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CAS No. : | 927-63-9 | MDL No. : | MFCD00006999 |
Formula : | C5H9NO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RRLMPLDPCKRASL-ONEGZZNKSA-N |
M.W : | 99.13 | Pubchem ID : | 638320 |
Synonyms : |
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Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | 3267 |
Hazard Statements: | H314 | Packing Group: | Ⅱ |
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 |
---|---|---|
93.9% | Stage #1: at 140℃; for 1 h; Microwave irradiation |
In a reactor, 59 mL (0.5 mol) of methyl cyanoacetate was added to the reactor,N-ethylpyridine tetrafluoroborate 50 mL,3-dimethylaminopropenal 62 mL (0.5 mol) was homogeneously mixed,Microwave heating to 140 temperature and heat for 1h to carry out the reaction, TLC detection (oilEther: methylene chloride 1: 2 developed, sublimed iodine color)3-dimethylaminopropenal reaction completely, cooled to room temperature, organic solvent BEther 60mL extraction 3 times, residual phase ion water washing vacuum drying after repeated use, organic phase into the dry HCl gas, HPLC withThe reaction is continued until the reaction ends. Add the mass fraction of 20percent sodium hydroxide solution to adjust the pH = 5-6, separated, the water layer with ether20mL × 3 times extraction, combined organic layer, washed with water, molecular sieve drying, filtration, evaporation of solvent ether recovery, the residue byThe product was distilled at 110-115 ° C / 1 mmHg to prepare methyl 2-chloronicotinate and 80.6 g of colorless liquid in a yield of 93.9percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: at 90℃; for 4 h; |
Ethyl cyanoacetate (59 mL, 0.5 mol) was added to the reactor,1-dodecyl-3-methylimidazolium chloride50 mL,3-dimethylaminopropenal 62 mL (0.5 mol) was homogeneously mixed,The oil bath was heated to 90 ° C and incubated for 4 hours. TLC detection (petroleum ether: methylene chloride 1: 2 expansion, sublimed iodine coloring) 3-dimethylaminophenaldehyde was complete,Cool to room temperature, organic solvent1,2-dichloroethane 60mL extraction 3 times, residual phase ion water washing vacuum drying and reuse,The organic phase was passed through a dry HBr gas and the HPLC was followed by the reaction until the reaction was complete.Add the mass fraction of 20percent sodium carbonate solution to adjust the pH = 5-6, liquid,For water use1,2-dichloroethane 20mL × 3 times extraction, the organic layer, combined with water,The molecular sieves were dried, filtered and the solvent was evaporated under reduced pressure1,2-dichloroethane was recovered to give ethyl 2-bromonicotinate, 108.4 g of a light brown liquid in a yield of 94.0percent. |
93.5% | Stage #1: at 40℃; Sonication Stage #2: at 40℃; Sonication |
In a 500 mL three-necked flask equipped with a thermometer, first, 2-dimethylaminoacrolein (62 mL, 0.5 mol) and pyridine (20 mL) were added, and then 65 mL (0.6 mol) of ethyl cyanoacetate was added to prepare the prepared device. Into the ultrasonic instrument. Ultrasonic radiation conditions were set, and the reaction was carried out at a temperature of 40 °C, an ultrasonic power of 150 W, and a frequency of 20KHz TLC test (petroleum ether:dichloromethane 1:2 development, sublimation iodine development) 3-dimethylaminopropylene Aldehyde reaction is complete. After that, HBr gas was introduced and the ultrasonic irradiation conditions were as above, and the reaction was followed by HPLC until the reaction was completed. After the reaction is completed, add 30percent sodium hydroxide solution to adjust ρΗ = 5-6, and separate the layers. The aqueous layer is extracted with dichloromethane 20 mL x 3 times. The organic layers are combined, and the deionized water is washed with 10 mL of water. The organic layer was dried over anhydrous Na2SO4 , filtered, and the solvent was evaporated under reduced pressure in the liquid phase to obtain ethyl 2-bromonicotinate as light brown liquid, 107.5 g, with a yield of 93.5percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | for 6 h; Reflux | Preparation of compound 23a: pyrazolo[1,5-a]pyrimidineA mixture of 1 H-pyrazol-3-ylamine (32 g, 0.386 mol) and (E)-3-dimethylamino- propenal (38.2 g, 0.386 mol) in EtOH (500 ml_) was refluxed for 6 h. The solvent was removed in vacuo and the residue was purified via column chromatography (petroleum ether/EtOAc = 10:1 -2:1 ) which gave the title compound 23a as a white solid (30 g, 65percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | at 120℃; for 10 h; | Part I-- Synthesis of [1,8]-Naphthyridin-2-ylamine; Pyridine-2,6-diamine (0.30 g, 2.8 mmol), 3-dimethylaminoacrolein (90percent, 0.30 g, 2.8mmol), and polyphosphoric acid (PPA) (2.7 mL) were combined and the reaction mixture washeated to 120 oc for 10 hours. Then, the reaction mixture was poured on ice water and neutralized with solid sodium carbonate. The resulting aqueous mixture was extracted threetimes with ethyl acetate and the combined organic extracts were washed with brine,concentrated, and purified by column chromatography (EtOAc/hexanes) to give [1,8]naphthyridin-2-ylamine. Yield 85 mg (21 percent). LCMS (ESI): calc. C8H7N3 = 145; obs. M+H =146. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.42 g | Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -70 - -60℃; for 1.5 h; Inert atmosphere Stage #2: at -70 - 20℃; for 0.833333 h; Inert atmosphere |
Intermediate 7: 5,7-Dichloro-1,6-naphthyridine[0384]N-(2,6-Dichloro-4-pyridinyl)-2,2-dimethylpropanamide (1 g, 4.05 mmol) was taken up in THF (10 ml) under nitrogen and cooled to n-Butyl lithium (4.05 ml, 10.12 mmol, 2.5M solution in hexanes) was added over 30 min keeping the temperature below −60° C. and then stirred at below −70° C. for 1 h. (2E)-3-(dimethylamino)-2-propenal (0.607 ml, 6.07 mmol) in THF (2 ml) was added over 30 min keeping the temperature below −60° C. The reaction was stirred at below −70° C. for 20 min and then allowed to warm to room temperature. LCMS showed that no starting material remained so the reaction was quenched with 5M HCl (5 ml) and refluxed overnight. LCMS showed good conversion to product so the reaction was cooled to room temperature. The reaction mixture was basified with solid K2CO3 and extracted with EtOAc (4×25 ml). The combined organics were dried with Na2SO4, filtered and concentrated to yield a brown solid. The crude product was applied to a samplet and columned using a 40+M eluting with 12percent diethyl ether in cyclohexane for 2 CVs, then with 12percent-63percent diethyl ether in cyclohexane over 10 CVs then held at 63percent for SCVs. Appropriate fractions were combined and evaporated to give the title compound as a yellow solid (0.42 g).[0386]LCMS (Method B): Rt=0.89 min, MH+ 199/201 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | In ethanol; for 6.0h;Reflux; | Preparation of compound 23a: pyrazolo[1,5-a]pyrimidineA mixture of 1 H-pyrazol-3-ylamine (32 g, 0.386 mol) and (E)-3-dimethylamino- propenal (38.2 g, 0.386 mol) in EtOH (500 ml_) was refluxed for 6 h. The solvent was removed in vacuo and the residue was purified via column chromatography (petroleum ether/EtOAc = 10:1 -2:1 ) which gave the title compound 23a as a white solid (30 g, 65%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium methylate; In ethanol;Heating / reflux; | 2-(Diethoxymethyl)pyrimidine was prepared as follows:-2,2-Diethoxy-acetamidinehydrochloride (71.43 g, 391.08 mmol) and <strong>[927-63-9]3-dimethylaminoacrolein</strong> (37.51 ml, 337.13 mmol) were dissolved in dry ethanol (440 ml).The reaction mixture was brought to reflux in an oil bath and 25% wt. sodium methoxide solution (120.26 ml, 525.92 mmol) was then added dropwise over 50 mins and the resulting suspension stirred at reflux overnight. The reaction mixture was cooled to room temperature, filtered and the filtrate evaporated to dryness giving a thick brown cloudy oil. Purified by column chromatography using 50% EtOAc in isohexane as eluant. The appropriate fractions were combined and evaporated to give the desired product (53.46 g, 87%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With acetic acid; In ethanol;Heating / reflux; | Step Two: To a suspension of 32 (851 mg, 1.71 mmol) in ethanol (absolute, 6.8 mL) and acetic acid (glacial, 0.34 mL) at room temperature under nitrogen, 3-(dimethylamino)acrolein (1.02 mL, 10.2 mmol) was added by syringe. The resulting mixture was heated to reflux overnight, cooled to room temperature and diluted with ethyl acetate. This mixture was washed with HCl (2N, twice) and brine. The organic phase was dried over MgSO4 and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 3:2 hexanes:ethyl acetate to give 33 (476 mg, 52%) as a light yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; at 125℃; for 2h;Microwave irradiation; | A mixture of nitrile 4 (0. 500g, 1.7 mmol), 0. 50g <strong>[354-38-1]trifluoroacetamide</strong> and 0.25g dimethylaminoacrolein in 5 mL ethanol was heated to 125 C for 2h by microwave irradiation (CEM, 300 watt). The reaction was then evaporated in vacuo and the residue was purified by silica gel chromatography (gradient elution: 0-20% ethyl acetate/dichloromethane) to give pyrimidine 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.0% | With ammonium acetate; sodium hydroxide; acetic acid; triethylamine; In tetrahydrofuran; | EXAMPLE 2 Synthesis of 3-(2-pyridyl) quinoline (VI) 5.14 g (0.030 mol) of 3-acetyl quinoline and 3.12 g (0.031 mol) of 3-dimethylaminopropenal were dissolved in 35 ml of tetrahydrofuran, 3.64 g (0.032 mol) of potassium t-butoxide was added, and heated at 60 C. for 10 minutes. Subsequently, 18.50 g (0.24 mol) of ammonium acetate and 14 ml of acetic acid were added and, after allowing to react at 60 C. for 2 hours, the internal temperature was raised up to 105 C. to remove tetrahydrofuran, followed by allowing to react at 105 C. for 2 hours. After the reaction solution was allowed to cool, 60 ml of a 25% NaOH aqueous solution was added, then the mixture was extracted with 4*100 ml ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was distilled under reduced pressure (bp. 165 to 170 C./0.1 Torr) to obtain 2.88 g (yield: 56.0%) of pale yellow liquid. HPLC analysis (column: ODS-80TM; detecting UV: 264 nm; flow rate: 1.0 ml/min; eluant: acetonitrile/water=82/18; buffer: triethylamine 0.1%, acetic acid 0.1%) revealed that purity of the product was 98.7%, boiling point: 165 C. to 170 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51.2% | With ammonium acetate; sodium hydroxide; acetic acid; triethylamine; In tetrahydrofuran; water; | EXAMPLE 3 Synthesis of 2,4'-dipyridyl (VII) 2.91 g (0.024 mol) of 4-acetylpyridine and 2.97 g (0.030 mol) of 3-dimethylaminopropenal were dissolved in 100 ml of THF, 2.69 g (0.024 mol) of potassium t-butoxide was added, and heated at 60 C. for 10 minutes. Subsequently, 23.12 g (0.30 mol) of ammonium acetate and 60 ml of acetic acid were added and, after allowing to react at 60 C. for 3.5 hours, THF was removed in an evaporator. Then, 100 ml of water and 150 ml of a 25% NaOH aqueous solution were added, and the mixture was extracted with 4*100 ml ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under A reduced pressure, and recrystallized from hexane to obtain 1.92 g (yield: 51.2%) of colorless platy crystals. HPLC analysis (column: ODS-80TM; detecting UV: 264 nm; flow rate: 1.0 ml/min; eluant: acetonitrile/water=50/50; buffer: triethylamine 0.1%, acetic acid 0. 1%) revealed that purity of the product was 99.3%, melting point: 55.8 C. to 56.0 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With ammonium acetate; In acetic acid; for 18h;Heating / reflux; | Hydromorphone hydrochloride (1.0 g, 3.10 mmol), 3- (DIMETHYLAMINO) acrolein (0.369 g, 3.72 mmol) and ammonium acetate (0.477 g, 6.20 mmol) and ACOH (20 mL) is refluxed in an oil bath at 130-135 C for 18 h. Work up of the reaction mixture and purification of the crude product as described for the preparation OF 7A gives the desired product 7f (0.215 g, 22%): mp 164-166 C ; TLC, Rf 0.3 (CH2Cl2-MeOH-NH40H, 95: 4.5 : 0.5) ;.H NMR (CDC13) 6 2.01-2. 34 (M, 2H, C-15 H2), 2.54-2. 77 (M, 6H, C-8 H2, C-10 H, C-14 H, C-16 H2), 2.69 (s, 3H, NCH3), 3.16 (d, 1H, J = 18. 7 Hz, C-10 H), 3.39-3. 41 (M, 1H, C-9 H), 5.51 (s, 1H, C-5 H), 6. 58 (d, 1H, J = 8.1 Hz, C-2 H), 6.66 (d, 1H, J = 8.1 Hz, C-1 H), 7.15 (dd, 1H, J= 7.8 and 4.7 Hz, C-5' H), 7.34 (M, 1H, C-4'H), 8.52 (dd, 1H, J= 4.7 and 1.1 Hz, C-6'H), 8.52-8. 58 (br s, lH, C-3 OH); ESI MS m/z 321 (MH) + Anal. (C2OH2ON202-0. 