (9·HCl) (1 g,4.7 mmol) was added. The resulting mixture was stirred at50 C overnight, then cooled, and ice-cold H2O(50 mL) wasadded. The mixture was extracted with Et2O(3 × 15 mL), thecombined organic extracts were dried over Na2SO4and evaporatedin vacuo. The crude product was purified by columnchromatography (EtOAc-Hexanes (2:1) as eluent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | Stage #1: nitroacetic acid ethyl ester With titanium tetrachloride In tetrahydrofuran; dichloromethane at 0℃; for 0.166667h; Stage #2: 3,3-dimethylcyclohexanone In tetrahydrofuran; dichloromethane at 0℃; for 0.25h; Further stages; | Ethyl 2-amino-2-(3,3-dimethylcyclohexyl)acetate To a solution of TiCl4 (1M in DCM, 15.4 mL, 15.4 mmol) in THF (7.7 mL) at 0°C was added ethyl nitroacetate (0.85 mL, 7.70 mmol) dropwise over 5 minutes. The reaction mixture was stirred for 5 minutes, then 3,3-dimethylcyclohexanone (1.10 mL, 7.70 mmol) was added dropwise over 5 minutes. Following an additional 15 minutes at 0°C, a solution of 4-methylmorpholine (3.40 mL, 30.8 mmol) in THF (31 mL) was added via syringe pump dropwise over 2 h. The reaction mixture was slowly warmed to r.t. over 2 days, then diluted with EtOAc (30 mL) and H2O (30 mL). The layers were separated. The aqueous layer was re-extracted with EtOAc (2 x 50 mL), and the combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with EtOAc/hexanes (0-20% gradient). The isolated material was taken up in CHCl3 (24 mL) and isopropanol (7.2 mL). To this solution was added silica (3.82 g), followed by NaBH4 (365 mg, 9.26 mmol), portionwise over 5 minutes. The mixture was stirred vigorously at r.t. over 16 h, then AcOH (0.56 mL) was added. The mixture was filtered and concentrated in vacuo. The residue was re-dissolved in DCM (30 mL), and water (30 mL) was added. The aqueous layer was re-extracted with DCM (2 x 50 mL), and the combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude material was re-dissolved in EtOH (56 mL), and 10% Pd/C (56 mg) was added. The suspension was evacuated and back-filled three times with hydrogen, then left to stir at r.t. under a hydrogen atmosphere for 2 days. The mixture was filtered through a pad of Celite ^ (10 g) under suction using EtOH (100 mL), and concentrated in vacuo. Purification by flash column chromatography, eluting with EtOAc/hexanes (0-100% gradient), gave the title compound (1:1 mixture of diastereomers) (80 mg, 16% overall) as a colourless oil. Rf 0.14 (EtOAc:isohexanes, 70:30), KMnO4 stain. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine In acetonitrile at 20℃; for 0.5h; | 3.2. Synthesis of Isoxazoline N-oxide 4b To a solution of ethyl α-nitrocinnamate 1b (94.6 mg, 0.43 mmol) in acetonitrile (1.3 mL), ethyl nitroacetate (48 μL, 0.43 mmol) and triethylamine (60 μL, 0.43 mmol) were added, and the resultant mixture was stirred at room temperature for 30 min. After removal of the solvent under reduced pressure, the residual brown oil was dissolved in ethyl acetate (10 mL) and washed with water (10 mL × 4), and then dried over magnesium sulfate. After removal of the solvent, the residue was purified by column chromatography on silica gel to afford isoxazoline N-oxide 4b (eluted with hexane/EtOAc = 8/2, 121 mg, 0.41 mmol, 95%) as a yellow solid.3,5-Bis(ethoxycarbonyl)-4-phenyl-2-isoxazoline 2-oxide (4b) [22]. Yellow solid, yield; 95%, m.p. 75-76 °C. 1H NMR (400 MHz, CDCl3) δ 7.40-7.30 (m, 5H), 4.93 (d, J = 2.8 Hz, 1H), 4.84 (d, J = 2.8 Hz, 1H), 4.35 (dq, J = 10.8, 7.2 Hz, 1H), 4.32 (dq, J = 10.8, 7.2 Hz, 1H), 4.21 (dq, J = 10.8, 7.2 Hz, 1H), 4.17 (dq, J = 10.8, 7.2 Hz, 1H), 1.35 (dd, J = 7.2, 7.2 Hz, 3H), 1.17 (dd, J = 7.2, 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.2 (C), 158.1 (C), 138.1 (C), 129.3 (CH), 128.7 (CH), 127.0 (CH), 109.0 (C), 78.8 (CH), 62.7 (CH2), 62.0 (CH2), 52.7 (CH), 14.1 (CH3), 13.9 (CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.52% | Stage #1: nitroacetic acid ethyl ester; 2-chloro-benzaldehyde With titanium tetrachloride In tetrahydrofuran at -10 - 0℃; for 0.5h; Stage #2: With 