CN115322081A - Synthesis method of alkyl alkenyl ketone - Google Patents

Synthesis method of alkyl alkenyl ketone Download PDF

Info

Publication number
CN115322081A
CN115322081A CN202210007594.3A CN202210007594A CN115322081A CN 115322081 A CN115322081 A CN 115322081A CN 202210007594 A CN202210007594 A CN 202210007594A CN 115322081 A CN115322081 A CN 115322081A
Authority
CN
China
Prior art keywords
formula
alkyl
reaction
synthesis
alkenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN202210007594.3A
Other languages
Chinese (zh)
Other versions
CN115322081B (en
Inventor
毛建友
叶雨
林庭志
熊丹
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nanjing Tech University
Original Assignee
Nanjing Tech University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nanjing Tech University filed Critical Nanjing Tech University
Priority to CN202210007594.3A priority Critical patent/CN115322081B/en
Publication of CN115322081A publication Critical patent/CN115322081A/en
Application granted granted Critical
Publication of CN115322081B publication Critical patent/CN115322081B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/49—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with carbon monoxide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B41/00—Formation or introduction of functional groups containing oxygen
    • C07B41/06—Formation or introduction of functional groups containing oxygen of carbonyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of alkyl alkenyl ketone. The invention adopts three-component reduction cross-coupling reaction of alkyl chloride, alkenyl bromide and carbon monoxide catalyzed by transition metal to prepare various alkyl alkenyl ketones and derivatives thereof. The invention takes carbon monoxide as a carbonyl source, and the reaction is carried out at lower temperature and pressure, compared with the prior synthesis method, the invention has mild reaction conditions and simple and convenient operation.