6H20) C, H, N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With ammonium acetate; In acetic acid; for 18h;Heating / reflux; | Oxycodone hydrochloride (2.0 g, 5.69 mmol), 3- (DIMETHYLAMINO) ACROLEIN (0.845 g, 8.52 mmol) and ammonium acetate (1.31 g, 17.04 mmol) and ACOH (30 mL) is refluxed in an oil bath at 130-135 C under an atmosphere of argon for 18 h. Work up of the reaction mixture and purification of the crude product as described above for the preparation OF 7A gives 6,7-Didehydro-4, 5A-EPOXY-14- hydroxy-3-methoxy-17-methylpyrido [2', 3 : 6,7] morphinan (7m) (0.792 g, 40 %): mp 210-212 C ; TLC, Rf 0.4 (CH2CI2-MEOH-NH4OH, 94.5 : 5: 0.5) ;H NMR (CDC13) 8 1.80-1. 83 (m, 1H, C-15 H), 2.35-2. 40 (m, 2H, C-15 H, C-16 H), 2.43 (s, 3H, NCH3), 2.50-2. 78 (m, 4H, C-8 H2, C-10 H, C-16 H), 2.95 (d, 1H, J= 6.5 Hz, C-9 H), 3.26 (d, 1H, J= 18.7 Hz, C-10 H), 3.79 (s, 3H, OCH3), 4.5-5. 8 (broad hump, LH, C-14 OH), 5. 53 (s, 1H, C-5 H), 6.61 (d, 1 H, J = 8.1 Hz, C-2 H), 6.66 (d, 1H, J = 8.1 Hz, C-1 H), 7.10 (dd, 1H, J= 7.7 and 4.6 Hz, C-5'H), 7.34 (d, 1H, J = 7.7 Hz, C-4'H), 8.56-8. 58 (m, 1H, C-6' H); ESI MS M/Z 351 (MH) +. Anal. (C2LH22N203-0. 2H20) C, H, N. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | <strong>[4318-42-7]1-Isopropylpiperazine</strong> (4.4 ml, 30.6 mmol) was added to a solution of 3-(dimethylamino)acrolein (2.82 g, 25.5 mmol) in ethanol (100 ml), followed by formaldehyde (37percent solution in water, 2.3 ml, 30.6 mmol) and acetic acid (100 mul). The mixture was stirred at 50° C. for 3.5 hours, then room temperature for 15 hours. The solution was concentrated in vacuo, re-dissolved in ethanol (25 ml) and then formaldehyde (2.3 ml) and acetic acid (100 mul) were added. The mixture was stirred at 60° C. for 4 hours then concentrated in vacuo to yield the title compound as a pale yellow oil (6.10 g, 90percent).NMR Spectrum: (CDCl3) 1.02 (d, 6H), 2.51 (m, 8H), 2.67 (m, 1H), 3.19 (s, 2H), 3.24 (s, 6H), 6.61 (s, 1H), 8.92 (s, 1H); Mass spectrum: M+H+ 240. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dimethyl amine; In tetrahydrofuran; ethanol; at 70℃; for 18h; | To a solution of (1-Carbamimidoyl-cyclopropyl)-carbamic acid tert-butyl ester hydrochloride (3.62 g, 15.4 mmol) in anhydrous EtOH (62 mL) was added dimethylaminoacrolein (3.6 mL, 36. mmol) and dimethylamine (2 M in THF, 10. mL, 20. mmol). The reaction was heated at 70 C for 18 h. The EtOH was removed in vacuo and the residue was dissolved in EtOAc (150 mL) and washed with water (3x 100 ml). The organic phase was dried with Na2SO4 and concentrated to give a red oil. The product was crystallized from the oil using warm hexanes (30 mL) and the light orange solids were collected by filtration. The filtrate was re-processed in the same manner two additional times. In total 2.23 g of the title compound was isolated as a light orange powder, m/z 236.40 [M+l]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With acetic acid; In isopropyl alcohol; at 85℃; for 8h; | 4-(3,5-Diaminopyrazolo-3-yl)-6-thiomethylpyrimidine (21', 21 g, 94.5 mmol) was heated in 250 mL of 2-propanol with N,N-dimethylacrolein (15.3 mL, 15 4 g, 154 mmol) and 10 mL of glacial acetic acid at 85 0C for 8 hours. A gentle stream of nitrogen gas was swept over the top of the flask to aid in the removal of the dimethylamine generated. The reaction was cooled and the dark ppt was isolated via suction filtration. The ppt was then washed with 2-propanol and acetonitrile. The crude material was re- crystallized from glacial acetic acid to furnish 11.2 g of material (1st crop) and 7.2 g (2nd crop) (75% ) LC/MS (M+l): 259. <n="68"/>1H NMR (SOO MHZ, d6-DMSO): delta 8.9 (dd,lH), 8.85 (s,lH), 8.58 (m,lH), 8.32 (s,lH), 7.03 (m,2H), 7.00 (m,lH), 2,57 (s,3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With acetic acid; In isopropyl alcohol; at 160℃; for 0.166667h;Microwave irradiation; | (l(S)-2-(6-(l-(4-Fluorophenyl)ethylamino)-2-(methylthio)pyrimidin-4- yl)malononitrile (16c, 110 mg, 0.33 mmol) was suspended in IPA (6.0 mL). Hydrazine was then added (11.0 mg, 0.34 mmol). The reaction mixture was heated at 160 0C with microwave irradiation. After 10 minutes, the reaction mixture was allowed to cool to rt. LC/MS showed the presence of product (LC / MS (M+ 1): 360.5). In the same pot, glacial acetic acid (130 mg) was added, followed by N,N-dimethyl acrolein (130 mg, 1.3 mmol). The reaction mixture was heated at 160 0C with microwave irradiation for 10 minutes. The mixture was then allowed to cool down to rt. All volatiles were removed at reduced pressure and the crude residue was purified on a combi-flash system (0 -100 % Hexane/EtOAc). Yield: 55 mg (45%) of the title compound.1H NMR (300 MHz, CDCl3): delta 8.30 (dd, 2H), 7.32 (dd, 2H), 6.94 (t, 2H), 6.63 (dd, IH), 6.10 (br s, 2H), 5.10 (br d, IH), 4.93 (m, IH), 2.42 (s, 3H), 1.50 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid; In ethanol; at 160℃; for 0.25h;Microwave irradiation; | A solution of 3aa (349 mg, 1.2 mmol), 3-dimethylacrylaldedhyde (0.24 mL, 2.4 mmol) and acetic acid (144 mg, 2.4 mmol) in ethanol (4 mL) was exposed to microwave irradiation for 15 min at 160 0C. A solid was formed and was isolated by filtration, yielding the title compound 4aa as a brown solid which was used in the next step without further purification. LC/MS: 2.9 min, 332.4 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bromine; In benzene; at 15 - 20℃; | 3-Dimethylaminoacrolein (1.98 g, 20 mmol) was dissolved in benzene (20 mL). Br2 (1.07 mL, 21 mmol) was added dropwise slowly at 15 C. The obtained curds-like mass was stirred for 16 h. The solid phase was filtered off, washed on the filter with benzene, and transferred into a beaker. A 20% solution OfK2CO3 and benzene were added. The organic layer was separated. The aqueous one was washed twice more with benzene. The combined organic phases were washed with brine and concentrated to give (2Z)-2-bromo-<strong>[927-63-9]3-(dimethylamino)acrylaldehyde</strong>. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 42; Synthesis of 2,3'-Bipyridyl-6'-one3 g (0.019 mol) of <strong>[55676-22-7]3-acetyl-6-chloropyridine</strong> and 5.9 g (0.020 mol) of 3-piperidino-2-prop-2-enylidene piperidinium tetrafluoroborate were dissolved in 15 ml of THF and after cooling to 0 C., 2.6 g (0.023 mol) of potassium tert-butoxide was added, followed by stirring at 30 C. for 1 hours. Subsequently, 7 ml of acetic acid and g (0.115 mol) of ammonium acetate were added and the reaction was allowed to proceed at 100 C. for 5 hours. The reaction solution was cooled to 50 C. and after further adding 1.0 g (3.4 mmol) of 3-piperidino-2-prop-2-enylidene piperidinium tetrafluoroborate, the reaction was allowed to proceed at 100 C. for 4 hours. | ||
With ammonium formate; at 90℃;Large scale; | BL03 compound is added to polyphosphoric acid, was added Compound BL-b, warmed to 90 , followed by slow addition of ammonium formate, the reaction was continued for 4-5 hours.After the reaction was cooled to room temperature, ice water was added 30L, stirring, 8kg sodium hydroxide was added, the reaction was heated to 70-80 deg.] C for 1 hour.After the reaction was cooled to room temperature.Filtration, the solid was washed with water 40-50 deg.] C for 20-24 hours blast drying, to obtain a gray powder 998g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | To a solution of 15B (414.3 mg, 1.4 mmol) in chloroform (4.4 ml) was added N-chlorosuccinimde (307 mg, 2.25 mmol) slowly over 30 min followed by stirring at r.t. for 30 min and at 45 C. for 20 min. To the mixture was added 3-dimethylamino-propenal (314 mul, 2.82 mmol) and TEA (217 mul, 1.6 mmol) in chloroform (1.0 ml) slowly while heating at 45 C. The mixture was heated at 45 C. for 1 h and then warmed to r.t. over 4 h. The solution was diluted with EtOAc, washed with 0.5M potassium hydrogen phosphate, 5% aqueous NaHCO3, brine, dried, filtered and concentrated. Purification by flash chromatography on silica gel (85:15 CH2Cl2/ether as eluant) gave 15C (246 mg, 51%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bromine; In chloroform; at 20℃; for 0.583333h; | 3-Dimethylamino-propenal (50 mL, 500 mmol) is dissolved in CHCI3 (400 mL) at room temperature. Bromine (25.7 mL, 0.500 mol) is added neat via syringe over 5 minutes. After 30 minutes, the reaction is poured into a mixture of 200 mL saturated aqueous Na2S203 and 200 mL saturated aqueous NaHCC>3, and the mixture is extracted with CH2CI2 (3 x 100 mL). The combined organic layers are dried over MgS04 and concentrated to give a solid. The solid is dissolved in EtOAc (200 mL), insoluble materials are filtered off, the filtrate is concentrated in vacuo and the resulting solid is washed with a solution of 50% EtOAc in hexanes to afford 3- dimethylamino-2-bromo-propenal as a solid (ES+ m/z 178.28). | |
With bromine; In chloroform; at 20℃; for 0.583333h; | -Dimethylamino-2-bromo-propenal^N-^-^H ^NBr3-Dimethylamino-propenal (50 mL, 500 mmol) was dissolved in CHCI3 (400 mL) at room temperature. Bromine (25.7 mL, 500 mmol) was added neat via syringe over 5 min. After 30 min, the reaction was poured into 200 mL saturated aqueous Na2S2Os and 200 mL sat NaHCO3. This mixture was extracted with CH2Cl2 (3 x 100 mL). The combined organic layers were dried over MgStheta4 and concentrated to give dark colored solids. These solids were dissolved in EtOAc (200 mL) and the insoluble materials were filtered off. The filtrate was concentrated in vacuo and the resulting solids were washed with 50% EtOAc/hexanes to give 50.0 g of the title compound as a pale yellow solid, m/z 178.28 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-iodo-succinimide; In dichloromethane; at 20℃; for 1h; | 3-Dimethylamino-2-iodo-propenalTo a solution of 3-dimethylamino-propenal (1.5 niL, 15 mmol) in CH2CI2 (60 niL) at room temperature was added N-iodosuccinimide (3.38 g, 15 mmol) as a solid in a single portion. The reaction was stirred for 1 h followed by the addition of CH2CI2 (25 mL).The reaction mixture was washed with sat aqueous Na2S2O3 (1 x 75 mL) and water (2 x50 mL). The organic phase was dried over Na2SCU and concentrated to give a black solid. Recrystallized from EtOAc/hexanes to give 1.27 g of the title compound as reddish crystals, m/z 226.3 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium acetate; In ethanol; at 70℃; for 16h; | l-Cyclopropyl-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-pyrazoleCyclopropylhydrazine oxalate (162 mg, 1.00 mmol) and NaOAc (82 mg, 1.0 mmol) were combined in EtOH (200 proof, 1.5 niL) and 3-dimethylamino-propenal (0.10 niL, 1.0 mmol) was added in one portion via syringe. The suspension was stirred at 70 0C for 16 h then allowed to cool to room temperature. The reaction was diluted with sat. aq. NaHCtheta3 (3 mL) and extracted with EtOAc (4 x 5 mL). The combined organic layers were dried over Na2Stheta4 and concentrated on a rotary evaporator without heating the sample to give the 1 -cyclopropyl- lH-pyrazole as a volatile, liquid that was used without further purification, m/z 109.4 [M + H]+ |
Yield | Reaction Conditions | Operation in experiment |
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65% | With acetic anhydride; pyridinium tetrafluoroborate; acetic acid; at 0 - 20℃; for 5h; | Example 1.3: Synthesis of 5-Dimethylamino-4-methoxycarbonyl-penta-2,4- dienylidene-dimethyl-ammoniumtetrafluoroboratePyridiniumtetrafluoroborate (283.7 g, 1.70 mol) was added to a solution of methyl- (2E)-3-(3-dimethylamino)prop-2-enoate in 442.5 ml acetic anhydride / acetic acid(2:1). The resulting suspension was cooled to 0C and <strong>[927-63-9]3-dimethylaminoacrolein</strong>e(169.9 ml, 1.70 mol) was added slowly (3 h) under vigorously stirring and cooling with an ice bath receiving an yellow-brown precipitate. After further stirring for 2 h at room temperature the reaction mixture was filtered. The remaining solid was washed with diethylether several times and dried under reduced pressure.Recrystallization from i-propanol / ethanol (2:1) gave 326.7 g (65%) of the pentamethinium salt as yellow crystals. |
Yield | Reaction Conditions | Operation in experiment |
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89% | With pyridine; at 120℃; for 0.0333333h;Microwave irradiation; | A mixture of 9a (2.15 g, 5 mmol) and 3-(dimethylamino)acrolein (0.5 g, 5 mmol) in pyridine (10 mL) was refluxed for 48 h or heated in the microwave oven at the maximum power and 120 C for 2 min. Then, the solvent was removed under reduced pressure and the remaining residue was triturated with MeOH to afford crystals, which were then collected by filtration and recrystallized from DMF as pale brown crystals. Yield: thermally (57%), by microwave (89%), mp 234-236 C; IR (KBr): nu/cm-1 3420 (NH), 1683, 1615 (2CO); 1H NMR (CDCl3): delta 3.93 (s, 3H, CH3), 7.09 (t, J = 7.6 Hz, 1H, Ar-H), 7.26-7.50 (m, 6H, Ar-H), 8.19 (d, J = 7.6 Hz, 2H, Ar-H), 8.61-8.73 (m, 2H, Ar-H), 8.80 (s, 1H, Ar-H), 8.99 (s, 1H, indole H-2) and 11.84 ppm (s, 1H, NH). 13C NMR (CDCl3): delta 33.88 (CH3), 105.88, 109.48, 109.75, 114.31, 119.31, 122.87, 123.57, 127.50, 127.94, 129.26, 135.01, 136.27, 137.15, 139.04, 139.46, 145.97, 147.51, 147.86, 151.86, 157.11, 158.85 and 180.68 ppm (Ar-C and CO); MS (EI): m/z (%) 462 (M+, 75.6), 363 (M+ + 1, 23.9). Anal. Calcd. for C25H18N8O2 (462.47): C, 64.93; H, 3.92; N, 24.23; Found: C, 64.87; H, 3.95; N, 24.19. |
