A method for constructing a cyclopentene skeleton by direct cyclization of an allyl alcohol

Abstract

The application discloses a method for constructing a cyclopentene skeleton by directly forming a ring from an allyl alcohol, which comprises the following steps: under an inert gas atmosphere, directly adding an allyl alcohol compound, an electron-deficient olefin, an organic phosphine catalyst and a boron compound into a reaction solvent, stirring and reacting at 120 DEG C for 3-8 hours, removing the reaction solvent from the obtained reaction solution, and then purifying through a thin layer chromatography / column chromatography method to obtain a compound with a cyclopentene skeleton in a reaction formula. In the method, the allyl alcohol is simple to synthesize and can be directly used in the reaction without pre-activation, the phosphine and the boron compound are cheap and have high reactivity, the method has simple steps, is convenient to operate, has high product yield, does not use any metal compound, and has the characteristics of high atomic economy and green environmental protection.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic chemical synthesis, and particularly relates to a method for directly forming a cyclopentene skeleton by cyclization of an allyl alcohol. BACKGROUND

[0002] The construction of highly functionalized carbocyclic and heterocyclic rings with specific configurations is an extremely important topic in modern organic synthesis, which is determined by the unique advantages of these cyclic skeletons in natural products and drugs. In recent years, Lewis base catalysis has received extensive attention and has become a general method for synthesizing cyclic and heterocyclic compounds.

[0003] Cyclopentene skeletons are widely present in drugs and natural products. Traditional methods for constructing cyclopentene skeletons include using activated allyl alcohol and electron-deficient olefins to perform [3+2] cycloaddition under the catalysis of phosphine catalysts with additional or in situ generated base.

[0004] Among numerous organic raw materials, alcohol compounds are inexpensive, less toxic, and widely exist in natural products and human bodies, and are increasingly favored by chemical synthesis workers. However, the traditional reaction has always been to convert the hydroxyl group of allyl alcohol into a leaving halogen atom, carboxylate or tert-butyloxycarbonyl, and then to react with an organic phosphine. Jianqing Feng et al. (see reference: A highly regio-and stereo-selective [3+2] annulation of allylic compounds and 2-substituted 1,1-dicyanoalkenes through a catalytic carbon-phosphorus ylide reaction) disclosed a preparation method of a cyclopentene skeleton compound, but the preparation method has many steps and cannot avoid the generation of a large amount of intermediate products. In theory, a method for directly preparing a phosphorus ylide from an allyl alcohol is more atomically and step-economical, and is a better synthesis method, but the activation of the hydroxyl group has always been a problem that people need to solve.

[0005] Therefore, from the environmental and economic points of view, it is extremely attractive to develop an energy-saving and efficient green synthesis method using non-toxic, inexpensive, easily available and relatively harmless raw materials and catalysts, especially a method using a non-metal catalyst, which is in line with the concept of "green chemistry". SUMMARY

[0006] In order to overcome the shortcomings and deficiencies of the prior art, the purpose of the present application is to provide a method for directly forming a cyclopentene skeleton by cyclization of an allyl alcohol.

[0007] The present application is achieved by a method for constructing a cyclopentene skeleton by direct cyclization of an allyl alcohol, which comprises the following steps:

[0008] (1) under an inert gas atmosphere, an allyl alcohol compound, an electron-deficient olefin, an organic phosphine catalyst, a boron compound are added into a reaction solvent, and the reaction is stirred at 120±2℃ for 3-8h; wherein the chemical structural formula of the allyl alcohol is:

[0009]

[0010] the chemical structural formula of the electron-deficient olefin compound is:

[0011]

[0012] (2) after the reaction is completed by TLC monitoring, the reaction solution obtained in step (1) is removed of the solvent, and purified and separated to obtain a compound with a cyclopentene skeleton; the chemical structural formula of the compound with a cyclopentene skeleton is:

[0013]

[0014] wherein R 1 is any one selected from methyl, ethyl, phenyl and tert-butyl;

[0015] R 2 is any one selected from phenyl, p-fluorophenyl, p-methoxyphenyl, p-trifluoromethyl, m-fluorophenyl, naphthyl, pyridyl, thienyl, cyclohexyl, cyclopropyl, ferrocenyl, 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthyl.

