CN113548968A - Method for synthesizing (Z) -olefin by nickel-catalyzed iron-mediated alkyne fluoroalkyl and product - Google Patents

Method for synthesizing (Z) -olefin by nickel-catalyzed iron-mediated alkyne fluoroalkyl and product Download PDF

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CN113548968A
CN113548968A CN202110827235.8A CN202110827235A CN113548968A CN 113548968 A CN113548968 A CN 113548968A CN 202110827235 A CN202110827235 A CN 202110827235A CN 113548968 A CN113548968 A CN 113548968A
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CN113548968B (en
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沈志良
褚雪强
王雅文
李祥瑞
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Nanjing Tech University
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Abstract

The invention discloses a method for synthesizing (Z) -olefin by nickel-catalyzed iron-mediated alkyne fluoroalkylation and a product thereof, wherein the method comprises the steps of sequentially adding a metal promoter and an ultra-dry solvent, and sequentially activating metals by using 1, 2-dibromoethane and trimethylchlorosilane; cooling, then sequentially adding alkyne, fluoroalkyl halide, catalyst, ligand and additive, and violently stirring the reaction mixture in a nitrogen atmosphere; quenching by using a saturated ammonium chloride solution, washing, extracting and drying a reaction product, and separating by column chromatography to obtain a target product. The invention uses cheap and easily obtained iron powder as a reaction accelerator to synthesize the (Z) -fluoroalkyl olefin, thereby expanding the substrate preparation range of the compound; the preparation method provided by the invention is mild in condition, can be compatible with various functional groups, and also shows good applicability in functional group modification of some complex molecules.

Description

Method for synthesizing (Z) -olefin by nickel-catalyzed iron-mediated alkyne fluoroalkyl and product
Technical Field
The invention belongs to the technical field of organic compound synthesis, and particularly relates to a method for synthesizing (Z) -olefin by nickel-catalyzed iron-mediated alkyne fluoroalkyl and a product.
Background
In recent decades, it has been generally recognized that the introduction of fluorine atoms or fluorine-containing functional groups into organic molecules results in a significant enhancement of the lipophilicity, metabolic stability and bioavailability of the parent molecule, which makes it potentially useful in medicine, agrochemicals and material science. Since olefins are commonly used as raw materials in chemical synthesis, it is important to develop a synthetic method of fluoroalkylated olefins.
The hydro-hydroalkylation reaction of alkyne has the disadvantages that the used catalyst (Pt, Ir) is relatively expensive, has no wide economic practicability, the E/Z selectivity is unstable, or a special substrate is required, and the like. Iron (0) is one of the most abundant and inexpensive metals on earth compared to other metals (e.g., lithium, magnesium, aluminum, zinc, manganese, tin), but its use in organic synthesis has not been widely exploited.
Disclosure of Invention
This section is for the purpose of summarizing some aspects of embodiments of the invention and to briefly introduce some preferred embodiments. In this section, as well as in the abstract and the title of the invention of this application, simplifications or omissions may be made to avoid obscuring the purpose of the section, the abstract and the title, and such simplifications or omissions are not intended to limit the scope of the invention.
The present invention has been made keeping in mind the above and/or other problems occurring in the prior art.
The invention provides a novel method for coupling alkyne and bromodifluoroacetic acid ethyl ester or perfluoroalkyl halide under the catalysis of nickel and mediation of iron with high efficiency. The reaction produces highly stereoselective (Z) -fluoroalkylated olefins in moderate to good yields and excellent Z/E selectivity (up to >99: 1Z/E). In addition, the present invention allows for facile functionalization of alkyne complex molecules of carbohydrates, drugs and biologically active compounds.
