CN108610249B - Synthetic method of 1, 4-disubstituted cyclohexene derivative - Google Patents
Synthetic method of 1, 4-disubstituted cyclohexene derivative Download PDFInfo
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Abstract
The invention discloses a synthesis method of a 1, 4-disubstituted cyclohexene derivative, which comprises the steps of carrying out one-pot reaction on an acetophenone compound and an alpha-methyl styrene compound in a dimethyl sulfoxide solution system containing potassium persulfate to obtain the cyclohexene derivative; the method is characterized in that the acetophenone compound provides alpha carbon, the alpha-methyl styrene compound provides propenyl, and the dimethyl sulfoxide provides methyl to jointly construct the cyclohexene ring for the first time, the synthesis method is realized by a one-pot method, the reaction condition is mild, no additional catalyst is needed, the selectivity is good, the yield is high, and the method is favorable for industrial production.
Description
Technical Field
The invention relates to a method for synthesizing cyclohexene derivatives, in particular to a method for jointly constructing cyclohexene rings by acetophenone compounds, DMSO (dimethyl sulfoxide) and alpha-methylstyrene compounds, belonging to the field of organic synthesis.
Background
The cyclohexene derivatives are a series of cyclohexene derivatives derived from cyclohexene ring parent by introducing different substituent groups on cyclohexene, and the cyclohexene derivatives reported at present are mainly used for medicines and perfumes. For example, Chinese patent (CN106496100A) discloses a cyclohexene compound, the structural formula of which is as follows:
(wherein, R is selected from H, M ion, C1-C6 alkyl; R6、R7、R8Independently selected from: H. C1-C4 alkyl, etc.; r1Selected from: amino groups, etc.; r2Selected from: H. C1-C4 alkyl, etc.; m is selected from: 0, 1; r3、R4Independently selected from: H. C1-C4 alkyl, etc.; n is selected from: 1-4; x is selected from: CH (CH)2O, S, etc.; r5Selected from: H. C1-C4 alkyl, etc.; r9、R10Independently selected from: H. C1-C4 alkyl and the like) which are mainly used as drugs for inhibiting influenza viruses, such as wild type and drug-resistant influenza viruses, have good inhibitory activity. Such as Swiss QihuaThe chinese patent (CN103068785A) by dunn gmbh discloses a cyclohexene derivative as perfume, having the following structural formula:
(wherein R is an isobutyl group at C-3 or C-4; R 'is a hydrogen at C-3 or C-4 and the bond between C-3 and C-4 together with the dotted line represents a double bond; or R' is-CH 2-and represents a cyclopropane ring together with C-3 and C-4 and the bond between C-3 and C-4 together with the dotted line represents a single bond; R1 and R2 independently represent a group selected from hydrogen and the like; R3 is a group selected from methyl and the like; and R4 is a hydroxyl group and R5 is hydrogen; or R1 and R2 independently represent a group selected from hydrogen and the like; R3 is a methyl group and the like; and R1、R2And R3Independently represent a group selected from hydrogen, methyl, etc.; and R is4And R5Together with the carbon atom to which they are attached represent a carbonyl group), compounds of this class of cyclohexene-type compounds having appreciable floral and citrus (hespercidic) odour notes, may be used as perfume ingredients. Based on the importance of cyclohexene derivatives in the prior art, the method for synthesizing cyclohexene becomes a research hotspot.
The existing cyclohexene is mainly obtained by monocyclic aromatic selective hydrogenation, transition metal is required to be used as a hydrogenation catalyst in the selective hydrogenation process, and the hydrogenation reaction conditions are harsh and difficult to control. Although cyclohexene can be obtained by the method, the method is not suitable for synthesizing most cyclohexene derivatives, and the main reason is that a substituent is easily influenced by hydrogenation reaction, and particularly when the substituent contains an unsaturated group or an active group, the target product of the cyclohexene derivative is difficult to obtain by hydrogenation reduction. The synthesis method of cyclohexene derivatives reported in the prior art mainly utilizes a diels alder addition reaction. The Diels-Alder addition reaction is an ideal method for constructing six-membered rings, and can utilize the reaction of conjugated diene and substituted olefin (dienophile) to generate substituted cyclohexene, such as the classical reaction, the synthesis of 3, 4-dimethylcyclohexene or 3, 5-dimethylcyclohexene from 1, 3-pentadiene and propylene, and the synthesis of 1, 4-dimethylcyclohexene or 2, 4-dimethylcyclohexene from isoprene and propylene. The patent (CN 102725258A) applied by Amelis company in China in the United states discloses cyclohexene 1, 4-carboxylate, and proposes that the cyclohexene 1, 4-carboxylate is synthesized by diels Alder addition reaction of muconic acid or carboxylate derivatives thereof and acrylic acid or esters thereof and the like. The diels alder addition reaction is a reversible reaction, it is difficult to obtain a high yield, and the addition reaction has two additions, the selectivity is poor, it is difficult to obtain a pure single addition, and in addition, the diels alder addition reaction often uses lewis acid as a catalyst, and lewis acid also has a promoting effect on the polymerization of the alkene, thereby generating a side reaction.
