CN114507121B - Preparation method and product of alpha-alkenyl-alpha, alpha-difluoro aryl ketone compound - Google Patents
Preparation method and product of alpha-alkenyl-alpha, alpha-difluoro aryl ketone compound Download PDFInfo
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- CN114507121B CN114507121B CN202210071125.8A CN202210071125A CN114507121B CN 114507121 B CN114507121 B CN 114507121B CN 202210071125 A CN202210071125 A CN 202210071125A CN 114507121 B CN114507121 B CN 114507121B
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- B01J27/00—Catalysts comprising the elements or compounds of halogens, sulfur, selenium, tellurium, phosphorus or nitrogen; Catalysts comprising carbon compounds
- B01J27/06—Halogens; Compounds thereof
- B01J27/128—Halogens; Compounds thereof with iron group metals or platinum group metals
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- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0272—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255
- B01J31/0275—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255 also containing elements or functional groups covered by B01J31/0201 - B01J31/0269
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- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/26—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24
- B01J31/28—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24 of the platinum group metals, iron group metals or copper
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- 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
- C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
- C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
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- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
- B01J2231/4272—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type via enolates or aza-analogues, added as such or made in-situ, e.g. ArY + R2C=C(OM)Z -> ArR2C-C(O)Z, in which R is H or alkyl, M is Na, K or SiMe3, Y is the leaving group, Z is Ar or OR' and R' is alkyl
Abstract
The invention discloses a preparation method and a product of an alpha-alkenyl-alpha, alpha-difluoro aryl ketone compound, which comprises the steps of carrying out direct cross coupling reaction on an aryl alkyne compound and difluoro enol silyl ether in a solvent under the action of a catalyst to obtain the alpha-alkenyl-alpha, alpha-difluoro aryl ketone compound. The preparation method uses the difluoro enol silyl ether as a coupling substrate, so that the reaction has the characteristics of mild condition and convenience in operation, simple post-treatment, cheap and small catalyst, high economic benefit and the like.
Description
Technical Field
The invention belongs to the technical field of organic compounds, and particularly relates to a preparation method and a product of an alpha-alkenyl-alpha, alpha-difluoro aryl ketone compound.
Background
In recent years, research has shown that the incorporation of a difluoroalkyl group into an organic molecule can impart significantly enhanced lipophilicity, metabolic stability, and bioavailability to the parent molecule, making it potentially useful in pharmaceutical, agrochemical, and materials science. In addition to the commonly used difluoroalkyl-containing compounds (e.g., halodifluoromethyl compounds, α -difluoroketones) which have been widely used as difluoroalkylating agents, it has recently been demonstrated that difluoro enol silyl ethers can also be used as universal reagents, enabling efficient various organic transformations while introducing difluoro alkyl groups into organic molecules.
On the other hand, the addition of non-fluorinated silyl enol ethers to alkynes has proven to be an effective method for synthesizing β, γ -unsaturated carbonyl compounds. The Yamaguchi group reports the use of 4 to 12 equivalents of GaCl 3 As a reaction catalyst, silyl enol silyl ether can be added to trimethylsilylacetylene to give the corresponding β, γ -unsaturated ketone. Later Baba, yasuda, nishimoto found that alkyne and silyl enol silyl ether in stoichiometric amounts of metal salts (e.g., inBr 3 、GaBr 3 、BiBr 3 And ZnBr 2 ) Can effectively react in the presence to form alkenyl goldAn genus-allyl compound. Furthermore, by using catalytic amounts of gold (I)/silver (I) as reaction catalysts, intramolecular reactions have also been developed to build such conversions of cyclic compounds.
These reactions, whether intermolecular or intramolecular, can be carried out in the presence of stoichiometric amounts of gallium (III), indium (III), bismuth (III) and Zn (II) or catalytic amounts of gold (I)/silver (I). However, although the reaction of non-fluorinated enol silyl ether with alkynes has been reported, no method for obtaining α -alkenyl- α, α -difluoroketone compounds by direct addition of difluoro enol silyl ether with aryl alkynes has been developed. Furthermore, iron (III) salts have proven to be more attractive than most of the relatively expensive metal catalysts described above (typically stoichiometric) as stable lewis acids for catalyzing various organic transformations, as they are cheaper and less toxic. Therefore, it is necessary to realize the cross coupling of aryl alkyne and difluoro enol silyl ether and develop a new method for preparing alpha-alkenyl-alpha, alpha-difluoro aryl ketone compound, so improving the complex synthesis conditions is one of the research hot spots of the current synthesis.