Description

Synthesis method of alkyl alkenyl ketone
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of alkyl alkenyl ketone.
Background
The cross coupling reaction catalyzed by transition metal is an effective organic synthesis method, is widely applied to the efficient construction of various carbon-carbon bonds and carbon heteroatom bonds, and has important significance for the synthesis of drug molecules and natural products. Alkyl alkenyl ketones are an important class of organic compounds which are intermediates in the synthesis of many drugs. However, most of the conventional synthesis methods require the use of a previously prepared organometallic reagent, which is very inconvenient in operation. The three-component reduction cross-coupling reaction of alkyl chloride, alkenyl bromide and carbon monoxide carried out under the catalysis of transition metal is prepared by a one-pot method, is simple to operate and is suitable for large-scale production.
Disclosure of Invention
The invention adopts three-component reduction cross-coupling reaction of alkyl chloride, alkenyl bromide and carbon monoxide catalyzed by transition metal to prepare various alkyl alkenyl ketones and derivatives thereof. The invention takes carbon monoxide as the source of carbonyl, and the reaction is carried out at lower temperature and pressure, compared with the prior synthesis means, the reaction condition is very mild, and the operation is simple and convenient. In addition, the reaction has good functional group tolerance and high yield, and is a simple, efficient, green and economic synthesis method.
The specific scheme is as follows:
Figure BSA0000262879140000011
a method for synthesizing alkyl alkenyl ketone comprises the steps of mixing an alkyl chloride shown in a formula 1, carbon monoxide shown in a formula 2 and an alkenyl bromide shown in a formula 3 with an organic solvent in the presence of a transition metal catalyst and a reducing agent to carry out reduction cross-coupling reaction to synthesize the alkyl alkenyl ketone shown in a formula 4 and derivatives thereof.
Wherein R is 1 Selected from hydrogen, halogen, trifluoromethyl or tert-butyl, R 2 Selected from hydrogen, methyl, methoxy, halogen radical. The method can realize the three-component one-pot method to generate the alkyl alkenyl ketone, reduces the reaction steps and can improve the product yield; the raw materials used in the synthesis method are simple and economical; r in the invention 1 、R 2 The selectivity is much broader.
Preferably, R 1 Selected from hydrogen, halogen, trifluoromethyl or tert-butyl, R 2 Selected from hydrogen, methyl, methoxy, halogen and isopropyl.
More preferably, R 1 Selected from hydrogen, halogen radicals, R 2 Selected from hydrogen, methyl, isopropyl.
More preferably, R 1 Selected from hydrogen, R 2 Selected from isopropyl.
Preferably, the reaction is carried out under the protection of inert gas, and preferably, the inert gas is nitrogen or argon;
preferably, the synthesis occurs in the presence of a transition metal catalyst, a transition metal reducing agent, and an organic solvent.
Preferably, the transition metal catalyst is a palladium catalyst; the transition metal reducing agent is zinc powder.
Preferably, the palladium catalyst is bis (cyanophenyl) palladium dichloride, palladium acetate and palladium chloride; more preferably, the transition metal palladium catalyst is bis (cyanophenyl) palladium dichloride.
Preferably, the ligand is tris (4-methoxyphenyl) phosphine, tris (4-trifluoromethyl) phosphine or tris (3-methoxyphenyl) phosphine.
More preferably, the ligand is tris (4-methoxyphenyl) phosphine.
Preferably, the organic solvent is N, N-dimethylacetamide, N-dimethylformamide, tetrahydrofuran.
Preferably, the additive is sodium bromide or sodium fluoride.
More preferably, the additive is sodium bromide.
Preferably, the molar ratio of the alkyl chloride shown in the formula 1 to the alkenyl bromide shown in the formula 3, the reducing agent, the additive and the catalyst in the reaction is as follows: 2-1: 1-2: 0.5-2: 0.05-0.2, more preferably the molar ratio is 2: 1: 1.5: 1: 0.075; the reaction temperature is 40 ℃ to 80 ℃, and the preferred temperature is 60 ℃.
Preferably, the method of the invention can be used for synthesizing the alkyl alkenyl ketone compound with the following structure:
Figure BSA0000262879140000021
under the existence of catalyst, the low valence metal palladium and alkenyl bromide are subjected to oxidative addition and then to carbonyl insertion, and further react with alkyl chloride to finally prepare alkyl alkenyl ketone.
The technical scheme of the invention can achieve at least one of the following beneficial effects:
r in the invention 1 、R 2 The method can be selected in various ways, so that the method has wider applicability and can synthesize various alkyl alkenyl ketones.
The synthesis method of the invention adopts carbon monoxide as a source of carbonyl, and is green and environment-friendly;
the invention adopts a one-pot three-component synthesis method, reduces the loss of raw materials and improves the yield of products due to less reaction steps;
the required operation steps are simple and convenient, extreme temperature rise or temperature reduction is not needed, the reaction can be carried out only under normal pressure, and the method is safe and convenient;
drawings
The attached drawings are hydrogen spectrum and carbon spectrum nuclear magnetic resonance spectrums of products of all embodiments, the numbers of the attached drawings correspond to the numbers of the embodiments, a graph A is a hydrogen spectrum nuclear magnetic resonance spectrum, and a graph B is a carbon spectrum nuclear magnetic resonance spectrum. FIG. 1A shows the hydrogen spectra of the products obtained in example 1, and FIGS. 2A to 12A show the hydrogen spectra of the products obtained in examples 2 to 12 in this order. FIG. 1B is a carbon spectrum diagram of the product obtained in example 1, and FIGS. 2B to 12B are carbon spectra diagrams of the products obtained in examples 2 to 12, in this order.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