The chemical equation for this reaction is shown below:
Figure BDA0003174052170000011
in order to solve the technical problems, the invention provides the following technical scheme: a process for synthesizing (Z) -olefin by iron-mediated fluoro-alkylation of alkyne in the presence of Ni catalyst includes,
sequentially adding a metal promoter and an ultra-dry solvent, and sequentially activating metals by using 1, 2-dibromoethane and trimethylchlorosilane; cooling, then sequentially adding alkyne, fluoroalkyl halide, catalyst, ligand and additive, and violently stirring the reaction mixture in a nitrogen atmosphere;
quenching by using a saturated ammonium chloride solution, washing, extracting and drying a reaction product, and separating by column chromatography to obtain a target product.
As a preferred embodiment of the nickel-catalyzed iron-mediated process for the fluoroalkylation of alkynes to (Z) -alkenes according to the invention, wherein: the alkyne comprises phenylacetylene, 4-chlorphenyl acetylene, 4-bromophenyl acetylene, 2-trifluoromethyl phenylacetylene, 4-acetylene methyl benzoate, 2-cyano phenylacetylene, 3-cyano phenylacetylene, 4-acetyl phenylacetylene, 4-aldehyde phenylacetylene and one of 4-tert-butyl phenylacetylene;
the fluoroalkylated halide includes one of 2-bromo-2, 2-difluoro-3-acetic acid ethyl ester, 2-bromo-N, N-diethyl-2, 2-difluoro-3-acetamide, 2-bromo-2, 2-difluoro-3-acetylpiperidine, 2-bromo-2, 2-difluoro-3-acetylmorpholine, perfluoroiodoethane, perfluoroiodobutane, perfluoroiodohexane, perfluorobromoheptane, perfluoroiodooctane, and perfluoroiododecane.
As a preferred embodiment of the nickel-catalyzed iron-mediated process for the fluoroalkylation of alkynes to (Z) -alkenes according to the invention, wherein: the additive comprises lithium iodide;
the catalyst comprises one of ferric chloride, ferric trichloride, cobalt bromide, cobalt acetylacetonate, cuprous iodide, nickel chloride and nickel bromide;
the ligand comprises one of bis (2-diphenylphosphinophenyl) ether, bis (dicyclohexylphosphinophenyl) ether, 4, 5-bis (dicyclohexylphosphine) -dibenzopyran derivative, 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl, 2- (di-tert-butylphosphino) biphenyl, 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl and 2- (dicyclohexylphosphino) biphenyl.
As a preferred embodiment of the nickel-catalyzed iron-mediated process for the fluoroalkylation of alkynes to (Z) -alkenes according to the invention, wherein: the catalyst is nickel chloride; the ligand is bis (2-diphenylphosphinophenyl) ether.
As a preferred embodiment of the nickel-catalyzed iron-mediated process for the fluoroalkylation of alkynes to (Z) -alkenes according to the invention, wherein: the solvent comprises one of acetonitrile, N-dimethylacetamide, toluene, N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane and 1, 2-dichloroethane;
the metal promoter comprises one of indium, chromium, manganese, zinc, magnesium and iron.
As a preferred embodiment of the nickel-catalyzed iron-mediated process for the fluoroalkylation of alkynes to (Z) -alkenes according to the invention, wherein: the solvent is N, N-dimethylformamide; the metal promoter is iron.
As a preferred embodiment of the nickel-catalyzed iron-mediated process for the fluoroalkylation of alkynes to (Z) -alkenes according to the invention, wherein: the molar ratio of alkyne to fluoroalkylated halide is 1: 3.
as a preferred embodiment of the nickel-catalyzed iron-mediated process for the fluoroalkylation of alkynes to (Z) -alkenes according to the invention, wherein: the vigorous stirring is carried out at the temperature of 60-100 ℃ for 24 hours.