Disclosure of Invention
This section is intended to outline some aspects of embodiments of the invention and to briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section as well as in the description summary and in the title of the application, to avoid obscuring the purpose of this section, the description summary and the title of the invention, which should not be used to limit the scope of the invention.
The present invention has been made in view of the above and/or problems occurring in the prior art.
One of the purposes of the invention is to provide a preparation method of an alpha-alkenyl-alpha, alpha-difluoro aryl ketone compound, which has the characteristics of simple post-treatment, cheap catalyst, small amount, high economic benefit and the like.
In order to solve the technical problems, the invention provides the following technical scheme: a process for preparing alpha-alkenyl-alpha, alpha-difluoro aryl ketone compound,
performing direct cross-coupling reaction on an aryl alkyne compound shown in a formula I and difluoro enol silyl ether shown in a formula II in a solvent under the action of a catalyst to obtain a compound shown in a formula III;
wherein Ar and Ar' comprise one of phenyl, halogen substituted phenyl, methyl substituted phenyl, propyl substituted phenyl, tertiary butyl substituted phenyl, methoxy substituted phenyl, naphthalene substituent, thiophene substituent and biphenyl.
As a preferred embodiment of the process for producing an α -alkenyl- α, α -difluoroaryl ketone compound of the present invention, wherein: the molar ratio of the aryl alkyne compound to the difluoro enol silyl ether is 1:1.5-2.
As a preferred embodiment of the process for producing an α -alkenyl- α, α -difluoroaryl ketone compound of the present invention, wherein: the aryl alkyne compound comprises one of 4-fluorophenylacetylene, 4-chlorophenylacetylene, 4-bromophenylacetylene, 4-phenylphenylacetylene, 4-methylphenylacetylene, 3-methylphenylacetylene, 4-propylphenylacetylene, 4-tert-butylphenylacetylene, 4-methoxyphenylacetylene, 2-methoxyphenylacetylene, 5-ethynylbenzo [ d ] [1,3] dioxolane and 3-ethynylthiophene.
As a preferred embodiment of the process for producing an α -alkenyl- α, α -difluoroaryl ketone compound of the present invention, wherein: the difluoro enol silicon ether compound comprises ((1-phenyl-2, 2-difluoro vinyl) oxy) trimethylsilane, ((1- (4-fluoro phenyl) -2, 2-difluoro vinyl) oxy) trimethylsilane, ((1- (4-chlorophenyl) -2, 2-difluoro vinyl) oxy) trimethylsilane, ((1- (4-bromophenyl) -2, 2-difluoro vinyl) oxy) trimethylsilane, ((1- (4-methylphenyl) -2, 2-difluoro vinyl) oxy) trimethylsilane, ((1- (4-tert-butylphenyl) -2, 2-difluoro vinyl) oxy) trimethylsilane, ((1- (4-methoxy phenyl) -2, 2-difluoro vinyl) oxy) trimethylsilane, ((1- (4-phenoxy) -2, 2-difluoro vinyl) oxy) trimethylsilane, ((1- (4-biphenyl) -2, 2-difluoro vinyl) oxy) trimethylsilane, ((1- (4-naphthalene) -2, 2-difluoro vinyl) oxy) trimethylsilane, one of (Z) - ((2-fluoro-1- (p-tolyl) vinyl) oxy) trimethylsilane.
As a preferred embodiment of the process for producing an α -alkenyl- α, α -difluoroaryl ketone compound of the present invention, wherein: the catalyst is a ferric salt catalyst.
As a preferred embodiment of the process for producing an α -alkenyl- α, α -difluoroaryl ketone compound of the present invention, wherein: the catalyst is ferric trichloride.
As a preferred embodiment of the process for producing an α -alkenyl- α, α -difluoroaryl ketone compound of the present invention, wherein: the additive is trimethylchlorosilane.
As a preferred embodiment of the process for producing an α -alkenyl- α, α -difluoroaryl ketone compound of the present invention, wherein: the solvent is a non-coordinating solvent, including dichloromethane and 1, 2-dichloroethane.