In order to facilitate understanding for those skilled in the art, the concept of the present invention will be further described with reference to the following examples. The following specific description of the embodiments is not intended to limit the invention, but is merely provided to facilitate the understanding of the present disclosure by those skilled in the art. The raw materials referred to in the specification are purchased from the market, or simply synthesized, other medicines and the like are purchased from Sigma-Aldrich, acros, alfa Aesar, TCI China, adamas-beta or J & K, and the model of a nuclear magnetic resonance spectrometer is Bruker 400 Mm.
Example 1
Bis (cyanophenyl) palladium dichloride (2.9mg, 0.0075mmol), tris (4-methoxyphenyl) phosphine (6.6mg, 0.01875mmol), zinc powder (9.8mg, 1.5 equiv.), naBr (10.3mg, 1.0 equiv.) were added to the microwave tube in a glove box, followed by 0.2mL of N, N-dimethylacetamide, removed from the glove box with a cap, evacuated first for ten minutes with a vacuum pump, then inserted into the microwave tube with a carbon monoxide-containing balloon, and the procedure was repeated three times with a carbon monoxide-containing balloon inserted onto the microwave tube. Then, (1-chloroethyl) benzene (0.2mmol, 2.0 equiv.) and (E) - (2-bromovinyl) benzene (0.1mmol, 1.0 equiv.) are added and refluxed at 60 ℃ for 6 hours, cooled to room temperature, the reaction is quenched by opening the cap and adding three drops of water, the solvent is removed under reduced pressure, and the crude product is separated by column chromatography (petroleum ether: ethyl acetate = 50: 1) to obtain (E) -1, 4-diphenyl-1-penten-3-one (21.3mg, 90% yield). The hydrogen spectrum and the carbon spectrum nuclear magnetic resonance spectrogram of the product are respectively shown as a figure 1A and a figure 1B, and the spectrogram data is as follows: 1 H NMR(400MHz，CDCl 3 )δ：7.64(d， J＝15.9Hz，1H)，7.47-7.43(m，2H)，7.37-7.30(m，5H)，7.29-7.23(m，3H)，6.70(d，J＝15.9Hz，1H)，4.02(q，J＝ 7.0Hz，1H)，1.49(d，J＝7.0Hz，3H)ppm. 13 C{ 1 H}NMR(101MHz，CDCl 3 )δ：199.5，142，6，140.6，134.5，130.4， 129.0，128.8，128.3，128.1，127.1，124.5，51.9，17.9ppm.
the raw materials in example 1 are changed to design the following 12 groups of experimental examples, wherein the 1 st group of experiments is example 1, and the nuclear magnetic resonance spectrum chart of the corresponding product is shown in fig. 1. The numbers of the NMR spectra of the remaining 2-12 groups correspond to the numbers of the corresponding examples.
The table shows the structural formula of the product in each example 1-12, the types of alkenyl bromide and alkyl chloride used in the first 12 examples are different, the amounts and conditions of other raw materials are consistent, and the final column shows the yield of the product in each example.
Figure BSA0000262879140000031
Figure BSA0000262879140000041
Example 2
Bis (cyanophenyl) palladium dichloride (2.9mg, 0.0075mmol), tris (4-methoxyphenyl) phosphine (6.6mg, 0.01875mmol), zinc powder (9.8mg, 1.5 equiv.), naBr (10.3mg, 1.0 equiv.) were added to the microwave tube in a glove box, followed by 0.2mL of N, N-dimethylacetamide, removed from the glove box with a cap, evacuated first for ten minutes with a vacuum pump, then inserted into the microwave tube with a carbon monoxide-containing balloon, and the procedure was repeated three times with a carbon monoxide-containing balloon inserted onto the microwave tube. Then (1-chloroethyl) benzene (0.2mmol, 2.0 equiv.) and (E) -1- (2-bromoethenyl) -4-methylbenzene (0.1mmol, 1.0 equiv.) are added and refluxed at 60 ℃ for 6 hours, cooled to room temperature, the reaction is quenched by opening the cap and adding three drops of water, the solvent is removed under reduced pressure, and the crude product is separated by column chromatography (petroleum ether: ethyl acetate = 50: 1) to obtain (E) -4-phenyl-1- (4-methylphenyl) -1-penten-3-one (23.3mg, 93% yield). The hydrogen spectrum and the carbon spectrum nuclear magnetic resonance spectrogram of the product are respectively shown in fig. 2A and fig. 2B, and the spectrogram data is as follows: 1 H NMR(400 MHz，CDCl 3 )δ：7.59(d，J＝15.9Hz，1H)，7.36-7.32(m，4H)，7.30-7.22(m，3H)，7.13(d，J＝8.0Hz，2H)， 6.66(d，J＝15.9Hz，1H)，4.01(q，J＝6.9Hz，1H)，2.34(s，3H)，1.48(d，J＝6.9Hz，3H)ppm. 13 C{ 1 H}NMR (101MHz，CDCl 3 )δ：199.5，142.7，140.8，140.7，131.8，129.5，128.9，128.3，128.0，127.0，123.6，51.8，21.5，17.9 ppm.
example 3
In a glove box, bis (cyanophenyl) palladium dichloride (2.9mg, 0.0075mmol), tris (4-methoxyphenyl) phosphine (6.6mg, 0.01875mmol), zinc powder (9.8mg, 1.5 equiv.), naBr (10.3mg, 1.0 equiv.) were charged into a microwave tube, followed by addition of 0.2mL of N, N-dimethylacetamide, taken out from the glove box with a lid,the microwave tube was evacuated for ten minutes by a vacuum pump, then inserted with a balloon containing carbon monoxide, the procedure was repeated three times and the balloon containing carbon monoxide was inserted on the microwave tube. Then (1-chloroethyl) benzene (0.2mmol, 2.0 equiv.) and (E) -2-bromovinyl-4-isopropylbenzene (0.1mmol, 1.0 equiv.) are added and refluxed at 60 ℃ for 6 hours, cooled to room temperature, uncapped and quenched by three drops of water, depressurized to remove the solvent, and the crude product is separated by column chromatography (petroleum ether: ethyl acetate = 50: 1) to obtain (E) -1- (4-isopropylphenyl) -4-phenyl-1-pentadien-3-one (26.4mg, 95% yield). The hydrogen spectrum and the carbon spectrum nuclear magnetic resonance spectrogram of the product are respectively shown in fig. 3A and fig. 3B, and the spectrogram data is as follows: 1 H NMR (400MHz，CDCl 3 )δ：7.59(d，J＝15.9Hz，1H)，7.39(d，J＝7.9Hz，2H)，7.36-7.29(m，2H)，7.29-7.21(m，3H)， 7.19(d，J＝8.1Hz，2H)，6.66(d，J＝15.9Hz，1H)，4.02(q，J＝6.9Hz，1H)，2.89(m，1H)，1.48(d，J＝7.0Hz， 3H)，1.22(d，J＝6.9Hz，6H)ppm. 13 C{ 1 H}NMR(101MHz，CDCl 3 )δ：199.6，151.8，142.6，140.8，132.2，128.9，128.5，128.0，127.0，126.9，123.8，51.8，34.1，23.7，17.9ppm.