Yield | Reaction Conditions | Operation in experiment |
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/V-(2,6-Dichloro-4-pyridinyl)-2,2-dimethylpropanamide (1 g, 4.05mmol) was taken up in THF (10ml) under nitrogen and cooled to <-70C. n-Butyl lithium (4.05ml, 10.12mmol, 2.5M solution in hexanes) was added over 30min keeping the temperature below -60C and then stirred at below -70C for 1 h. (2£)-3- (dimethylamino)-2-propenal (0.607ml, 6.07mmol) in THF (2ml) was added over 30min keeping the temperature below -60C. The reaction was stirred at below -70C for 20min and then allowed to warm to room temperature. LCMS showed that no starting material remained so the reaction was quenched with 5M HCI (5ml) and refluxed overnight. LCMS showed good conversion to product so the reaction was cooled to room temperature. The reaction mixture was basified with solid K2C03 and extracted with EtOAc (4x25ml). The combined organics were dried with Na2S04, filtered and concentrated to yield a brown solid. The crude product was applied to a samplet and columned using a 40+M eluting with 12% diethyl ether in cyclohexane for 2CVs, then with 12%-63% diethyl ether in cyclohexane over 10CVs then held at 63% for 5CVs. Appropriate fractions were combined and evaporated to give the title compound as a yellow solid (0.42g).LCMS (Method B): Rt = 0.89min, MH+ 199/201 | ||
0.42 g | Intermediate 7: 5,7-Dichloro-1,6-naphthyridine[0384]N-(2,6-Dichloro-4-pyridinyl)-2,2-dimethylpropanamide (1 g, 4.05 mmol) was taken up in THF (10 ml) under nitrogen and cooled to n-Butyl lithium (4.05 ml, 10.12 mmol, 2.5M solution in hexanes) was added over 30 min keeping the temperature below -60 C. and then stirred at below -70 C. for 1 h. (2E)-3-(dimethylamino)-2-propenal (0.607 ml, 6.07 mmol) in THF (2 ml) was added over 30 min keeping the temperature below -60 C. The reaction was stirred at below -70 C. for 20 min and then allowed to warm to room temperature. LCMS showed that no starting material remained so the reaction was quenched with 5M HCl (5 ml) and refluxed overnight. LCMS showed good conversion to product so the reaction was cooled to room temperature. The reaction mixture was basified with solid K2CO3 and extracted with EtOAc (4×25 ml). The combined organics were dried with Na2SO4, filtered and concentrated to yield a brown solid. The crude product was applied to a samplet and columned using a 40+M eluting with 12% diethyl ether in cyclohexane for 2 CVs, then with 12%-63% diethyl ether in cyclohexane over 10 CVs then held at 63% for SCVs. Appropriate fractions were combined and evaporated to give the title compound as a yellow solid (0.42 g).[0386]LCMS (Method B): Rt=0.89 min, MH+ 199/201 |
Yield | Reaction Conditions | Operation in experiment |
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38% | To a solution of 6 (1.52 mg, 2 mmol) in dry THF (50 mL) was added dropwise 1.6 Mn-BuLi in hexane solution (3.0 mL, 4.8 mmol) at -78 C under nitrogen atmosphere.After the mixture was stirred at -78 C for 1 h, anhydrous N,N-dimethylacrolein (990mg, 10 mmol) was added into the mixture. After it was slowly warmed up to roomtemperature and was stirred for 4 h, the mixture was poured into aqueous NH4Clsolution. The aqueous layer was extracted with ethyl acetate, and the combinedorganic phase was washed with saturated brine and dried over anhydrous Na2SO4.The solvent was removed under vacuum and the residue was purified by columnchromatography (silica gel, DCM: hexane = 1:2) to afford 8 as an orange waxy solid(539 mg, 38%). |
Yield | Reaction Conditions | Operation in experiment |
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Example 145C 4-(1-Vinylcyclohexyl)-1H-pyrazole-3,5-diamine Hydrazine monohydrate (0.098 mL, 1.69 mmol) was added to a solution of the product from Example 145B (295 mg, 1.69 mmol) in n-butanol (5 mL), and the mixture was heated at 100 C. under nitrogen for 36 hours. The reaction solution was cooled to room temperature and concentrated under vacuum. The residue was dilute with water (15 mL) and extracted with EtOAc (2*15 mL). The combined organic phase was dried (MgSO4), filtered, and concentrated under vacuum to provide the title compound as an inseparable 1:1 mixture with 3,5-diamino-4-(1-ethylcyclohexyl)pyrazole, used directly in the next step.Example 145D3-(1-Vinylcyclohexyl)pyrazolo[1,5-a]pyrimidin-2-amineAcetic acid (0.02 mL) was added to a solution of <strong>[927-63-9]3-(dimethylamino)acrylaldehyde</strong> (218 mg, 2.199 mmol) and the product from Example 145C (335 mg, 1.624 mmol) in EtOH (7 mL). The reaction mixture was heated at 90 C. for 2 hours, then cooled to room temperature and concentrated under vacuum. The residue was purified by HPLC (30×100 mm XBridge column eluted with 0.1 M aqueous (NH4)2CO3-MeOH, 80:20-0:100 over 15 min) to provide the title compound. 1H NMR (300 MHz, CD3OD) delta ppm 1.41-1.77 (m, 8 H), 2.59-2.71 (m, 2H), 4.92 (d, J=17.4 Hz, 1H), 5.04 (d, J=10.7 Hz, 1H), 5.98 (dd, J=17.4, 10.7 Hz, 1H), 6.63 (dd, J=6.7, 4.2 Hz, 1H), 8.23 (dd, J=4.2, 1.8 Hz, 1H), 8.44 (dd, J=6.9, 1.8 Hz, 1H).Example 145E3-(1-Ethyllcyclohexyl)pyrazolo[1,5-a]pyrimidin-2-amineA second-eluting component was isolated from the chromatographic purification described in Example 145D, and identified as the title compound. 1H NMR (300 MHz, CD3OD) delta ppm 0.68 (t, J=7.5 Hz, 3H), 1.32-1.61 (m, 8H), 1.67 (q, J=7.4 Hz, 2H), 2.67-2.83 (m, 2H), 6.61 (dd, J=6.8, 4.0 Hz, 1H), 8.20 (dd, J=4.0, 2.0 Hz, 1H), 8.42 (dd, J=6.9, 1.8 Hz, 1H); MS (DCI/NH3) m/z 245 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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59% | acetic acid; In ethanol; at 140℃; for 0.25h;microwave; | Example 1C 3-(4-(trifluoromethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-2-amine In a microwave vessel containing the product from Example 1B (0.4 g, 1.549 mmol) and <strong>[927-63-9]3-(dimethylamino)acrylaldehyde</strong> (0.155 g, 1.549 mmol) in ethanol (5 mL) was added two drops of acetic acid. The mixture was irradiated with microwave at 140 C. for 15 minutes and concentrated. The resulting solid was purified by flash chromatography on silica gel, eluting with EtOAc/Hexanes (40-70% gradient), to yield the title compound (0.49 g, 59%). MS ESI m/z 295.5 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
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43% | acetic acid; In ethanol; at 150℃; for 0.5h;microwave; | Example 105B 3-tert-butylpyrazolo[1,5-a]pyrimidin-2-amine A mixture from Example 105A (2.61 g, 16.9 mmol), 3-dimethylaminoacrylaldehyde (2.0 mL, 20.0 mmol) and acetic acid (25 muL, 0.44 mmol) in ethanol (18 mL) was heated by microwave to 150 C. for 30 minutes. The mixture was cooled to ambient temperature and concentrated. Purification by silica gel chromatography (EtOAc, Rf=0.39) afforded 2.34 g (43%) of the title compound. MS (DCI) m/z 191 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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acetic acid; In ethanol; at 80℃; for 4h; | Example 112C 3-Isopropylpyrazolo[1,5-a]pyrimidin-2-amine Acetic acid (0.038 mL, 0.67 mmol) was added to a solution of 3-dimethylaminoacrylaldehyde (624 mg, 4.43 mmol) and the product from Example 112B (414 mg, 2.95 mmol) in ethanol (9 mL), and the reaction mixture was heated at 80 C. for 4 hours, then concentrated under vacuum to a dark oil. The residue was purified by flash chromatography (silica gel eluted with hexanes-EtOAc 50:50-0:100) to provide the title compound as a yellow solid. MS (ESI) m/z 177 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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In acetic anhydride; acetic acid; at 0℃; for 1h;Cooling with ice; | Example 3:Synthesis of 5-Dimethylamino-4-acetyl-penta-2,4-dienylidene- dimethylammonium tetrafluoroboratePyridinium tetrafluoroborate (2.21 g, 13.3 mmol) was added to a solution of (3E)- 4-(dimethylamino)-3-buten-2-one (1.54 ml, 13.3 mmol) in 13.5 ml acetic anhydride/acetic acid (2: 1). The resulting suspension was cooled to 0C and 3- dimethylaminoacroleine (1.33 ml, 13.3 mmol) was added over a period of 1 h under vigorous stirring and cooling with an ice bath receiving a red-brown precipitate. The cool reaction mixture was filtered and the remaining solid was washed with diethylether several times and dried under reduced pressure. The pentamethinium salt was obtained as orange crude product (2.69 g, 96%) and was used without any further purification |
Yield | Reaction Conditions | Operation in experiment |
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Intermediate 88G(E)-/V,//-Diisopentyl-2-(4-methoxyphenyl)-3-(3-oxoprop-1-en-1-yl)pyrazolo[1 ,5- a]pyrimidine-5-carboxamideTo a solution of 3-(dimethylamino)acrolein (0,22 mL; 218 mg; 2,2 mmol) in N,N - dimethylformamide (3 mL) was added phosphoryl chloride (0,16 mL; 269 mg; 1 ,76 mmol) and the mixture was stirred at room temperature for 10 min. Then /V,/V-diisopentyl-2-(4- methoxyphenyl)pyrazolo[1 ,5-a]pyrimidine-5-carboxamide (180 mg; 0,44 mmol) in N,N - dimethylformamide ( 2mL) was added and the mixture was heated to 65 C for 4 h. Then triethylamine (2 mL) and water (2 mL) were slowly added at 60 C and the mixture was stirred for 30 min. The mixture was cooled to room temperature and diluted with methylene choride and water. The aqueous layer was back extracted with methylene chloride and the combined organic layers were washed with water (3 x 10 mL), brine and concentrated. The residue was purified by flash-chromatography using 5% methanol in methylene chlorideas eluant. LCMS m/z 463.3(M + H)+, . ret. time= 2.98 min |
Yield | Reaction Conditions | Operation in experiment |
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With acetic anhydride; pyridinium tetrafluoroborate; acetic acid; at 0℃; for 1h;Cooling with ice; | Synthesis of 5-Dimethylamino-4-acetyl-penta-2,4-dienylidene-dimethylammonium tetrafluoroborate Pyridinium tetrafluoroborate (2.21 g, 13.3 mmol) was added to a solution of <strong>[2802-08-6](3E)-4-(dimethylamino)-3-buten-2-one</strong> (1.54 ml, 13.3 mmol) in 13.5 ml acetic anhydride/acetic acid (2:1). The resulting suspension was cooled to 0 C. and 3-dimethylaminoacroleine (1.33 ml, 13.3 mmol) was added over a period of 1 h under vigorous stirring and cooling with an ice bath receiving a red-brown precipitate. The cool reaction mixture was filtered and the remaining solid was washed with diethylether several times and dried under reduced pressure. The pentamethinium salt was obtained as orange crude product (2.69 g, 96%) and was used without any further purification. |
Yield | Reaction Conditions | Operation in experiment |
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21% | at 120℃; for 10h; | Part I-- Synthesis of [1,8]-Naphthyridin-2-ylamine; Pyridine-2,6-diamine (0.30 g, 2.8 mmol), 3-dimethylaminoacrolein (90%, 0.30 g, 2.8mmol), and polyphosphoric acid (PPA) (2.7 mL) were combined and the reaction mixture washeated to 120 oc for 10 hours. Then, the reaction mixture was poured on ice water and neutralized with solid sodium carbonate. The resulting aqueous mixture was extracted threetimes with ethyl acetate and the combined organic extracts were washed with brine,concentrated, and purified by column chromatography (EtOAc/hexanes) to give [1,8]naphthyridin-2-ylamine. Yield 85 mg (21 %). LCMS (ESI): calc. C8H7N3 = 145; obs. M+H =146. |
Yield | Reaction Conditions | Operation in experiment |
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85% | Example 7 Preparation of octyl (2E,4E)-2-cyano-5-(dimethylamino)penta-2,4-dienoate N,N-Dimethylacrolein (37.4 ml, 0.374 mol) is dissolved in 500 ml of toluene while bubbling with nitrogen and the catalyst, a mixture of acetic acid (4.1 ml, 0.2 equiv.) and of n-octylamine (1.8 ml, 0.03 equiv.), is added. The mixture is heated to reflux and <strong>[15666-97-4]n-<strong>[15666-97-4]octyl cyanoacetate</strong></strong> (76 ml, 0.359 mol) is added dropwise over 25 minutes. The water is removed by azeotropic distillation. The reaction is halted after 2 hours. The solvent is evaporated under vacuum. 123 g of an orangey brown solid are obtained, which solid is recrystallized from isopropanol to give 118.5 g (yield: 85%) of the derivative of Example 7 in the form of pale yellow needles: M.P.: 80-81 C. UV (Ethanol): lambdamax=380 nm, E1%=2186. |