Disclosure of Invention
Aiming at the defects of the existing cyclohexene construction method, the invention aims to provide a method for constructing cyclohexene by using acetophenone compounds to provide alpha-carbon, DMSO to provide methyl and alpha-methylstyrene compounds to provide propylene.
The invention also provides a synthesis method of the 1, 4-disubstituted cyclohexene derivative, which comprises the step of carrying out one-pot reaction on an acetophenone compound and an alpha-methyl styrene compound in a dimethyl sulfoxide solution system containing potassium persulfate to obtain the cyclohexene derivative;
the 1, 4-disubstituted cyclohexene derivative has a structure of formula 1:
the acetophenone compound has a structure shown in formula 2:
the alpha-methyl styrene compound has a structure of formula 3:
wherein the content of the first and second substances,
R1selected from hydrogen, halogen substituents or alkyl;
R2and R3Independently selected from hydrogen, alkoxy, alkylthio, alkyl, trifluoromethoxy, halogen substituent, cyano, ester group, nitro or hydroxyl;
R4selected from hydrogen, acyl or cyano.
The substituent contained in the benzene ring in the α -methylstyrene compound of the present invention is selected from a halogen substituent or an alkyl group. Halogen substituents such as fluorine, chlorine, bromine, iodine, and the like. Alkyl is C1～C10Alkyl groups of (a); more preferably C1～C5The lower alkyl group of (2) such as methyl, ethyl, propyl, etc., may also be a branched alkyl group such as isopropyl, isobutyl, etc. The selection range of the alpha-methyl styrene compound is limited to the selection of phenyl or substituted phenyl, and the phenyl ring substituent provides a large conjugated system, so that the methyl on the alkenyl has enough activity to participate in cyclization. The substituted phenyl group can not be replaced by other substituent groups at will, and the target product can not be obtained by replacing the substituted phenyl group by aromatic heterocyclic, alkyl and the like. And the position of the substituent on the benzene ring is preferably para-position of the alkenyl, and the substituent can be a weak electron-pushing group such as alkyl or a weak electron-pulling group such as halogen. However, it is difficult to obtain an ideal yield from a strongly electron-withdrawing group such as an amino group and an alkoxy group, and a strongly electron-withdrawing group such as a nitro group.
The number of the substituent groups contained on the benzene ring in the acetophenone compound is 1-2 or no substituent group, and the substituent group is selected from at least one of alkoxy, alkylthio, alkyl, trifluoromethoxy, halogen substituent group, cyano, ester group, nitro and hydroxyl. Preferred alkoxy is C1～C10Further preferably C1～C5Alkoxy group of (2). Preferred alkylthio is C1～C10Alkylthio group of (3), more preferably C1～C5Alkylthio groups of (2). Preferred alkyl is C1～C10Alkyl groups of (a); more preferably C1～C5Short-chain alkyl groups such as methyl, ethyl, propyl, etc., and also branched alkyl groups such as isopropylAlkyl, isobutyl, and the like. Preferred halogen substituents are fluorine, chlorine, bromine, iodine, and the like. Preferred ester groups are methoxyacetyl groups.
In the technical scheme of the invention, the acetophenone compound has a wide selection range, and the yield is kept about 60% when various common substituent groups on phenyl are substituted. The position of the substituent is not particularly limited, and may be ortho, meta or para to the carbonyl group.
R4An acyl group or a cyano group is selected. R4When an acyl group is selected, the acyl group is an acetyl group or a benzoyl group.
In a preferable scheme, the molar ratio of the potassium persulfate to the acetophenone compound is 0.5-1.5: 1. More preferably 0.8 to 1.2: 1.
In a preferable scheme, the molar ratio of the acetophenone compound to the alpha-methyl styrene compound is 1: 1-1.5.