[0016] Preferably, in step (1), the organic phosphine catalyst is any one selected from triphenylphosphine, diphenyl ethyl phosphine, diphenyl chlorophosphine, phenyl dichlorophosphine.

[0017] Preferably, in step (1), the boron compound is any one selected from boron tribromide, tetra(dimethylamino)diboron, tetrahydroxydiboron, tris(pentafluorophenyl)borane, bis(pinacolato)diboron, trimethyl borate.

[0018] Preferably, in step (1), the reaction solvent is any one selected from dichloromethane, acetonitrile, tetrahydrofuran, ethylene glycol dimethyl ether, toluene, methanol, dimethyl sulfoxide, 1,2-dichloroethane, N,N-dimethylformamide and N,N-dimethylacetamide.

[0019] Preferably, in step (1), the molar volume ratio of the allyl alcohol, electron-deficient olefin, phosphine catalyst, boron compound, and reaction solvent is 0.3-0.45 mmol: 0.2-0.3 mmol: 0.02-0.06 mmol: 1-3 mL.

[0020] Preferably, in step (2), the solvent removal is performed by a vacuum rotary evaporator; and the purification is performed by thin layer chromatography / column chromatography, with a developing agent system of petroleum ether / ethyl acetate = 10 / 1.

[0021] The present application overcomes the deficiencies of the prior art and provides a method for directly forming a cyclopentene skeleton from an allyl alcohol, which comprises the following steps:

[0022] (1) under an inert gas atmosphere, directly adding an allyl alcohol compound, an electron-deficient olefin, an organic phosphine catalyst, and a boron compound into a reaction solvent, and stirring the reaction at 120°C for 3-8 h; an exemplary chemical equation of the reaction is as follows:

[0023]

[0024] In the reaction equation, R 1 is selected from any one of methyl, ethyl, phenyl, and tert-butyl; R 2 is selected from any one of phenyl, p-fluorophenyl, p-methoxyphenyl, p-trifluoromethyl, m-fluorophenyl, naphthyl, thienyl, cyclohexyl, cyclopropyl, ferrocenyl, and 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthyl;

[0025] Specifically, the allyl alcohol is selected from any one of 2-(hydroxymethyl) methyl acrylate, 2-(hydroxymethyl) ethyl acrylate, 2-(hydroxymethyl) tert-butyl acrylate, and 2-(hydroxymethyl) phenyl acrylate; and the electron-deficient olefin is selected from any one of benzal malononitrile, 2-(4-fluorobenzylidene) malononitrile, 2-(4-methoxybenzylidene) malononitrile, 2-(4-trifluoromethylbenzylidene) malononitrile, 2-(3-fluorobenzylidene) malononitrile, 2-(naphth-2-ylmethylidene) malononitrile, 2-(thiophene-2-ylmethylidene) malononitrile, 2-(cyclohexylmethylidene) malononitrile, 2-(cyclopropylmethylidene) malononitrile, 2-(ferrocenylmethylidene) malononitrile, and 2-(6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthylmethylidene) malononitrile.

[0026] (2) removing the reaction solvent of the reaction solution obtained in step (1), and then purifying by thin layer chromatography / column chromatography, to obtain a compound having a cyclopentene skeleton in the reaction equation.

[0027] The present application directly uses unactivated allyl alcohol as a C3 synthon, selects an electron-deficient olefin as a C2 synthon, and then directly performs a [3+2] cycloaddition reaction in the presence of a catalyst and a solvent at 120 DEG C to obtain the final product.

[0028] Compared with the disadvantages and deficiencies of the prior art, the present application has the following beneficial effects:

[0029] (1) The allyl alcohol used in the method of the present application is simple to synthesize and can be directly used in the reaction without pre-activation, and the phosphine and boron compound used are commercially available and inexpensive, and have high reactivity;

[0030] (2) The method of the present application has simple steps, convenient operation, and high product yield, and does not use any metal compound, and has the characteristics of high atomic economy and green environmental protection;

[0031] (2) The cyclization method used in the present application is not only suitable for the synthesis of cyclopentene compounds, but also is expected to be used in more cycloaddition reactions in the future, so as to be widely applied in natural products, biological and pharmaceutical molecules, and organic optoelectronic materials, and has broad prospects. BRIEF DESCRIPTION OF DRAWINGS