It is another object of the present invention to provide a product obtained by the method for synthesizing (Z) -alkene by nickel-catalyzed iron-mediated fluoroalkylation of alkyne, wherein the product is a (Z) -fluoroalkylated alkene compound, and the chemical structural formula of the product is as follows:
Figure BDA0003174052170000031
wherein R comprises one of phenyl, halogen substituted phenyl, 2-trifluoromethyl substituted phenyl, 4-benzoate, 2-cyano substituted phenyl, 3-cyano substituted phenyl, 4-acetyl substituted phenyl, 4-aldehyde substituted phenyl and 4-tert-butyl substituted phenyl;
r' comprises one of 2, 2-difluoro-3-acetic acid carbethoxy, N-diethyl-2, 2-difluoro-3-acetamido, 2-difluoro-3-acetyl heterocycle, perfluoroethyl, perfluorobutyl, perfluorohexyl, perfluoroheptyl, perfluorooctyl and perfluorodecyl.
As a preferred embodiment of the product of the present invention, wherein: the halogen comprises chlorine or bromine; the heterocyclic ring includes piperidine or morpholine.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a method for realizing cross coupling reaction of alkyne and bromodifluoroacetic acid ethyl ester or perfluoroalkyl halide in N, N-dimethylformamide by using nickel chloride as a catalyst, bis (2-diphenylphosphinophenyl) ether as a ligand, iron as a metal promoter and lithium iodide as an additive; the invention uses cheap and easily obtained iron powder as a reaction accelerator to synthesize the (Z) -fluoroalkyl olefin, thereby expanding the substrate preparation range of the compound; the preparation method provided by the invention is mild in condition, can be compatible with various functional groups, and also shows good applicability in functional group modification of some complex molecules.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the description of the embodiments will be briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings based on these drawings without inventive exercise. Wherein:
FIG. 1 is a hydrogen spectrum of a target product (Z) -ethyl 4- (4-chlorophenyl) -2, 2-difluorobutyl-3-enoate of example 1 according to the present invention;
FIG. 2 is a carbon spectrum of a target product (Z) -ethyl 4- (4-chlorophenyl) -2, 2-difluorobutyl-3-enoate according to example 1 of the present invention;
FIG. 3 is a hydrogen spectrum of (Z) -4- (2-perfluoroethylvinyl) benzonitrile, which is the target product of example 2 according to the present invention;
FIG. 4 is a carbon spectrum of (Z) -4- (2-perfluoroethylvinyl) benzonitrile, which is the target product of example 2 according to the present invention;
FIG. 5 is a hydrogen spectrum of ethyl (Z) -2, 2-difluoro-4- (2- (((2- (4-isobutylphenyl) propionyl) oxy) methyl) phenyl) but-3-enoate, the target product of example 3 of the present invention;
FIG. 6 is a carbon spectrum of ethyl (Z) -2, 2-difluoro-4- (2- (((2- (4-isobutylphenyl) propionyl) oxy) methyl) phenyl) but-3-enoate, which is the target product of example 3 of the present invention.
Detailed Description
In order to make the aforementioned objects, features and advantages of the present invention more comprehensible, specific embodiments thereof are described in detail below with reference to examples of the specification.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways than those specifically described and will be readily apparent to those of ordinary skill in the art without departing from the spirit of the present invention, and therefore the present invention is not limited to the specific embodiments disclosed below.
Furthermore, reference herein to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one implementation of the invention. The appearances of the phrase "in one embodiment" in various places in the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments.
Example 1
(1) To a 10mL Schlenk flask were added iron powder (168.0mg,3.0mmol,3.0equiv.) and DMF (2mL) in that order. 1, 2-dibromoethane (28mg,0.15mmol) was added, and the reaction flask was heated to 320 ℃ for 35 seconds and then cooled to room temperature. Trimethylchlorosilane (22mg,0.15mmol) was then added, heated using an electric heat gun at 320 ℃ for 35 seconds, and cooled again to room temperature to complete activation of the iron powder.