In a preferable scheme, the concentration of the acetophenone compounds in a dimethyl sulfoxide solution system is 0.1-0.5 mol/L. Dimethyl sulfoxide serves mainly as a benign solvent on the one hand and as a reaction substrate on the other hand, two methyl groups are provided by two dimethyl sulfoxides as two carbon atoms in the cyclohexene ring.
In a preferred embodiment, the reaction conditions are as follows: and reacting for 18-30 h at the temperature of 100-160 ℃ in a protective atmosphere. The protective atmosphere is generally nitrogen or an inert atmosphere. More preferred conditions are: reacting for 22-26 h at 135-145 ℃ in a nitrogen atmosphere.
The invention explains the reaction mechanism by constructing a cyclohexene ring by the acetophenone, dimethyl sulfoxide and 2-phenyl propylene together. After reviewing and referring to relevant documents, a series of mechanism research experiments were designed, as shown in the following reaction equations (1) to (6). In order to prove whether the reaction goes through the reaction course of a free radical, the reaction (1) is designed, 2.0 equivalent (relative to acetophenone) of 2, 6-di-tert-butyl-p-cresol (BHT) is added under standard reaction conditions, the reaction is carried out for 8 hours, and the generation of a target product of the cyclohexene derivative can still be successfully detected through GC-MS, which indicates that the reaction is not inhibited and does not go through the reaction course of a free radical. To is coming toAnd (3) verifying whether a reaction intermediate exists in the reaction, reacting acetophenone with dimethyl sulfoxide and 2-phenyl propylene under standard reaction conditions for 8 hours, and detecting by GC-MS (gas chromatography-mass spectrometry), wherein the existence of a target product cyclohexene derivative is detected, and the existence of a compound B and a compound C is also detected. In order to prove whether the compounds B and C are intermediates in the cyclohexene construction process, the reaction (2) and the reaction (3) are designed, the compound B is used as a raw material to replace 2-phenylpropylene, the reaction is carried out under standard conditions, and the compound C is used as a raw material to replace acetophenone. To further clarify the source of compound B, reaction (4) was further designed to react 2-phenylpropylene with dimethylsulfoxide directly under standard conditions, and the presence of compound B was detected by GC-MS, while compound A was also obtained. To further clarify the source of compound C, reaction (5) was further designed to react 2-phenylpropylene with dimethylsulfoxide directly under standard conditions, and the presence of compound C was detected by GC-MS, while compound D was also obtained. To obtain a more accurate verification of whether dimethyl sulfoxide is involved in cyclohexene cyclization, reaction (6) was designed to replace conventional dimethyl sulfoxide with isotopically labeled deuterated dimethyl sulfoxide under standard conditions, successfully detecting the presence of deuterium in the cyclohexene product and at two carbon atoms, indicating that two methyl groups are provided by dimethyl sulfoxide. Standard reaction conditions: in N2Then, acetophenone (0.5mmol), α -methylstyrene (0.75mmol) and DMSO (2mL) were reacted at 140 ℃ for 24 hours.
Reaction formula (1):
reaction formula (2):
reaction formula (3):
reaction formula (4):
reaction formula (5):
reaction formula (6):
according to the experiment, the invention provides a reasonable mechanism for constructing cyclohexene by acetophenone, dimethyl sulfoxide and 2-phenyl propylene: the following reaction equation. First, adopt K2S2O8Activating DMSO to obtain DMSO converted into dimethyl sulfide positive ions, simultaneously 2-phenylpropylene releases hydrogen protons to be converted into 2-phenylpropylene negative ions, acetophenone also releases hydrogen protons to be converted into acetophenone negative ions, the 2-phenylpropylene negative ions and the acetophenone negative ions are easy to couple with the dimethyl sulfide positive ions to generate sulfur methyl ether compounds A and D, and the sulfur methyl ether compounds A and D are in K2S2O8Under the action of oxidation, removing the micromolecule methyl mercaptan compound through a demethylation reaction to obtain compounds B and C, and carrying out Diels Alder reaction on the compound B and the compound C to finally obtain a target product.
Compared with the prior art, the technical scheme of the invention has the beneficial technical effects that:
1) the 1-position aryl substituent and the 4-position acyl substituent on the cyclohexene ring are easy to modify groups, and provide an effective intermediate for the synthesis of a compound taking cyclohexene as a parent.