Yield | Reaction Conditions | Operation in experiment |
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85% | Example 6 Preparation of methyl (2E,4E)-2-cyano-5-(dimethylamino)-penta-2,4-dienoate N,N-Dimethylacrolein (80.52 ml, 0.772 mol) is dissolved in 460 ml of toluene while bubbling with nitrogen and the catalyst, a mixture of acetic acid (8.85 ml, 0.2 equiv.) and of n-octylamine (3.83 ml, 0.03 equiv.), is added. The mixture is heated to reflux and methyl cyanoacetate (69.48 ml, 0.787 mol) is added dropwise over 45 minutes. The water is removed by azeotropic distillation. The reaction is halted after 2 hours 30 minutes. The solvent is evaporated under vacuum. 152 g of a light brown powder are obtained, which powder is crystallized from isopropanol to give 118.5 g (yield: 85%) of the derivative of Example 6 in the form of a pale yellow powder: M.P.: 158-159 C. UV (Ethanol): lambdamax=378 nm, E1%=3564. |
Yield | Reaction Conditions | Operation in experiment |
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97% | Second Stage: Preparation of (2,2-dimethyl-1,3-dioxolan-4-yl)methyl (2E,4E)-2-cyano-5-(dimethylamino)penta-2,4-dienoate The preceding product (50 mg, 0.254*10-3 mol) and the catalysts, n-octylamine (1.3 mul, 0.03 equiv.) and acetic acid (3 mul, 0.2 equiv.), in 0.8 ml of toluene are brought to reflux in a reactor rendered inert with nitrogen. N,N-Dimethylacrolein (26 mul, 0.25*10-3 mol), dissolved in 0.8 ml of toluene, is added dropwise to the reaction mixture. Reflux is maintained for 36 hours while adding the same amounts of catalyst every 8 hours. After cooling, the solvent is evaporated under vacuum and the brown paste obtained is crystallized from 2 ml of isopropanol. 68 mg (yield: 97%) of (2,2-dimethyl-1,3-dioxolan-4-yl)methyl (2E,4E)-2-cyano-5-(dimethylamino)penta-2,4-dienoate are thus obtained in the form of a beige powder used as is in the following stage: UV (Ethanol): lambdamax=379 nm, E1%=1974. |
Yield | Reaction Conditions | Operation in experiment |
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21% | Diacroleindithienopyrrole 34To a solution of 490 mg (2.22 mmol) of 4-propyl-4H-dithieno[3,2-b;2?,3?-d]pyrrole (32) in 9 ml of THF are added dropwise 1.9 ml (4.66 mmol) of 2.5 M n-butyllithium/hexane solution at -78 C. The mixture is stirred at -78 C. for 5 min, then stirred at -10 C. for 1 h. 770 mg (7.77 mmol) of <strong>[927-63-9]3-dimethylaminoacrolein</strong> (33) are added to the mixture which is stirred at -5 C. for 30 min. The cooling is removed and the mixture is stirred at room temperature for a further 4 h. 20 ml of sat. NH4Cl solution are added and the reaction mixture is stirred for 1 h. 100 ml of DCM are added thereto, and the organic phase is separated and dried over sodium sulfate. After the solvents have been distilled off, the residue is purified by chromatography (SiO2, DCM: ethyl acetate (10:1)) to obtain 152 mg (21%) of product. 1H NMR (CDCl3): 9.64 ppm (d, 2H), 7.58 (d, 2H), 7.24 (s, 2H), 6.54 (dd, 2H), 5.14 (dd, 2H), 1.93 (qa, 2H), 0.97 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
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51.2% | 3-Dimethylamino acrolein (0.8 ml) and dried phosphoryl chloride (POCl3, 0.8 ml) were slowly added at 0 C and stirred for30 minutes, Here into the compound (156 mg, 0.3 mmol) of [formula 15] was dissolved in MC, and stirring at 50 C for 7 hours, After completion of the reaction, 100 ml of a saturated sodium acetate (NaOAc) aqueous solution was added to the reaction product,and after stirring for 2 hours at 60C , the reaction was extracted three times with dichloromethane and saturated aqueous sodium bicarbonate (NaHCO3) solution, After removing the moisture with a magnesium sulfate (MgSO4) to column with toluene, compound 88 mg(Yield: 51.2%) of the formula [16] was obtained. |
Yield | Reaction Conditions | Operation in experiment |
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56% | With acetic acid; for 1h;Reflux; | General procedure: A mixture of 1.5 mmol of 2-(chloromethyl)-phenol 1a or 1b and 1.5 mmol of enaminone 3 or 4 in5 mL of acetic acid was refluxed for 1 h. The solvent was distilled under reduced pressure, and the residue was recrystallized from isopropyl alcohol. 6-Acetyl-4H-chromene-3-carbaldehyde (6a).Yield 56%, colorless crystals, mp 133-135C. IR spectrum,nu, cm-1: 1680 (C=O), 1672 (C=O), 1645(C=Cpyran), 1578, 1495, 1435, 1423, 1362, 1275, 1233,1190, 1175, 1150, 1113, 966, 899, 826, 773. 1H NMR spectrum, delta, ppm: 2.57 s (3H, CH3), 3.58 s (2H, CH2),7.06 d (1H, 8-H, 3J = 8.5 Hz), 7.38 s (1H, 5-H),7.78-7.81 m (2H, 2-H, 7-H), 9.48 s (1H, CHO).13C NMR spectrum, deltaC, ppm: 20.6 (CH2), 26.6 (CH3),117.3 (CH), 118.5, 119.9, 128.8 (CH), 130.8 (CH),134.3, 153.6, 158.5 (CH), 189.7 (CHO), 196.6 (C=O).Found, %: C 71.35; H 4.89. C12H10O3. Calculated, %:C 71.28; H 4.98. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With acetic acid; for 1h;Reflux; | General procedure: A mixture of 1.5 mmol of 2-(chloromethyl)-phenol 1a or 1b and 1.5 mmol of enaminone 3 or 4 in5 mL of acetic acid was refluxed for 1 h. The solvent was distilled under reduced pressure, and the residue was recrystallized from isopropyl alcohol. |
Yield | Reaction Conditions | Operation in experiment |
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With L-Tryptophan; at 50℃;Microwave irradiation; Green chemistry; | A 500 mL three-necked flask reactor equipped with a thermometer was charged with 66.6 g (0.5 mol) of ethyl cyanoethylsulfone , 50 mL of L-tryptophan, 62 mL (0.5 mol) of 3-dimethylaminoprop-2-enal, mixed well, the prepared reactor into the microwave, set the microwave radiation conditions, 50 C temperature, microwave power of 500W and the frequency of 915MHz under the conditions of the reaction, TLC detection (petroleum ether: dichloromethane 1: 2 expansion, sublimation iodine color) 3-dimethylaminoprop-2-enal was completely reacted to prepare an intermediate. Cooled to 5 C, passed HF gas, reacted at 5 C, and the reaction was followed by HPLC until the reaction was completed and the reaction time was 50 min. Add 5% potassium hydroxide solution to adjust the pH = 7-8, separated, the water layer with ethyl acetate 100mL × 3 times extraction, the organic layer, washed with water, separated, dried over anhydrous sodium sulfate, filtered and evaporated. After solvent ethyl acetate was recovered. The yield of 2-fluoro-3-ethylsulfonylpyridine and 86.6 g of a light brown liquid was 91.5%. | |
In dichloromethane;Reflux; | In a 500 mL three-necked flask equipped with a thermometer, 62 mL (0.5 mol) of 3-dimethylaminopropene and 100 mL of dichloromethane were added, followed by addition of 66.6 g (0.5 mol) of ethyl cyanoethyl sulfone, homogeneously mixed, Reaction, TLC detection (petroleum ether: methylene chloride 1: 2 expansion, sublimed iodine color) 3-dimethylaminopropenal reaction completely, then cooled to 25 C, into the HBr gas, HPLC tracking reaction until the end of the reaction. After the completion of the reaction, the addition of 30% sodium hydroxide solution to adjust the pH = 7-8, separated, the water layer with dichloromethane 120mL × 3 times extraction, the organic layer, 10mL of deionized water washed and separated, The organic layer was dried over Na2SO4, filtered and the solvent was removed under reduced pressure to give compound 2 (structural formula see Table 1), namely 2-bromo-3-ethylsulfonylpyridine, 112.5g as pale yellow crystals, 65-67 C, the yield was 90.0%. | |
With benzyltriethylammonium bromide; In water; at 40℃; | In a 500 mL three-necked flask equipped with a thermometer, 62 mL (0.5 mol) of 3-dimethylaminopropenal was added,1.0 g of triethylbenzylammonium bromide and 100 mL of deionized water were added to 66.6 g (0.5 mol) of ethyl cyanoethyl sulfone, and the mixture was homogeneously reacted at a temperature of 40 C,TLC detection (petroleum ether: methylene chloride 1: 2 expansion, sublimed iodine color) 3-dimethylaminopropenal reaction is complete,Cooled to 25 C, HBr gas was passed at 25 C, and the reaction was followed by HPLC until the reaction was completed.Then after the end of the reaction, add the mass fraction of 30% sodium hydroxide solution to adjust the pH = 7-8, separated, the water layer with dichloromethane 60mL × 3 times extraction,The organic layer was combined with 10 mL of deionized water and then partitioned. The organic layer was dried over Na2SO4, filtered and the solvent was removed under reduced pressure to give 2-bromo-3-ethylsulfonylpyridine,Pale yellow crystals 116.3g, melting point of 65-67 C, the yield was 93.0% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrabutylammomium bromide; at 40℃;Microwave irradiation; Green chemistry; | In a 500 mL three-necked flask reactor equipped with a thermometer, 73.6 g (0.5 mol) of isopropyl cyanoethylsulfone, 10 mL of tetrabutylammonium bromide, and 3-dimethylaminoprop-2-enal 62 mL (0.5 mol) were mixed and homogenized. The prepared reactor was placed in a microwave oven. The reaction was carried out under the conditions of microwave irradiation, 40 C temperature, microwave power of 100W and the frequency of 2450MHz under the conditions of the reaction,TLC detection (petroleum ether: dichloromethane 1: 2 expansion, sublimation iodine color) 3-dimethylaminoprop-2-enal was completely reacted to prepare an intermediate. Cooled to room temperature, passed HCl gas, reacted at room temperature, and the reaction was followed by HPLC until the reaction was complete and the reaction time was 1 h. Add 5% potassium hydroxide solution to adjust the pH = 7-8, separated, the water layer with dichloromethane 100mL × 3 times extraction, combined organic layer. After washing with water, the molecular sieves were dried and filtered and the solvent was distilled off. The dichloromethane was recovered to give 2-chloro-3-isopropylsulfonylpyridine, 101.0 g of a colorless liquid in a yield of 92.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.5% | With tetrabutyl-ammonium chloride; In water; at 90℃; for 1h; | 61 mL (0.5 mol) of n-butyl cyanoethylsulfone,Tetrabutylammonium chloride (3.0 g) and deionized water (50 mL) were charged into a reactor,Then add 3 - dimethyl amino acrolein 50mL (0.4mol), mixed evenly, at a certain 90 reaction for about 1h,TLC detection (petroleum ether: methylene chloride 1: 2 expansion, sublimed iodine color) 3-dimethylaminopropenal reaction is complete,The reaction solution by adding 5% sodium hydroxide lye to adjust the pH to neutral, dichloromethane solvent 100mL × 3 times extraction,The organic phase was washed with water, dried over anhydrous sodium sulfate for 6 h, and the solvent methylene chloride was distilled off (recovered)A 92.6 g yield of a pale brown oil was obtained in a yield of 95.5%.The product was characterized by HR-MS, i.e., 2-n-butylsulfonyl-5- (N, N-dimethyl) amino-2,4-pentadienenitrile. |
95% | With N,N-butyl-methyl-piperidinium bromide; at 46℃; for 4h;Microwave irradiation; | In the reactor, 61 mL (0.5 mol) of n-butylcyanoethylsulfone and 50 mL of N-butyl-N-methylpiperidine bromide were added,<strong>[927-63-9]3-dimethylaminoacrolein</strong> 50mL (0.4mol), mixed, heated to a temperature of 46 microwave and incubated for 4h reaction, TLC detection(Petroleum ether: dichloromethane 1: 2 expansion, sublimation of iodine color) 3 - dimethylamino acrolein reaction was complete, cooled to room temperature, organic solvent Agent extraction of ethyl acetate 60mL × 3, I phase ionic liquid water washing, vacuum drying repeated use, the organic phase of water 10mL impurities After the toluene was distilled off under reduced pressure, toluene was recovered to give 92.1 g of light brown oil in a yield of 95.0% |
95.7% | With sodium ethanolate; at 60℃;Sonication; | In a 500 mL three-necked round bottom flask,50 mL (0.4 mol) of <strong>[927-63-9]3-dimethylaminoacrolein</strong> was added,Sodium ethoxide 10mL and n-butyl cyanoethyl sulfone 61mL (0.5mol),well mixed,The prepared reactor into the ultrasonic instrument,Set the ultrasonic radiation conditions, at a temperature of 60 , ultrasonic power of 300W and the frequency of 80KHz reaction conditions, TLC test (oil Ether: dichloromethane 1: 2 expansion, sublimation of iodine color) 3 - dimethylamino acrolein reaction was complete, add deionized water 10mL impurities, Evaporation of the solvent from the organic phase gave 92.8 g of light brown oil in a yield of 95.7%. |