[0032] Figure 1 is the nuclear magnetic resonance hydrogen spectrum of compound 5 in Example 1 of the present application;

[0033] Figure 2 is the nuclear magnetic resonance carbon spectrum of compound 5 in Example 1 of the present application;

[0034] Figure 3 is the nuclear magnetic resonance hydrogen spectrum of compound 8 in Example 2 of the present application;

[0035] Figure 4 is the nuclear magnetic resonance carbon spectrum of compound 8 in Example 2 of the present application;

[0036] Figure 5 is the nuclear magnetic resonance hydrogen spectrum of compound 12 in Example 3 of the present application;

[0037] Figure 6 is the nuclear magnetic resonance carbon spectrum of compound 12 in Example 3 of the present application;

[0038] Figure 7 is the nuclear magnetic resonance hydrogen spectrum of compound 15 in Example 4 of the present application;

[0039] Figure 8 is the nuclear magnetic resonance carbon spectrum of compound 15 in Example 4 of the present application;

[0040] Figure 9 is the nuclear magnetic resonance hydrogen spectrum of compound 18 in Example 5 of the present application;

[0041] Figure 10 is the nuclear magnetic resonance hydrogen spectrum of compound 21 in the present embodiment 6;

[0042] Figure 11 is the nuclear magnetic resonance hydrogen spectrum of compound 21 in the present embodiment 6;

[0043] Figure 12 is the nuclear magnetic resonance hydrogen spectrum of compound 21 in the present embodiment 6;

[0044] Figure 13 is the nuclear magnetic resonance hydrogen spectrum of compound 25 in the present embodiment 7;

[0045] Figure 14 is the nuclear magnetic resonance hydrogen spectrum of compound 25 in the present embodiment 7. DETAILED DESCRIPTION

[0046] In order to make the purpose, technical scheme and advantages of the present application more clear, the present application is further described in detail below in combination with the drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application and do not limit the present application.

[0047] Embodiment 1

[0048] In the synthesis process of the cyclopentene compound in the present embodiment, the synthesis step of the allyl alcohol compound (methyl 2-(hydroxymethyl) acrylate) used is as follows:

[0049] (1) Under the condition of nitrogen atmosphere and room temperature, 10 mmol of triethylenediamine, 10 mmol of 37% formaldehyde aqueous solution and 25 mmol of methyl acrylate are directly added to a round-bottom flask, and stirred for 72 hours under the condition of no solvent. The reaction equation is as follows:

[0050]

[0051] (2) A proper amount of saturated ammonium chloride solution is added to the reaction mixture to quench, and ethyl acetate is extracted for 3-4 times. The organic phase is combined and dried with anhydrous sodium sulfate. The solvent is removed under reduced pressure, and the product is separated by silica gel column chromatography with petroleum ether / ethyl acetate system as the developing agent. 0.93 g of the target product MBH alcohol 3 is obtained as a colorless liquid, and the yield is 80%, which is calculated as follows:

[0052] y = m 醇 / (M w醇 × n 丙烯酸酯 ) × 100%

[0053] Wherein, y represents the yield of the target product, m 醇 represents the actual weight of the target product MBH alcohol, M w醇 represents the relative molecular mass of the target product MBH alcohol, n丙烯酸酯 The amount of substance of the added acrylate raw material.

[0054] On this basis, the [3+2] cycloaddition reaction of colorless liquid 3 (methyl 2-(hydroxymethyl)acrylate) with an electron-deficient olefinic hydrocarbon compound is carried out, and the specific process is as follows:

[0055] (3) In a 10 mL Schlenk tube, 0.3 mmol of methyl 2-(hydroxymethyl)acrylate, 0.2 mmol of benzyl acrylonitrile, 0.2 mmol of trimethyl borate and 0.02 mmol of diphenyl ethyl phosphine are added under a nitrogen atmosphere, 2 mL of toluene is added, and stirring is carried out at 120°C for 3 h, and the reaction equation is as follows:

[0056]

[0057] (4) After TLC monitoring of the completion of the reaction, the solvent is removed by a vacuum rotary evaporator, the product is separated by thin layer chromatography, and the developing agent is a petroleum ether / ethyl acetate system = 10 / 1, and 40 mg of cyclopentene 5 is obtained as a colorless oily liquid, with a yield of 80%, and the calculation method is as follows:

[0058] y = m 环戊烯 / (M w环戊烯 × n 二氰基烯烃 ) × 100%

[0059] Wherein, y represents the yield of the target product, m 环戊烯 represents the actual mass of the target product cyclopentene, M w环戊烯 represents the relative molecular mass of the target product cyclopentene, and n 二氰基烯烃 represents the amount of substance of the added dicyano olefin raw material.

[0060] Compound 5 is characterized, and the results are shown in Table 1. Figures 1-2 The characterization results show that compound 5 is methyl 3,3-dicyano-4-phenylcyclopent-1-ene-1-carboxylate.

[0061] 1 H NMR (400 MHz, Chloroform-d) δ 7.49-7.38 (m, 5H), 6.66-6.59 (m, 1H), 4.23-4.13 (m, 1H), 3.85 (s, 3H), 3.32-3.11 (m, 2H); 13 C NMR (101 MHz, Chloroform-d) δ 162.94, 144.16, 133.87, 131.75, 129.64, 129.38, 128.21, 111.45, 55.89, 52.81, 46.48, 35.35.

[0062] Example 2

[0063] In the synthesis of the cyclopentene compound of the present embodiment, the allyl alcohol compound (ethyl 2-(hydroxymethyl)acrylate) used in the synthesis step is as follows:

[0064] (1) 10 mmol of triethylenediamine, 10 mmol of 37% formaldehyde aqueous solution, and 25 mmol of ethyl acrylate were directly added to a round-bottom flask under a nitrogen atmosphere at room temperature, and stirred for 72 hours without a solvent. The reaction equation is as follows:

[0065]

[0066] (2) The reaction mixture was quenched by adding an appropriate amount of saturated ammonium chloride solution, extracted with ethyl acetate for 3 to 4 times, and the organic phase was combined and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was separated by silica gel column chromatography using a petroleum ether / ethyl acetate system as the developing agent. A total of 1.04 g of the product 7 was obtained as a colorless oily liquid, with a yield of 80%, and the calculation method was the same as that of compound 3.

[0067] On this basis, the [3+2] cyclization reaction was carried out between the colorless oily liquid 7 (methyl 2-(hydroxymethyl)acrylate) and the electron-deficient hydrocarbon compound, and the specific process was as follows:

[0068] (3) In a 10 mL Schlenk tube, 0.3 mmol of ethyl 2-(hydroxymethyl)acrylate, 0.2 mmol of benzal malonitrile, 0.2 mmol of trimethyl borate, and 0.02 mmol of diphenyl ethyl phosphine were added under a nitrogen atmosphere, 2 mL of toluene was added, and stirring was carried out at 120°C for 3 hours. The reaction equation is as follows:

[0069]

[0070] (4) After the reaction was completed by TLC monitoring, the solvent was removed by a vacuum rotary evaporator, and the product was separated by thin layer chromatography using a petroleum ether / ethyl acetate system = 10 / 1 as the developing agent. A total of 46 mg of the target product 8 was obtained as a colorless oily liquid, with a yield of 87%, and the calculation method was the same as that of compound 5.

[0071] Compound 8 was characterized, and the results are shown in Table 1. Figures 3-4 The characterization results showed that compound 8 was ethyl 3,3-dicyano-4-phenylcyclopenta-1-ene-1-carboxylate.

[0072] 1H NMR (400 MHz, Chloroform-d) δ 7.65 - 7.33 (m, 5H), 6.62 (s, 1H), 4.31 (q, J = 7.1 Hz, 2H), 4.19 (t, J = 8.8 Hz, 1H), 3.10 - 3.35 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, Chloroform-d) δ 162.51, 144.55, 133.94, 131.44, 129.60, 129.36, 128.22, 114.21, 111.52, 62.00, 55.91, 46.48, 35.36, 14.24.

[0073] Example 3

[0074] In the synthesis of the cyclopentene compound of this example, the synthesis step of the electron-deficient olefin compound 2-(4-fluorobenzylidene) malononitrile used is as follows:

[0075] (1) 10 mmol of 4-fluorobenzaldehyde, 10 mmol of malononitrile and 10 mL of 95% ethanol solvent were directly added to a round-bottom flask and stirred at room temperature, followed by dropwise addition of 2-3 drops of piperidine to produce a precipitate. The solid was just dissolved by heating, and stirring was continued for 10 minutes. The reaction equation is as follows:

[0076]

[0077] (2) The reaction solution was cooled and recrystallized to precipitate a solid, which was washed with cold ethanol several times to obtain a yellowish solid 11 of 1.50 g in yield of 74%, which was calculated as follows:

[0078] y = m 烯烃 / (M w二氰基烯烃 x n 醛 ) x 100%

[0079] wherein y represents the yield of the target product, m 二氰基烯烃 represents the actual mass of the target product dicyano olefin, M w二氰基烯烃 represents the relative molecular mass of the target product dicyano olefin, and n 醛 represents the amount of substance of the added aldehyde raw material.

[0080] On this basis, the [3+2] cyclization reaction was carried out between the dicyano olefin 11 (2-(4-fluorobenzylidene) malononitrile) and the allyl alcohol compound, and the specific process is as follows:

[0081] (3) In a 10 mL Schlenk tube, 0.3 mmol of methyl 2-(hydroxymethyl)acrylate, 0.2 mmol of 2-(4-fluorobenzylidene)malononitrile, 0.2 mmol of trimethyl borate and 0.02 mmol of diphenyl ethyl phosphine were added under nitrogen atmosphere, 2 mL of toluene was added, and the mixture was stirred at 120 °C for 3 h. The reaction equation is as follows:

[0082]

[0083] (4) After TLC monitoring the reaction was complete, the solvent was removed by a vacuum rotary evaporator, and the product was separated by thin layer chromatography with a developing agent of petroleum ether / ethyl acetate system = 10 / 1 to obtain 49 mg of cyclopentene 12 as a light yellow solid with a yield of 87%, the calculation method being the same as that of compound 5.

[0084] Compound 12 was characterized, and the results are shown in Table 1. Figures 5-6 The characterization results show that compound 12 is methyl 3,3-dicyano-4-(4-fluorophenyl)-cyclopent-1-en-1-carboxylate.

[0085] 1 H NMR (400 MHz, Chloroform-d) δ 7.50-7.41 (m, 2H), 7.15 (t, J = 8.5 Hz, 2H), 6.63 (s, 1H), 4.31 (q, J = 7.1 Hz, 2H), 4.17 (t, J = 8.8 Hz, 1H), 3.24-3.14 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, Chloroform-d) δ 164.58, 162.40, 162.11, 144.48, 131.30, 130.11, 130.03, 129.72, 129.69, 116.53, 116.32, 114.03, 111.43, 62.05, 55.29, 46.50, 35.55, 14.22.

[0086] Example 4

[0087] In the synthesis process of the cyclopentene compound of the present example, the synthesis step of the electron-deficient olefin compound 2-(thiophen-2-ylmethylidene)malononitrile is as follows:

[0088] (1) 10 mmol of 2-thiophene carboxaldehyde, 10 mmol of malononitrile and 10 mL of 95% ethanol solvent were directly added to a round-bottom flask under stirring at room temperature, followed by dropwise addition of 2-3 drops of piperidine to produce a precipitate, heating to just dissolve the solid, and continuing stirring for 10 minutes. The reaction equation is as follows:

[0089]

[0090] (2) The reaction solution was cooled and recrystallized, and a solid was precipitated. The solid was washed with cold ethanol for several times, to obtain 1.18 g of white solid 14, with a yield of 74%, using the same calculation method as that of compound 11.

[0091] On this basis, a [3+2] cyclization reaction was carried out between the white solid 14 (2-(thiophene-2-ylmethyl) malononitrile) and an allyl alcohol compound, and the specific process was as follows:

[0092] (3) In a 10 mL Schlenk tube, 0.3 mmol of 2-(hydroxymethyl) methyl acrylate, 0.2 mmol of 2-(thiophene-2-ylmethyl) malononitrile, 0.2 mmol of trimethyl borate and 0.02 mmol of diphenyl ethyl phosphine were added under a nitrogen environment, 2 mL of toluene was added, and stirring was carried out at 120°C for 3 h, and the reaction equation was as follows:

[0093]

[0094] (4) After the reaction was completed by TLC monitoring, the solvent was removed by a vacuum rotary evaporator, and the product was separated by thin layer chromatography, using a petroleum ether / ethyl acetate system = 10 / 1 as the developing agent, to obtain 44 mg of cyclopentene 15 in the form of a light yellow oil, with a yield of 80%, using the same calculation method as that of compound 5.

[0095] Compound 15 was characterized, and the results are shown in Table 1. Figures 7-8 The characterization results show that compound 15 is 3,3-dicyano-4-(thiophene-2-yl)-cyclopent-1-ene-1-carboxylic acid methyl ester.

[0096] 1 H NMR (400 MHz, Chloroform-d) δ 7.37 (dd, J = 5.1, 1.2 Hz, 1H), 7.24 (dt, J = 3.6, 1.0 Hz, 1H), 7.13 - 7.06 (m, 1H), 6.63 (dd, J = 2.5, 1.3 Hz, 1H), 4.48 - 4.40 (m, 1H), 4.31 (q, J = 7.1 Hz, 1H), 3.35 - 3.14 (m, 2H), 1.36 (t, J = 7.1 Hz, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 162.27, 144.26, 136.22, 131.59, 127.78, 127.58, 126.50, 113.83, 111.10, 62.06, 51.55, 46.96, 36.93, 14.22.

[0097] Example 5

[0098] In the synthesis of the cyclopentene compound of the present embodiment, the electron-deficient olefin compound 2-(cyclohexylmethylidene) propanedinitrile (CAS: 73776-46-2) is synthesized by the following steps:

[0099] (1) 10 mmol of 2-naphthaldehyde, 10 mmol of malononitrile and 10 mL of 95% ethanol solvent were directly added into a round-bottom flask and stirred at room temperature, followed by dropwise addition of 2-3 drops of piperidine to generate a precipitate. The solid was just dissolved by heating, and stirring was continued for 10 minutes. The reaction equation is as follows:

[0100]

[0101] (2) The reaction solution was directly concentrated, and column chromatography was performed with a petroleum ether / ethyl acetate system = 10 / 1 as the developing agent to obtain 0.896 g of white solid 17 with a yield of 56%, and the calculation method was the same as that of compound 11.

[0102] On this basis, the [3+2] cyclization reaction was carried out between the white solid 17 (2-(cyclohexylmethylidene) propanedinitrile) and the allyl alcohol compound, and the specific process was as follows:

[0103] (3) In a 10 mL Schlenk tube, 0.3 mmol of 2-(hydroxymethyl) methyl acrylate, 0.2 mmol of 2-(cyclohexylmethylidene) propanedinitrile, 0.2 mmol of trimethyl borate and 0.02 mmol of diphenyl ethyl phosphine were added under a nitrogen atmosphere, 2 mL of toluene was added, and stirring was carried out at 120°C for 3 h. The reaction equation is as follows:

[0104]

[0105] (4) After the reaction was completely monitored by TLC, the solvent was removed by a vacuum rotary evaporator, and the product was separated by thin layer chromatography with a petroleum ether / ethyl acetate system = 10 / 1 as the developing agent to obtain 40 mg of cyclopentene 18 as a white solid with a yield of 74%, and the calculation method was the same as that of compound 5.

[0106] Compound 18 was characterized, and the results are shown in Table 1. Figures 9-10 The characterization results show that compound 18 is 3,3-dicyano-4-cyclohexyl-cyclopent-1-ene-1-carboxylic acid methyl ester.

[0107] 1 H NMR (400 MHz, Chloroform-d) δ 6.54 (d, J = 1.7 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.08-2.87 (m, 1H), 2.80-2.42 (m, 2H), 2.21-2.03 (m, 1H), 1.97-1.67 (m, 5H), 1.53-0.93 (m, 8H).13 C NMR (101 MHz, Chloroform-d) δ 162.66, 144.03, 131.89, 114.93, 111.56, 61.79, 56.82, 42.18, 40.45, 35.34, 32.06, 31.26, 25.84, 25.66, 25.48, 14.20.

[0108] Example 6

[0109] In the synthesis of the cyclopentene compound, the electron-deficient olefin compound 2-(naphthalen-2-ylmethylidene) malononitrile (CAS: 2972-84-1) was synthesized by the following steps:

[0110] (1) 10 mmol of 2-naphthaldehyde, 10 mmol of malononitrile and 10 mL of 95% ethanol solvent were directly added into a round-bottom flask and stirred at room temperature, followed by the dropwise addition of 2-3 drops of piperidine to produce a precipitate. The solid was just dissolved by heating, and the stirring was continued for 10 minutes. The reaction equation is as follows:

[0111]

[0112] (2) The reaction solution was cooled and recrystallized to precipitate a solid, which was washed with cold ethanol for several times to obtain 1.14 g of white solid 20 with a yield of 56%, and the calculation method was the same as that of compound 11.

[0113] On this basis, the [3+2] cyclization reaction was carried out between the white solid 20 (2-(naphthalen-2-ylmethylidene) malononitrile) and the allyl alcohol compound, and the specific process was as follows:

[0114] (3) In a 10 mL Schlenk tube, 0.3 mmol of methyl (hydroxymethyl) acrylate, 0.2 mmol of 2-(cyclohexylmethylidene) malononitrile, 0.2 mmol of trimethyl borate and 0.02 mmol of diphenyl ethyl phosphine were added under nitrogen atmosphere, 2 mL of toluene was added, and the stirring was carried out at 120°C for 3 h. The reaction equation is as follows:

[0115]

[0116] (4) After the reaction was completed by TLC monitoring, the solvent was removed by a vacuum rotary evaporator, and the product was separated by thin layer chromatography with a developing agent of petroleum ether / ethyl acetate system = 10 / 1 to obtain 55 mg of cyclopentene 21 as a white solid with a yield of 74%, and the calculation method was the same as that of compound 5.

[0117] Compound 21 was characterized, and the results were as follows: Figures 11-12As shown, the characterization results indicate that compound 21 is 3,3-dicyano-4-(naphthalen-2-ylmethylidenyl)-cyclopent-1-en-1-carboxylic acid methyl ester.

[0118] 1 H NMR (400 MHz, Chloroform-d) δ 7.96-7.80 (m, 4H), 7.61-7.48 (m, 3H), 6.66 (s, 1H), 4.32 (q, J = 7.1, 5.8 Hz, 3H), 3.46-3.19 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, Chloroform-d) δ 162.55, 144.56, 133.65, 133.28, 131.52, 131.33, 129.35, 128.30, 127.91, 127.08, 126.96, 125.17, 114.32, 111.57, 62.05, 56.03, 46.46, 35.51, 14.27.

[0119] Example 7

[0120] In the synthesis of the cyclopentene compound, the electron-deficient olefin compound 2-(6-(3-(1-adamantyl)-4-methoxyphenyl)-2-naphthylmethylidenyl)propanedinitrile (synthetic raw material from the drug molecule adapalene) was synthesized by the following steps:

[0121] (1) 50 mmol of adapalene 22, 200 mmol of lithium aluminum hydride, and 200 mL of tetrahydrofuran were slowly added to a round-bottom flask under room temperature and nitrogen protection and stirred overnight, then quenched with 250 mL of water and extracted with dichloromethane, and the organic phase was dried and concentrated without purification for the next step. The crude product of the previous step was directly added to a round-bottom flask with 75 mmol of pyridine chlorochromate and 200 mL of dichloromethane under room temperature, and the reaction was monitored by thin layer chromatography until it was complete. The reaction liquid was filtered and extracted, and then column chromatography was performed on silica gel with petroleum ether / ethyl acetate as the eluent to obtain yellow solid 23.

[0122]

[0123] (2) The reaction liquid was cooled and recrystallized to precipitate a solid, which was washed with cold ethanol several times to obtain 3.77 g of white solid 24 with a yield of 85%, and the calculation method was the same as that of compound 11.

[0124] On this basis, the [3+2] cyclization reaction of white solid 32 (2-(6-(3-(1-adamantyl)-4-methoxyphenyl)-2-naphthylmethyl)propanedinitrile) with allyl alcohol compound was carried out, and the specific process was as follows:

[0125] (3) In a 10 mL Schlenk tube, 0.3 mmol of ethyl 2-(hydroxymethyl)acrylate, 0.2 mmol of 2-(6-(3-(1-adamantyl)-4-methoxyphenyl)-2-naphthylmethyl)propanedinitrile, 0.2 mmol of trimethyl borate and 0.02 mmol of diphenyl ethyl phosphine were added under nitrogen atmosphere, 2 mL of toluene was added, and stirring was carried out at 120 °C for 3 h, and the reaction equation was as follows:

[0126]

[0127] (4) After TLC monitoring of the completion of the reaction, the solvent was removed by vacuum rotary evaporator, and the product was separated by thin layer chromatography, and the developing agent was petroleum ether / ethyl acetate system = 10 / 1, and 95 mg of cyclopentene 25 was obtained as a white solid, with a yield of 85%, and the calculation method was the same as that of compound 5.

[0128] Compound 25 was characterized, and the results were as shown in Figures 13-14 The characterization results showed that compound 25 was 3,3-dicyano-4-(6-(3-(1-adamantyl)-4-methoxyphenyl)-2-naphthyl)-cyclopenta-1-ene-1-carboxylic acid ethyl ester.

[0129] 1 H NMR (400 MHz, Chloroform-d) δ 8.08-7.85 (m, 4H), 7.84-7.72 (m, 1H), 7.67-7.45 (m, 3H), 6.99 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 2.1 Hz, 1H), 4.32 (q, J = 7.1, 5.8 Hz, 3H), 3.89 (s, 3H), 3.50-3.13 (m, 2H), 2.32-2.04 (m, 9H), 1.90-1.72 (m, 6H), 1.37 (t, J = 7.1 Hz, 3H); 13CNMR (101 MHz, Chloroform-d) δ 162.57, 158.87, 144.59, 140.21, 139.05, 134.06, 132.82, 132.05, 131.55, 130.90, 129.45, 128.65, 127.64, 126.82, 126.05, 125.80, 125.49, 124.93, 114.37, 112.20, 111.59, 62.05, 56.11, 55.28, 46.50, 40.69, 37.29, 37.24, 35.52, 29.21, 14.29.

[0130] Examples 8-12

[0131] Examples 8-12 are substantially the same as Example 2 described above, and the product obtained is the same, which is 3,3-dicyano-4-phenylcyclopenta-l-en-1-carboxylic acid methyl ester. The difference is shown in Table 1 below:

[0132] Table 1 Comparison of differences in implementation

[0133] Number Reaction solvent Phosphine catalyst Boron additive Temperature Yield Example 8 Toluene Ethyl diphenylphosphine Tetrakis(dimethylamino)diboron 120℃ 66％ Example 9 Toluene Ethyl diphenylphosphine Tris(pentafluorophenyl)borane 120℃ 57％ Example 10 Toluene Ethyl diphenylphosphine Trimethyl borate 100℃ 57％ Example 11 Toluene Triphenylphosphine Trimethyl borate 120℃ 2％ Example 12 N,N-Dimethylformamide Ethyl diphenylphosphine Trimethyl borate 120℃ 5％

[0134] The above description is merely preferred embodiments of the present application, and is not used to limit the present application. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present application shall fall within the protection scope of the present application.

Claims

1. A method for directly cyclizing a cyclopentene skeleton from allyl alcohol, characterized in that, The method includes the following steps: (1) Under an inert gas atmosphere, allyl alcohol compounds, electron-deficient olefin compounds, organophosphorus catalysts, and boron compounds are added to the reaction solvent and stirred at 120±2℃ for 3~8 h; wherein, the chemical structural formula of the allyl alcohol compounds is: The chemical structural formula of the electron-deficient olefin compound is as follows: The organophosphorus catalyst is diphenylethylphosphorus; the boron compound is selected from any one of tetra(dimethylamino)diborane, tris(pentafluorophenyl)borane, and trimethyl borate. The reaction solvent is toluene; (2) After the reaction was completed as monitored by TLC, the reaction solution obtained in step (1) was removed from the solvent, purified, and separated to obtain a compound with a cyclopentene skeleton; the chemical structural formula of the compound with the cyclopentene skeleton is: Among them, R 1 Selected from methyl, ethyl, and tert-butyl; R 2 It is selected from any one of phenyl, p-fluorophenyl, p-methoxyphenyl, p-trifluoromethyl, m-fluorophenyl, naphthyl, pyridyl, thiophene, cyclohexyl, cyclopropyl, and 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthyl.

2. The method as described in claim 1, characterized in that, In step (2), the solvent removal is performed by vacuum rotary evaporator to remove the reaction solvent; the purification is performed by thin-layer chromatography / column chromatography, with the developing solvent system being petroleum ether / ethyl acetate = 10 / 1.

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