(2) After cooling to room temperature, NiCl is added into the reaction flask in sequence2(13mg,0.1mmol,0.1equiv.), LiI (267.7mg,2.0mmol,2.0equiv.), DPEPhos (108mg,0.2mmol,0.2equiv.), ethyl 2-bromo-2, 2-difluoro-3-acetate (3.0mmol,3.0equiv.), and 4-chlorophenylacetylene (1.0mmol,1.0 equiv.). The reaction mixture was stirred at 60 ℃ for 24h and then saturated NH4The Cl solution was quenched and extracted with ethyl acetate (20 mL. times.3). The combined organic phases were washed with saturated brine (20mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (using ethyl acetate/petroleum ether as eluent) to finally obtain 224.2mg of the desired product ethyl (Z) -4- (4-chlorophenyl) -2, 2-difluorobutyl-3-enoate, which has the formula:
Figure BDA0003174052170000051
characterization of the above ethyl (Z) -4- (4-chlorophenyl) -2, 2-difluorobutyl-3-enoate, as shown in FIGS. 1 and 2, resulted in: a colorless liquid;1H NMR(400MHz,CDCl3):δ7.34-7.28(m,4H),6.88(dd,J＝12.6,2.1Hz,1H),5.88(q,J＝13.3Hz,1H),4.12(q,J＝7.1Hz,2H),1.19(t,J＝7.2Hz,3H)ppm.13C NMR(100MHz,CDCl3):δ163.3(t,J＝33.8Hz),137.4(t,J＝8.4Hz),134.7,132.6-132.5(m),130.3(t,J＝3.0Hz),128.4,122.3(t,J＝27.6Hz),112.1(t,J＝245.6Hz),63.1,13.6ppm.IR(KBr):ν＝3411,2985,1768,1493,1153,1094,844cm-1.HRMS(m/z):calcd for C12H12ClF2O2[M+H]+261.0488,found:261.0494.
according to the characterization data, the obtained reaction product is (Z) -4- (4-chlorphenyl) -2, 2-difluorobutyl-3-ethyl enoate (purity is more than 98%); the product yield was calculated to be 86%.
Example 2
(1) To a 10mL Schlenk flask were added iron powder (168.0mg,3.0mmol,3.0equiv.) and DMF (2mL) in that order. 1, 2-dibromoethane (28mg,0.15mmol) was added, and the reaction flask was heated to 320 ℃ for 35 seconds and then cooled to room temperature. Trimethylchlorosilane (22mg,0.15mmol) was then added, heated using an electric heat gun at 320 ℃ for 35 seconds, and cooled again to room temperature to complete activation of the iron powder.
(2) After cooling to room temperature, NiCl is added into the reaction flask in sequence2(13mg,0.1mmol,0.1equiv.), LiI (267.7mg,2.0mmol,2.0equiv.), DPEPhos (108mg,0.2mmol,0.2equiv.), perfluoroiodoethane (3.0mmol,3.0equiv.), and 4-cyanobenzene acetylene (1.0mmol,1.0 equiv.). The reaction mixture was stirred at 100 ℃ for 24h and then saturated NH4The Cl solution was quenched and extracted with ethyl acetate (20 mL. times.3). The combined organic phases were washed with saturated brine (20mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (using ethyl acetate/petroleum ether as eluent) to finally obtain 168.0mg of the objective product (Z) -4- (2-perfluoroethylvinyl) benzonitrile, which has the structural formula:
Figure BDA0003174052170000061
characterization of the above (Z) -4- (2-perfluoroethylvinyl) benzonitrile, as shown in FIGS. 3 and 4, resulted in: a colorless liquid;1H NMR(400MHz,CDCl3):δ7.66(d,J＝8.4Hz,2H),7.44(d,J＝8.1Hz,2H),7.15(dt,J＝12.8,2.9Hz,1H),5.87(td,J＝14.9,12.6Hz,1H)ppm.13C NMR(100MHz,CDCl3):δ140.1(t,J＝5.0Hz),138.5,131.9,129.1(t,J＝3.6Hz),118.4(t,J＝22.1Hz),118.4,112.4ppm.IR(KBr):ν＝3413,2232,1339,1204,1109,880,582cm-1.HRMS(m/z):calcd for C11H7F5N[M+H]+248.0493,found:248.0499.
according to the characterization data, the obtained reaction product is (Z) -4- (2-perfluoroethylvinyl) benzonitrile (purity is more than 98%); the product yield was calculated to be 68%.