2) According to the invention, the acetophenone compound provides alpha carbon, the alpha-methyl styrene compound provides propenyl, and the dimethyl sulfoxide provides methyl to successfully construct the cyclohexene derivative for the first time, so that a brand new synthetic idea is provided for the construction of a cyclohexene ring.
3) The cyclohexene derivative of the invention does not need to use a catalyst in the synthesis process, and compared with the existing Diels-Alder reaction, the use of a Lewis catalyst is avoided, and the possibility of side reaction of olefin polymerization is reduced.
4) In the synthesis process of the cyclohexene derivative, the acetophenone compound, the alpha-methylstyrene compound and the dimethyl sulfoxide are used as basic raw materials, which are conventional chemical raw materials, so that the cyclohexene derivative is low in cost and beneficial to industrial production.
5) The cyclohexene derivative synthesis process adopts a one-pot reaction, has mild reaction conditions and simple operation, and meets the requirements of industrial production.
6) The cyclohexene derivative synthesis process has high utilization rate of raw materials and the product yield is about 60 percent.
7) The application range of the cyclohexene derivative in the synthesis process of the cyclohexene derivative is wider, the cyclohexene derivative with various substituent groups can be constructed, the position selectivity of the substituent groups is strong, and the 1, 4-disubstituted cyclohexene derivative is obtained.
Drawings
FIG. 1 is a single crystal structural diagram of a compound (2,3,4,5-tetrahydro- [1,1' -biphenyl ] -4,4-diyl) bis (phenylmethanone).
Detailed Description
The following examples are intended to further illustrate the present disclosure, but not to limit the scope of the claims.
All reactions were performed in Schlenk tubes unless otherwise noted.
All reaction starting solvents were obtained from commercial sources and used without further purification.
The product is separated by silica gel chromatographic column and silica gel (granularity is 300-400 meshes).
1H NMR (400MHz), 13C NMR (100MHz) and 19F NMR (376MHz) measurements were performed using Bruker ADVANCEIII Spectroscopy with CDCl3As solvent, TMS as internal standard, chemical shifts in parts per million (ppm) and reference shifts of 0.0ppm tetramethylsilane. The following abbreviations (or combinations thereof) are used to explain the multiplicity: s is singlet, d is doublet, t is triplet, q is quartet, m is multiplet, br is broad. Coupling constant J is in Hertz (Hz). Chemical shifts are expressed in ppm, with the center line for the triplet state referenced to deuterated chloroform at 77.0ppm or the center line for the heptad state referenced to deuterated DMSO at 39.52 ppm.
The GC-MS adopts a GC-MS QP2010 device for detection, the HRMS adopts an Electron Ionization (EI) method for measurement, the type of the mass analyzer is TOF, and the EI is detected by an Esquire 3000plus instrument.
1. Condition optimization experiment:
the cyclohexene ring is constructed by acetophenone, dimethyl sulfoxide and 2-phenyl propylene, and a plurality of influencing factors such as oxidant and dosage thereof, reaction temperature, reaction solvent and additive are discussed to search for optimal reaction conditions.
The specific reaction process is as follows: acetophenone (0.5mmol), alpha-methylstyrene (0.75mmol), oxidant, additive (0.5mmol) and DMSO (2mL) in N2And reacting for 24 hours under the atmosphere.
The reaction route is as follows:
table 1: yield of target product cyclohexene derivative under different reaction conditions
1) Selection of additives
As can be seen from Table 1, the use of the additive has a great influence on the reaction, and a large number of experimentsAs shown in items 1 to 6 and 11 in Table 1, no benign additive such as DABCO, DBU and K, which is beneficial to improving the reaction efficiency and increasing the yield, has been found in the reaction process of constructing cyclohexene ring by acetophenone, dimethyl sulfoxide and 2-phenylpropylene2CO3、Cs2CO3、Et3When alkaline substances such as N or NaOAc and the like are used as additives, the reaction is obviously inhibited, and the target product cyclohexene derivative is basically not obtained.
3) Selection of oxidizing agent
The invention tries a plurality of common oxidants in the field, such as items 11 and 12-17 in table 1, and oxidants such as persulfate, organic peroxide, inorganic hydrogen peroxide and the like are found to have good reaction effect only when the persulfate is used as the oxidant, and when tert-butyl hydroperoxide (TBHP), DTBP or hydrogen peroxide (H) is used2O2) As the oxidizing agent, almost no target product is obtained, and potassium persulfate has the best reaction effect among the persulfates.