94.5% | With pyridine; at 40℃; for 2h;Microwave irradiation; Green chemistry; | In a 500 mL three-necked flask equipped with a thermometer, 61 mL (0.5 mol) of n-butyl cyanoethylsulfone and 20 mL of pyridine were added. Then, 50 mL (0.4 mol) of 3-dimethylaminoprop-2-enal was added, the prepared reactor was placed in a microwave oven, and the microwave irradiation conditions were set. The reaction was carried out at a temperature of 40 C, a microwave power of 150 W and a frequency of 2450 MHz. TLC detection (petroleum ether: dichloromethane 1: 2 developed, sublimed iodine color) 3-dimethylaminoprop-2-enal reaction is complete, the reaction time 2h. Add 30% sodium hydroxide solution to adjust the pH = 7-8, separated, the water layer with dichloromethane 100mL × 3 times extraction, combined organic layer. After washing with water, the organic layer was dried with Na2SO4 anhydrous, filtered and the solvent was removed by liquid distillation to give 91.6 g of a pale brown oil in a yield of 94.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 5,5-dimethyl-1,3-cyclohexadiene; at 90℃;Microwave irradiation; Green chemistry; | To a 500 mL reactor was added 105.6 g (0.5 mol) of (p-hydroxybenzyl) cyanoethylsulfone, 200 mL of xylene, 62 mL (0.5 mol) of 3-dimethylaminoprop-2-enal, mixed evenly and the prepared reactor was placed in a microwave oven. The microwave irradiation conditions were set at a temperature of 90 C, a microwave power of 100 W and a frequency of 915 MHz. TLC detection (petroleum ether: dichloromethane 1: 2 developed, sublimed iodine color) 3-dimethylaminoprop-2-enalwas completely reacted to prepare an intermediate. Cooled to 25 C, passed HBr gas, reaction at room temperature, reaction for about 50min, HPLC tracking reaction until the end of the reaction,Add concentrated ammonia to adjust the pH = 7-8, separated, the water layer with xylene 50mL × 3 times extraction, the organic layer. The solvent was distilled off under reduced pressure to give 2-bromo-3-(4-hydroxybenzyl)sulfonylpyridine and 156.7 g of a light brown liquid in a yield of 95.5%. | |
In 5,5-dimethyl-1,3-cyclohexadiene;Reflux; | To the 500 mL reactor, 105.6 g (0.5 mol) of (p-hydroxy) benzylcyanoethylsulfone, 200 mL of xylene, 62 mL (0.5 mol) of 3-dimethylaminopropenal were added, mixed uniformly, heated to reflux reaction, and TLC (Petroleum ether: dichloromethane 1: 2 developed, sublimed iodine color) 3-dimethylaminopropenal reaction completely, cooled to room temperature, access to HBr gas, HPLC tracking reaction until the end of the reaction. Add the concentrated ammonia to adjust the pH = 7-8, and the aqueous layer was extracted with xylene of 50mL × 3 times. The organic layer was combined and the solvent was distilled off under reduced pressure to obtain compound 20 (structural formula see Table 1), light brown Liquid 148.5 g, the yield was 90.5%. The HR-MS of the product is characterized as follows: | |
With octadecyltrimethylammonium bromide; In water; at 70℃; | To a 500 mL reactor, 105.6 g (0.5 mol) of (p-hydroxy) benzylcyanoethylsulfone, 1.0 g of trimethyl dodecylammonium bromide,Deionized water 100 mL and 3-dimethylaminopropenal 62 mL (0.5 mol), mixed homogeneously, reacted at 70 C,TLC detection (petroleum ether: methylene chloride 1: 2 expansion, sublimation iodine color) 3-dimethylaminopropenal reaction completely, cooled to room temperature,Pass HBr gas, HPLC to track the reaction until the end of the reaction, adding concentrated ammonia to adjust the pH = 7-8,The aqueous layer was extracted with xylene in 50 mL x 3 times, the organic layers were combined,The solvent was distilled off under reduced pressure to give 2-bromo-3- (4'-hydroxy) benzylsulfonylpyridine and 150.2 g of a light brown liquid in a yield of 91.5%. |
With tetrabutylammomium bromide; at 70℃;Sonication; | In a 500 mL reactor,105.6 g (0.5 mol) of (p-hydroxy) benzyl cyanoethyl ethyl sulfone10 mL of tetrabutylammonium bromide, 62 mL (0.5 mol) of <strong>[927-63-9]3-dimethylaminoacrolein</strong>,Mix well, the prepared reactor into the ultrasonic instrument, Set the conditions of ultrasonic radiation, 70 temperature, ultrasonic power of 100W and the frequency of 60KHz reaction conditions,TLC detection (petroleum ether: dichloromethane 1: 2 expansion, sublimation of iodine color) 3 - dimethylaminoacrolein reaction was completed, cooled to room temperature,The conditions of ultrasonic radiation were the same as above, the reaction temperature was 10 C, HBr gas was introduced and the reaction was followed by HPLC until the reaction was over. Concentrated aqueous ammonia was added to adjust the pH to 7-8. The mixture was separated and the aqueous layer was extracted with xylene (50 mL × 3) The solvent xylene was distilled off under reduced pressure to obtain 2-bromo-3- (4'-hydroxy) benzylsulfonylpyridine, and 148.5 g of a light brown liquid in a yield of 90.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In m-xylene; at 60℃;Microwave irradiation; Green chemistry; | To a 500 mL reactor, 112.6 g (0.5 mol) of m-methoxybenzyl cyanoethylsulfone was added, 200 mL of xylene, 3-dimethylaminoprop-2-enal 62mL (0.5mol), mixed evenly, the prepared reactor into the microwave instrument. The microwave irradiation conditions were set and reacted at a temperature of 60 C, a microwave power of 100 W and a frequency of 915 MHz. TLC detection (petroleum ether: dichloromethane 1: 2 developed, sublimed iodine color) 3-dimethylaminoprop-2-enal was completely reacted to prepare an intermediate. Cooling to 10 C, passing HF gas, reaction at 10 C, reaction for about 20 min, HPLC tracking reaction until the end of the reaction. Add concentrated ammonia to adjust the pH = 7-8, separated, the water layer with xylene 50mL × 3 times extraction, the organic layer, 2-fluoro-3-(3'-methoxybenzyl)sulfonylpyridine was obtained by distilling off the solvent xylene under reduced pressure to give 131.1 g of a pale brown liquid in a yield of 93.2%. | |
In 5,5-dimethyl-1,3-cyclohexadiene;Reflux; | o the 500 mL reactor, 112.6 g (0.5 mol) of (m-methoxy) benzyl cyanoethylsulfone was added, 0.5 mL of xylene, 62 mL (0.5 mol) of 3-dimethylaminopropenal, mixed and heated to reflux, TLC detection (petroleum ether: methylene chloride 1: 2 expansion, sublimed iodine color) 3-dimethylaminopropenal reaction completely, cooled to 5 C, into the HF gas, HPLC tracking reaction until the end of the reaction. Add the concentrated ammonia to adjust the pH = 7-8, the liquid layer, the water layer with xylene 50mL × 3 times extraction, the organic layer, combined with solvent evaporation of solvent xylene recovery, compound 21 (structural formula see Table 1), light brown 128.0 g of liquid, the yield was 91.0%. The HR-MS of the product is characterized as follows: | |
With dodecyltrimethylammonium bromide; In water; at 50℃; | In a 500 mL reactor, 112.6 g (0.5 mol) of (m-methoxy) benzylcyanoethyl sulfone was added,Trimethyl dodecylammonium bromide 1.0 g,Deionized water 100 mL and 3-dimethylaminopropenal 62 mL (0.5 mol), mixed uniformly, reacted at 50 C, TLC (petroleum ether: methylene chloride 1: 2 developed, sublimed iodine) 3-dimethylamino Acrolein reaction is complete,Cooled to 10 C, passed HF gas, and the HPLC was followed by the reaction until the reaction was completed.Add concentrated ammonia to adjust the pH = 7-8, separated, the water layer with xylene 50mL × 3 times extraction, combined organic layer, vacuum distillation solvent xylene recovery,2-fluoro-3- (3'-methoxy) benzylsulfonylpyridine, 127.4 g of a light brown liquid in a yield of 90.6%. |
With tetrabutylammomium bromide; at 70℃;Sonication; | In a 500 mL reactor,112.6 g (0.5 mol) of (m-methoxy) benzyl cyanoethyl ethyl sulfoneTetrabutylammonium bromide 10mL,<strong>[927-63-9]3-dimethylaminoacrolein</strong> 62mL (0.5mol), mixed well,The prepared reactor into the ultrasonic equipment, Set the ultrasonic radiation conditions,70 temperature, ultrasonic power of 100W and frequency of 60KHz under the reaction conditions, TLC test (petroleum ether: dichloromethane 1: 2 developed sublimation of iodine color) 3 - dimethylamino acrolein reaction was complete, cooled to 5 ,The conditions of ultrasonic irradiation are the same as above, the reaction temperature is 5 C, HF gas is introduced, and the reaction is followed by HPLC until the reaction is completed. Adding concentrated aqueous ammonia to adjust the pH to 7-8, separating the liquid, extracting the aqueous layer with xylene 50mL × 3 times, combining the organic layers and recovering the solvent xylene under reduced pressure to obtain 2-fluoro-3- (3'-a Oxy) benzylsulfonylpyridine as a light brown liquid in a yield of 91.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 5,5-dimethyl-1,3-cyclohexadiene; at 70℃;Microwave irradiation; Green chemistry; | To the 500 mL reactor, 137.1 g (0.5 mol) of p-bromobenzyl cyanoethylsulfone, 200 mL of xylene, 3-dimethylaminoprop-2-enal 62 mL (0.5 mol), mix well, put the prepared reactor into a microwave. The microwave irradiation conditions were set at a temperature of 70 C, a microwave power of 100 W and a frequency of 915 MHz. TLC detection (petroleum ether: dichloromethane 1: 2 developed, sublimed iodine color) 3-dimethylaminoprop-2-enal was completely reacted to prepare an intermediate. Cooled to 20 C, passed HBr gas, reacted at 20 C for about 30 min, and the reaction was followed by HPLC until the reaction was completed. Add concentrated ammonia to adjust the pH = 7-8, separated, the water layer with xylene 50mL × 3 times extraction. The organic layer was combined and the solvent xylene was distilled off under reduced pressure to give 2-bromo-3-(4'-bromobenzyl)sulfonylpyridine and 181.2 g of a light brown liquid in a yield of 92.8%. | |
In 5,5-dimethyl-1,3-cyclohexadiene;Reflux; | In a 500 mL reactor, 137.1 g (0.5 mol) of p-bromobenzylcyanoethylsulfone, 200 mL of xylene, 62 mL (0.5 mol) of 3-dimethylaminopropenal was added, mixed uniformly, heated to reflux reaction, and TLC Ether: methylene chloride 1: 2 developed, sublimed iodine color) 3-dimethylaminopropenal reaction completely, cooled to 20 C, into the HBr gas, HPLC tracking reaction until the end of the reaction. Add the concentrated ammonia to adjust the pH = 7-8, the liquid layer, the water layer with xylene 50mL × 3 times extraction, combined organic layer, vacuum distillation of solvent xylene recovery, obtained compound 24 (structural formula see Table 1), light brown Liquid 165.2 g, the yield was 84.5%. The HR-MS of the product is characterized as follows: | |
With dodecyltrimethylammonium bromide; In water; at 70℃; | To the 500 mL reactor, 137.1 g (0.5 mol) of p-bromobenzylcyanoethylsulfone, 1.0 g of trimethyl dodecylammonium bromide,Deionized water 100 mL and 3-dimethylaminopropenal 62 mL (0.5 mol), mixed homogeneously, 70 C,TLC detection (petroleum ether: methylene chloride 1: 2 expansion, sublimed iodine color) 3-dimethylaminopropenal reaction is complete,Cooled to 20 C, passed HBr gas, and the HPLC was followed by the reaction until the reaction was completed.Add concentrated ammonia to adjust the pH = 7-8, liquid, the water layer with xylene 50mL × 3 times extraction, the organic layer,2-bromo-3- (4'-bromo) benzylsulfonylpyridine was obtained by distilling off the solvent xylene to remove 174.4 g of a light brown liquid in a yield of 89.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In toluene; at 70℃;Microwave irradiation; Green chemistry; | In a 500 mL reactor, 13.2 g (0.5 mol) of 3,4-dichlorobenzyl cyanoethylsulfone, 200 mL of toluene, 3-dimethylaminoprop-2-enal 62 mL (0.5 mol) were added and mixed well, the prepared reactor into the microwave instrument, set the microwave radiation conditions, the temperature is 70 C, microwave power of 100W and the frequency of 915MHz under the conditions of reaction, TLC detection (petroleum ether: dichloromethane 1: 2 developed, sublimed iodine color) 3-dimethylaminoprop-2-enal was completely reacted to prepare an intermediate. Cooled to 25 C, passed HCl gas, reacted at 25 C for about 30 min, and the reaction was followed by HPLC until the reaction was completed. Add concentrated ammonia to adjust the pH = 7-8, separated, the water layer with toluene 50mL × 3 times extraction. The organic layer was combined and the solvent was distilled off to remove the solvent to give 2-chloro-3-(3',4'-dichlorobenzyl)sulfonylpyridine and 155.2 g of a light brown liquid in a yield of 92.2%. | |
In 5,5-dimethyl-1,3-cyclohexadiene;Reflux; | To the 500 mL reactor was added 132.1 g (0.5 mol) of (3,4-dichloro) benzylcyanoethylsulfone, 0.5 mL of xylene, 62 mL (0.5 mol) of 3-dimethylaminopropenal, mixed uniformly, Reaction, TLC detection (petroleum ether: methylene chloride 1: 2 development, sublimation iodine color) 3-dimethylaminopropenal reaction completely, cooled to room temperature, into the HCl gas, HPLC tracking reaction until the end of the reaction. (50mL x 3 times), the organic layer was combined, and the solvent was distilled off under reduced pressure to obtain compound 27 (structural formula is shown in Table 1). The compound was treated with xylene, Light brown liquid 139.1g, the yield was 82.6%. The HR-MS of the product is characterized as follows: | |