Example 3
(1) To a 10mL Schlenk flask were added iron powder (168.0mg,3.0mmol,3.0equiv.) and DMF (2mL) in that order. 1, 2-dibromoethane (28mg,0.15mmol) was added, and the reaction flask was heated to 320 ℃ for 35 seconds and then cooled to room temperature. Trimethylchlorosilane (22mg,0.15mmol) was then added, heated using an electric heat gun at 320 ℃ for 35 seconds, and cooled again to room temperature to complete activation of the iron powder.
(2) After cooling to room temperature, NiCl is added into the reaction flask in sequence2(13mg,0.1mmol,0.1equiv.), LiI (267.7mg,2.0mmol,2.0equiv.), DPEPhos (108mg,0.2mmol,0.2equiv.), ethyl 2-bromo-2, 2-difluoro-3-acetate (3.0mmol,3.0equiv.), and 2-ethynyl benzyl 2- (4-isobutylphenyl) propionate (1.0mmol,1.0 equiv.). The reaction mixture was stirred at 60 ℃ for 24h and then saturated NH4The Cl solution was quenched and extracted with ethyl acetate (20 mL. times.3). The combined organic phases were washed with saturated brine (20mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (using ethyl acetate/petroleum ether as eluent) to give 270.8mg of the desired product (Z) -2, 2-difluoro-4- (2- (((2- (4-isobutylphenyl) propionyl) oxy) methyl) phenyl) but-3-enoic acid ethyl ester 3 having the formula:
Figure BDA0003174052170000062
characterization of the above ethyl (Z) -2, 2-difluoro-4- (2- (((2- (4-isobutylphenyl) propionyl) oxy) methyl) phenyl) but-3-enoate, as shown in figures 5 and 6, gave: a colorless liquid;1H NMR(400MHz,CDCl3):δ7.20–7.08(m,6H),7.03–6.99(m,2H),6.75(dt,J＝12.1,1.6Hz,1H),5.76(q,J＝12.0Hz,1H),4.96(d,J＝2.1Hz,2H),3.82(q,J＝7.2Hz,2H),3.66(q,J＝7.2Hz,1H),2.38(d,J＝7.2Hz,2H),1.82–1.72(m,1H),1.42(d,J＝7.1Hz,3H),1.04(t,J＝7.2Hz,3H),0.83(d,J＝6.6Hz,6H)ppm.13C NMR(100MHz,CDCl3):δ174.3,163.2(t,J＝33.5Hz),140.7,137.5,136.5(t,J＝9.2Hz),133.9(t,J＝1.1Hz),133.4(t,J＝1.2Hz),129.3,128.6,128.4,128.0,127.2,123.8(t,J＝27.5Hz),112.0(t,J＝246.3Hz),64.5,62.9,45.0,45.0,30.2,22.4,22.3,18.2,13.6ppm.IR(KBr):ν＝2957,1771,1738,1455,1318,1156,1073cm-1.HRMS(m/z):calcd for C26H31F2O4[M+H]+445.2185,found:445.2190.
according to the characterization data, the reaction product obtained was (Z) -ethyl 2, 2-difluoro-4- (2- (((2- (4-isobutylphenyl) propionyl) oxy) methyl) phenyl) but-3-enoate (purity > 98%); the product yield was calculated to be 61%.