4) Selection of the quantity of oxidant
After determining potassium persulfate, sodium persulfate, etc. as the optimal oxidizing agents, the influence of different amounts of the oxidizing agents on the reaction was explored. As in items 11, 18 and 19 of table 1. When the amount of the oxidant is 0.5-1 equivalent, the conversion rate of the raw materials and the yield of the product are increased with the increase of the amount of the oxidant. And when the amount of the oxidizing agent is more than 1 equivalent, the yield is remarkably decreased. Therefore, 1 equivalent of persulfate is the optimum amount for the reaction.
5) Selection of reaction temperature
The reaction temperature is an important factor affecting the chemical reaction process, and in order to obtain the optimum reaction temperature, the yield of the reaction at different temperatures was investigated, as in items 7 to 11 in Table 1. The target product can not be obtained basically at the temperature of less than 100 ℃, the reaction yield is obviously improved when the temperature reaches more than 120 ℃, the reaction yield reaches the highest when the temperature is raised to 140 ℃, and the reaction side reaction is obvious when the temperature is higher than 140 ℃. Thus, 140 ℃ is the optimum temperature for the reaction.
6) Selection of reaction solvent
Since DMSO is used as a reaction substrate and a solvent in the process of synthesizing dihydropyran, the DMSO is not replaceable by other solvents. The solvent of the invention can adopt DMSO, and can also adopt a mixed solvent of DMSO and other solvents.
2. Selection range of reaction substrates:
after the optimal cyclohexene synthesis conditions are determined, the substrate range and applicability of the reaction are explored, and the experimental results are shown in tables 2,3 and 4. Tables 2 and 3 show the reaction results of different acetophenones with α -methylstyrene and DMSD. As can be seen from tables 2 and 3, acetophenones and the like can effectively synthesize corresponding cyclohexene ring structures with 2-phenylpropene and DMSD under standard reaction conditions, and the yield of the target product is about 60%. Moreover, a large number of experiments show that the substituent on the benzene ring of the acetophenone containing the substituent has no obvious influence on the reaction, and various substituted acetophenones can be successfully used for constructing the cyclohexene derivative with 2-phenylpropene and DMSD. Mainly aryl or aromatic heterocyclic radical can provide a large conjugated system, can activate alpha methyl and easily lose hydrogen protons. Cyclohexene could not be constructed with other nonconjugated groups such as alkyl etc. with 2-phenylpropene and DMSD. In addition, it can be seen from table 3 that an electron-withdrawing substituent may be included on the α -methyl group, which may increase the hydrogen activity on the α -methyl group, such as cyano group, acyl group, etc., but an electron-donating substituent, which may decrease the hydrogen activity on the α -methyl group, such as alkyl group, etc., may not be included on the α -methyl group.
(1) The reaction equation for different acetophenones with 2-phenylpropene and DMSD is as follows:
weighing potassium peroxodisulfate (K)2S2O8) (135mg,0.5mmol) was placed in a 25ml Schlenk reaction tube, and dimethyl sulfoxide (DMSO, 2ml), a ketone compound (0.5mmol), and 2-phenylpropylene (89mg, 0.75mmol) were added thereto, followed by nitrogen gas injection. Stirring was carried out at 140 ℃ for 24 hours. After the reaction is completed, cooling to room temperature, addingWater (4ml), ethyl acetate extraction (3 x 5ml), anhydrous Na2SO4Drying, distilling off the solvent under reduced pressure, and separating by a silica gel column (200-300 meshes) to obtain the target product.
TABLE 2 reaction results of different acetophenones with 2-phenylpropene and DMSD
TABLE 3 results of different acetophenone compounds with 2-phenylpropene and DMSD
(2) The reaction equation of acetophenone with different alpha-methyl styrene compounds and DMSD is as follows:
weighing potassium peroxodisulfate (K)2S2O8) (135mg,0.5mmol) was placed in a 25ml Schlenk reaction tube, to which was added dimethylsulfoxide (DMSO, 2ml), acetophenone (60mg, 0.5mmol), 2-aryl-propene (99mg, 0.75mmol), and nitrogen gas was introduced. Stirring was carried out at 140 ℃ for 24 hours. After completion of the reaction, it was cooled to room temperature, water (4ml) was added, and extraction was performed with ethyl acetate (3 x 5ml) and anhydrous Na2SO4Drying, distilling off the solvent under reduced pressure, and separating by a silica gel column (200-300 meshes) to obtain the target product.