As a preferred embodiment of the process for producing an α -alkenyl- α, α -difluoroaryl ketone compound of the present invention, wherein: the reaction temperature is-78 to 60 ℃ after the direct cross coupling reaction.
As a preferred embodiment of the process for producing an α -alkenyl- α, α -difluoroaryl ketone compound of the present invention, wherein: the method also comprises the step of adding molecular sieve with water absorption function into the reaction system, wherein the adding amount of the molecular sieve is 0.1-0.2 g, preferably
Molecular sieves.
In summary, the chemical equation for the optimal reaction conditions for the direct cross-coupling reaction of the present invention is shown below:
in the preparation of the compound, a series of alpha-alkenyl-alpha, alpha-difluoro aryl ketone compounds can be efficiently synthesized by regulating and controlling a series of conditions such as the types of the selected catalysts, the types of the additives, the reaction solvents, the reaction temperature and the like, and corresponding products can be obtained after the reaction for 6 to 12 hours, so that the reaction time is optimal in 12 hours, and the yield is highest.
Another object of the present invention is to provide an α -alkenyl- α, α -difluoroaryl ketone compound obtained by the above-described preparation method, wherein the chemical structural formula of the compound is shown as follows:
wherein Ar and Ar' comprise one of phenyl, halogen substituted phenyl, methyl substituted phenyl, propyl substituted phenyl, tertiary butyl substituted phenyl, methoxy substituted phenyl, naphthalene substituent, thiophene substituent and biphenyl;
wherein the halogen substituted phenyl comprises one of fluorophenyl, chlorophenyl and bromophenyl.
Compared with the prior art, the invention has the following beneficial effects:
the invention uses difluoro enol silyl ether as a coupling substrate, so that the reaction has mild condition and convenient operation, and a difluoro alkyl molecular fragment can be successfully introduced into the molecule; the preparation method has the characteristics of simple post-treatment, cheap and small catalyst, high economic benefit and the like.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the description of the embodiments will be briefly described below, it being obvious that the drawings in the following description are only some embodiments of the present invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art. Wherein:
FIG. 1 is a hydrogen spectrum of the product of example 1 of the present invention;
FIG. 2 is a fluorine spectrum of the product of example 1 of the present invention;
FIG. 3 is a carbon spectrum of the product of example 1 of the present invention;
FIG. 4 is a hydrogen spectrum of the product of example 5 of the present invention;
FIG. 5 is a fluorine spectrum of the product of example 5 of the present invention;
FIG. 6 is a carbon spectrum of the product of example 5 of the present invention;
FIG. 7 is a hydrogen spectrum of the product of example 6 of the present invention;
FIG. 8 is a fluorine spectrum of the product of example 6 of the present invention;
FIG. 9 is a carbon spectrum of the product of example 6 of the present invention.
Detailed Description
In order that the above-recited objects, features and advantages of the present invention will become more apparent, a more particular description of the invention will be rendered by reference to specific embodiments thereof which are illustrated in the appended drawings.
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 other than those described herein, and persons skilled in the art will readily appreciate that the present invention is not limited to the specific embodiments disclosed below.
Further, reference herein to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic can be 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) A20 mL Schlenk tube equipped with a magnetic stirrer was placed in an oven and dried for one hour, to which was added 0.2 g
Drying the molecular sieve in an oven for half an hour, taking out, and plugging a rubber plug and a nitrogen balloon when the molecular sieve is hot. After cooling, an overdry 1, 2-dichloroethane solvent (2 mL) was added thereto, followed by pumping the lock tube with nitrogen three times, followed by sequentially adding 1-ethynyl-4-methoxybenzene (66.1 mg,0.5mmol,1 equiv.), ((2, 2-difluoro-1-phenylvinyl) oxy) trimethylsilane (172.2 mg,0.75mmol,1.5 equiv.) and ferric trichloride (16.2 mg,0.1mmol,0.2 equiv.) to the Schlenk tube.) And trimethylchlorosilane (108.7 mg,1mmol,2 equiv.). The mixture was stirred at-78 ℃ for 12 hours.
(2) Then removing the solvent by rotary evaporation, purifying the crude product by a silica gel column chromatography (column chromatography separation condition: the stationary phase is 300-400 meshes of silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), the solvent ratio of the mobile phase (A: B) is 1:200), and finally obtaining 113.6mg of target product 2, 2-difluoro-3- (4-methoxyphenyl) -1-phenyl-3-en-1-one, wherein the structural formula of the compound is shown in the specification.