With dodecyltrimethylammonium bromide; In water; at 70℃; | In a 500 mL reactor,(13 mol) of (3,4-dichloro) benzylcyanoethylsulfone, 1.0 g of trimethyl dodecylammonium bromide,Deionized water 100 mL and 3-dimethylaminopropenal 62 mL (0.5 mol), mixed homogeneously, reacted at 70 C,TLC detection (petroleum ether: methylene chloride 1: 2 expansion, sublimed iodine color) 3-dimethylaminopropenal reaction is complete,Cooled to 25 C, passed HCl gas, and the HPLC was followed by the reaction until the reaction was completed.Add concentrated ammonia to adjust the pH = 7-8, separated, the water layer with toluene 50mL × 3 times extraction, the organic layer,2-chloro-3- (3 ', 4'-dichloro) benzylsulfonylpyridine and 150.6 g of a light brown liquid were obtained in a yield of 89.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.2% | With potassium hydrogencarbonate; at 60℃; for 0.5h;Microwave irradiation; Green chemistry; | In a 500 mL three-necked flask equipped with a thermometer, 59.6 g (0.5 mol) of methyl cyanoethylsulfone and 5.0 g of KHCO3 were added. Then add 3-dimethylaminoprop-2-enal 62mL (0.5mol), mixed evenly, the prepared reactor into the microwave, set the microwave radiation conditions. The reaction was carried out at a temperature of 60 C, a microwave power of 100 W and a frequency of 915 MHz, TLC detection (petroleum ether: dichloromethane 1: 2 expansion, sublimation iodine color) 3-dimethylaminoprop-2-enal reaction is complete, the reaction time 0.5h. Add sodium carbonate solution to adjust the pH = 7-8, separated, the water layer with ethyl acetate 100mL × 3 times extraction. The organic layers were combined, dried over a molecular sieve overnight, filtered and the solvent recovered by distillation, to give 97.3 g of a pale yellow solid. The melting point of 169-171 C, the product yield was 97.2%. |
97.1% | With tetra(n-butyl)ammonium hydroxide; In water; at 90℃; for 2h; | A 500 mL three-necked round bottom flask was charged with 62 mL (0.5 mol) of 3-dimethylaminopropenal, 59.6 g (0.5 mol) of methyl cyanoethylsulfone,Tetrabutylammonium hydroxide 10.0g and deionized water 200mL, mixed evenly, heated to 90 , constant temperature reaction for about 2h, to 3-dimethylaminopropenal reaction completely (HPLC detection),Vacuum distillation in addition to 60mL water, cooled to room temperature, crystallization, filtration crude product, and then recrystallized from anhydrous ethanol to obtain light yellow solid 97.2g, melting point 169-171 , product yield was 97.1%.The product was characterized by HR-MS, 1H NMR, 13C NMR spectroscopy, i.e., product 2-methylsulfonyl-5- (N, N-dimethyl) amino-2,4-pentadienenitrile. |
96.7% | With triethylamine; at 120℃;Sonication; | In a 500 mL three-necked round bottom flask,62 mL (0.5 mol) of 3-dimethylacropenal was added,10 mL of triethylamine and 59.6 g (0.5 mol) of methyl cyanoethyl sulfone,Mix well, the prepared reactor into the ultrasonic instrument,Set the ultrasonic radiation conditions, at a temperature of 120 ,Ultrasonic power of 350W and the frequency of 100KHz reaction conditions,High-performance liquid phase tracking reaction process until the end of the reaction, add deionized water 10mL impurities, filtered to give the crude product,Then recrystallized from absolute ethanol to give a pale yellow solid 96.8g, mp 169-171 C, the product yield was 96.7%. |
95.6% | With N-butyl-N-ethylpiperidinium bromide; at 55℃; for 1h;Microwave irradiation; | The reactor was charged with 59.6 g (0.5 mol) of methyl cyanoethyl sulfone, 50 mL of N-butyl-N-ethylpiperidine bromide,3-dimethylaminoacrolein 62mL (0.5mol), mixed, heated to 55 microwave temperature and incubated for 1h reaction, TLC detection (petroleum ether: dichloromethane 1: 2 developed sublimation iodine color) 3-bis Methylaminoacrolein reaction was complete, cooled to room temperature, the organic solvent was extracted with methylene chloride 60mL × 3, the remaining phase ionic liquid washed, vacuum dried and reused, the organic solvent was evaporated to give methylene dichloride recovered 95.7g light yellow solid, Melting point 169-171 C, product yield 95.6%. |
With trimethyldodecylammonium chloride; In dichloromethane; water; at 95℃; | In a 500 mL three-necked flask equipped with a thermometer, 62 mL (0.5 mol) of 3-dimethylaminopropenal, 2.0 g of trimethyl dodecylammonium chloride and 100 mL of deionized water were added, followed by addition of methylcyanoethyl Sulfone 59.6 g (0.5 mol) was homogeneously mixed at a temperature of 95 C, TLC was detected (petroleum ether: methylene chloride 1: 2 developed, sublimed iodine developed) 3-dimethylaminopropenal was completely reacted and then cooled to 10 C, then the HCl gas is passed and the reaction is followed by HPLC until the reaction is complete. After the completion of the reaction, add the mass fraction of 10% sodium hydroxide solution to adjust the pH = 7-8, separated, the water layer with dichloromethane 100mL × 3 times extraction, the organic layer, add anhydrous Na2SO4 dry, The compound was recovered from solvent methylene chloride to give compound 1 (structural formula see Table 1), namely 2-chloro-3-methylsulfonylpyridine, 89.6 g of pale yellow crystals, 63-65 C in a yield of 93.5% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With triethylamine; In isopropyl alcohol; at 50℃; for 51h;Reflux; | solution of [9-(prop-2-en-l-yl)-6-oxaspiro[4.5]decan-9-yl]hydrazine (250 mg, 1.0 mmol) in 4 mL of i-PrOH were added Et3N and <strong>[927-63-9]3-dimethylaminoacrolein</strong>. The solution was refluxed for 3h and then at 50 oC for 2d. The solvent removed and the residue was purified on 25 g Biotage snap column, eluted with 0-18% EtOAc in Hex (12CV) to give l-[9-(prop-2-en-l-yl)-6-oxaspiro[4.5]decan-9-yl]-lH-pyrazole (80 mg, 31% yield).LCMS m/z 247.1 (M + 1) observed |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In chloroform;Reflux; | In a 500 mL three-necked flask equipped with a thermometer, 62 mL (0.5 mol) of 3-dimethylaminopropenal, 200 mL of chloroform and 178.8 g (0.5 mol) of n-octadecyl cyanoethylsulfone were added, The reaction was carried out under heating and refluxing, and TLC was detected (petroleum ether: methylene chloride 1: 2 developed, sublimed iodine) 3-dimethylaminopropenal was completely reacted, then cooled to 25 C, passed through HCl gas, The reaction is completed until the reaction ends. Then, after the completion of the reaction, the aqueous solution was adjusted to pH = 7-8, and the aqueous layer was extracted with 50 mL of chloroform. The organic layers were combined and washed with 10 mL of deionized water. The organic layer was washed with anhydrous Na2SO4 , And the solvent was removed by heating and evaporation to give compound 7 (structural formula see Table 1), namely 2-chloro-3-n-octadecylsulfonylpyridine, 173.1 g as a colorless liquid in 80% yield. | |
With trimethyldodecylammonium chloride; In water; at 80℃; | In a 500 mL three-necked flask equipped with a thermometer, 62 mL (0.5 mol) of 3-dimethylaminopropenal, 1.0 g of trimethyl dodecylammonium bromide and 100 mL of deionized water were added,And then adding 18.8 g (0.5 mol) of n-octadecyl cyanoethylsulfone,The reaction was carried out at a temperature of 80 C,TLC detection (petroleum ether: methylene chloride 1: 2 expansion, sublimed iodine color) 3-dimethylaminopropenal reaction is complete,Cooled to 20 C, HCl gas was passed at 20 C, and the reaction was followed by HPLC until the reaction was completed.After the completion of the reaction, the aqueous solution was adjusted to pH = 7-8, and the aqueous layer was extracted with methylene chloride 100 mL x 3 times. The organic layers were combined, washed with 10 mL of deionized water,Organic layer and anhydrous Na2SO4 dry, filtered, heated to remove the solvent,2-chloro-3-n-octadecylsulfonylpyridine was obtained as a colorless liquid (194.0 g) in a yield of 90.2%. | |
With sodium t-butanolate; at 80℃;Sonication; | In a 500 mL three-necked flask equipped with a thermometer,First, 62 mL (0.5 mol) of 3-dimethylacropenoid and 2.0 g of sodium tert-butoxide were added,Then add octadecyl cyanoethyl ethyl ketone 178.8g (0.5mol), mixed,The prepared reactor into the ultrasonic equipment, set the ultrasonic radiation conditions, at a temperature of 80 ,Ultrasonic power of 300W and frequency of 40KHz under the conditions of reaction, TLC test (petroleum ether: dichloromethane 1: 2 developed sublimation of iodine color) 3 - dimethylaminoacrolein reaction was complete, cooled to 20 C, HCl Gas, ultrasonic radiation conditions as above,The reaction temperature was 20 C and the reaction was followed by HPLC until the reaction was completed. After the reaction was finished, ammonia solution was added to adjust pH = 7-8, liquid separation was carried out, and the aqueous layer was extracted with dichloromethane (100 mL × 3). The combined organic layers were washed with 10 mL of deionized water and washed with water. The organic layer was dried over anhydrous Na 2 SO 4 , Filtered and the solvent removed by evaporation of the solvent to give 2-chloro-3-n-octadecylsulfonylpyridine. 194.6 g of a colorless liquid was obtained in a yield of 90.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,2-dichloro-ethane;Reflux; | To a 500 mL reactor, 97.6 g (0.5 mol) of benzyl cyanoethylsulfone, 150 mL of 1,2-dichloroethane and 62 mL (0.5 mol) of 3-dimethylaminopropenal were added, mixed and heated to reflux, TLC detection (petroleum ether: methylene chloride 1: 2 expansion, sublimed iodine color) 3-dimethylaminopropenal reaction completely, cooled to room temperature, into the HBr gas, HPLC tracking reaction until the end of the reaction. Add concentrated ammonia water to adjust the pH = 7-8, the liquid layer, the water layer with 1,2-dichloroethane 50mL × 3 times extraction, the organic layer, the solvent evaporated under pressure, 1,2-dichloroethane recovery, Compound 14 (structural formula is shown in Table 1), namely 2-bromo-3-benzylsulfonylpyridine, 133.5 g of light brown liquid, and 85.5% yield. The HR-MS of the product is characterized as follows: | |
With octadecyltrimethylammonium bromide; In water; at 120℃; | In a 500 mL reactor, 97.6 g (0.5 mol) of benzyl cyanoethylsulfone, 2.0 g of trimethyl octadecyl bromide and 150 mL of deionized water were added,3-dimethylaminopropenal 62mL (0.5mol), mixed evenly, 120 temperature reaction,TLC detection (petroleum ether: methylene chloride 1: 2 expansion, sublimation iodine color) 3-dimethylaminopropenal reaction completely, cooled to room temperature,The HBr gas was passed and the reaction was followed by HPLC until the reaction was complete.Add concentrated ammonia to adjust the pH = 7-8, liquid, the water layer with 1,2-dichloroethane 100mL × 3 times extraction, the organic layer, 10mL of deionized water washed and separated,The solvent was distilled off under reduced pressure to give 1,2-dichloroethane to give 2-bromo-3-benzylsulfonylpyridine and 143.6 g of a pale brown liquid in a yield of 92.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 111 - 117℃; for 4h; | in a glass flask having an inner volume of 50 ml and equipped with a stirrer, a thermometer and a reflux condenser,(3.04 mmol) of tetrahydropyran-4-carboxamidine hydrochloride, 5 ml of N, N-dimethylformamide,420 mg (3.04 mmol) of potassium carbonate and602 mg (6.07 mmol) of 3- (dimethylamino) acrylaldehyde was added,The mixture was reacted at a temperature of 111 C. to 117 C. for 4 hours with stirring.After completion of the reaction, the reaction solution was analyzed by high performance liquid chromatography,2- (4-tetrahydropyranyl) pyrimidine was produced in an area percentage of 3.0%.In addition, the reaction selectivity calculated from the area percentage was 94%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
350 mg | With sodium methylate; In methanol; at 75℃; for 24h; | To a mixture of 3-(benzyloxy)-1-(1,1- dimethylethylsulfinamido)cyclobutanecarboximidamide (crude 1 g, assumed 3.09 mmol, prepared as above) in methanol (10 ml) was added N,N-dimethylamino-2- propen-3-al(0.619 ml, 6.18 mmol) and sodium methoxide (3.98 g, 15.46 mmol).The resulting reaction mixture was heated to and stirred at 75 C for 24 hr. After completion of the reaction, the mixture was concentrated and the residue dissolved in ethyl acetate (100 ml) and then water (15 ml) was added to it. The organic layer was separated, dried over sodium sulphate and concentrated to give the crude compound. This was further purified by Combiflash using a mixture of 1:9 MeOH/CHC13 as aneluent to obtain the desired product. Yield 350 mg, (28.3 %). ?H NMR (400 MHz,CDC13) & 1.14 - 1.28 (s, 9 H), 2.57 -2.73 (m, 2 H), 2.84 - 3.00 (m, 1 H), 3.02 - 3.22(m, 1 H), 4.31 -4.56 (m, 3 H), 7.17 (s, 1 H), 7.23 - 7.43 (m, 6 H), 8.66 - 8.82 (m, 2H).LCMS: (ES+) m/z = 360 (M+H)Column : PUROSPHERstar RP-18 (4X55 )mm,3iimBuffer: 20mM NH4OAc in waterM phase A: Buffer + MeCN(90+10)M phase B : Buffer + MeCN(10+90)Fl ow: 2.5m1/minTime (mm.): 0 2 2.5 3%B: 0 100 100 0Rt= 1.531 mm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.9% | In a reactor, 59 mL (0.5 mol) of methyl cyanoacetate was added to the reactor,N-ethylpyridine tetrafluoroborate 50 mL,3-dimethylaminopropenal 62 mL (0.5 mol) was homogeneously mixed,Microwave heating to 140 temperature and heat for 1h to carry out the reaction, TLC detection (oilEther: methylene chloride 1: 2 developed, sublimed iodine color)3-dimethylaminopropenal reaction completely, cooled to room temperature, organic solvent BEther 60mL extraction 3 times, residual phase ion water washing vacuum drying after repeated use, organic phase into the dry HCl gas, HPLC withThe reaction is continued until the reaction ends. Add the mass fraction of 20percent sodium hydroxide solution to adjust the pH = 5-6, separated, the water layer with ether20mL × 3 times extraction, combined organic layer, washed with water, molecular sieve drying, filtration, evaporation of solvent ether recovery, the residue byThe product was distilled at 110-115 ° C / 1 mmHg to prepare methyl 2-chloronicotinate and 80.6 g of colorless liquid in a yield of 93.9percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.1% | The reactor is addedCyanoacetic acidOctadecyl ester73 mL (0.5 mol),1-hexyl-3-methylimidazolium chloride 50 mL,3-diethylaminoacrolein 61 mL (0.5 mol) was mixed uniformly,Microwave heating to 200 temperature and 0.5h for the reaction,TLC detection (petroleum ether: dichloromethane 1: 2 expansion, sublimation iodine color)3-diethylamino acrolein is completely reacted, cooled to 50 C,The ionic liquid was washed with water and dried,The organic phase was passed through a dry HCl gas and the HPLC was followed by the reaction until the reaction was complete.Add the mass fraction of 10% sodium hydroxide solution to adjust the pH = 5-6, separated, the water layer with ethyl acetate 20mL × 3 times extraction, the organic layer, washed with water, molecular sieve drying, filtration, Ethyl ester after recovery2-nicotinate of 2-chloronicotinic acid, 186.8 g of colorless liquid, the yield was 91.1% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.3% | In a 500 mL reactor, 63 mL (0.5 mol) of <strong>[14447-18-8]benzyl cyanoacetate</strong>, 5 mL of acridine, and 62 mL (0.5 mol) of 3-dimethylaminoacrolein were added, and the prepared apparatus was placed in an ultrasonic apparatus. Ultrasonic irradiation conditions were set, and the reaction was carried out at a temperature of 120 C., an ultrasonic power of 1000 W and a frequency of 250 KHz TLC test (petroleum ether:dichloromethane 1:2 development, sublimation iodine coloration) 3-dimethylaminoacrolein reaction Completely, cool to room temperature, pass HBr gas, and follow the reaction by HPLC until the reaction is complete. Add concentrated ammonia to adjust pEta = 5-6, and separate the liquid. The aqueous layer is extracted with 1,2-dichloroethane 20mL X 3 times. Combine the organic layers. After deionized water is washed with 10mL of water, the solvent is distilled off. 2_Dichloroethane was recovered to obtain benzyl 2-bromonicotinate as a light brown liquid (137.7 g). The yield was 94.3%. | |
92.3% | 63 mL (0.5 mol) of <strong>[14447-18-8]benzyl cyanoacetate</strong> was added to the reactor,1-methyl-1-hexylpyridinium bromide300 mL,3-dimethylaminopropenal 62 mL (0.5 mol) was homogeneously mixed,Oil bath heated to 120 temperature and heat 3h reaction,TLC detection (petroleum ether: dichloromethane 1: 2 expansion, sublimed iodine color) 3-dimethylaminopropenal reaction completely, cooled to room temperature, organic solvent1,2-dichloroethane (60 mL) was extracted three times. The residue was washed with water and dried in vacuo. The organic phase was passed through the HBr gas and the reaction was followed by HPLC until the reaction was completed.Add concentrated ammonia to adjust the pH = 5-6, liquid separation, water use1,2-dichloroethane 20mL × 3 times extraction, the organic layer, washed with water and then separated from the solvent and evaporated to remove the solvent 1,2-dichloroethane to obtain 2-bromonicotinic acid benzyl ester, light brown Liquid 134.8 g, the yield was 92.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Ethyl cyanoacetate (59 mL, 0.5 mol) was added to the reactor,1-dodecyl-3-methylimidazolium chloride50 mL,3-dimethylaminopropenal 62 mL (0.5 mol) was homogeneously mixed,The oil bath was heated to 90 C and incubated for 4 hours. TLC detection (petroleum ether: methylene chloride 1: 2 expansion, sublimed iodine coloring) 3-dimethylaminophenaldehyde was complete,Cool to room temperature, organic solvent1,2-dichloroethane 60mL extraction 3 times, residual phase ion water washing vacuum drying and reuse,The organic phase was passed through a dry HBr gas and the HPLC was followed by the reaction until the reaction was complete.Add the mass fraction of 20% sodium carbonate solution to adjust the pH = 5-6, liquid,For water use1,2-dichloroethane 20mL × 3 times extraction, the organic layer, combined with water,The molecular sieves were dried, filtered and the solvent was evaporated under reduced pressure1,2-dichloroethane was recovered to give ethyl 2-bromonicotinate, 108.4 g of a light brown liquid in a yield of 94.0%. | |
93.5% | In a 500 mL three-necked flask equipped with a thermometer, first, 2-dimethylaminoacrolein (62 mL, 0.5 mol) and pyridine (20 mL) were added, and then 65 mL (0.6 mol) of ethyl cyanoacetate was added to prepare the prepared device. Into the ultrasonic instrument. Ultrasonic radiation conditions were set, and the reaction was carried out at a temperature of 40 C, an ultrasonic power of 150 W, and a frequency of 20KHz TLC test (petroleum ether:dichloromethane 1:2 development, sublimation iodine development) 3-dimethylaminopropylene Aldehyde reaction is complete. After that, HBr gas was introduced and the ultrasonic irradiation conditions were as above, and the reaction was followed by HPLC until the reaction was completed. After the reaction is completed, add 30% sodium hydroxide solution to adjust rhoEta = 5-6, and separate the layers. The aqueous layer is extracted with dichloromethane 20 mL x 3 times. The organic layers are combined, and the deionized water is washed with 10 mL of water. The organic layer was dried over anhydrous Na2SO4 , filtered, and the solvent was evaporated under reduced pressure in the liquid phase to obtain ethyl 2-bromonicotinate as light brown liquid, 107.5 g, with a yield of 93.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.9% | Ethyl cyanoacetate (59 mL, 0.5 mol) was added to the reactor,1-hydroxyethyl-3- methyl imidazole chloride50 mL,3-dimethylaminopropenal 62 mL (0.5 mol) was homogeneously mixed,Electric furnace sets heated to 110 temperature and heat 3h reaction,TLC detection (petroleum ether: dichloromethane 1: 2 expansion, sublimation iodine color)3-dimethylaminopropenal reaction is complete, cool to room temperature,Organic solvent ethyl acetate 60mL extraction 3 times, residual phase ionic liquid washing after vacuum drying, the organic phase into the dry HI gas, HPLC tracking reaction until the end of the reaction. Add the mass fraction of 10% ammonia to adjust the pH = 5-6, liquid,The aqueous layer was extracted with ethyl acetate 20 mL x 3 times. The organic layers were combined, washed with water, separated by filtration, dried over a molecular sieve, filtered and the solvent was evaporated under reduced pressure.Recovery, the preparation of 2-iodonicotinic acid ethyl ester, light brown liquid 128.7g, the yield was 92.9% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.4% | In a reactor, 59 mL (0.5 mol) of cyanoacetic acid ethyl ester was added,1-butyl-3-methylImidazole trifluoroAcetate50 mL,3-dimethylaminopropenal 62 mL (0.5 mol) was homogeneously mixed,Electric furnace sets heated to 120 temperature and heat 2h reaction,TLC detection (petroleum ether: methylene chloride 1: 2 expansion, sublimation iodine color) 3-dimethylaminopropenal reaction completely, cooled to room temperature, organic solvent extraction of 60mL of toluene 3 times,The residual phase was washed with water and dried in vacuo. The organic phase was passed through a dry HF gas and the reaction was followed by HPLC until the reaction was complete. Add the mass fraction of 20% potassium carbonate solution to adjust the pH = 5-6, liquid, water layerWith toluene 20mL × 3 times extraction,The organic layers were combined, washed with water, separated by molecular sieves, filtered, and the solvent was distilled off under reduced pressure.The yield of ethyl 2-fluoronicotinate and 76.5 g of light brown liquid was 90.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.2% | With N-butyl-N-ethylpiperidinium bromide; In water; at 55℃; for 1h;Sonication; | The reactor is addedCyanoacetic acid ethyl ester 59 mL (0.5 mol)N-butyl-N-ethylpiperidineBromide salt50 mL,3-dimethylaminopropenal 62 mL (0.5 mol) was homogeneously mixed,Ultrasonic heating to 55 temperature and heat for 1h to react,TLC detection (petroleum ether: methylene chloride 1: 2 expansion, sublimation iodine color) 3-dimethylaminopropenal reaction completely, cooled to room temperature, organic solvent dichloromethane 60mL extraction 3 times,The residual phase of the ionic liquid was washed with water and dried, and the organic phase was distilled off. The solvent was recovered from the dichloromethane,The crude product was recrystallized from anhydrous ethanol to give 101.7 g of a white powder, melting at 134-135 C and a product yield of 94.2% |
93.1% | With triethylamine; at 120℃;Sonication; | In a 500 mL three-necked round bottom flask, 62 mL (0.5 mol) of <strong>[927-63-9]3-dimethylaminoacrolein</strong>, 10 mL of triethylamine, and 65 mL (0.6 mol) of ethyl cyanoacetate were added, and the prepared device was placed in the sonicator. Ultrasonic radiation conditions were set. The reaction temperature was 120 C, the ultrasonic power was 350W, and the frequency was 100 KappaEtaz. The reaction was monitored by high-performance liquid phase until the end of the reaction. Deionized water was added in 10 mL to remove impurities and the crude product was filtered. Recrystallization from anhydrous ethanol gave 90.4 g of a white powder having a melting point of 134-135C and a product yield of 93.1%. |
90.9% | With triethylamine; at 50℃;Microwave irradiation; | In a 500 mL three-neck round bottom flask,Add 62 mL (0.5 mol) of <strong>[927-63-9]3-dimethylaminoacrolein</strong>,Triethylamine 10 mL and ethyl cyanoacetate 65 mL (0.6 mol),Place the prepared device in the microwave. Set microwave radiation conditions,At a temperature of 50 C, a microwave power of 200 W and a frequency of 2450 MHz,High-performance liquid phase tracking detection reaction process until the end of the reaction, plus deionized water 10mL impurities,Filter to obtain a crude product, which is then recrystallized from anhydrous ethanol, filtered, and dried.A white powder of 88.3 g was obtained with a melting point of 134-135C and a product yield of 90.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.7% | In a reactor, 59 mL (0.5 mol) of cyanoacetic acid ethyl ester was added,N-butyl-N-methylpiperidine chloride salt 50 mL,3-dimethylaminopropenal 62mL (0.5mol) mixed evenly, the oil bath heated to 80 temperature and heat 6h reaction,TLC detection (petroleum ether: dichloromethane 1: 2 expansion, sublimation iodine color)3-dimethylaminopropenal reaction is complete, cool to room temperature,Organic solvent methyl acetate 60mL extraction 3 times, residual phase ion liquid water vacuum drying and reuse,The organic phase is passed through a dry HCl gas,The HPLC was followed by the reaction until the reaction was complete.Add the mass fraction of 10% sodium hydroxide solution to adjust the pH = 5-6, liquid,The aqueous layer was extracted with methyl acetate 20 mL x 3 times, the organic layers were combined,Add anhydrous Na2SO4 dry, filter, evaporated solvent methyl acetate recovery, the residue under reduced pressure distillation, collecting 110-115 / 1mmHg fraction,Ethyl 2-chloronicotinate was obtained as a colorless liquid (85.8 g) in a yield of 92.7%. | |