Example 4
Example 4 is essentially the same as example 1, except that in step (1), the catalyst is different and the ligand is 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl (SPhos), as shown in Table 2 below:
TABLE 2
Figure BDA0003174052170000071
Figure BDA0003174052170000081
As can be seen from Table 2, the reaction yield was very low without any catalyst, and the desired product was obtained only in a 12% yield. Subsequently, when a metal salt such as Fe (II or III), Co (II), or Cu (I or II) is added to the reaction system, it was found that NiCl is used2When used as a catalyst, the desired product was obtained in 77% yield. However, other Ni catalysts [ Ni (acac) ]2Or NiBr2]The yield was not improved.
Example 5
Example 5 is essentially the same as example 1, except that in step (1), the solvent is different and the ligand is 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl (SPhos), as shown in Table 3 below:
TABLE 3
Solvent(s) Ligands Yield (%)
MeCN SPhos <5
DMA SPhos 72
Toluene SPhos <5
DMF SPhos 77
DMSO SPhos 46
1,4-dioxane SPhos 21
DCE SPhos 15
As can be seen from table 3, in the difluoroalkylation of alkynes, solvents were used, such as: the yields of MeCN, Toluene, DMSO, 1,4-dioxane, DCE and other solvents are lower; the yield can reach 72% when DMA is used as the solvent, and is optimal when DMF is used as the solvent, and the yield is 77%.
Example 6
Example 6 is essentially the same as example 1, except that in step (1), the ligands are different, as shown in table 4 below:
TABLE 4
Ligands Yield (%) (Z/E)
Ligand-free 61(72:28)
Bis (2-diphenylphosphinophenyl) ether 86(95:5)
Bis (dicyclohexylphosphinophenyl) ether 53(88:12)
4, 5-bis (dicyclohexylphosphine) -dibenzopyran derivatives 66(94:6)
2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl 59(88:12)
2- (di-tert-butylphosphino) biphenyl 48(93:7)
2-dicyclohexylphosphonium-2, 4, 6-triisopropylbiphenyl 62(70:30)
2- (dicyclohexylphosphino) biphenyl 59(88:12)
As can be seen from table 4, in the difluoroalkylation reaction of alkynes, different phosphine ligands showed different catalytic activities in both reaction yield and stereoselectivity. Using ligands such as: bis (2-diphenylphosphinophenyl) ether, bis (dicyclohexylphosphinophenyl) ether, 4, 5-bis (dicyclohexylphosphine) -dibenzopyran derivative, 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl, 2- (di-t-butylphosphino) biphenyl, 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl and 2- (dicyclohexylphosphino) biphenyl, it was found that the effect was most excellent when bis (2-diphenylphosphinophenyl) ether was used as a ligand, and the target product was obtained in a yield of 86% (95: 5Z/E).
Example 7
Example 7 is essentially the same as example 1, except that in step (1), the metal promoter is different, as shown in table 5 below:
TABLE 5
Figure BDA0003174052170000091
Figure BDA0003174052170000101
As can be seen from table 5, in the difluoroalkylation of alkynes, metal promoters were used, such as: in, Cr, Mn, Zn, Mg, Fe, all of which can be obtained In moderate to good yields, with Fe being the most preferred.
Example 8
Example 8 is essentially the same as example 1, except that in step (1), the alkyne and fluoroalkylated halide are different, as shown in table 6 below:
TABLE 6
Figure BDA0003174052170000102
Figure BDA0003174052170000111
Figure BDA0003174052170000121
The invention provides a method for realizing cross coupling reaction of alkyne and bromodifluoroacetic acid ethyl ester or perfluoroalkyl halide in N, N-dimethylformamide by using nickel chloride as a catalyst, bis (2-diphenylphosphinophenyl) ether as a ligand, iron as a metal promoter and lithium iodide as an additive; the invention uses cheap and easily obtained iron powder as a reaction accelerator to synthesize the (Z) -fluoroalkyl olefin, thereby expanding the substrate preparation range of the compound; the preparation method provided by the invention is mild in condition, can be compatible with various functional groups, and also shows good applicability in functional group modification of some complex molecules.
