| 97% |
Stage #1: malonic acid dimethyl ester With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 0.5h;
Stage #2: propargyl bromide In toluene at 0 - 20℃; for 5h; |
|
| 95% |
With potassium carbonate In acetone; toluene for 65h; Inert atmosphere; Reflux; |
|
| 95% |
With potassium carbonate In acetone; toluene at 20℃; for 48h; Inert atmosphere; Schlenk technique; |
|
| 94% |
Stage #1: malonic acid dimethyl ester With sodium hydride In diethyl ether; mineral oil at 0℃;
Stage #2: propargyl bromide In diethyl ether; toluene; mineral oil at 0 - 20℃; |
|
| 93% |
With sodium hydride In tetrahydrofuran for 24h; Schlenk technique; |
|
| 92% |
With sodium hydroxide In water |
Dimethyl 2,2-di(2-propynyl)malonate. 40
Dimethyl 2,2-di(2-propynyl)malonate. 40 Aqueous sodium hydroxide (1500 ml of a 12 N solution) was placed in a flask fitted with an overhead stirrer. Benzytriethylammonium chloride (54 g) was added and the solution was cooled to 0° C. With vigorous stirring, a solution of dimethylmalonate (79.3 g) and propargyl bromide (3 eq., 214 g) were added with an addition funnel over 25 minutes, keeping the temperature below 25° C. (R. K. Singh, Synthesis 1985, 54). The slurry was then allowed to stir for 3 hr at 25° C. The slurry was then cooled in an ice bath and then carefully added to an ice/water mixture. This was extracted with t-butyl methyl ether, washing the organic layer with water (2*) and then with brine. Drying over sodium sulfate and solvent removal afforded the title compound as a crystalline solid (92% yield). |
| 90% |
Stage #1: malonic acid dimethyl ester With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Inert atmosphere; Schlenk technique;
Stage #2: propargyl bromide In tetrahydrofuran; toluene; mineral oil at 0℃; Inert atmosphere; Schlenk technique; |
|
| 87% |
With potassium carbonate In acetone; toluene at 60℃; for 168h; Inert atmosphere; |
|
| 87% |
With potassium carbonate In acetone; toluene at 60℃; for 168h; Inert atmosphere; |
|
| 87% |
With potassium carbonate In acetone; toluene at 60℃; for 168h; Inert atmosphere; |
II Dimethyl 2,2.di(prop-2-.yn4l)malonate SI
Propargyl bromide (7.8 mL, 80 wt. % in toluene, 70 mmoi) was added to a stirredsuspension of dimethyl malonate (2.00 mL, 17.5 mmol) and K2C03 (5.32 g, 38.5 mmol) inacetone (30 mL) under a N2 atmosphere. This mixture was brought to reflux (ca. 60 °C). After 7 d the reaction mixture was filtered through Celite (acetone eluent) and concentrated. The residue was partitioned between water and EtOAc and the aqueous phase further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), and concentrated.This residue was dissolved in a mixture of DCM and hexanes (Ca. 1:10). A portion of the more volatile DCM was removed under reduced pressure .A precipitate appeared; this slurry was cooled and the solid collected by filtration. The filtrate was treated in the same fashion, and the process was repeated 2-3 more times to give 51 (3.15 g, 15.2 mmol, 87%) as a white solid. The NMR spectral data were consistent with reported values (Parsons, P. J.; Jones, 1). R,; Padgham,A. C.; Allen, L. A. T.; Penkett, C. S.; Green, R. A.; White, A. J. P. Chemistry -A European Journal 2016, 22, 3981-3984.) |
| 84% |
Stage #1: malonic acid dimethyl ester With sodium hydride In tetrahydrofuran; mineral oil at -10℃; for 0.25h; Inert atmosphere;
Stage #2: propargyl bromide In tetrahydrofuran; toluene; mineral oil at -10 - 25℃; Inert atmosphere; |
|
| 84% |
Stage #1: malonic acid dimethyl ester With sodium hydride In tetrahydrofuran; mineral oil at 10℃; for 0.166667h;
Stage #2: propargyl bromide In tetrahydrofuran; toluene; mineral oil at 20℃; |
Dimethyl 2,2-bis(2-propynyl)-malonate (4):
A procedure similar to a literature reported process1 was employed: Dimethyl malonate (6.0 ml,52 mmol) was added dropwise to a stirred suspension of NaH (60% wt in mineral oil, 4.22 g,106 mmol) in dry THF (100 mL) at 10°C. After 10 min propargyl bromide (80% w/w in toluene,12.0 mL, 108 mmol) was added dropwise. The reaction was allowed to warm to room temperatureand stirred overnight. The reaction mixture was distributed between water and ether, and theaqueous phase was extracted twice with ether. The combine organic phases were washed with brine,dried over MgSO4, filtered and concentrated on a rotary evaporator leaving white solid. The solidwas crystallized from ethyl acetate to give 1A3,4 (9.44 g, 84%) as crystalline white solid. |
| 84% |
Stage #1: malonic acid dimethyl ester With sodium hydride In tetrahydrofuran; mineral oil at -10℃; for 0.25h;
Stage #2: propargyl bromide In tetrahydrofuran; toluene; mineral oil at -10 - 25℃; for 20h; |