4-methyl-morpholine at 15 - 20℃; for 1h; | 1.1 Step 1 Preparation of Intermediate 1-1 To a 10L three-necked flask equipped with mechanical stirring and nitrogen protection, THF (3500mL) was added, o-chlorobenzaldehyde (341g, 2.43mol) and nitroethyl acetate (323g, 2.43mol) were added successively, and then cooled to Internal temperature -10, slowly add TiCl dropwise under mechanical stirring4(920g, 4.85mol), control the internal temperature not to exceed 0 during the dripping. After dripping, keep at 0 and continue the reaction for 0.5h, and then add N-methylmorpholine (981.51g, 9.70mol) dropwise. Control the internal temperature not to exceed 15, after dropping, allow to warm to room temperature and stir for 1h, finally add 500mL saturated ammonium chloride to quench, extract with ethyl acetate (1000mL×3), wash with saturated brine, and dry with anhydrous sodium sulfate , Filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether/ethyl acetate 100:1) to obtain Intermediate 1-1 (580 g, 2.27 mol, 93.52% yield). |
93.52% | Stage #1: nitroacetic acid ethyl ester; 2-chloro-benzaldehyde With titanium tetrachloride In tetrahydrofuran at -10 - 0℃; for 0.5h; Inert atmosphere; Stage #2: With 4-methyl-morpholine In tetrahydrofuran at 15 - 20℃; for 1h; Inert atmosphere; | 1.1 Step 1 Preparation ofIntermediate 1-1 Add THF (3500 mL) to a 10L three-necked flask equipped with mechanical stirring and nitrogen protection, add o-chlorobenzaldehyde (341g, 2.43mol) and ethyl nitroacetate (323g, 2.43mol) successively, then cool to an internal temperatureof -10°C in an ice-salt bath, slowly add TiCl4 (920g, 4.85mol) dropwise with mechanical stirring, control the internal temperature not to exceed 0during dripping, keep at 0 and continue to react for 0.5h, then add N-methylmorpholine (981.51g, 9.70mol) dropwise, control the internaltemperature not to exceed 15 during dripping, after dripping,warm to room temperature and stir for 1h, finally, add 500mL saturated ammonium chloride to quench,extract with ethyl acetate (1000mL×3), Washed with saturated brine, dried over anhydrous sodiumsulfate, filtered, concentrated under reduced pressure, It was separated by silica gel column chromatography (volumeratio of petroleum ether/ethyl acetate 100:1) to obtain Intermediate 1-1 (580g, 2.27 mol, 93.52% yield). |
93.52% | Stage #1: nitroacetic acid ethyl ester; 2-chloro-benzaldehyde With titanium tetrachloride In tetrahydrofuran at -10 - 0℃; for 0.5h; Inert atmosphere; Stage #2: With 4-methyl-morpholine In tetrahydrofuran at 15 - 20℃; for 1h; Inert atmosphere; | 1.1 Step 1. Preparation of Intermediate 1-1 To a 10L three-necked flask equipped with mechanical stirring and nitrogen protection, THF (3500mL) was added, o-chlorobenzaldehyde (341g, 2.43mol) and nitroethyl acetate (323g, 2.43mol) were added successively, and then cooled to Internal temperature -10, slowly add TiCl dropwise under mechanical stirring4(920g, 4.85mol), control the internal temperature not to exceed 0 during the dripping, after dripping, maintain 0 to continue the reaction for 0.5h, and then add N-methylmorpholine (981.51g, 9.70mol) dropwise. Control the internal temperature not to exceed 15, after dropping, allow to warm to room temperature and stir for 1h, finally add 500mL saturated ammonium chloride to quench, extract with ethyl acetate (1000mL×3), wash with saturated brine, and dry with anhydrous sodium sulfate , Filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether/ethyl acetate 100:1) to obtain Intermediate 1-1 (580 g, 2.27 mol, 93.52% yield). |