Table 4 shows the reaction results of different α -methylstyrene compounds with acetophenone and DMSD, and the experimental results show that the substituent at the 2-position of propylene must be a group having a large conjugated system, such as aryl or a combination of alkenyl and aryl, and other aromatic heterocycles, alkyls, etc. cannot meet the requirements, and the aryl of the large conjugated system is favorable for improving the activity of α -methyl. The substituent on the aryl is also selected according to the requirement, and can not be a substituent group with stronger electron pushing or pulling capacity, such as nitro, alkoxy and the like, while the substituent group with stronger electron pushing or pulling capacity, such as halogen, alkyl and the like, can meet the requirement.
TABLE 4 reaction results of acetophenone with various alpha-methylstyrene compounds and DMSD
Structural characterization of some dihydropyran derivatives in tables 2-4:
phenyl(2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methanone；
(3,4-dimethoxyphenyl)(2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methanone；
6.21(d,J＝4.2Hz,1H),3.98(s,3H),3.97(s,3H),3.64–3.53(m,1H),2.64–2.60 (m,2H),2.52(ddd,J＝42.4,12.1,3.8Hz,2H),2.22–2.14(m,1H),1.92(ddd,J＝ 16.9,10.5,5.9Hz,1H).
13C NMR(101MHz,CDCl3)δ201.93,153.26,149.23,141.74,136.23,129.43, 128.31,126.88,125.03,123.25,122.76,110.58,110.03,56.10,56.02,40.82,29.08, 27.24,26.54.
(4-methoxyphenyl)(2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methanone；
13C NMR(101 MHz,CDCl3)δ201.85,163.44,141.78,136.23,130.61,129.26, 128.30,126.86,125.05,123.28,113.85,55.50,40.95,28.92,27.26,26.43.
(4-(methylthio)phenyl)(2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methanone；
13C NMR(101 MHz,CDCl3)δ202.30,145.77,141.74,136.27,132.52,128.79, 128.32,126.90,125.15,125.06,123.16,41.09,28.81,27.21,26.34,14.82.
(2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)(p-tolyl)methanone；
13C NMR(101 MHz,CDCl3)δ202.94,143.78,141.77,136.24,133.76,129.39, 128.47,128.29,126.86,125.05,123.22,41.16,28.81,27.22,26.33,21.64.
(2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)(m-tolyl)methanone；
13C NMR(101 MHz,CDCl3)δ203.58,141.78,138.54,136.34,133.78,128.88, 128.59,128.33,126.91,125.56,125.08,123.19,41.33,28.83,27.22,26.29,21.46.
(2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)(o-tolyl)methanone；
1H),2.56(d,J＝11.8 Hz,2H),2.49(s,2H),2.45(s,3H),2.15(d,J＝14.4 Hz,1H), 1.83(dt,J＝18.3,11.4 Hz,1H).
13C NMR(101 MHz,CDCl3)δ207.83,141.77,138.45,137.62,136.36,131.76, 130.81,128.32,127.61,126.91,125.65,125.07,123.03,44.40,28.18,27.13,25.61, 20.84.
(2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)(4-(trifluoromethoxy)phenyl)methanone；
2H),2.17(d,J＝12.7 Hz,1H),1.95–1.82(m,1H).
19F NMR(376 MHz,CDCl3)δ-57.56.
13C NMR(101 MHz,CDCl3)δ201.71,152.58,141.62,136.35,134.49,130.37, 128.35,126.99,125.07,122.85,120.54,41.40,28.65,27.13,26.20.
(4-fluorophenyl)(2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methanone；
13C NMR(101 MHz,CDCl3)δ201.67,141.65,136.31,130.96,128.32,126.94, 125.05,122.96,115.91,115.70,41.26,28.73,27.15,26.25.
(4-chlorophenyl)(2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methanone；
13C NMR(101 MHz,CDCl3)δ202.07,141.64,139.45,136.34,134.56,129.79, 129.05,128.34,126.97,125.06,122.90,41.33,28.68,27.14,26.20.
4-(2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-carbonyl)benzonitrile；
13C NMR(101 MHz,CDCl3)δ201.89,141.48,139.35,136.43,132.64,128.76, 128.37,127.08,125.07,122.52,117.98,116.29,41.69,28.45,27.02,26.01.
methyl 4-(2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-carbonyl)benzoate；
13C NMR(101 MHz,CDCl3)δ202.79,166.25,141.61,139.61,136.36,133.79, 129.95,128.28,126.97,125.06,122.81,52.48,41.70,28.56,27.11,26.11.