example 4
In a glove box, bis (cyanophenyl) palladium dichloride (2.9mg, 0.0075mmol), tris (4-methoxyphenyl) phosphine (6.6mg, 0.01875mmol), zinc powder (9.8mg, 1.5 equiv.), naBr (10.3mg, 1.0 equiv.) were added to a microwave tube, followed by addition of 0.2mL of N, N-dimethylacetamide, taken out of the glove box with a lid, evacuated with a vacuum pump for ten minutes, followed by insertion of a balloon containing carbon monoxide into the microwave tube, the procedure was repeated three times and a balloon containing carbon monoxide was inserted onto the microwave tube. Then adding (1-chloroethyl) benzene (0.2mmol, 2.0 equivalent) and (E) -4- (2-bromovinyl) -N, N-dimethylaniline (0.1mmol, 1.0 equivalent) to reflux at 60 ℃ for 6 hours, cooling to room temperature, opening the cover, adding three drops of water to quench the reaction, decompressing to remove the solvent, and carrying out column chromatography separation on a crude product (petroleum ether: ethyl acetate = 50: 1) to obtain (E) -1- [4- (dimethylamino) phenyl]4-phenyl-1-penten-3-one (20.1mg, 72% yield). The hydrogen spectrum and the carbon spectrum nuclear magnetic resonance spectrogram of the product are respectively shown in figure 4A and figure 4B, and the spectrogram data are： 1 H NMR(400MHz，CDCl 3 )δ：7.57(d，J＝15.7Hz，1H)，7.36(d，J＝8.9Hz，2H)，7.34-7.27(m，4H)，7.23 (m，1H)，6.60(d，J＝8.9Hz，2H)，6.52(d，J＝15.7Hz，1H)，4.01(q，J＝6.9Hz，1H)，2.99(s，6H)，1.47(d，J＝6.9 Hz，3H)ppm. 13 C{ 1 H}NMR(101MHz，CDCl 3 )δ：199.6，151.8，143.4，141.4，130.1，128.8，128.0，126.8，122.1， 119.7，111.6，51.4，40.1，18.1ppm.
Example 5
Bis (cyanophenyl) palladium dichloride (2.9mg, 0.0075mmol), tris (4-methoxyphenyl) phosphine (6.6mg, 0.01875mmol), zinc powder (9.8mg, 1.5 equiv.), naBr (10.3mg, 1.0 equiv.) were added to the microwave tube in a glove box, followed by 0.2mL of N, N-dimethylacetamide, removed from the glove box with a cap, evacuated first for ten minutes with a vacuum pump, then inserted into the microwave tube with a carbon monoxide-containing balloon, and the procedure was repeated three times with a carbon monoxide-containing balloon inserted onto the microwave tube. Then (1-chloroethyl) benzene (0.2 mmol,2.0 equiv.) and (E) -1-bromo-4- (2-bromovinyl) benzene (0.1mmol, 1.0 equiv.) were added and refluxed at 60 ℃ for 6 hours, cooled to room temperature, capped and quenched with three drops of water, the solvent was removed under reduced pressure, and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate = 50: 1) to give (E) -1- (4-bromophenyl) -4-phenyl-1-penten-3-one (21.2 mg,67% yield). The hydrogen spectrum and the carbon spectrum nuclear magnetic resonance spectrogram of the product are respectively shown in fig. 5A and 5B, and the spectrogram data are as follows: 1 H NMR(400MHz， CDCl 3 )δ：7.53(d，J＝15.9Hz，1H)，7.46(d，J＝8.5Hz，2H)，7.38-7.31(m，3H)，7.32-7.23(m，4H)，6.67(d，J ＝15.9Hz，1H)，3.99(q，J＝6.9Hz，1H)，1.48(d，J＝6.9Hz，3H)ppm. 13 C{ 1 H}NMR(101MHz，CDCl 3 )δ： 199.2，141.2，140.4，133.4，132.0，129.7，129.0，128.1，127.2，125.0，124.6，52.1，17.8ppm.
example 6
In a glove box, bis (cyanophenyl) palladium dichloride (2.9mg, 0.0075mmol), tris (4-methoxyphenyl) phosphine (6.6mg, 0.01875mmol), zinc powder (9.8mg, 1.5 equiv.), naBr (10.3mg, 1.0 equiv.) were charged into a microwave tubeThen 0.2ml of n, n-dimethylacetamide was added, the glove box was removed with a lid, evacuated for ten minutes by a vacuum pump, and then inserted into a microwave tube with a balloon containing carbon monoxide, and the procedure was repeated three times with the balloon containing carbon monoxide inserted onto the microwave tube. Then (1-chloroethyl) benzene (0.2 mmol,2.0 equiv.) and (E) -2-bromovinyl-2-methoxybenzene (0.1mmol, 1.0 equiv.) were added and refluxed at 60 ℃ for 6 hours, cooled to room temperature, capped and quenched with three drops of water, the solvent was removed under reduced pressure, and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate = 50: 1) to give (E) -1- (2-methylphenyl) -4-phenyl-1-penten-3-one (21.3mg, 80% yield). The hydrogen spectrum and the carbon spectrum nuclear magnetic resonance spectrogram of the product are respectively shown in fig. 6A and 6B, and the spectrogram data are as follows: 1 H NMR(400 MHz，CDCl 3 )δ：7.97(d，J＝16.1Hz，1H)，7.42(dd，J＝7.7，1.7Hz，1H)，7.36-7.26(m，5H)，7.26-7.21(m， 1H)，6.93-6.83(m，2H)，6.75(d，J＝16.1Hz，1H)，4.07(q，J＝7.0Hz，1H)，3.83(s，3H)，1.49(d，J＝6.9Hz，3H) ppm. 13 C{ 1 H}NMR(101MHz，CDCl 3 )δ：200.0，158.5，141.0，137.9，131.6，128.9，128.5，128.1，126.9，125.2，123.5，120.6，111.1，55.4，51.4，17.9ppm.
example 7
Bis (cyanophenyl) palladium dichloride (2.9mg, 0.0075mmol), tris (4-methoxyphenyl) phosphine (6.6mg, 0.01875mmol), zinc powder (9.8mg, 1.5 equiv.), naBr (10.3mg, 1.0 equiv.) were added to the microwave tube in a glove box, followed by 0.2mL of N, N-dimethylacetamide, removed from the glove box with a cap, evacuated first for ten minutes with a vacuum pump, then inserted into the microwave tube with a carbon monoxide-containing balloon, and the procedure was repeated three times with a carbon monoxide-containing balloon inserted onto the microwave tube. Then, 1-bromo-4- (1-chloroethyl) benzene (0.2mmol, 2.0 equiv.) and (E) - (2-bromovinyl) benzene (0.1mmol, 1.0 equiv.) were added and refluxed at 60 ℃ for 6 hours, cooled to room temperature, uncapped and quenched with three drops of water, the solvent was removed under reduced pressure, and the crude product was separated by column chromatography (petroleum ether: ethyl acetate = 50: 1), to obtain (E) -4- (4-bromophenyl) -1-phenyl-1-penten-3-one (25.2mg, 80% yield). The hydrogen spectrum and the carbon spectrum nuclear magnetic resonance spectrogram of the product are respectivelyFig. 7A and 7B, the spectrogram data is: 1 H NMR(400 MHz，CDCl 3 )δ：7.61(d，J＝15.9Hz，1H)，7.49-7.44(m，4H)，7.38-7.32(m，3H)，7.20-7.11(m，2H)，6.68(d， J＝15.9Hz，1H)，3.99(q，J＝6.9Hz，1H)，1.46(d，J＝6.9Hz，3H)ppm. 13 C{ 1 H}NMR(101MHz，CDCl 3 )δ： 198.9，143.1，139.6，134.3，132.1，130.5，129.8，128.9，128.4，124.2，121.1，51.2，17.8ppm.