It should be noted that the above-mentioned embodiments are only for illustrating the technical solutions of the present invention and not for limiting, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, which should be covered by the claims of the present invention.

Claims (10)

1. A method for synthesizing (Z) -olefin by iron-mediated alkyne fluoroalkyl catalysis through nickel, which is characterized by comprising the following steps: comprises the steps of (a) preparing a mixture of a plurality of raw materials,
sequentially adding a metal promoter and an ultra-dry solvent, and sequentially activating metals by using 1, 2-dibromoethane and trimethylchlorosilane; cooling, then sequentially adding alkyne, fluoroalkyl halide, catalyst, ligand and additive, and violently stirring the reaction mixture in a nitrogen atmosphere;
quenching by using a saturated ammonium chloride solution, washing, extracting and drying a reaction product, and separating by column chromatography to obtain a target product.
2. The nickel-catalyzed iron-mediated fluoroalkylation of alkynes to (Z) -alkenes of claim 1, wherein: the alkyne comprises phenylacetylene, 4-chlorphenyl acetylene, 4-bromophenyl acetylene, 2-trifluoromethyl phenylacetylene, 4-acetylene methyl benzoate, 2-cyano phenylacetylene, 3-cyano phenylacetylene, 4-acetyl phenylacetylene, 4-aldehyde phenylacetylene and one of 4-tert-butyl phenylacetylene;
the fluoroalkylated halide includes one of 2-bromo-2, 2-difluoro-3-acetic acid ethyl ester, 2-bromo-N, N-diethyl-2, 2-difluoro-3-acetamide, 2-bromo-2, 2-difluoro-3-acetylpiperidine, 2-bromo-2, 2-difluoro-3-acetylmorpholine, perfluoroiodoethane, perfluoroiodobutane, perfluoroiodohexane, perfluorobromoheptane, perfluoroiodooctane, and perfluoroiododecane.
3. The nickel-catalyzed iron-mediated fluoroalkylation of alkynes to (Z) -alkenes of claim 1 or 2, wherein: the additive comprises lithium iodide;
the catalyst comprises one of ferric chloride, ferric trichloride, cobalt bromide, cobalt acetylacetonate, cuprous iodide, nickel chloride and nickel bromide;
the ligand comprises one of bis (2-diphenylphosphinophenyl) ether, bis (dicyclohexylphosphinophenyl) ether, 4, 5-bis (dicyclohexylphosphine) -dibenzopyran derivative, 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl, 2- (di-tert-butylphosphino) biphenyl, 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl and 2- (dicyclohexylphosphino) biphenyl.
4. The nickel-catalyzed iron-mediated fluoroalkylation of alkynes to (Z) -alkenes of claim 3, wherein: the catalyst is nickel chloride; the ligand is bis (2-diphenylphosphinophenyl) ether.
5. The nickel-catalyzed iron-mediated fluoroalkylation of alkynes to (Z) -alkenes of any of claims 1,2 or 4, wherein: the solvent comprises one of acetonitrile, N-dimethylacetamide, toluene, N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane and 1, 2-dichloroethane;
the metal promoter comprises one of indium, chromium, manganese, zinc, magnesium and iron.
6. The nickel-catalyzed iron-mediated fluoroalkylation of alkynes to (Z) -alkenes of claim 5, wherein: the solvent is N, N-dimethylformamide; the metal promoter is iron.
7. The nickel-catalyzed iron-mediated fluoroalkylation of alkynes to (Z) -alkenes of any of claims 1,2, 4 or 6, wherein: the molar ratio of alkyne to fluoroalkylated halide is 1: 3.
8. the nickel-catalyzed iron-mediated fluoroalkylation of alkynes to (Z) -alkenes of claim 7, wherein: the vigorous stirring is carried out at the temperature of 60-100 ℃ for 24 hours.