43.1 Step 1: Synthesis of diethyl 2,2-di(prop-2-yn-1-yl)malonate.
To a suspension of sodium hydride (60% wt in mineral oil, 4.22 g, 105.5 mmol) in dry THF (100 mL) stirring at -10 °C, dimethyl malonate (6.0 mL, 52.5 mmol) was added dropwise over 10 min. The reaction mixture was stirred at -10 °C for 5 min, and then propargyl bromide (80% wt. in toluene, 12.0 mL, 107.7 mmol) was added dropwise. The reaction mixture was warmed to 25 °C and stirred for 20 h. The reaction mixture was then poured into H2O (50 mL) and Et2O (50 mL), and the layers were separated. The aq layer was extracted with Et2O (3 × 50 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated on a rotary evaporator leaving a white solid. The solid was recrystallized from ethyl acetate and hexanes resulting in 9.44 g of a crystalline white solid (84% yield). |
| 83% |
Stage #1: malonic acid dimethyl ester With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.5h; Inert atmosphere;
Stage #2: propargyl bromide In tetrahydrofuran; mineral oil at 20℃; for 2h; Inert atmosphere; |
Synthesis of dimethyl 2,2-di(prop-2-yn-1-yl) malonate (1)
To 100mL round bottom flask was charged with 60 % sodium hydride in mineral oil(1.43 g, 35.94 mmol, 3.0 eq) and dry THF (27 mL) at 0 . The mixture was added dimethylmalonate (1.5826 g, 11.98 mmol, 1.0 eq) in dry THF (5 mL) at room temperature underArgon atmosphere. The reaction mixture was stirred at room temperature for 30 minutes.The reaction mixture was added propargyl bromide (3.56 g, 29.95 mmol, 2.5 eq) in dryTHF (5 mL) by cannula and stirred at room temperature for 2 hours. After completion ofthe reaction (monitored by TLC), the reaction mixture was quenched with a saturatedaqueous NH4Cl solution (30 mL) at 0 . The mixture was extracted with ethyl ether (50mL x 2) and water (50 mL). The organic layer was washed with brine (50 mL) and driedover anhydrous MgSO4 and filtered. The solvent was removed under reduced pressure.Crude products dissolved in hexane and filtered. Solid in round bottom flask remainedwas removed solvent by vacuum to give a pure product 1 (2.06 g, 83 %, yellow solid); 1HNMR (400 MHz, CDCl3) δ 3.77 (s, 6H), 3.00 (d, J = 2.6 Hz, 4H), 2.04 (t, J = 2.6 Hz, 2H); 13CNMR (101 MHz, CDCl3, 300 K) δ 169.0, 78.3, 71.9, 56.5, 53.2, 22.7. |
| 82% |
Stage #1: malonic acid dimethyl ester With sodium hydride In tetrahydrofuran at -10℃; for 0.5h; Inert atmosphere;
Stage #2: propargyl bromide In tetrahydrofuran at 20℃; Inert atmosphere; |
|
| 82.5% |
Stage #1: malonic acid dimethyl ester With sodium hydride In tetrahydrofuran at 20℃; for 1h;
Stage #2: propargyl bromide In tetrahydrofuran at 110℃; for 3h; |
|
| 81% |
With potassium carbonate In toluene at 60℃; Inert atmosphere; |
|
| 79% |
Stage #1: malonic acid dimethyl ester With sodium ethanolate In ethanol for 0.0833333h;
Stage #2: propargyl bromide In ethanol; toluene for 0.5h; Heating; |
|
| 73% |
Stage #1: malonic acid dimethyl ester With sodium hydride In tetrahydrofuran at 0 - 20℃; for 1h; Inert atmosphere;
Stage #2: propargyl bromide In tetrahydrofuran; toluene at 90℃; for 2h; |
|
| 72% |
With sodium hydride In tetrahydrofuran at 20℃; for 18h; |
|
| 71% |
Stage #1: malonic acid dimethyl ester With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; Inert atmosphere;
Stage #2: propargyl bromide In tetrahydrofuran; mineral oil at 20℃; for 2.5h;
Stage #3: propargyl bromide Further stages; |
|
| 71% |
Stage #1: malonic acid dimethyl ester With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; Inert atmosphere;
Stage #2: propargyl bromide In tetrahydrofuran; mineral oil at 0 - 20℃; for 7.5h; Inert atmosphere; |
|
| 66% |
With potassium carbonate In acetone; toluene Reflux; |
|
| 61% |
With potassium carbonate In acetone at 20℃; |
|
| 60% |
Stage #1: malonic acid dimethyl ester With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.25h;
Stage #2: propargyl bromide In tetrahydrofuran; toluene; mineral oil at 20℃; |
|
| 49% |
Stage #1: malonic acid dimethyl ester With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 1h;
Stage #2: propargyl bromide In tetrahydrofuran; toluene; mineral oil at 20℃; |
|
|
With sodium hydride In acetonitrile for 8h; |
1.1 Example 1
Using sodium hydride as catalyst, will 200mmol malonic acid dimethyl ester with 440mmol alkyne-propyl bromide is added to the anhydrous acetonitrile in ice-water bath, stirring for 8 hours, product washing with water, extraction with ethyl acetate, decompression turns on lathe does , column chromatography (volume ratio ethyl acetate: petroleum ether = 1:100) to obtain white solid product |
|
With sodium hydride In acetonitrile for 8h; Cooling with ice; |
2.1 Embodiment 2
(1) in order to 830mmol sodium hydride as catalyst, will 200mmol malonic acid dimethyl ester with 440mmol alkyne-propyl bromide is added to the 250 ml anhydrous acetonitrile in ice-water bath, stirring for 8 hours, product washing with water, extraction with ethyl acetate, decompression turns on lathe does, the volume ratio of 1:100 ethyl acetate: petroleum ether column chromatography separation, to obtain white solid product, i.e. compound 1; |
|
With sodium hydride In acetonitrile at 0 - 5℃; for 8h; |
1.1 Example 1
sodium hydride as catalyst to 830mmol, 200mmol the malonate 440mmol with propargyl bromide was added to 210mL of anhydrous acetonitrile ice-water bath (ice-water bath temperature of 0-5 deg.] C) the reaction was stirred for 8 hours, the product was washed with water, added, extracted with ethyl acetate, dried under reduced pressure to spin, with a volume ratio of 1:40 ethyl acetate: petroleum ether column chromatography to give a tan solid product, i.e. compound 1 |
|
With sodium hydride In acetonitrile for 10h; Cooling with ice; |
2.1
A, to sodium hydride (700mmol, 16 . 8g) as a catalyst, the malonic acid dimethyl ester (200mmol, 26 . 6g) with propargyl bromide that is commercialized (440mmol, 52 . 3g) into 330 ml in anhydrous second grade nitrile, ice stirring reaction in 10 hours, the crude product is water and ethyl acetate extraction, after concentrating under reduced pressure, purification by silica gel column chromatography, elution agent is ethyl acetate: petroleum ether = 1:60, to obtain white solid product, i.e. compound 1 |
|
With sodium hydride In acetonitrile for 8h; Cooling with ice; |
2.A
A. To 820mmol sodium hydride as the catalyst, 200mmol of dimethyl malonate and 450mmol of propargyl bromide were added to 250mL anhydrous acetonitrile, stirred in ice water bath for 8 hours, the product was washed with water, extracted with ethyl acetate, The residue was purified by chromatography on a column of ethyl acetate: petroleum ether = 1: 100 (volume ratio). The product was collected by filtration and concentrated to dryness to give the compound a-2 as a white solid. |
|
With sodium hydride In acetonitrile for 8h; Cooling with ice; |
1.a.1
Dimethyl malonate (200 mmol) and propargyl bromide (440 mmol) were added to anhydrous acetonitrile and stirred for 8 hours with sodium hydride (400 mmol) as a catalyst. The reaction product was washed with water, Ethyl acetate: petroleum ether = 1: 100) gave a white solid product in which the molar ratio of dimethyl malonate to propargyl bromide was 1: 2.2. |
|
With potassium carbonate In toluene; acetonitrile for 24h; Glovebox; |
|
|
With sodium hydride In acetonitrile for 8h; |
1.1
To 20 g of sodium hydride as a catalyst,200 mmol of dimethyl malonate and 440 mmol of propargyl bromide were added to anhydrous acetonitrile,Ice bath, stirring reaction 8 hours, the product was washed with water,Extracted with ethyl acetate, dried under reduced pressure,Column chromatography (vol. Ethyl acetate: petroleum ether = 1: 100) gave the product as a white solid, |
|
With sodium hydride In acetonitrile for 8h; Cooling with ice; |
To 830 mmol of Sodium hydride as a catalyst,A mixture of 200 mmol of dimethyl malonate was added440 mmol of propargyl bromide was added to anhydrous acetonitrile in an ice-water bath,Stirring reaction for 8 hours, the product was washed with water, extracted with ethyl acetate, dried under reduced pressure,Column chromatography (vol. Ethyl acetate: petroleum ether = 1: 100) gave the product as a white solid, |
|
With sodium hydride In acetonitrile at 0℃; for 8h; |
1.1 Example 1
(1) 200 mmol of dimethyl malonate was added to 440 mmol of propargyl bromide with 830 mmol of sodium hydride as a catalyst To 210 mL of anhydrous acetonitrile in an ice-water bath. The reaction was stirred for 8 hours. The product was washed with water, extracted with ethyl acetate and dried under reduced pressure to give a yellow-brown solid product.I.e. compound a-1; |
|
With sodium hydride In acetonitrile for 8h; Cooling with ice; |
1.1
(1) Using 830 mmol of sodium hydride as a catalyst,200 mmol of dimethyl malonate and 440 mmol of propargyl bromide were added to 210 mL of anhydrous acetonitrile in an ice-water bath,Stirring reaction for 8 hours, the product was washed with water, extracted with ethyl acetate, dried under reduced pressure,To give the product as a brown solid, i.e., compound 1a; |
|
With sodium hydride In acetonitrile for 8h; Cooling with ice; |
1.1
(1) Using 830 mmol of sodium hydride as a catalyst,200 mmol of dimethyl malonate and 440 mmol of propargyl bromide were added to 210 mL of anhydrous acetonitrile in an ice-water bath,The reaction was stirred for 8 hours. The product was washed with water, extracted with ethyl acetate and dried under reduced pressure to give the product as a Brown solid. Compound 1 |
|
With sodium hydride In acetonitrile for 8h; Cooling with ice; |
1.1
(1) Using 830 mmol of sodium hydride as a catalyst,200 mmol of dimethyl malonate was added to 440 mmol of propargyl bromideTo 210 mL of anhydrous acetonitrile in an ice bath,Stirring reaction for 8 hours,The product was washed with water,Extracted with ethyl acetate,Decompression dry dry,To give a tan solid product,I.e. Compound 1 |
|
With sodium hydride In acetonitrile for 8h; Cooling with ice; |
1.1
(1) 830mmol sodium hydride as catalyst,200 mmol of dimethyl malonate and 440 mmol of propargyl bromide were addedTo 210 mL of anhydrous acetonitrile in ice water bath,The reaction was stirred for 8 hours,The product was washed with water,Extraction with ethyl acetate,Vacuum drying,Get brownYellow solid product, Compound 1 |
|
With sodium hydride In acetonitrile for 8h; Cooling with ice; |
2.1
1) 830 mmol of sodium hydride as a catalyst, 200 mmol of diethyl carbonate and 440 mmol of propargyl bromide were added to 210 mL of anhydrous acetonitrile in an ice water bath, and the mixture was stirred for 8 hours. The product was washed with water, extracted with ethyl acetate and dried under reduced pressure. The residue was purified by column chromatography (ethyl acetate: petroleum ether = 1: 75) to give the product as a yellow solid. |
|
In tetrahydrofuran at 20℃; for 9h; |
|
|
With sodium hydride In acetonitrile for 8h; Cooling with ice; |
3.1