93.52% | Stage #1: nitroacetic acid ethyl ester; 2-chloro-benzaldehyde With titanium tetrachloride In tetrahydrofuran at -10 - 0℃; for 0.5h; Inert atmosphere; Stage #2: With 4-methyl-morpholine In tetrahydrofuran at 15℃; for 1h; | 1.1 Step 1 Preparation of Intermediate 1-1 To a 10L three-necked flask equipped with mechanical stirring and nitrogen protection, THF (3500mL) was added, o-chlorobenzaldehyde (341g, 2.43mol) and nitroethyl acetate (323g, 2.43mol) were added successively, and then cooled to Internal temperature -10, slowly add TiCl dropwise under mechanical stirring4(920g, 4.85mol), control the internal temperature not to exceed 0 during the dripping. After dripping, keep at 0 and continue the reaction for 0.5h, and then add N-methylmorpholine (981.51g, 9.70mol) dropwise. Control the internal temperature not to exceed 15, after dropping, allow to warm to room temperature and stir for 1h, finally add 500mL saturated ammonium chloride to quench, extract with ethyl acetate (1000mL×3), wash with saturated brine, and dry with anhydrous sodium sulfate , Filtered, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether/ethyl acetate 100:1) to obtain Intermediate 1-1 |
93.52% | Stage #1: nitroacetic acid ethyl ester; 2-chloro-benzaldehyde With titanium tetrachloride In tetrahydrofuran at -10 - 0℃; for 0.5h; Inert atmosphere; Cooling with ice; Stage #2: With 4-methyl-morpholine In tetrahydrofuran at 15 - 20℃; for 1h; Inert atmosphere; | Step 1 Preparation of Intermediate Z-15-1 To a 10L three-necked flask equipped with mechanical stirring and nitrogen protection, THF (3500mL) was added, followed by o-chlorobenzaldehyde (341g, 2.43mol)and ethyl nitroacetate (323g, 2.43mol), then the ice-salt bath was cooled to an internal temperature of -10°C, and TiCl (920g, 4.85mol) was slowly added dropwise under mechanical stirring, and the internal temperature was controlled not to exceed 0°C during the dropwise addition, dripping,Maintain the reaction at 0 °C for 0.5 h, then add N-methylmorpholine (981.51 g, 9.70 mol) dropwise, control the internal temperature to not exceed 15 °C during the dropwise addition, allow to rise to room temperature and stir for 1 h after the dropwise addition Quenched with 500 mL of saturated ammonium chloride, extracted with ethyl acetate (1000 mL×3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and isolated by silica gel column chromatography to obtain intermediate Z-15-1 (580 g, 2.27 mol, 93.52% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.8% | With piperidine; acetic acid In butan-1-ol at 130℃; for 24h; Molecular sieve; | 4.2.12 7-(Diethylamino)-3-nitro-2H-chromen-2-one (12) To a solution of 4-(Diethylamino) salicylaldehyde (4.26g, 21.90mmol) in n-Butanol (50mL), Ethyl nitroacetate (2.46mL, 21.90mmol), Piperidine (0.3mL), AcOH (0.6mL) and molecular sieve added. The mixture was refluxed at 130°C for 24h. The mixture was cooled to room temperature, and the precipitate was filtered out, then dissolved in 40mL of DMF at 80°C. The filtered filtrate was added dropwise to 500mL ice water, the precipitated precipitate was filtered out, and a yellow solid was obtained after drying (4.06g, 69.8% yield). 1H NMR (400MHz, DMSO-d6) δ 9.04 (s, 1H), 7.74 (d, J=9.1Hz, 1H), 6.92 (dd, J=9.1, 1.9Hz, 1H), 6.65 (s, 1H), 3.54 (q, J=7.0Hz, 4H), 1.16 (t, J=7.0Hz, 6H). ESI-MS: m/z [M+ H]+ calcd for C13H15N2O4+ 263.10, found 263.22. Mp 195.2-198.4°C. |
69.8% | With piperidine; acetic acid In butan-1-ol at 130℃; for 24h; Molecular sieve; | 4.2.12 7-(Diethylamino)-3-nitro-2H-chromen-2-one (12) To a solution of 4-(Diethylamino) salicylaldehyde (4.26g, 21.90mmol) in n-Butanol (50mL), Ethyl nitroacetate (2.46mL, 21.90mmol), Piperidine (0.3mL), AcOH (0.6mL) and molecular sieve added. The mixture was refluxed at 130°C for 24h. The mixture was cooled to room temperature, and the precipitate was filtered out, then dissolved in 40mL of DMF at 80°C. The filtered filtrate was added dropwise to 500mL ice water, the precipitated precipitate was filtered out, and a yellow solid was obtained after drying (4.06g, 69.8% yield). 1H NMR (400MHz, DMSO-d6) δ 9.04 (s, 1H), 7.74 (d, J=9.1Hz, 1H), 6.92 (dd, J=9.1, 1.9Hz, 1H), 6.65 (s, 1H), 3.54 (q, J=7.0Hz, 4H), 1.16 (t, J=7.0Hz, 6H). ESI-MS: m/z [M+ H]+ calcd for C13H15N2O4+ 263.10, found 263.22. Mp 195.2-198.4°C. |
[ 5616-81-9 ]
tert-Butyl 2-(methylamino)acetate
Similarity: 0.55
[ 5616-81-9 ]
tert-Butyl 2-(methylamino)acetate
Similarity: 0.55
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Sorry,this product has been discontinued.
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