example 8
In a glove box, bis (cyanophenyl) palladium dichloride (2.9mg, 0.0075mmol), tris (4-methoxyphenyl) phosphine (6.6mg, 0.01875mmol), zinc powder (9.8mg, 1.5 equiv.), naBr (10.3mg, 1.0 equiv.) were added to a microwave tube, followed by addition of 0.2mL of N, N-dimethylacetamide, taken out of the glove box with a lid, evacuated with a vacuum pump for ten minutes, followed by insertion of a balloon containing carbon monoxide into the microwave tube, the procedure was repeated three times and a balloon containing carbon monoxide was inserted onto the microwave tube. Then, 1- (1-chloroethyl) -4-fluorobenzene (0.2mmol, 2.0 equiv.) and (E) - (2-bromovinyl) benzene (0.1mmol, 1.0 equiv.) were added and refluxed at 60 ℃ for 6 hours, cooled to room temperature, capped and quenched by three drops of water, the solvent was removed under reduced pressure, and the crude product was isolated by column chromatography (petroleum ether: ethyl acetate = 50: 1) to give (E) -4- (4-fluorophenyl) -1-phenyl-1-penten-3-one (23.4 mg,92% yield). The hydrogen spectrum and the carbon spectrum nuclear magnetic resonance spectrogram of the product are respectively shown in fig. 8A and fig. 8B, and the spectrogram data is as follows: 1 H NMR(400 MHz，CDCl 3 )δ：7.66(d，J＝15.9Hz，1H)，7.43(dd，J＝6.7，2.9Hz，2H)，7.30-7.22(m，5H)，7.01(t，J＝8.6Hz， 2H)，6.76(d，J＝16.0Hz，1H)，4.04(q，J＝6.9Hz，1H)，1.49(d，J＝6.9Hz，3H). 13 C{ 1 H}NMR(101MHz， CDCl 3 )δ：198.74，161.63(d，J＝245.4Hz)，142.53，136.26(d，J C-F ＝3.2Hz)，134.13，130.20，129.37(d，J C-F ＝ 8.0Hz)，128.58，128.08，124.17，115.53(d，J C-F ＝21.3Hz)，50.57，17.80ppm.
example 9
In a glove box, bis (cyanophenyl) palladium dichloride (2.9mg, 0.0075mmol) and tris (4-methyl) were placedOxyphenyl) phosphine (6.6mg, 0.01875mmol) and zinc powder (9.8mg, 1.5 equiv.), naBr (10.3mg, 1.0 equiv.) were added to the microwave tube, followed by the addition of 0.2mL of N, N-dimethylacetamide, removed from the glovebox with a lid, evacuated with a vacuum pump for ten minutes, then inserted into the microwave tube with a balloon containing carbon monoxide, the procedure was repeated three times and the balloon containing carbon monoxide was inserted onto the microwave tube. Then, 1- (1-chloroethyl) -3-fluorobenzene (0.2mmol, 2.0 equiv.) and (E) - (2-bromovinyl) benzene (0.1mmol, 1.0 equiv.) are added, the mixture is refluxed at 60 ℃ for 6 hours, cooled to room temperature, uncovered and quenched by three drops of water, the solvent is removed under reduced pressure, and the crude product is separated by column chromatography (petroleum ether: ethyl acetate = 50: 1), thus obtaining (E) -4- (3-fluorophenyl) -1-phenyl-1-penten-3-one (22.9 mg,90% yield). The hydrogen spectrum and the carbon spectrum nuclear magnetic resonance spectrogram of the product are respectively shown in fig. 9A and 9B, and the spectrogram data are as follows: 1 H NMR(400MHz， CDCl 3 )δ：7.62(d，J＝15.9Hz，1H)，7.50-7.46(m，2H)，7.38-7.33(m，3H)，7.32-7.24(m，1H)，7.06(d，J＝ 7.7Hz，1H)，7.03-6.91(m，2H)，6.70(d，J＝15.9Hz，1H)，4.03(q，J＝6.9Hz，1H)，1.48(d，J＝6.9Hz，3H)ppm. 13 C{1H}NMR(101MHz，CDCl 3 )δ：198.9，163.2(d，J 1 C-F ＝247.9Hz)，143.2(d，J 4 C-F ＝6.7Hz)，134.5，130.7，130.6(d，J 3 C-F ＝8.7Hz)，128.9，128.5，124.3，123.9(d，J 5 C-F ＝2.9Hz)，115.2，114.9，114.2(d，J 2 C-F ＝21.3Hz)， 51.6，17.9ppm.
example 10
In a glove box, bis (cyanophenyl) palladium dichloride (2.9mg, 0.0075mmol), tris (4-methoxyphenyl) phosphine (6.6mg, 0.01875mmol), zinc powder (9.8mg, 1.5 equiv.), naBr (10.3mg, 1.0 equiv.) were added to a microwave tube, followed by addition of 0.2mL of N, N-dimethylacetamide, taken out of the glove box with a lid, evacuated with a vacuum pump for ten minutes, followed by insertion of a balloon containing carbon monoxide into the microwave tube, the procedure was repeated three times and a balloon containing carbon monoxide was inserted onto the microwave tube. Then 1- (1-chloroethyl) -2-fluorobenzene (0.2mmol, 2.0 eq.) and (E) - (2-bromovinyl) benzene (0.1mmol, 1.0 eq.) were addedRefluxing at 60 deg.C for 6 hr, cooling to room temperature, uncapping and adding three drops of water to quench the reaction, removing the solvent under reduced pressure, and separating the crude product by column chromatography (petroleum ether: ethyl acetate = 50: 1) to obtain (E) -4- (2-fluorophenyl) -1-phenyl-1-penten-3-one (23.6 mg,93% yield). The hydrogen spectrum and the carbon spectrum nuclear magnetic resonance spectrum of the product are respectively shown in fig. 10A and fig. 10B, and the spectrum data are as follows: 1 H NMR (400MHz，CDCl 3 )δ：7.64(d，J＝16.0Hz，1H)，7.50-7.45(m，2H)，7.39-7.31(m，3H)，7.28-7.17(m，2H)， 7.15-7.02(m，2H)，6.71(d，J＝16.0Hz，1H)，4.41(q，J＝6.9Hz，1H)，1.48(d，J＝7.0Hz，3H)ppm. 13 C{ 1 H} NMR(101MHz，CDCl 3 )δ：198.9，161.7(d，J 1 C-F ＝246.2Hz)，143.1，134.5，130.6，129.2(d， J 3 C-F ＝3.9Hz)， 128.9，128.9(d，J 2 C-F ＝13.9Hz)，128.5，124.8(d，J 4 C-F ＝3.8Hz)，124.5，115.9，115.6，43.6(d，J 5 C-F ＝2.2Hz)， 16.7ppm.
example 11
In a glove box, bis (cyanophenyl) palladium dichloride (2.9mg, 0.0075mmol), tris (4-methoxyphenyl) phosphine (6.6mg, 0.01875mmol), zinc powder (9.8mg, 1.5 equiv.), naBr (10.3mg, 1.0 equiv.) were added to a microwave tube, followed by addition of 0.2mL of N, N-dimethylacetamide, taken out of the glove box with a lid, evacuated with a vacuum pump for ten minutes, followed by insertion of a balloon containing carbon monoxide into the microwave tube, the procedure was repeated three times and a balloon containing carbon monoxide was inserted onto the microwave tube. Then, 1-tert-butyl-4- (1-chloroethyl) benzene (0.2mmol, 2.0 equiv.) and (E) - (2-bromovinyl) benzene (0.1mmol, 1.0 equiv.) were added and refluxed at 60 ℃ for 6 hours, cooled to room temperature, capped and quenched by three drops of water, the solvent was removed under reduced pressure, and the crude product was separated by column chromatography (petroleum ether: ethyl acetate = 50: 1) to give (E) -4- (4-tert-butylphenyl) -1-phenyl-1-penten-3-one (25.1mg, 86% yield). The hydrogen spectrum and the carbon spectrum nuclear magnetic resonance spectrum of the product are respectively shown as a graph 11A and a graph 11B, and the spectrum data are as follows: 1 H NMR (400MHz，CDCl 3 )δ：7.61(d，J＝15.9Hz，1H)，7.47(dd，J＝6.7，2.9Hz，2H)，7.36-7.32(m，5H)，7.20(d，J＝ 8.3Hz，2H)，6.72(d，J＝15.9Hz，1H)，4.00(q，J＝6.9Hz，1H)，1.47(d，J＝6.9Hz，3H)，1.30(s，9H)ppm. 13 C { 1 H}NMR(101MHz，CDCl 3 )δ：199.6，149.9，142.4，137.3，134.6，130.3，128.8，128.3，127.6，125.9，124.6，51.4， 34.4，31.3，17.8ppm.