(1) Using 830 mmol of hydrogen as a catalyst,200 mmol with dimethyl malonate440 mmol propargyl bromide added to210mL anhydrous acetonitrile ice water bath,Stir the reaction for 8 hours,The product was washed with water, extracted with ethyl acetate, and spin-dried under reduced pressure to give a brown-yellow solid product, Compound No. 1; |
|
With sodium hydride In acetonitrile for 8h; Cooling with ice; |
1.1
(1) 830 mmol sodium hydride as catalyst200 mmol of dimethyl malonate and 440 mmol of propargyl bromide were added to 210 mL of anhydrous acetonitrile in an ice water bath.Stir the reaction for 8 hours,The product is washed with water,Extract with ethyl acetate,Drying under reduced pressure,A brownish yellow solid product is obtained,That is compound 1; |
|
With sodium hydride In acetonitrile for 8h; Cooling with ice; |
1
(1) Using 830 mmol of sodium hydride as a catalyst, 200 mmol of dimethyl malonate and 440 mmol of propargyl bromide were added to 210 mL of anhydrous acetonitrile in an ice water bath, and the reaction was stirred for 8 hours. The product was washed with water and extracted with ethyl acetate. reduced pressure spin dry, Obtaining a brownish yellow solid product, Compound 1; |
|
With sodium hydride In acetonitrile at 0 - 5℃; for 8h; |
1.1
(1) using 830 mmol of sodium hydride as a catalyst,200mmol of dimethyl malonate and440 mmol of propargyl bromide was added to 210 mL of anhydrous acetonitrile in an ice water bath.The reaction was stirred for 8 hours at 0-5 ° C.The product was washed with water, extracted with ethyl acetate and evaporated to dryness |
|
With sodium hydride In acetonitrile for 8h; Cooling with ice; |
1.1
(1) using 830 mmol of sodium hydride as a catalyst,200 mmol of dimethyl malonate and 440 mmol of propargyl bromide were added to 210 mL of anhydrous acetonitrile in an ice water bath.Stir the reaction for 8 hours,The product was washed with water, was added, extracted with ethyl acetate, dried under reduced pressure to spin, to give the product,That is, compound 1; |
|
With sodium hydride In acetonitrile for 8h; Cooling with ice; |
2.1
Using 830 mmol of sodium hydride as a catalyst, 200 mmol of dimethyl malonate and 440 mmol of propargyl bromide were added to 210 mL of anhydrous acetonitrile in an ice water bath, and the reaction was stirred for 8 hours. The product was washed with water and extracted with ethyl acetate. Press to dry, to obtain the product, compound 1, |
|
With sodium hydride In acetonitrile at 0℃; |
|
|
With sodium hydride In acetonitrile for 8h; Cooling with ice; |
1.1 The synthesis method of the above polysubstituted dibenzoylbenzene derivatives includes the following steps:
(1) Using 830 mmol of sodium hydride as a catalyst, convert200mmolDimethyl malonate and440mmol propargyl bromide was added to 210mL anhydrous acetonitrile in ice water bath,The reaction was stirred for 8 hours. The product was washed with water, extracted with ethyl acetate, and dried under reduced pressure.A brown-yellow solid product was obtained, namely Compound 1; |
|
With sodium hydride In acetonitrile at 0℃; |
|
|
With sodium hydride In acetonitrile at 0℃; |
Preparation of diyne substrate
General procedure: 10 g NaH (60%) and 200-300 mL acetonitrile were added in 500 mL three-necked flask with magnetic stirring. 100 mmol malonate and 30 g 3-bromopropyne (98%) were added in the above 500 mL three-necked flask dropwise in turn by separatory funnel, magnetically stirred for 8-10 h under ice-water bath. The organic phase was extracted with ethyl acetate and dried with anhydrous MgSO4. The solvent was evaporated in vacuo and diyne substrate as white solid were obtained finally. |
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