CN107954872B - Method for synthesizing malonate type compound - Google Patents
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- CN107954872B CN107954872B CN201711342257.5A CN201711342257A CN107954872B CN 107954872 B CN107954872 B CN 107954872B CN 201711342257 A CN201711342257 A CN 201711342257A CN 107954872 B CN107954872 B CN 107954872B
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Abstract
The invention discloses a method for synthesizing malonate compounds, which adopts 3-halopropynyl ester compounds shown in formula 1, alcohol shown in formula 2 and water as raw materials, and prepares the malonate compounds shown in formula 3 by reacting in the air atmosphere at room temperature under the conditions of palladium catalyst and alkali:
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing malonate compounds.
Background
1, 3-dicarbonyl compounds, particularly malonates, are important organic synthesis intermediates, hydrogen on methylene is easily substituted by other groups due to two adjacent electron-withdrawing groups in a molecule, and the substituted malonates can be subjected to various substitution reactions such as alkylation, alkoxylation, acylation, hydroxylation, amidation and the like, have high reaction activity, are widely applied to the fields of medicines, pesticides, perfumes, dyes and the like, and are extremely important fine organic chemicals.
Because malonate compounds have the excellent properties, development of simple and efficient synthetic methods for the malonate compounds has attracted scientists' extensive interest. Traditionally, malonates are synthesized by direct condensation of malonic acid and an alcohol. However, such methods generally require more stringent conditions, have less functional groups available, and tend to produce toxic by-products.
For the synthesis of malonate type compounds, a large number of synthetic methods have also been widely reported in the prior art, and the group of subjects to which the inventors have focused has also made a large amount of research work. Qianpeng et al reported the reaction of 3-halopropynyl ester compounds with Water and alcohol under DABCO as base (see prior art documents (1) "study on the Synthesis of cyclic compounds and Malonates by reaction of alkyne functional groups", Qianpeng, Vol.K. database engineering science I of the university of doctor, 2017, stage 02; (2) "Synthesis of Malonates from 3-Halopropylates, Alcohols, and Water Using DABCO", Peng-Cheng Qian et al, Synthesis 2015,47, 3309-. The method takes a 3-iodine/bromoalkyne ester compound as a raw material, takes DABCO as alkali, and reacts for 8 hours at room temperature to obtain a series of malonate compounds with good yield and substrate adaptability (see the following formula I).
In fact, the inventors have also conducted extensive and intensive studies with respect to the reaction in which an alkyne halide compound participates. Among them, the inventors reported in 2015 the coupling reaction of 3-iodopropynyl amide compounds with water and alcohol (see prior art document (3) "Palladium-catalysis Alcoholysis of 3-Iodopropropylamides: selected Synthesis of Carbamoylacetates", Jian-Sheng Tang et al, Synthesis 2015,47, 108. 112; (4) "Palladium-Catalyzed alkyne halide coupling reaction study", Tang Jiansheng, full text data base engineering science I of doctor's institute of China, "2017, No. 02. in this study, they found that the reaction of 3-iodopropynyl amide compounds with water and alcohol must take place under the condition of Palladium catalyst and the reaction time is longer than that of 12 hours (see formula II below), although the structure of the reaction raw material is similar to the aforementioned 3-iodopropynyl ester compounds.
The inventor accidentally finds out in experimental research that for the reaction of synthesizing the malonate type compound by the 3-halopropynyl ester type compound, water and alcohol under the condition of DABCO as the base, the reaction yield is improved by adding a certain amount of palladium catalyst, and more surprisingly, the reaction rate of the reaction can be remarkably improved by adding the palladium catalyst, and the reaction time is suddenly reduced to 5 minutes from the original 8 hours. On the basis, the inventor provides an improved method for synthesizing malonate type compounds, which can obviously improve the reaction efficiency and shorten the reaction time.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide an improved method for synthesizing malonate type compounds. The method takes 3-halopropynyl ester compound, water and alcohol as raw materials, and the reaction is carried out under the condition of palladium catalyst/alkali to prepare the malonate compound, thereby obviously shortening the reaction time.