9. A product obtained by the method for synthesizing (Z) -olefin by nickel-catalyzed iron-mediated alkyne fluoroalkylation according to any one of claims 1 to 8, wherein the method comprises the following steps: the product is a (Z) -fluoroalkylated olefin compound having the chemical formula:
Figure FDA0003174052160000021
wherein R comprises one of phenyl, halogen substituted phenyl, 2-trifluoromethyl substituted phenyl, 4-benzoate, 2-cyano substituted phenyl, 3-cyano substituted phenyl, 4-acetyl substituted phenyl, 4-aldehyde substituted phenyl and 4-tert-butyl substituted phenyl;
r' comprises one of 2, 2-difluoro-3-acetic acid carbethoxy, N-diethyl-2, 2-difluoro-3-acetamido, 2-difluoro-3-acetyl heterocycle, perfluoroethyl, perfluorobutyl, perfluorohexyl, perfluoroheptyl, perfluorooctyl and perfluorodecyl.
10. The product of claim 9, wherein: the halogen comprises chlorine or bromine; the heterocyclic ring includes piperidine or morpholine.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114133329A (en) * 2021-11-23 2022-03-04 上海大学 Cis-configuration 2, 2-difluoro-4-phenylbutan-3-ethyl enoate compound and preparation method thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108834409A (en) * 2016-03-08 2018-11-16 大金工业株式会社 The manufacturing method of fluorochemical
CN109627164A (en) * 2019-01-21 2019-04-16 盐城锦明药业有限公司 A kind of preparation method of high allyl alcohols compound

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108834409A (en) * 2016-03-08 2018-11-16 大金工业株式会社 The manufacturing method of fluorochemical
CN109627164A (en) * 2019-01-21 2019-04-16 盐城锦明药业有限公司 A kind of preparation method of high allyl alcohols compound

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
CHUYI WU 等: "Decarboxylative Perfluoroalkylation of Vinyl Bromides with Copper(I) Perfluorocarboxylato Complexes", 《ASIAN JOURNAL OF ORGANIC CHEMISTRY》 *
HENG-RUI ZHANG 等: "Merging photoredox with copper catalysis: decarboxylative difluoroacetylation of alpha,beta-unsaturated carboxylic acids with ICF2CO2Et", 《CHEMICAL COMMUNICATIONS》 *
MIAOLIN KE 等: "Cu-catalyzed hydrofluoroacetylation of alkynes or alkynyl carboxylic acids leading highly stereoselectively to fluoroacetylated alkenes", 《ORGANIC CHEMISTRY FRONTIERS》 *
TOMOYA KITAZUME 等: "ULTRASOUND-PROMOTED SELECTIVE PERFLUOROALKYLATION ON THE DESIRED POSITION OF ORGANIC-MOLECULES", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 *
XIANG FANG 等: "AIBN-initiated radical addition of gem-difluorinated alkyl iodides to alkynes and the Pd-catalyzed Sonogashira coupling reaction of E-phenyl difluoromethylene vinylic iodides with terminal alkynes", 《TETRAHEDRON》 *
XIANG-RUI LI 等: "Stereoselective synthesis of fluoroalkylated (Z)-alkene via nickel-catalyzed and iron-mediated hydrofluoroalkylation of alkynes", 《ORGANIC CHEMISTRY FRONTIERS》 *
XIAORUI FENG 等: "Copper-mediated regioselective hydrodifluoroalkylation of alkynes", 《ORGANIC & BIOMOLECULAR CHEMIST》 *
YUJI FURUKAWA 等: "Visible-Light-Driven Direct 2,2-Difluoroacetylation Using an Organic Pigment Catalyst", 《ACS SUSTAINABLE CHEMISTRY & ENGINEERING》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114133329A (en) * 2021-11-23 2022-03-04 上海大学 Cis-configuration 2, 2-difluoro-4-phenylbutan-3-ethyl enoate compound and preparation method thereof

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