example 12
In a glove box, bis (cyanophenyl) palladium dichloride (2.9mg, 0.0075mmol), tris (4-methoxyphenyl) phosphine (6.6mg, 0.01875mmol), zinc powder (9.8mg, 1.5 equiv.), naBr (10.3mg, 1.0 equiv.) were added to a microwave tube, followed by addition of 0.2mL of N, N-dimethylacetamide, taken out of the glove box with a lid, evacuated with a vacuum pump for ten minutes, followed by insertion of a balloon containing carbon monoxide into the microwave tube, the procedure was repeated three times and a balloon containing carbon monoxide was inserted onto the microwave tube. Then, (1-chloroethyl) benzene (0.2mmol, 2.0 equiv.) and (E) -4- (2-bromovinyl) -1, 2-dimethoxybenzene (0.1mmol, 1.0 equiv.) are added to reflux at 60 ℃ for 6 hours, cooled to room temperature, the reaction is quenched by opening the lid and adding three drops of water, the solvent is removed under reduced pressure, and the crude product is separated by column chromatography (petroleum ether: ethyl acetate = 50: 1) to obtain (E) -1- (3, 4-dimethoxyphenyl) -4-phenyl-1-penten-3-one (23.1mg, 78% yield). The hydrogen spectrum and the carbon spectrum nuclear magnetic resonance spectrum of the product are respectively shown in fig. 12A and 12B, and the spectrum data are as follows: 1 H NMR(400MHz，CDCl 3 )δ：7.56(d，J＝15.8Hz，1H)，7.37-7.30(m，2H)，7.30-7.21(m，3H)，7.07(dd，J ＝8.4，1.9Hz，1H)，6.97(d，J＝2.0Hz，1H)，6.82(d，J＝8.3Hz，1H)，6.58(d，J＝15.8Hz，1H)，4.04(q，J＝7.0 Hz，1H)，3.88(d，J＝4.7Hz，6H)，1.48(d，J＝6.9Hz，3H)ppm. 13 C{ 1 H}NMR(101MHz，CDCl 3 )δ：199.5， 151.2，149.0，142.7，140.9，128.9，128.0，127.4，127.0，122.9，122.7，110.9，109.8，55.9，55.8，51.5，18.0ppm.
example 13
The catalyst in example 1 was changed from bis (cyanobenzene) palladium dichloride to palladium acetate, and the conditions such as the raw materials and the amount used in other steps were kept unchanged to finally obtain (E) -1, 4-diphenyl-1-penten-3-one (9.5mg, 40% yield).
Example 14
The catalyst in example 1 was changed from bis (cyanophenyl) palladium dichloride to palladium chloride, and the conditions such as raw materials and amounts used in other steps were kept unchanged to finally obtain (E) -1, 4-diphenyl-1-penten-3-one (12.5mg, 53% yield).
Example 15
The catalyst in example 1 was changed from bis (cyanobenzene) dichloropalladium to tetrakis (triphenylphosphine) palladium under the same conditions as those for the starting materials and the amounts in the other steps, to finally obtain (E) -1, 4-diphenyl-1-penten-3-one (8.3mg, 35% yield).
Example 16
The catalyst in example 1 was converted from bis (cyanobenzene) palladium dichloride to (1, 5-cyclooctadiene) palladium (II) dichloride while keeping the conditions such as raw materials and amounts in other steps unchanged, to finally obtain (E) -1, 4-diphenyl-1-penten-3-one (14.2mg, 60% yield).
Example 17
The ligand in example 1 was changed from tris (4-methoxyphenyl) phosphine to tris (4-trifluoromethylphenyl) phosphine, and the conditions such as the starting material and the amount used in the other steps were kept constant, to finally obtain (E) -1, 4-diphenyl-1-penten-3-one (7.1mg, 30% yield).
Example 18
The ligand in example 1 was changed from tris (4-methoxyphenyl) phosphine to tris (3-methoxyphenyl) phosphine, and the conditions such as the raw materials and the amounts in the other steps were kept unchanged, to finally obtain (E) -1, 4-diphenyl-1-penten-3-one (6.2mg, 26% yield).
Example 19
The amount of N, N-dimethylacetamide in example 1 was changed to 0.4mL, and the conditions such as raw materials and amounts in other steps were kept unchanged, to finally obtain (E) -1, 4-diphenyl-1-penten-3-one (5.3mg, 22% yield).
Example 20
The amount of N, N-dimethylacetamide in example 1 was changed to 0.1mL, and the conditions such as the raw materials and the amounts in the other steps were kept unchanged, to obtain (E) -1, 4-diphenyl-1-penten-3-one (9.7 mg,40% yield).
Example 21
The sodium bromide in example 1 was changed to sodium fluoride, and the conditions such as the raw materials and the amounts used in the other steps were kept unchanged, to finally obtain (E) -1, 4-diphenyl-1-penten-3-one (14.8mg, 61% yield).
Example 22
The conditions of the raw materials and the amounts used in the other steps were kept unchanged without adding sodium bromide in example 1, and (E) -1, 4-diphenyl-1-penten-3-one (18.7 mg,77% yield) was obtained.
Example 23
The reaction time in example 1 was changed to 12h, and other conditions were not changed to obtain the product (E) -1, 4-diphenyl-1-penten-3-one in 82% yield.
Example 24
The reaction time in example 1 was changed to 18h, and other conditions were not changed to obtain the product (E) -1, 4-diphenyl-1-penten-3-one in 81% yield.
Example 25
The solvent in example 1 was changed to acetonitrile and other conditions were not changed to obtain (E) -1, 4-diphenyl-1-penten-3-one, and the formation of the product was detected by dot plate, but the product was very little and the yield was less than five percent.
Example 26
The solvent in example 1 was changed to tetrahydrofuran and the other conditions were not changed to obtain (E) -1, 4-diphenyl-1-penten-3-one in 20% yield.
Example 27
The solvent in example 1 was changed to N, N-dimethylformamide and the other conditions were not changed, (E) -1, 4-diphenyl-1-penten-3-one in 32% yield.