(4-nitrophenyl)(2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methanone；
8.0,5.4,2.7 Hz,1H),2.67–2.61(m,2H),2.60–2.44(m,2H),2.26–2.18(m,1H), 1.98–1.87(m,1H).
13C NMR(101 MHz,CDCl3)δ201.69,150.28,141.45,140.87,136.46,129.33, 128.36,127.08,125.06,123.98,122.44,41.96,28.42,27.01,25.98.
(3-nitrophenyl)(2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methanone；
13C NMR(101 MHz,CDCl3)δ201.01,148.60,141.49,137.56,136.47,133.97, 130.06,128.38,127.33,127.08,125.09,123.20,122.48,41.61,28.52,27.01,26.05.
(2-nitrophenyl)(2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methanone；
1H),3.02(d,J＝10.2 Hz,1H),2.71–2.55(m,2H),2.54–2.40(m,2H),2.22(d,J＝ 13.0 Hz,1H),1.95–1.81(m,1H).
13C NMR(101 MHz,CDCl3)δ205.58,145.78,141.62,137.69,136.38,134.33, 130.48,128.31,128.02,126.97,125.09,124.58,122.60,46.62,28.17,27.13,25.57.
(2-hydroxyphenyl)(2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methanone；
1H),6.91(t,J＝7.5 Hz,1H),6.17(s,1H),3.69–3.55(m,1H),2.61(s,2H),2.58– 2.40(m,2H),2.17(d,J＝13.7 Hz,1H),1.93(dd,J＝15.5,7.2 Hz,1H).
13C NMR(101 MHz,CDCl3)δ209.53,163.17,141.57,136.43,136.36,129.87, 128.37,127.03,125.08,122.77,118.94,118.88,118.45,40.94,28.91,27.13,26.47.
4-benzoyl-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-carbonitrile；
2.92(s,2H),2.88(s,1H),2.66(d,J＝14.9 Hz,1H),2.54(d,J＝12.6 Hz,1H),2.27 (td,J＝12.1,5.0 Hz,1H).
13C NMR(101 MHz,CDCl3)δ193.50,140.51,136.78,134.03,133.91,129.36, 128.80,128.44,127.54,125.23,120.69,118.97,44.59,33.97,30.10,24.63
1-(4-benzoyl-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)ethan-1-one；
13C NMR(101 MHz,CDCl3)δ207.12,198.48,141.02,136.09,135.51,132.99, 128.71,128.66,128.25,126.99,125.00,121.11,64.40,31.54,28.38,26.59,24.23. (2,3,4,5-tetrahydro-[1,1'-biphenyl]-4,4-diyl)bis(phenylmethanone)；
13C NMR(101 MHz,CDCl3)δ198.91,141.07,136.02,135.01,133.14,129.14, 128.72,128.27,126.92,125.00,121.36,62.56,33.83,30.10,23.91.
(4'-methyl-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)(phenyl)methanone；
3.67–3.52(m,1H),2.58(s,2H),2.48(dd,J＝32.4,14.1 Hz, 2H),2.34(s,3H),2.17(d,J＝11.2 Hz,1H),1.93–1.83(m,1H).
13C NMR(101 MHz,CDCl3)δ203.40J,138.89,136.57,136.34,136.09,132.98, 129.01,128.71,128.35,124.93,122.26,41.37,28.76,27.24,26.29,21.07
(4'-fluoro-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)(phenyl)methanone；
13C NMR(101 MHz,CDCl3)δ203.20,161.98(d,J＝245.7 Hz),137.86,136.25, 135.35,133.05,128.74,128.35,126.57(d,J＝7.8 Hz),123.03,115.07(d,J＝21.2 Hz),41.17,28.66,27.31,26.21.
(4'-chloro-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)(phenyl)methanone；
7.58(t,J＝7.2 Hz,1H),7.49(t,J＝7.4 Hz,2H),7.33(d,J＝8.0 Hz,2H),7.29(d,J＝ 8.1 Hz,2H),6.18(d,J＝2.6 Hz,1H),3.67–3.53(m,1H),2.55(s,2H),2.45(d,J＝ 17.7 Hz,2H),2.18(d,J＝12.8 Hz,1H),1.94–1.81(m,1H).