Characterization of the above 2, 2-difluoro-3- (4-methoxyphenyl) -1-phenyl-3-en-1-one, with a hydrogen spectrum as shown in fig. 1, a fluorine spectrum as shown in fig. 2, and a carbon spectrum as shown in fig. 3, resulted in: a colorless liquid; 1 H NMR(400MHz,CDCl 3 ):δ8.01(d,J＝8.4Hz,2H),7.65-7.54(m,1H),7.48-7.40(m,2H),7.35(d,J＝8.4Hz,2H),6.92-6.80(m,2H),5.82(t,J＝1.5Hz,1H),5.72(t,J＝1.3Hz,1H),3.79(s,3H)ppm. 13 C NMR(100MHz,CDCl 3 ):δ188.5(t,J＝29.5Hz),159.9,142.0(t,J＝22.0Hz),134.2,132.1(t,J＝1.0Hz),130.0(t,J＝2.5Hz),129.2(t,J＝1.0Hz),128.5,127.0(t,J＝1.5Hz),119.4(t,J＝8.5Hz),116.1(t,J＝252.0Hz),113.8,55.1ppm. 19 F NMR(376MHz,CDCl 3 ):δ-96.7ppm.HRMS(ESI,m/z):[M+H] + ,calcd.for C 17 H 15 F 2 O 2 + :289.1035,found:289.1040.FTIR(KBr,neat):ν3063,2960,1707,1609,1515,1450,1253,1152,836,721,687cm -1 .
from the characterization data, the reaction product 1 obtained was 2, 2-difluoro-3- (4-methoxyphenyl) -1-phenyl-3-en-1-one (purity > 98%); the product yield was calculated to be 79%.
Example 2
Example 2 is essentially the same as example 1, except that in step (1), the catalyst is different, as shown in Table 1 below.
TABLE 1
| Catalyst | Yield (%) |
| MgBr 2 (1equiv.) | <10 |
| AlCl 3 (1equiv.) | <10 |
| TiBr 4 (1equiv.) | <10 |
| CuBr 2 (1equiv.) | <10 |
| GaBr 3 (1equiv.) | <10 |
| InCl 3 (1equiv.) | 16 |
| SnCl 4 (1equiv.) | 32 |
| BiBr 3 (1equiv.) | <10 |
| FeCl 3 (1equiv.) | 57 |
| FeBr 3 (1equiv.) | 34 |
| FeBr 2 (1equiv.) | <10 |
| Fe(OTf) 3 (1equiv.) | 18 |
| FeCl 3 (0.2equiv.) | 39 |
| FeCl 3 (0.2equiv.),TMSCl(2equiv.) | 79 |
| TMSCl(2equiv.) | <5 |
As can be seen from table 1, under the same reaction conditions, catalysts were used, such as: synthesizing 2, 2-difluoro-3- (4-methoxyphenyl) -1-phenyl-3-en-1-one by magnesium bromide, aluminum trichloride, titanium tetrabromide, copper bromide, gallium bromide, indium trichloride, tin tetrachloride, bismuth tribromide, ferrous bromide and ferric triflate with extremely low yield; when ferric salt is used as a catalyst, the yield is obviously improved, wherein FeCl is used 3 The yield as catalyst was highest.
In the test, it is also found that when ferric trichloride is used as a catalyst and trimethylchlorosilane is added as an additive, higher reaction yield can be obtained when the adding amount of the ferric trichloride is low, and the yield is as high as 79% when 0.2 equivalent of the ferric trichloride and 2 equivalent of trimethylchlorosilane are used as mixed catalysts.
Example 3
Example 3 is essentially the same as example 1, except that in step (1), the solvents and temperatures are different, as shown in Table 2 below.
TABLE 2
| Solvent(s) | Temperature (. Degree. C.) | Yield (%) |
| Tetrahydrofuran (THF) | -78 |
0 |
| 1, 4-Dioxahexacyclic ring | -78℃ | 0 |
| N, N-dimethylformamide | -78 |
0 |
| Acetonitrile | -78℃ | 0 |
| N, N-dimethylacetamide | -78℃ | 0 |
| N-hexane | -78 |
0 |
| Toluene (toluene) | -78 |
0 |
| Dichloromethane (dichloromethane) | -78 |
40 |
| 1, 2-dichloroethane | -78℃ | 79 |
| 1, 2-dichloroethane | -40℃ | 46 |
| 1, 2- |
0℃ | 41 |
| 1, 2- |
60℃ | 12 |
As can be seen from Table 3, at-78deg.C, a heteroatom-containing solvent is used, such as: tetrahydrofuran, acetonitrile, N-dimethylformamide, N-dimethylacetamide and 1, 4-dioxane to synthesize 2, 2-difluoro-3- (4-methoxyphenyl) -1-phenyl-3-en-1-one with extremely low yield; at-78 ℃, non-coordinating solvents are used, such as: synthesizing a target product by toluene or n-hexane, wherein the yield is very small; at-78 ℃, non-coordinating solvents are used, such as: the target products can be obtained by using dichloromethane and 1, 2-dichloroethane, and the optimal yield of the 1, 2-dichloroethane is 79%. Under different temperatures, the target product can be obtained by taking 1, 2-dichloroethane as a solvent, and the optimal temperature is at-78 ℃.
Example 4
Example 4 is essentially the same as example 1, except that part of the reaction conditions are absent in step (1), as shown in Table 3 below.
TABLE 3 Table 3
As can be seen from table 3, under the same reaction conditions, no trimethylchlorosilane was added, and the yield was only 36%; ferric trichloride is not added, and the yield is very small; not adding
Molecular sieve only has 47% yield.
Example 5
(1) A20 mL Schlenk tube equipped with a magnetic stirrer was placed in an oven and dried for one hour, to which was added 0.2 g
Drying the molecular sieve in an oven for half an hour, taking out, and plugging a rubber plug and a nitrogen balloon when the molecular sieve is hot. After cooling, an overdry 1, 2-dichloroethane solvent (2 mL) was added thereto, followed by pumping the tube lock with nitrogen three times, followed by sequentially adding 1-ethynyl-4-methoxybenzene (66.1 mg,0.5mmol,1 equiv.), ((1- (4-methylphenyl) -2, 2-difluorovinyl) oxy) trimethylsilane (193.6 mg,0.75mmol,1.5 equiv.)) and ferric trichloride (16.2 mg,0.1mmol,0.2 equiv.)) and trimethylchlorosilane (108.7 mg,1mmol,2 equiv.), to the Schlenk tube. The mixture was stirred at-78 ℃ for 12 hours.
(2) Then removing the solvent by rotary evaporation, purifying the crude product by a silica gel column chromatography (column chromatography separation condition: the stationary phase is 300-400 meshes of silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), the solvent ratio of the mobile phase (A: B) is 1:200), and finally obtaining 129.4mg of target product 2, 2-difluoro-3- (4-methoxyphenyl) -1-p-methoxyphenyl-3-en-1-one, wherein the structural formula of the compound is shown in the following formula.
The product was characterized, the hydrogen spectrum is shown in fig. 4, the fluorine spectrum is shown in fig. 5, the carbon spectrum is shown in fig. 6, and the result is: a colorless liquid; 1 H NMR(400MHz,CDCl 3 ):δ8.00(d,J＝9.0Hz,2H),7.35(d,J＝8.8Hz,2H),6.92-6.87(m,2H),6.87-6.81(m,2H),5.80(t,J＝1.8Hz,1H),5.69(t,J＝1.3Hz,1H),3.84(s,3H),3.77(s,3H)ppm. 13 C NMR(100MHz,CDCl 3 ):δ186.8(t,J＝29.5Hz),164.3,159.8,142.4(t,J＝22.5Hz),132.6(t,J＝3.0Hz),129.1(t,J＝1.0Hz),127.1(t,J＝1.5Hz),124.9(t,J＝1.0Hz),119.1(t,J＝8.5Hz),116.3(t,J＝231.0Hz),113.8,113.7,55.4,55.1ppm. 19 F NMR(376MHz,CDCl 3 ):δ-96.2ppm.HRMS(ESI,m/z):[M+H] + ,calcd.for C 18 H 17 F 2 O 3 + :319.1140,found:319.1146.FTIR(KBr,neat):ν2965,2870,1704,1607,1515,1464,1252,1153,1101,919,836,775,564cm -1 .
from the characterization data, the prepared 2, 2-difluoro-3- (4-methoxyphenyl) -1-p-methoxyphenyl-3-en-1-one (purity > 98%); the product yield was calculated to be 81%.
Example 6
(1) A20 mL Schlenk tube equipped with a magnetic stirrer was placed in an oven and dried for one hour, to which was added 0.2 g
Drying the molecular sieve in an oven for half an hour, taking out, and plugging a rubber plug and a nitrogen balloon when the molecular sieve is hot. After cooling, an overdry 1, 2-dichloroethane solvent (2 mL) was added thereto, followed by pumping the lock tube with nitrogen three times, followed by sequentially adding 1-ethynyl-4-methoxybenzene (66.1 mg,0.5mmol,1 equiv.), (Z) - ((2-fluoro-1- (p-tolyl) vinyl) oxy) trimethylsilane (157.6 mg,0.75mmol,1.5 equiv.), and ferric trichloride (16.2 mg,0.1mmol,0.2 equiv.) and trimethylchlorosilane (108.7 mg,1mmol,2 equiv.) to the Schlenk tube. The mixture was stirred at-78 ℃ for 12 hours.
(2) Then removing the solvent by rotary evaporation, purifying the crude product by a silica gel column chromatography (column chromatography separation condition: the stationary phase is 300-400 meshes of silica gel powder, the mobile phase is ethyl acetate (A) and petroleum ether (B), the solvent ratio of the mobile phase (A: B) is 1:200), and finally obtaining 97.3mg of target product 2-difluoro-3- (4-methoxyphenyl) -1- (p-methylphenyl) -3-alkene-1-ketone, wherein the structural formula of the compound is shown in the specification.
The product was characterized, the hydrogen spectrum is shown in fig. 7, the fluorine spectrum is shown in fig. 8, the carbon spectrum is shown in fig. 9, and the result is: 1 H NMR(400MHz,CDCl 3 ):δ7.78(d,J＝8.3Hz,2H),7.44-7.32(m,2H),7.20(dd,J＝8.6,0.6Hz,2H),6.92-6.83(m,2H),6.39(d,J＝0.6Hz,0.5H),6.27(d,J＝0.5Hz,0.5H),5.62(d,J＝1.1Hz,1H),5.46(dd,J＝3.9,0.5Hz,1H),3.81(s,3H),2.38(s,3H)ppm. 13 C NMR(100MHz,CDCl 3 ):δ193.5(d,J＝20.0Hz),159.7,144.7,142.6(d,J＝16.0Hz),131.6,129.9(d,J＝2.0Hz),129.3,129.0(d,J＝3.0Hz),128.0(d,J＝1.0Hz),118.9(d,J＝9.0Hz),113.9,94.1(d,J＝184.0Hz),55.3,21.7ppm. 19 F NMR(376MHz,CDCl 3 ):δ-177.6ppm.HRMS(ESI,m/z):[M+H] + ,calcd.for C 18 H 18 FO 2 + :285.1285,found:285.1290.FTIR(KBr,neat):ν2930,1698,1607,1514,1463,1252,1183,1031,930,872,835,546cm -1 .
from the characterization data, the reaction product obtained is 2-difluoro-3- (4-methoxyphenyl) -1- (p-methylphenyl) -3-en-1-one (purity > 98%); the product yield was calculated to be 68%.
Example 7
Example 7 is essentially the same as example 1, except that in step (1) the aryl substituted alkyne and the difluoro enol silyl ether are selected differently, and the final product obtained is specifically shown in table 4 below.
TABLE 4 Table 4
The invention provides a method for preparing ferric trichloride serving as a catalyst and trimethylchlorosilane serving as an additive, wherein cross coupling reaction of aryl substituted alkyne and difluoro enol silyl ether is realized in DCE; the reaction uses difluoro enol silyl ether as a coupling substrate, so that the reaction has mild condition and convenient operation, and can successfully introduce difluoro alkyl molecular fragments into molecules.
In the preparation of the compound, a series of alpha-alkenyl-alpha, alpha-difluoro aryl ketone compounds can be efficiently synthesized by regulating and controlling a series of conditions such as the types of the selected catalysts, the types of the additives, the solvent for reaction, the reaction temperature and the like. Wherein for different catalysts, such as: ferric trichloride, zinc dichloride, stannic chloride, indium trichloride, ferric triflate and the like, and the effect of the ferric trichloride is optimal and the yield is highest; for different solvents, such as: 1, 2-dichloroethane, N-dimethylacetamide, toluene, N-hexane, dichloromethane, tetrahydrofuran and 1, 4-dioxane are preferably selected, and the effect of the 1, 2-dichloroethane is optimal, and the yield is highest; the additive in the reaction is optimized, the effect of trimethylchlorosilane is optimal, and the yield is highest; the target product can be obtained at different temperatures within the range of-78 to 60 ℃, the temperature of-78 ℃ is optimal, and the yield is highest; the corresponding product can be obtained after the reaction for 6 to 12 hours, the reaction time is optimal in 12 hours, and the yield is highest.
The preparation method has the characteristics of simple post-treatment, cheap and small catalyst, high economic benefit and the like.
It should be noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, 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 the technical solution of the present invention may be modified or substituted without departing from the spirit and scope of the technical solution of the present invention, which is intended to be covered in the scope of the claims of the present invention.
Claims (6)
1. A preparation method of an alpha-alkenyl-alpha, alpha-difluoro aryl ketone compound is characterized by comprising the following steps of: comprising the steps of (a) a step of,
performing direct cross-coupling reaction on an aryl alkyne compound shown in a formula I and difluoro enol silyl ether shown in a formula II in a solvent under the action of a catalyst to obtain a compound shown in a formula III;
wherein Ar and Ar' comprise one of phenyl, halogen substituted phenyl, methyl substituted phenyl, propyl substituted phenyl, tertiary butyl substituted phenyl, methoxy substituted phenyl, naphthalene substituent, thiophene substituent and biphenyl;
the catalyst is a ferric salt catalyst;
the solvent is a non-coordinating solvent, including dichloromethane or 1, 2-dichloroethane;
the additive is trimethylchlorosilane.
2. The method for preparing the alpha-alkenyl-alpha, alpha-difluoro aryl ketone compound according to claim 1, wherein the method comprises the following steps: the molar ratio of the aryl alkyne compound to the difluoro enol silyl ether is 1:1.5-2.
3. Preparation of alpha-alkenyl-alpha, alpha-difluoroaryl ketones according to claim 1 or 2The preparation method is characterized in that: the arylalkyne compound comprises 4-fluorophenylacetylene, 4-chlorophenylacetylene, 4-bromophenylacetylene, 4-phenylphenylacetylene, 4-methylphenylacetylene, 3-methylphenylacetylene, 4-propylphenylacetylene, 4-tert-butylphenylacetylene, 4-methoxyphenylacetylene, 2-methoxyphenylacetylene, 5-ethynylbenzo [d][1,3]One of dioxolane and 3-ethynyl thiophene.
4. The method for producing α -alkenyl- α, α -difluoroaryl ketone compound according to claim 3, wherein: the difluoro enol silicon ether compound comprises ((1-phenyl-2, 2-difluoro vinyl) oxy) trimethylsilane, ((1- (4-fluoro phenyl) -2, 2-difluoro vinyl) oxy) trimethylsilane, ((1- (4-chlorophenyl) -2, 2-difluoro vinyl) oxy) trimethylsilane, ((1- (4-bromophenyl) -2, 2-difluoro vinyl) oxy) trimethylsilane, ((1- (4-methylphenyl) -2, 2-difluoro vinyl) oxy) trimethylsilane, ((1- (4-tert-butylphenyl) -2, 2-difluoro vinyl) oxy) trimethylsilane, ((1- (4-methoxy phenyl) -2, 2-difluoro vinyl) oxy) trimethylsilane, ((1- (4-phenoxy) -2, 2-difluoro vinyl) oxy) trimethylsilane, ((1- (4-biphenyl) -2, 2-difluoro vinyl) oxy) trimethylsilane, ((1- (4-naphthyl) -2, 2-difluoro-vinyl) oxy) - ((Z) - ((1- (4-naphthyl) -2-difluoro vinyl) oxy) trimethylsilanep-tolyl) vinyl) oxy) trimethylsilane.
5. The method for producing an α -alkenyl- α, α -difluoroaryl ketone compound according to any one of claims 1,2 and 4, wherein: the catalyst is ferric trichloride.
6. The method for producing α -alkenyl- α, α -difluoroaryl ketone compound according to claim 5, wherein: and the direct cross-coupling reaction is carried out, and the reaction temperature is-78-60 ℃.
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