92.1% | In a 500 mL three-necked flask equipped with a thermometer, first, <strong>[927-63-9]3-dimethylaminoacrolein</strong> (62 mol, 0.5 mol) and acridine (10 mL) were added, and then 65 mL (0.6 mol) of ethyl cyanoacetate was added to prepare the apparatus. Put into a sonicator. Ultrasonic irradiation conditions were set, and the reaction was carried out at a temperature of 100 C, an ultrasonic power of 250 W, and a frequency of 40 KHz. TLC test (petroleum ether: dichloromethane 1:2 development, sublimation iodine development) 3-dimethylaminopropylene Aldehyde reaction is complete. After that, the HCl gas was again introduced and the ultrasonic irradiation conditions were as above. The reaction was followed by HPLC until the reaction was completed. After the reaction was completed, add 10% sodium hydroxide solution to adjust rhoEta = 5-6, and separate the layers. The aqueous layer was extracted with dichloromethane (20 mL×3 times). The organic layers were combined, dried over Na 2 SO 4 , filtered, and heated. The solvent was removed by evaporation, and the residue was subjected to vacuum distillation to collect 110-115 C/lmmHg fraction to obtain ethyl 2-chloronicotinate, 85.5 g of a colorless liquid, yield of 92.1 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.9% | A reactor was charged with 66.6 g (0.5 mol) of ethyl cyanoethyl ethyl sulfone, 50 mL of 1-dodecyl-3-methylimidazolium chloride,50mL (0.4mol) <strong>[927-63-9]3-dimethylaminoacrolein</strong> was added and mixed well. The mixture was heated in an oil bath at 90 for 3h, and the reaction was monitored by TLC. The crude product was chromatographed by TLC (petroleum ether: dichloromethane 1: 2, Dimethylaminoacrolein reaction is complete, cooled to room temperature,60 mL of organic solvent 1,2-dichloroethane was extracted three times,Yu phase ionic liquid water washing, vacuum drying repeated use, The organic phase leads to dry HBr gas,The reaction was followed by HPLC until the reaction was complete.Join mass fraction of 20% sodium carbonate solution to adjust the pH = 7-8, points The liquid and the aqueous layer were extracted with 100 mL × 3 of 1,2-dichloroethane. The organic layers were combined, washed with water, separated from water, dried over molecular sieves, filtered and reduced in pressure The solvent 1,2-dichloroethane was distilled off to obtain 2-bromo-3-ethylsulfonylpyridine, 117.4 g of light yellow crystals, melting at 65 -67 C, 93.9% yield, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.7% | A reactor was charged with 66.6 g (0.5 mol) of ethyl cyanoethyl ethyl sulfone, 50 mL of 1-butyl-3-methylimidazolium trifluoroacetate,(0.5mol) of <strong>[927-63-9]3-dimethylaminoacrolein</strong> was added and mixed uniformly. The electric furnace was heated to 120 C and incubated for 0.5h for reaction. TLC (petroleum ether: dichloromethane 1: 2 expansion and sublimation of iodine) 3 - dimethylaminoacrolein reaction was complete, cooled to 5 C, the organic solvent was extracted with toluene 60mL 3 times, the remaining ionic liquid was washed with water, dried in vacuo and reused, the organic phase was passed into a dryHF gas, followed by HPLC until the reaction is complete. Join mass fraction of 20% potassium carbonate solution to adjust pH = 7-8, liquid separation, The aqueous layer was extracted with toluene 100 mL × 3, and the organic layers were combined, washed with water, separated by liquid, dried over molecular sieves, and filtered. The solvent toluene was distilled off under reduced pressure This was recovered to give 85.8 g of 2-fluoro-3-ethylsulfonylpyridine as a pale brown liquid in a yield of 90.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.5% | The reactor was charged with 73.6 g (0.5 mol) of isopropyl cyanoethyl ethyl sulfone, 50 mL of tetrabutylphosphine bromide,3-dimethylaminoacrolein 62mL (0.5mol), mixed well,Microwave heating to 140 C and incubated for 20min reaction, TLC detection (petroleum ether: dichloromethane 1: 2 expansion, sublimation of iodine color) 3 - dimethylaminoacrolein reaction was complete, cooled to 10 C, the organic solvent ether 60mL Extraction 3 times, I phase ionic liquid washing, reuse after vacuum drying, the organic phase was dried HCl gas, HPLCThe reaction is followed until the reaction is complete. Join mass fraction of 20% sodium hydroxide solution to adjust the pH = 7-8, liquid separation, aqueous layer with B. Ether 100mL × 3, the organic layer was combined, washed with water, liquid separation, molecular sieve drying, filtration, the solvent was evaporated under reduced pressure diethyl ether recovery, There was 2-chloro-3-isopropylsulfonylpyridine as a colorless liquid, 101.6 g, yield 92.5%. The product was characterized by HR-MS as follows: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.7% | In a 500 mL reactor, 105.6 g (0.5 mol) of (p-hydroxy) benzyl cyanoethyl ethyl sulfone,N-methyl-N-butylpyrrolidine bis (trifluoromethanesulfonyl) imide 150 mL,3-Dimethylamino acrolein62mL (0.5mol), mixed well, oil bath Heated to 110 temperature and incubated for 1h reaction, TLC detection (petroleum ether: dichloromethane 1: 2 developed sublimation iodine color) 3-Dimethylaminoacrolein reaction is complete, the organic solvent extraction of butyl acetate 100mL 3 times, the remaining ionic liquid water washing, vacuum drying Reuse, the organic phase into HBr gas, HPLC tracking reaction until the end of the reaction, adding concentrated ammonia to adjust the pH = 7-8, points The aqueous layer was extracted with xylene 50 mL × 3 times. The organic layers were combined and the solvent xylene was distilled off under reduced pressure to obtain 2-bromo-3-(4'-hydroxy) benzylsulfonylpyridine, 153.7 g of a light brown liquid in a yield of 93.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In a 500 mL reactor, 112.6 g (0.5 mol) of (m-methoxy) benzyl cyanoethyl ethyl sulfone,200 mL of N-methyl-N-butylpyrrolidinebis (trifluoromethanesulfonyl) imide and 62 mL (0.5 mol) of <strong>[927-63-9]3-dimethylaminoacrolein</strong> were added and mixed well to add Heated to 100 temperature and incubated for 1.5h reaction, TLC detection (petroleum ether: dichloromethane 1: 2 developed sublimation iodine color) 3-Dimethylaminoacrolein reaction is complete, the organic solvent extraction of butyl acetate 100mL 3 times, the remaining ionic liquid water washing, vacuum drying Reuse, the organic phase was cooled to 5 C, the introduction of HF gas, HPLC tracking reaction until the end of the reaction, adding concentrated ammonia to adjust the pH= 7-8. The layers were separated and the aqueous layer was extracted with xylene 50 mL × 3 times. The organic layers were combined and the solvent xylene was distilled off under reduced pressure to obtain 2-Fluoro-3- (3'-methoxy) benzylsulfonylpyridine and 129.4 g of a pale brown liquid in a yield of 92.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.8% | In a 500 mL reactor, p-bromobenzyl cyanoethyl ethylsulfone (137.1 g, 0.5 mol), N-methyl-N-butylpyrrole 200 mL of bis (trifluoromethanesulfonyl) imide and 62 mL (0.5 mol) of <strong>[927-63-9]3-dimethylaminoacrolein</strong> were added and mixed well and heated to 100 temperature and incubated for 1.5h reaction, TLC detection (petroleum ether: dichloromethane 1: 2 developed sublimation of iodine color) 3-dimethylamino Acrolein reaction is complete, cooled to 25 C, the organic solvent extracted with 100mL butyl acetate 100mL three times, the residual phase was washed with water, dried under vacuum Dry and reused, the organic phase into the HBr gas, HPLC tracking reaction until the end of the reaction, adding concentrated ammonia to adjust the pH = 7-8, liquid separation, the aqueous layer was extracted with xylene 50mL × 3 times, the combined organic layer was evaporated under reduced pressure solvent xylene recovery, 2-bromo-3- (4'-Bromobenzylsulfonylpyridine, 179.2 g of pale brown liquid in 91.8% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.1% | The reactor was charged with 59.6 g (0.5 mol) of methyl cyanoethyl sulfone, 55 mL of N, N-dibutylpiperidine chloride,3-dimethylaminoacrolein 62mL (0.5mol), mixed well, the oil bath heated to 80 temperature and incubated for 4h reaction, TLC test (petroleum Ether: dichloromethane 1: 2 expansion, sublimation of iodine color) 3-dimethylaminoacrolein reaction was complete, cooled to room temperature, the organic solvent B Acid methyl ester 60mL extracted three times, the remaining ionic liquid water washing, vacuum drying repeated use; the organic phase leads to dry HCl gas,The reaction was followed by HPLC until the reaction was complete. Join mass fraction of 10% sodium hydroxide solution to adjust the pH = 7-8, liquid separation, water layer The mixture was extracted with 60 mL × 3 of methyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and the solvent was distilled off to recover the methyl acetate The product, 2-chloro-3-methylsulfonylpyridine, pale yellow crystals 90.2 g, mp 63-65 C, 94.1% yield, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.8% | Adding 145 g N-1,1,2,2-tetrafluoro-ethyl dimethyl amine (1.0 mol) and 700 g acetonitrile into a 2000 ml four orifices reaction bulb equipped with a stirring device and a thermometer, and then dropping 1650 g BF3 acetonitrile solution into the reaction bulb at 20 C. (wherein, with respect to the amount of N-1,1,2,2-tetrafluoro-ethyl dimethyl amine, containing 1.3 equivalents of BF3), dropwise over 15-30 min, and stirring the reactants in the reaction bulb for 30 min. Dropping 120 g 3-(dimethylamino)acrylaldehyde (1.10 mol) into the reaction bulb, dropwise over 30 min. Carrying out the reaction in the bulb with heat insulation for 2 hours. Cooling down the temperature of the reaction system to 5 C. after 2 hours heat insulation, and dropping acetonitrile solution of methyl hydrazine (wherein, with respect to the amount of 1,5-diaza pentadiene salt, containing 1 equivalents of hydrazine), dropwise over 30 min. Rising the temperature of the reaction system gradually to 20 C., and carrying out the reaction in the bulb with heat insulation for 2 hours. Conducting reduced pressure distillation of the resulting reaction product under 60 C. to recycle acetonitrile. Adding 600 g water with temperature around 50-60 C. to the resulting product. Stirring the resulting mixture slowly and gradually cooling it down to 0 C., meanwhile, crystallization from the resulting mixture is carried out, and the crystallization period lasts for 1-2 hour. Filtrating the above mixture to obtain crystal, then washing, draining and draying the crystal to obtain 148 g target product. The HPLC-purity of the target product is 99.3%, and the yield of this preparation method is 92.8% (the molar yield is calculated with respect to the mole of N-1,1,2,2-tetrafluoro-ethyl dimethyl amine). The target product has been analyzed by 1H NMR analysis, elemental analysis and mass spectrometry, which could be determined as 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde. Elemental analysis result and mass spectrometry result of 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde are as follows: mass spectrometry: m/z: 160.04 (100.0%), 161.05 (8.3%); elemental analysis: C, 45.01; H, 3.78; F, 23.73; N, 17.50; O, 9.99. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid; at 20℃; for 18h; | To a solution of <strong>[765-39-9]1H-<strong>[765-39-9]pyrrol-1-amine</strong></strong> (500 mg, 6.09 mmol) in acetic acid (4 mL) was added (E)-3-(dimethylamino)acrylaldehyde (0.7 mL, 7 mmol). The resulting mixture was stirred at room temperature for 18 hours and diluted with CH2Cl2. The organic layer was washed with water and aqueous, saturated NaHCO3. The aqueous layers were back-extracted with CH2Cl2 and the resulting organic layers were dried over MgSO4 and carefully concentrated. The resulting yellow oil was purified by bulb-to-bulb distillation to provide the product. ES/MS: 119.0 (M+H+). 1H NMR (400 MHz, Chloroform-d) delta 8.05-7.99 (m, 1H), 7.81-7.69 (m, 2H), 6.88 (dd, J=4.3, 2.7 Hz, 1H), 6.52 (dd, J=9.2, 4.3 Hz, 2H). |
Tags: 927-63-9 synthesis path| 927-63-9 SDS| 927-63-9 COA| 927-63-9 purity| 927-63-9 application| 927-63-9 NMR| 927-63-9 COA| 927-63-9 structure
[ 19125-76-9 ]
3-(Dimethylamino)-2-methylacrylaldehyde
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[ 1190-91-6 ]
4-(Dimethylamino)but-3-en-2-one
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[ 19125-76-9 ]
3-(Dimethylamino)-2-methylacrylaldehyde
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[ 1190-91-6 ]
4-(Dimethylamino)but-3-en-2-one
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(E)-4-(Dimethylamino)but-3-en-2-one
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[ 19125-76-9 ]
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3-(Dimethylamino)-2-methylacrylaldehyde
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4-(Dimethylamino)but-3-en-2-one
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(E)-4-(Dimethylamino)but-3-en-2-one
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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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