13C NMR(101 MHz,CDCl3)δ203.10,140.14,136.23,135.24,133.06,132.58, 128.75,128.40,128.34,126.33,123.73,41.11,28.66,27.08,26.17。
Claims (5)
1. a synthetic method of 1, 4-disubstituted cyclohexene derivatives is characterized in that: reacting acetophenone compounds and alpha-methyl styrene compounds in a dimethyl sulfoxide solution system containing potassium persulfate to obtain 1, 4-disubstituted cyclohexene derivatives;
the 1, 4-disubstituted cyclohexene derivative has a structure of formula 1:
formula 1
The acetophenone compound has a structure shown in formula 2:
formula 2
The alpha-methyl styrene compound has a structure of formula 3:
formula 3
Wherein the content of the first and second substances,
R1selected from hydrogen, halogen substituents or alkyl; r1When selected from halogen substituents, the halogen substituents are fluorine, chlorine, bromine or iodine; r1When selected from alkyl, the alkyl is C1~C5Alkyl groups of (a);
R2and R3Independently selected from hydrogen, alkoxy, alkylthio, alkyl, trifluoromethoxy, halogen substituent, cyano, ester group, nitro or hydroxyl; r2When selected from alkoxy, the alkoxy is C1~C5Alkoxy group of (a); r2When selected from alkylthio, the alkylthio is C1~C5Alkylthio groups of (a); r2When selected from alkyl, the alkyl is C1~C5Alkyl groups of (a); r2When selected from halogen substituents, the halogen substituents are fluorine, chlorine, bromine or iodine; r3When selected from alkoxy, the alkoxy is C1~C5Alkoxy group of (a); r3When selected from alkylthio, the alkylthio is C1~C5Alkylthio groups of (a); r3When selected from alkyl, the alkyl is C1~C5Alkyl groups of (a); r3When selected from halogen substituents, the halogen substituents are fluorine, chlorine, bromine or iodine;
R4selected from hydrogen, acyl or cyano; r4When selected from acyl, the acyl is acetyl or benzoyl;
the reaction conditions are as follows: and reacting for 18-30 h at the temperature of 100-160 ℃ in a protective atmosphere.
2. The method for synthesizing a 1, 4-disubstituted cyclohexene derivative according to claim 1, wherein the method comprises the following steps: the molar ratio of the potassium persulfate to the acetophenone compounds is 0.5-1.5: 1.
3. The method for synthesizing a 1, 4-disubstituted cyclohexene derivative according to claim 1, wherein the method comprises the following steps: the molar ratio of the acetophenone compound to the alpha-methyl styrene compound is 1: 1-1.5.
4. The method for synthesizing a 1, 4-disubstituted cyclohexene derivative according to claim 1, wherein the method comprises the following steps: the concentration of the acetophenone compounds in the dimethyl sulfoxide solution system is 0.1-0.5 mol/L.
5. The method for synthesizing a 1, 4-disubstituted cyclohexene derivative according to claim 1, wherein the method comprises the following steps: the reaction conditions are as follows: reacting for 22-26 h at 135-145 ℃ in a nitrogen atmosphere.
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Non-Patent Citations (5)
| Title |
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| A New Five-Membered Ring Forming Process Based on Palladium(0)-Catalyzed Arylative Cyclization of Allenyl Enones;Tsukamoto, Hirokazu;《Organic Letters》;20080530;第10卷(第13期);2633-2636 * |
| Design of a Small-Molecule Catalyst Using Intramolecular Cation−π Interactions for Enantioselective Diels-Alder and Mukaiyama-Michael Reactions: L-DOPA-Derived Monopeptide•Cu(II) Complex;Ishihara, Kazuaki;《Organic Letters》;20060406;第8卷(第9期);1921-1924 * |
| Tandem Diels-Alder and Retro-Ene Reactions of 1-Sulfenyl- and 1-Sulfonyl-1,3-dienes as a Traceless Route to Cyclohexenes;Jin Choi;《J. Am. Chem. Soc》;20140625;第136卷;9918-9921 * |
| Transition metal-free C(sp3)–H bond coupling among three methyl groups;Yufeng Liu;《Chem. Commun.》;20171231;第53卷;5346-5349 * |
| Transition Metal-Free α‑Csp3‑H Methylenation of Ketones to Form C=C Bond Using Dimethyl Sulfoxide as Carbon Source;Yu-Feng Liu;《The Journal of Organic Chemistry》;20170626;第82卷;7159-7164 * |
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