Claims (11)

1. A method for synthesizing alkyl alkenyl ketone is characterized in that:
Figure FSA0000262879130000011
adopting alkyl chloride shown in a formula 1, carbon monoxide shown in a formula 2 and alkenyl bromide shown in a formula 3 to mix with an organic solvent in the presence of a transition metal catalyst, a ligand, a reducing agent and an additive to carry out reduction cross-coupling reaction to synthesize alkyl alkenyl ketone shown in a formula 4 and derivatives thereof; wherein R is 1 Selected from hydrogen, halogen, trifluoromethyl or tert-butyl, R 2 Selected from hydrogen, methyl, methoxy, halogen radical, isopropyl.
2. The method of synthesis of claim 1, wherein R is 1 Selected from hydrogen, halogen, trifluoromethyl or tert-butyl, R 2 Selected from hydrogen, methyl, methoxy, halogen radical, isopropyl.
3. The method of synthesis of claim 1, wherein the synthesis occurs in the presence of a transition metal catalyst, a transition metal reducing agent, and an organic solvent.
4. A synthesis method according to claim 3, characterized in that the transition metal catalyst is a palladium catalyst; the transition metal reducing agent is zinc powder.
5. The method of claim 4, wherein the palladium catalyst is bis (cyanophenyl) palladium dichloride, palladium acetate or palladium chloride.
6. The method of claim 1, wherein the ligand is tris (4-methoxyphenyl) phosphine, tris (4-trifluoromethyl) phosphine, or tris (3-methoxyphenyl) phosphine.
7. The method according to claim 1, wherein the reaction is carried out under an inert gas atmosphere, and the inert gas is nitrogen or argon.
8. The method according to claim 1, wherein the organic solvent is N, N-dimethylacetamide, N-dimethylformamide or tetrahydrofuran.
9. The method of claim 1, wherein the additive is sodium bromide or sodium fluoride.
10. The synthesis method according to claim 1, wherein the molar ratio of the alkyl chloride represented by the reaction formula 1 to the alkenyl bromide represented by the reaction formula 3 to the reducing agent to the additive to the catalyst is: 1-2: 2-1: 1-2: 0.5-2: 0.05-0.2; the reaction temperature is 40-80 ℃.
11. The method of claim 1, wherein the alkenyl bromide, alkyl chloride and product alkyl alkenyl ketone are in one of the following tables:
Figure FSA0000262879130000012
Figure FSA0000262879130000021
the invention discloses a synthesis method of alkyl alkenyl ketone compounds, belonging to the field of organic synthesis. The invention uses alkyl chloride shown in formula 1, carbon monoxide shown in formula 2 and alkenyl bromide shown in formula 3 to mix with organic solvent in the presence of transition metal catalyst and reducing agent to carry out reduction cross-coupling reaction to synthesize alkyl alkenyl ketone shown in formula 4 and derivatives thereof. The invention adopts a one-pot method, has mild reaction conditions, simple and convenient operation and higher yield, and provides a new idea for synthesizing the alkyl alkenyl ketone compound.
CN202210007594.3A 2022-01-05 2022-01-05 Synthesis method of alkyl alkenyl ketone Active CN115322081B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202210007594.3A CN115322081B (en) 2022-01-05 2022-01-05 Synthesis method of alkyl alkenyl ketone