In order to realize the purpose of the invention, the invention is realized by the following technical scheme: the 3-halopropynyl ester compound shown in the formula 1, the alcohol shown in the formula 2 and water react under the conditions of a palladium catalyst and alkali and in the air atmosphere at room temperature to prepare the malonate compound (formula III) shown in the formula 3.
Wherein [ Pd ]]Represents a palladium catalyst selected from Pd (OAc)2、Pd(dba)2、PdCl2、PdCl2(PPh3)2Any one or a mixture of several of them. Further preferably, the palladium catalyst is Pd (OAc)2。
The alkali is selected from any one of DBACO and triethylamine. Further preferably, the base is selected from DBACO.
X represents halogen, and further can be selected from chlorine, bromine and iodine.
R1Is represented by C1-20Substituted or unsubstituted hydrocarbon group of (1), C3-C20Substituted or unsubstituted heterocyclic group of (a).
Preferably, said C1-20Is C1-C20Substituted or unsubstituted alkyl of, C2-C20Substituted or unsubstituted alkenyl of, C6-C20Substituted or unsubstituted aryl of (1), C3-C20Substituted or unsubstituted cycloalkyl of (a).
R2Represents C1-20Substituted or unsubstituted hydrocarbyl.
Preferably, said C1-20Is C1-C20Substituted or unsubstituted alkyl of, C2-C20Substituted or unsubstituted alkenyl of (a).
Wherein, the substituents in each of the aforementioned "substituted" may be selected from C1-C6Alkyl of (C)2-C6Alkenyl of, C6-12Aryl radical, C6-12aryl-C2Alkenyl-, C6-12aryl-C1-6Alkyl-, C1-C6Alkoxy, halogen, nitro, -CN.
Further preferably, R1Is represented by C1-6Alkyl radical, C6-12Aryl radical, C6-12aryl-C1-6Alkyl radical, C6-12aryl-C2alkenyl-C1-6An alkyl group; r2Is represented by C1-6Alkyl radical, C2-C6Alkenyl radical C1-6Alkyl radical, C6-12aryl-C1-6Alkyl radical, C6-12aryl-C2alkenyl-C1-6An alkyl group.
Even more preferably, R1Represents methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, phenyl, naphthyl, benzyl, phenylalkenylmethylene; r2Represents methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, allyl, benzyl, phenylvinylenemethylene.
In this context, unless otherwise specified, the heteroatoms of the heterocyclyl and/or heteroaryl groups are to be understood as a heteroatom species common in the art, which may be selected, for example, from O, S or N.
Optionally, the reaction of formula three may be optionally carried out in other organic solvents, and when not, it is understood that the reaction may increase the amount of the starting alcohol to be charged, and the corresponding starting alcohol may be used as the solvent for the reaction; when other organic solvents are selected as the reaction solvent, the organic solvent may be selected from acetonitrile, butyronitrile, tetrahydrofuran. Preferably, the reaction of formula three is carried out under conditions of acetonitrile as solvent.
According to the reaction of the formula III, the 3-halopropynyl ester compound shown in the formula 1: an alcohol represented by formula 2: water: palladium catalyst: the feeding molar ratio of the alkali is 1: 1-4: 0.001-0.05: 1-4, preferably, the 3-halopropynyl ester compound shown in the formula 1: an alcohol represented by formula 2: water: palladium catalyst: the molar ratio of alkali fed is 1:2:2:0.01: 2.
In the present invention, the amount of the solvent added is understood to be an amount conventionally added in the art, i.e., to sufficiently dissolve and uniformly diffuse the reaction mass, unless otherwise specified.
In the present invention, the DABCO has a meaning well known in the art and has the chemical name 1, 4-diazabicyclo [ 2.2.2 ] octane.
The reaction according to the third formula is typically carried out by adding the 3-halopropynyl ester compound of the formula 1, the alcohol of the formula 2, water, the palladium catalyst and the base in the above molar ratio in sequence into a reaction flask equipped with a magnetic stirrer, adding a certain amount of acetonitrile as a reaction solvent, stirring at room temperature under an air atmosphere for 5 minutes, detecting by GC or T L C analysis that the reaction is complete, and subjecting the reacted mixture to Na saturation2S2O3Washing, extracting with diethyl ether, drying with anhydrous sodium sulfate, distilling under reduced pressure to remove solvent, and separating the residue by silica gel column chromatography (n-hexane/ethyl acetate as eluent) to obtain target product 3.
The invention has the beneficial effects that: an improved method for synthesizing malonate compounds is provided, and the method obviously shortens the reaction time, improves the reaction efficiency and slightly improves the yield of target products by adding a very small amount (1-2%) of palladium catalyst into the reaction.
Detailed Description
The present invention will be described in further detail with reference to specific examples.
Example 1
To a 25m L reaction flask equipped with a magnetic stirrer were added 62.4mg (0.2mmol) of the 3-iodopropynyl ester compound represented by the formula 1-A, 18.4mg (0.4mmol) of ethanol, 7.2mg (0.4mmol) of water, Pd (OAc)20.45mg (1 mol%) of DABCO44.8mg (0.4mmol), 2m L acetonitrile as a reaction solvent, stirring and reacting at room temperature in an air atmosphere for 5 minutes, and detecting by GC or T L C analysis to confirm completion of the reaction2S2O3Washing, extracting with diethyl ether, drying with anhydrous sodium sulfate, distilling under reduced pressure to remove solvent, and separating the residue by silica gel column chromatography (with n-hexane/ethyl acetate as eluent) to obtain the desired product 3-A as colorless liquid with yield of 95%.
Example 2
To a 25m L reaction flask equipped with a magnetic stirrer were added 62.4mg (0.2mmol) of the 3-iodopropynyl ester compound represented by the formula 1-A, 12.8mg (0.4mmol) of methanol, 7.2mg (0.4mmol) of water, Pd (OAc)20.45mg (1 mol%) of DABCO44.8mg (0.4mmol), 2m L acetonitrile as a reaction solvent, stirring and reacting at room temperature in an air atmosphere for 5 minutes, and detecting by GC or T L C analysis to confirm completion of the reaction2S2O3Washing, extracting with diethyl ether, drying with anhydrous sodium sulfate, distilling under reduced pressure to remove solvent, and separating the residue by silica gel column chromatography (with n-hexane/ethyl acetate as eluent) to obtain the target product 3-B as colorless liquid with a yield of 96%.
Example 3
To a 25m L reaction flask equipped with a magnetic stirrer were added 62.4mg (0.2mmol) of the 3-iodopropynyl ester compound represented by the formula 1-A, 24mg (0.4mmol) of isopropyl alcohol, 7.2mg (0.4mmol) of water, Pd (OAc)20.45mg (1 mol%) of DABCO44.8mg (0.4mmol), 2m L acetonitrile as a reaction solvent, stirring and reacting at room temperature in an air atmosphere for 5 minutes, and detecting by GC or T L C analysis to confirm completion of the reaction2S2O3Washing, extracting with diethyl ether, drying with anhydrous sodium sulfate, distilling under reduced pressure to remove solvent, and separating the residue by silica gel column chromatography (with n-hexane/ethyl acetate as eluent) to obtain the desired product 3-C as colorless liquid with yield of 81%.
Example 4
To a 25m L reaction flask equipped with a magnetic stirrer, 62.4mg (0.2mmol) of the 3-iodopropynyl ester compound represented by the formula 1-A, 35.2mg (0.4mmol) of n-pentanol, 7.2mg (0.4mmol) of water, Pd (OAc)20.45mg (1 mol%) of DABCO44.8mg (0.4mmol), 2m L acetonitrile as a reaction solvent, stirring and reacting at room temperature in an air atmosphere for 5 minutes, and detecting by GC or T L C analysis to confirm completion of the reaction2S2O3Washing, extracting with diethyl ether, drying with anhydrous sodium sulfate, distilling under reduced pressure to remove solvent, and separating the residue by silica gel column chromatography (with n-hexane/ethyl acetate as eluent) to obtain the desired product 3-D, colorless liquid, and 91% yield.
Example 5
To a 25m L reaction flask equipped with a magnetic stirrer were added 62.4mg (0.2mmol) of the 3-iodopropynyl ester compound represented by the formula 1-A, 23.2mg (0.4mmol) of allyl alcohol, 7.2mg (0.4mmol) of water, Pd (OAc)20.45mg (1 mol%) of DABCO44.8mg (0.4mmol), 2m L acetonitrile as a reaction solvent, stirring and reacting at room temperature in an air atmosphere for 5 minutes, and detecting by GC or T L C analysis to confirm completion of the reaction2S2O3Washing, extracting with diethyl ether, drying with anhydrous sodium sulfate, distilling under reduced pressure to remove solvent, and separating the residue by silica gel column chromatography (with n-hexane/ethyl acetate as eluent) to obtain the desired product 3-E as colorless liquid with 86% yield.
Example 6
To a 25m L reaction flask equipped with a magnetic stirrer, sequential additions were made57.2mg (0.2mmol) of a 3-iodopropynyl ester compound represented by the formula 1-B, 12.8mg (0.4mmol) of methanol, 7.2mg (0.4mmol) of water, Pd (OAc)20.45mg (1 mol%) of DABCO44.8mg (0.4mmol), 2m L acetonitrile as a reaction solvent, stirring and reacting at room temperature in an air atmosphere for 5 minutes, and detecting by GC or T L C analysis to confirm completion of the reaction2S2O3Washing, extracting with diethyl ether, drying with anhydrous sodium sulfate, distilling under reduced pressure to remove solvent, and separating the residue by silica gel column chromatography (with n-hexane/ethyl acetate as eluent) to obtain the desired product 3-F as colorless liquid with 94% yield.
Example 7
To a 25m L reaction flask equipped with a magnetic stirrer were added 44.8mg (0.2mmol) of the 3-iodopropynyl ester compound represented by the formula 1-C, 18.4mg (0.4mmol) of ethanol, 7.2mg (0.4mmol) of water, Pd (OAc)20.45mg (1 mol%) of DABCO44.8mg (0.4mmol), 2m L acetonitrile as a reaction solvent, stirring and reacting at room temperature in an air atmosphere for 5 minutes, and detecting by GC or T L C analysis to confirm completion of the reaction2S2O3Washing, extracting with diethyl ether, drying with anhydrous sodium sulfate, distilling under reduced pressure to remove solvent, and separating the residue by silica gel column chromatography (with n-hexane/ethyl acetate as eluent) to obtain the desired product 3-G as colorless liquid with yield of 76%.
Example 8
The charge reaction and post-treatment were carried out in the same manner as in example 1 except that acetonitrile, an organic solvent, and ethanol were not used in an amount of 2m L, whereby the objective product 3-A was obtained as a colorless liquid in a yield of 92%.
Comparative example 1
The procedure is as reported in "Synthesis of Malonates from 3-Halopropynates, Alcohols, and Water Using DABCO", Peng-Cheng Qian et al, Synthesis 2015,47, 3309-. When the reaction is carried out for 5 minutes, the yield of the target product is only about 8 percent through GC detection, and the reaction is continued to be prolonged until the reaction time is 8 hours, so that the yield of the target product is 92 percent.
Comparative example 2
The same procedure as in example 1 was repeated except that copper acetate was used as the catalyst in place of the palladium acetate catalyst. Detection shows that after the reaction is carried out for 5 minutes, the yield of the target product is only 6%, the reaction is continued for 8 hours, and the yield of the target product is 78%.
The applicant states that the present invention is illustrated by the above examples to describe the synthesis method of the present invention, but the present invention is not limited to the above examples, and those skilled in the art should understand that various conventional substitutions, selections and/or adjustments of the preparation method and operation of the present invention are within the protection scope and disclosure scope of the present invention.
Claims (7)
1. A method for synthesizing malonate compounds is characterized in that 3-halopropynyl ester compounds shown in formula 1, alcohol shown in formula 2 and water react for 5 minutes in the air atmosphere at room temperature under the conditions of a palladium catalyst and alkali to prepare malonate compounds shown in formula 3;
wherein [ Pd ]]Represents a palladium catalyst selected from Pd (OAc)2；
The base is selected from DBACO;
x represents a halogen;
R1is represented by C1-20Substituted or unsubstituted hydrocarbon group of (1), C3-C20Substituted or unsubstituted heterocyclic group of (a);
R2represents C1-20Substituted or unsubstituted hydrocarbyl of (a);
the substituents in each of the above "substituents" are selected from C1-C6Alkyl of (C)2-C6Alkenyl of, C6-12Aryl radical, C6-12aryl-C2Alkenyl-, C6-12aryl-C1-6Alkyl-, C1-C6Alkoxy, halogen, nitro, -CN;
3-halopropynyl ester compounds represented by the formula 1: an alcohol represented by formula 2: water: palladium catalyst: the feeding molar ratio of the alkali is 1: 1-4: 0.001-0.05: 1-4.
2. The method of claim 1, wherein R is1Is represented by C1-20Is selected from C1-C20Substituted or unsubstituted alkyl of, C2-C20Substituted or unsubstituted alkenyl of, C6-C20Substituted or unsubstituted aryl of (1), C3-C20Substituted or unsubstituted cycloalkyl of (a); the R is2Is represented by C1-20Is selected from C1-C20Substituted or unsubstituted alkyl of, C2-C20Substituted or unsubstituted alkenyl of (a).
3. The method of claim 2, wherein R is1Is represented by C1-6Alkyl radical, C6-12Aryl radical, C6-12aryl-C1-6Alkyl radical, C6-12aryl-C2alkenyl-C1-6Alkyl radical R2Is represented by C1-6Alkyl radical, C2-C6Alkenyl radical C1-6Alkyl radical, C6-12aryl-C1-6Alkyl radical, C6-12aryl-C2alkenyl-C1-6An alkyl group.
4. The method of claim 3, wherein R is1Represents methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, phenyl, naphthyl, benzyl, phenylalkenylmethylene; r2Represents methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, allyl, benzyl, phenylvinylenemethylene.
5. The process according to any one of claims 1 to 4, wherein the reaction is optionally carried out with or without additional organic solvent selected from one or more of acetonitrile, butyronitrile, tetrahydrofuran.
6. The method according to claim 1, wherein the 3-halopropynyl ester compound represented by formula 1: an alcohol represented by formula 2: water: palladium catalyst: the molar ratio of alkali fed is 1:2:2:0.01: 2.
7. The method as claimed in claim 1, wherein the 3-halopropynyl ester compound of formula 1, the alcohol of formula 2, water, the palladium catalyst and the base are sequentially added to a reaction flask equipped with a magnetic stirrer in the above molar ratio, and then a certain amount of acetonitrile is added as a reaction solvent, and the mixture is stirred at room temperature under an air atmosphere for 5 minutes, and the reaction is confirmed to be complete by GC or T L C analysis, and the mixture after the reaction is saturated Na2S2O3Washing, extracting with diethyl ether, drying with anhydrous sodium sulfate, distilling under reduced pressure to remove the solvent, and separating the residue by silica gel column chromatography to obtain the target product 3.
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Non-Patent Citations (4)
| Title |
|---|
| Palladium-Catalyzed Alcoholysis of 3-Iodopropynamides: Selective Synthesis of Carbamoylacetates;Jian-Sheng Tang 等;《Synthesis》;20140925;108-112 * |
| Synthesis of Imidazoheterocycle-Hydrazine, -Carbamate, and Water Using DABCO;Peng-Cheng Qian 等;《Synthesis》;20150724;3309-3314 * |
| 炔烃官能团反应合成环状化合物和丙二酸酯的研究;钱鹏程;《万方数据库》;20160504;第4.2.2节 * |
| 钯催化炔卤化合物偶联反应研究;唐建生;《万方数据库》;20170103;第3.3节 * |
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