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210007594.3A CN115322081B (en) 2022-01-05 2022-01-05 Synthesis method of alkyl alkenyl ketone

Publications (2)

Publication Number Publication Date
CN115322081A true CN115322081A (en) 2022-11-11
CN115322081B CN115322081B (en) 2023-05-16

Family

ID=83916356

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210007594.3A Active CN115322081B (en) 2022-01-05 2022-01-05 Synthesis method of alkyl alkenyl ketone

Country Status (1)

Country Link
CN (1) CN115322081B (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002048072A2 (en) * 2000-12-14 2002-06-20 Personal Chemistry I Uppsala Ab Organic reactions with co generating materials
CN102887807A (en) * 2012-09-07 2013-01-23 大连理工大学 Method for preparing alpha, beta-unsaturated carbonyl compounds
CN104086385A (en) * 2014-07-14 2014-10-08 大连理工大学 Preparation method of unsaturated ketone
CN104892335A (en) * 2015-05-14 2015-09-09 南京师范大学 Metal catalysis-free method for synthesis of biaryl ketone under atmospheric pressure
CN110483223A (en) * 2019-09-11 2019-11-22 陕西师范大学 The method that pyridine palladium efficient catalytic prepares diaryl ketone compound

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002048072A2 (en) * 2000-12-14 2002-06-20 Personal Chemistry I Uppsala Ab Organic reactions with co generating materials
CN102887807A (en) * 2012-09-07 2013-01-23 大连理工大学 Method for preparing alpha, beta-unsaturated carbonyl compounds
CN104086385A (en) * 2014-07-14 2014-10-08 大连理工大学 Preparation method of unsaturated ketone
CN104892335A (en) * 2015-05-14 2015-09-09 南京师范大学 Metal catalysis-free method for synthesis of biaryl ketone under atmospheric pressure
CN110483223A (en) * 2019-09-11 2019-11-22 陕西师范大学 The method that pyridine palladium efficient catalytic prepares diaryl ketone compound

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ERIC DOLHEM, ET AL.: "Nickel catalyzed electrosynthesis of ketones from organic halides and iron pentacarbonyl. Part 2: unsymmetrical ketones" *
FU-PENG WU, ET AL.: "Pd/Cu-Catalyzed Defluorinative Carbonylative Coupling of Aryl Iodides and gem-Difluoroalkenes: Efficient Synthesis of α-Fluorochalcones" *
JIN-BAO PENG, ET AL.: "Palladium-Catalyzed Carbonylative Coupling of Aryl Iodides with Alkyl Bromides: Efficient Synthesis of Alkyl Aryl Ketones" *
XIAO-FENG WU, ET AL.: "Palladium-Catalyzed Carbonylative Negishi-type Coupling of Aryl Iodides with Benzyl Chlorides" *

Also Published As

Publication number Publication date
CN115322081B (en) 2023-05-16

Similar Documents

Publication Publication Date Title
JP3281920B2 (en) Method for producing allylfuran compound
CN110105305B (en) Transition metal catalyzed C-H activation/cyclization synthesis 1,2-benzothiazine derivative green synthesis method
CN110483223B (en) Method for preparing diaryl ketone compound by high-efficiency catalysis of palladium pyridine
Zhang et al. Alkoxyl-radical-mediated synthesis of functionalized allyl tert-(hetero) cyclobutanols and their ring-opening and ring-expansion functionalizations
CN114874081B (en) Preparation method of green efficient alpha-functionalized ketone
CN115322081A (en) Synthesis method of alkyl alkenyl ketone
CN109809967B (en) Method for synthesizing chiral alcohol
CN112062707A (en) Carbon-hydrogen bond activation method for nonmetal-participated inert alkane
JP2008088153A (en) Method for producing amide compound and catalyst used for the same method
US6025503A (en) Process for producing optically active titanium alkoxide complexes
CN113480416B (en) Preparation method of aryl ketone
JP2007238518A (en) Method for producing optically active 1,2-diamine compound and optically active niobium catalyst
Austeri et al. Enantio-and regioselective CpRu-catalyzed Carroll rearrangement
JP6054386B2 (en) Process for the production of palladium (I) tri-t-butylphosphine bromide dimer and process using it in isomerization reactions
CN1325457C (en) Preparation of fluorinated acetophenones
JP4827531B2 (en) Enantioselective method of nucleophilic addition reaction of enamide to imine and synthesis method of α-amino-γ-keto acid ester
CN108440307B (en) Preparation method of chiral amine compound
JP2017002002A (en) Fluorine-containing organic compound and manufacturing method of biaryl compound by the same and grignard reagent
JP2004269522A (en) New ruthenium complex, method for producing the same and method for producing amide compound using the same
CN113200832B (en) Method for catalyzing non-tension nonpolar carbon-carbon single bond hydrogenolysis of dicarbonyl compound
CN115385765B (en) Synthesis method of alkylaryl ketone
CN114031487B (en) Synthesis method of 2-aryl acetophenone compound
CN110028438B (en) Synthetic method of 3-phenyl-3-indole trifluoromethyl propyl ketone derivative
JP3724046B2 (en) Preparation method of asymmetric synthesis catalyst
CN109810036B (en) Synthesis method of 4-oxo-5- (arylformyl acetate-2-yl) naphthalene-sulfoxide ylide hybrid

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant