Method for synthesizing spiro compound through Lewis acid catalyzed [3+2] cycloaddition reaction
阅读说明：本技术 一种通过路易斯酸催化[3+2]环加成反应合成螺环类化合物的方法 (Method for synthesizing spiro compound through Lewis acid catalyzed [3+2] cycloaddition reaction ) 是由 刘继田 李孝训 余心惠 于 2021-08-18 设计创作，主要内容包括：本发明提供了一种通过路易斯酸催化[3+2]环加成反应合成螺环类化合物的方法,包括步骤：于有机溶剂中,在路易斯酸催化下,氮杂二烯化合物Ⅰ和乙烯基环丙烷化合物Ⅱ发生[3+2]环加成反应,得到螺环类化合物Ⅲ。本发明的方法通过一种新的乙烯基环丙烷活化方法,从而使苯并呋喃氮杂二烯烃或吲哚类氮杂二烯烃类底物的范围扩大,生成更为复杂的螺[苯并呋喃-环戊烷]和螺[吲哚-环戊烷]类化合物。本发明的通过路易斯酸催化的[3+2]环加成反应制备螺环类化合物的方法,具有操作方便,底物适用范围广泛,反应原料廉价易得等优点。(The invention provides a method for catalyzing [3+2] by Lewis acid]The method for synthesizing the spiro compound by cycloaddition reaction comprises the following steps: in an organic solvent, under the catalysis of Lewis acid, an aza diene compound I and a vinyl cyclopropane compound II generate [3+2]]Cycloaddition reaction to obtain spiro compound III. The method of the invention expands the range of benzofuran aza diene or indole aza diene substrates by a novel vinyl cyclopropane activation method to generate more complex spiro [ benzofuran-cyclopentane]And spiro [ indole-cyclopentane]A kind of compound is provided. [3+2] catalyzed by Lewis acids according to the invention]The method for preparing the spiro compound by cycloaddition reaction has the advantages of convenient operation, wide application range of substrates, cheap and easily obtained reaction raw materials and the like.)
1. A method for synthesizing spiro compounds through Lewis acid catalyzed [3+2] cycloaddition reaction comprises the following steps:
in an organic solvent, under the catalysis of Lewis acid, carrying out [3+2] cycloaddition reaction on an aza diene compound I and a vinyl cyclopropane compound II to obtain a spiro compound III;
in the structural formula of the compound of formula I, R1Is hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, cyano or nitro; r2Is hydrogen, halogen, C1-C3 alkoxy; r3Is p-toluenesulfonyl or methanesulfonyl; x is O or NAc;
in the structural formula of the compound of formula II, R4And R5The same is one of ethyl formate and methyl formate, or R4、R5With the carbon atom to which it is attached to form an indandionyl group; r6Is hydrogen, phenyl, methyl, ethyl or isopropyl; r7Is hydrogen, phenyl, substituted phenyl, furyl, thienyl, methyl, ethyl, benzyl or dimethyl; the substituent of the substituted phenyl is C1-C3 alkoxy or halogen; r8Is hydrogen or C1-C3 alkyl;
in the formula of the compound of formula III, the substituent R1、R2、R3X is the same as in the structural formula of the compound of formula I, and a substituent R4、R5、R6、R7、R8The structural formula of the compound is the same as that of the compound shown in the formula II.
2. According to claim1, the method for synthesizing the spiro compound is characterized in that in the structural formula of the compound shown in the formula I, R1Is hydrogen, halogen, methyl, methoxy, cyano or nitro; r2Is hydrogen, 6-chloro or 6-methoxy;
in the structural formula of the compound of formula II, R7When the substituted phenyl is substituted phenyl, the substituent of the substituted phenyl is 4-methoxy or 4-bromo.
3. The process for the synthesis of spirocyclic compounds according to claim 1, wherein said organic solvent is tetrahydrofuran, 2-methyltetrahydrofuran, 1, 2-dichloroethane, ethyl acetate, tert-butanol, acetonitrile or toluene; the ratio of the volume of the organic solvent to the mole number of the aza-diene compound I is 5-20 mL:1 mmol.
4. The method for synthesizing spiro-compounds according to claim 1, wherein said lewis acid is magnesium iodide, lanthanum iodide, lithium iodide, calcium iodide or cerium iodide; the molar ratio of the Lewis acid to the aza-diene compound I is 0.01-0.5: 1.
5. The method for synthesizing spiro compounds according to claim 1, wherein the molar ratio of said azadiene compound i and vinyl cyclopropane compound ii is 1: 1.
6. The method for synthesizing the spiro compound according to claim 1, wherein the temperature of the cycloaddition reaction is 50 to 70 ℃; the cycloaddition reaction time is 16-24 h.
7. The method for synthesizing spiro-compounds according to claim 6, wherein the temperature of cycloaddition reaction is 60 ℃.
8. The method for synthesizing spiro-compound according to claim 1, wherein the cycloaddition reaction is performed under an inert gas atmosphere, and the inert gas is nitrogen or argon.
9. A process for the synthesis of spirocyclic compounds according to claim 1, characterized in that the work-up of the reaction mixture obtained after the [3+2] cycloaddition reaction of the azadiene compound I and the vinylcyclopropan compound II is as follows: after the reaction is finished, cooling the reaction liquid to room temperature, then quenching the reaction liquid with water, extracting the reaction liquid with dichloromethane, drying an organic phase with anhydrous sodium sulfate, removing the solvent, and separating the obtained crude product through column chromatography to obtain a spiro compound III, wherein an eluent is a mixed solvent of ethyl acetate, dichloromethane and petroleum ether, and the volume ratio of the ethyl acetate, the dichloromethane and the petroleum ether is 1: 0-3: 5-20.
Technical Field
The invention relates to a method for synthesizing a spiro compound by Lewis acid catalyzed [3+2] cycloaddition reaction, belonging to the technical field of organic synthesis.
Background
Spiro [ benzofuran-cyclopentane ] and spiro [ indole-cyclopentane ] and analogues thereof have structures widely existing in natural products and derivatives thereof; meanwhile, the spiro compound has a rigid spatial structure, can stabilize the configuration of molecules, and can be better combined with receptor molecules, so that the spiro compound is widely applied to drug design (Luo, Q.; Wei, X. -Y.; Yang, J.; Luo, J. -F.; Liang, R.; Tu Z. -C.; Cheng, Y. -X.J.nat. prod.2017,80, 61-70). Many synthetic methods of spiro [ benzofuran-cyclopentane ], spiro [ indole-cyclopentane ] and analogues thereof have been developed, such as intramolecular reactions based on a phenylpropanoid skeleton, Semipinacol rearrangement, and the like (Liu, l.; Lei, l. -s.; Zhan, z. -s.; Liu, s. -z.; Tu, y. -q.; Zhang, f. -m.; Zhang, x. -m.; Ma, a. -j.; Wang, s. -h.chem.commu.2019, 55, 3789-3792), but these methods have problems of complicated precursor preparation, low yield, and the like.
In recent years, azadienes with a benzofuran skeleton have been widely used as quaternary synthons in cyclization reactions to perform a series of [4+ n ] (n.gtoreq.2) cycloaddition reactions (Trost, B.M.; Zuo, Z. -J.Angew.chem., int.Ed.2020,59, 1243-. In 2020, the Zhao topic group reported a method for the construction of cyclopropane from an azadiene of benzofuran skeleton and bromomalonate (Fang, Q. -Y.; Yi, M. -H.; Wu, X. -X.; Z hao, L. -M.Org.Lett.2020,22, 5266-.
Vinylcyclopropane is susceptible to carbon-carbon bond cleavage due to its large ring tension, and has been intensively and extensively studied by chemists. The Shibata task force developed a new complex of magnesium and iodide anions that activated vinylcyclopropane. Under the catalytic action of strong Lewis acid of magnesium ions, iodine negative ions generate class conjugate addition to form an intermediate, and the intermediate can generate intramolecular cyclization under the action of no receptor; in the presence of an electron-deficient isocyanate, a [3+2] ring closure reaction can take place. In their reports, reagents such as LiI which do not have strong Lewis acidity have no catalytic effect, and [3+2] cyclization reaction can be carried out only under the action of strong Lewis acid. This results in a limited range of lewis acids in the catalyst and a consequent reduction in catalytic efficiency.
Therefore, the method for synthesizing spiro [ benzofuran-cyclopentane ] and spiro [ indole-cyclopentane ] compounds by using the vinyl cyclopropane and benzofuran or indole skeleton aza-diene substituted by the gem-diester group as substrates and researching a new activation method of the vinyl cyclopropane so as to construct a synthetic method of the spiro [ benzofuran-cyclopentane ] and spiro [ indole-cyclopentane ] compounds by using the [3+2] cycloaddition reaction with wider substrate application range, and has important significance.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a method for synthesizing a spiro compound by Lewis acid catalyzed [3+2] cycloaddition reaction. The method takes the Lewis acid which is simple and easy to obtain and low in price as the catalyst to catalyze the [3+2] cyclization reaction of the vinyl cyclopropane compound and the benzofuran skeleton or indole skeleton aza diene to prepare the spiro [ benzofuran-cyclopentane ] and spiro [ indole-cyclopentane ] compounds, and has the advantages of convenience in operation, wide application range of substrates, low price and easiness in obtaining raw materials and the like.
The technical scheme of the invention is as follows:
a method for synthesizing spiro compounds through Lewis acid catalyzed [3+2] cycloaddition reaction comprises the following steps:
in an organic solvent, under the catalysis of Lewis acid, carrying out [3+2] cycloaddition reaction on an aza diene compound I and a vinyl cyclopropane compound II to obtain a spiro compound III;
in the structural formula of the compound of formula I, R1Is hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, cyano or nitro; r2Is hydrogen, halogen, C1-C3 alkoxy; r3Is p-toluenesulfonyl or methanesulfonyl; x is O or NAc;
in the structural formula of the compound of formula II, R4And R5The same is one of ethyl formate and methyl formate, or R4、R5With the carbon atom to which it is attached to form an indandionyl group; r6Is hydrogen, phenyl, methyl, ethyl or isopropyl; r7Is hydrogen, phenyl, substituted phenyl, furyl, thienyl, methyl, ethyl, benzyl or dimethyl; the substituent of the substituted phenyl is C1-C3 alkoxy or halogen; r8Is hydrogen or C1-C3 alkyl;
in the formula of the compound of formula III, the substituent R1、R2、R3X is combined with formula IIn the structural formula, the same as R4、R5、R6、R7、R8The structural formula of the compound is the same as that of the compound shown in the formula II.
Preferred according to the invention are compounds of the formula I in which R1Is hydrogen, halogen, methyl, methoxy, cyano or nitro; r2Is hydrogen, 6-chloro or 6-methoxy;
in the structural formula of the compound of formula II, R7When the substituted phenyl is substituted phenyl, the substituent of the substituted phenyl is 4-methoxy or 4-bromo.
According to the invention, the compound of formula II has the structural formula R7When dimethyl, the compound of formula II has the following structural formula:
preferably according to the invention, the organic solvent is tetrahydrofuran, 2-methyltetrahydrofuran, 1, 2-dichloroethane, ethyl acetate, tert-butanol, acetonitrile or toluene; the ratio of the volume of the organic solvent to the mole number of the aza-diene compound I is 5-20 mL:1 mmol.
Preferably according to the invention, the lewis acid is magnesium iodide, lanthanum iodide, lithium iodide, calcium iodide or cerium iodide; the molar ratio of the Lewis acid to the aza-diene compound I is 0.01-0.5: 1.
According to the invention, the molar ratio of the azadiene compound I to the vinyl cyclopropane compound II is preferably 1: 1.
According to the invention, the temperature of the cycloaddition reaction is preferably 50-70 ℃, and more preferably 60 ℃; the cycloaddition reaction time is 16-24 h.
Preferably, according to the present invention, the cycloaddition reaction is performed under an inert gas atmosphere, and the inert gas is nitrogen or argon.
According to the invention, the [3+2] cycloaddition reaction of the aza diene compound I and the vinyl cyclopropane compound II can be carried out, and the product can be separated and characterized according to the conventional separation and purification method. Preferably, the post-treatment step of the reaction solution obtained after the [3+2] cycloaddition reaction of the azadiene compound I and the vinylcyclopropan compound II is as follows: after the reaction is finished, cooling the reaction liquid to room temperature, then quenching the reaction liquid with water, extracting the reaction liquid with dichloromethane, drying an organic phase with anhydrous sodium sulfate, removing the solvent, and separating the obtained crude product through column chromatography to obtain a spiro compound III, wherein an eluent is a mixed solvent of ethyl acetate, dichloromethane and petroleum ether, and the volume ratio of the ethyl acetate, the dichloromethane and the petroleum ether is 1: 0-3: 5-20.
According to the present invention, the benzofuran azadiene compound or indole azadiene compound I is synthesized from the corresponding benzofuran or indole unsaturated ketone and its analogues by known methods (see the documents: Z. -Q.Rong, M.Wang, C.H.E.Chow, Y.ZHao, chem.Eur.J.2016,22, 9483-9487), and the reaction scheme is as follows:
wherein R is1、R2、R3And X is as defined above.
According to the invention, the vinylcyclopropan compound II is prepared from the corresponding malonate by known methods (see B. PIietker, M.S. Holzwarth, A.P.Dieskau, J.Am.chem.Soc.2012,134,5048-5051, KimSepielmanna, EleonoraTosia, Aur lilienLebrunb, GillesNiela, Arievan der Leecrenata, Marciade Figueiredo, Jean-MarcCampagne, Tetrahedron,2018,74(45),6497-
R8In the case of hydrogen, the reaction scheme is as follows:
R8in the case of C1-C3 alkyl, the reaction scheme is as follows:
wherein R is4、R5、R6、R7、R8As described above.
The invention has the following technical characteristics and beneficial effects:
1. the spiro [ benzofuran-cyclopentane ] and spiro [ indole-cyclopentane ] compounds III are prepared by taking azadiene I with a benzofuran skeleton substituted by different substituents or azadiene I with an indole skeleton substituted by different substituents and vinylcyclopropane II substituted by different substituents as raw materials and taking Lewis acid which is simple and easy to obtain and low in price as a catalyst through [3+2] cycloaddition reaction. The invention expands the range of benzofuran and indole aza-diene substrates by a novel vinyl cyclopropane activation method, and generates more complex spiro [ benzofuran-cyclopentane ] and spiro [ indole-cyclopentane ] compounds.
2. The catalyst used in the method is the Lewis acid which is simple and easy to obtain and low in price, and has the advantages of low cost, high efficiency and the like; the method for preparing the spiro compound through the [3+2] cycloaddition reaction catalyzed by Lewis acid has the advantages of convenient operation, wide substrate application range, cheap and easily obtained reaction raw materials and the like.
Detailed Description
The present invention will be further described with reference to the following examples, but is not limited thereto.
Meanwhile, the experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents, materials and equipment are commercially available, unless otherwise specified.
The yields described in the examples are molar yields.
Example 1
Synthesis of methyl 3-p-toluenesulfonylimino-2 ' -phenyl-5 ' - (E) -styryl-3H-spiro [ benzofuran-2, 1' -cyclopentane ] yl-3 ',3' -dicarboxylate (IIIaa)
The reaction route is as follows:
the preparation method comprises the following specific steps: in a glove box, N- ((E) -2- ((Z) -benzylidene) benzofuran-3 (2H) -methylidene) -4-methylbenzenesulfonylimide (Ia) (37.5mg, 0.1mmol), 2- (E) styrylcyclopropyl-1, 1-dicarboxylic acid methyl ester (IIa) (26.0mg,0.1mmol) and lanthanum iodide (3.6mg,0.007mmol) were added sequentially to a 5mL round bottom flask under a nitrogen atmosphere, and then chromatographic grade ethyl acetate (1.0mL) was added to the reaction flask, followed by stirring for 16H at 60 ℃ in an oil bath. After the reaction was completed, the reaction was cooled to room temperature, then quenched with water (1.0mL), extracted with dichloromethane (3 × 4mL), the organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness with a rotary evaporator, and the resulting crude product was separated and purified by column chromatography (eluent was ethyl acetate: dichloromethane: petroleum ether: 1:20, v/v/v) to give 58.5mg of 3-p-toluenesulfonylimino-2 ' -phenyl-5 ' - (E) -styryl-3H-spiro [ benzofuran-2, 1' -cyclopentane ] yl-3 ',3' -dicarboxylic acid methyl ester (iii aa) as a white solid in 92% yield.
The characterization data of the product (IIIaa) obtained are as follows:
white solid (58.5mg, 92%); m.p. 178-;
1H NMR(400MHz,CDCl3)δ8.38(d,J＝8.2Hz,1H),7.99(d,J＝8.2Hz,2H),7.49(t,J＝8.6Hz,1H),7.38(d,J＝8.0Hz,2H),7.20–7.06(m,11H),6.91(t,J＝7.7Hz,1H),6.41(d,J＝16.0Hz,1H),5.90(dd,J＝16.0,8.0Hz,1H),4.79(s,1H),3.76(s,3H),3.51(t,J＝13.8Hz,1H),3.28–3.26(m,4H),2.54(dd,J＝13.8,6.9Hz,1H),2.48(s,3H)；
13C NMR(100MHz,CDCl3)δ179.7,172.2,170.3,170.1,143.4,139.0,138.9,136.6,134.1,133.5,130.7,130.1,129.5,128.4,128.0,127.8,127.6,127.0,126.4,123.3,122.2,118.5,112.2,101.7,63.3,60.4,53.2,52.7,52.3,39.0,21.6；
HRMS(ESI):m/z calcd for C37H34NO7S:636.2050[M+H]+,found:636.2048。
example 2
Synthesis of methyl 3-p-toluenesulfonylimino-2 ' -phenyl-5 ' - (2-methylpropen-1-yl) -3H-spiro [ benzofuran-2, 1' -cyclopentane ] yl-3 ',3' -dicarboxylate (IIIab)
The reaction route is as follows:
the preparation method comprises the following specific steps: in a glove box, N- ((E) -2- ((Z) -benzylidene) benzofuran-3 (2H) -methylene) -4-methylbenzenesulfonylimide (Ia) (37.5mg, 0.1mmol), (2-methylpropen-1-yl) cyclopropane-1, 1-dicarboxylic acid methyl ester (IIb) (21.2mg,0.1mmol) and lanthanum iodide (3.6mg,0.007mmol) were added sequentially to a 5mL round-bottomed flask under a nitrogen atmosphere, and then chromatographic grade ethyl acetate (1.0mL) was added to the reaction, followed by stirring the reaction at 60 ℃ in an oil bath for 16H. After the reaction was completed, the reaction was cooled to room temperature, then quenched with water (1.0mL), extracted with dichloromethane (3 × 4mL), the organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness with a rotary evaporator, and the resulting crude product was separated and purified by column chromatography (eluent was ethyl acetate: dichloromethane: petroleum ether ═ 1:1:18, v/v/v) to give 41.7mg of methyl 3-p-toluenesulfonylimino-2 ' -phenyl-5 ' - (2-methylpropen-1-yl) -3H-spiro [ benzofuran-2, 1' -cyclopentane ] yl-3 ',3' -dicarboxylate (iiiab) as a white solid in 71 mg yield.
The characterization data of the product (IIIab) obtained are as follows:
white solid (41.7mg, 71% yield); m.p.76-78 deg.C;
1H NMR(400MHz,CDCl3)δ8.37–8.34(m,1H),7.94(d,J＝8.2Hz,2H),7.54–7.48(m,1H),7.37(d,J＝8.0Hz,2H),7.13–7.11(m,2H),7.09(s,1H),7.07–7.04(m,3H),6.93(t,J＝8.0Hz,1H),4.96–4.89(m,1H),4.72(s,1H),3.73(s,3H),3.32–3.26(m,2H),3.24(s,3H),2.47(s,3H),2.39–2.37(m,1H),1.53(d,J＝1.4Hz,3H),1.47(d,J＝1.3Hz,3H)；
13C NMR(100MHz,CDCl3)δ180.1,172.5,170.4,170.2,143.3,139.0,138.8,137.7,133.6,130.5,130.0,129.5,127.9,127.7,126.9,121.9,118.5,118.3,112.2,102.4,63.3,60.3,53.1,52.2,48.1,39.7,25.8,21.6,18.7；
HRMS(ESI):m/z calcd for C33H34NO7S:588.2050[M+H]+,found:588.2047。
example 3
Synthesis of 3-p-toluenesulfonylimino-2 ' -phenyl-5 ' - (buten-2-yl) -3H-spiro [ benzofuran-2, 1' -cyclopentane ] yl-3 ',3' -dicarboxylic acid ethyl ester (IIIac)
The reaction route is as follows:
the preparation method comprises the following specific steps: in a glove box under nitrogen atmosphere, N- ((E) -2- ((Z) -benzylidene) benzofuran-3 (2H) -methylidene) -4-methylbenzenesulfonylimide (Ia) (37.5mg, 0.1mmol), (buten-2-yl) cyclopropane-1, 1-dicarboxylic acid ethyl ester (IIc) (24.0mg,0.1mmol) and lanthanum iodide (3.6mg,0.007mmol) were added sequentially to a 5mL round bottom flask, and then chromatographic grade ethyl acetate (1.0mL) was added to the reaction, followed by stirring the reaction at 60 ℃ in an oil bath for 16H. After the reaction was completed, the reaction was cooled to room temperature, then quenched with water (1.0mL), extracted with dichloromethane (3 × 4mL), the organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness with a rotary evaporator, and the resulting crude product was separated and purified by column chromatography (eluent ethyl acetate: petroleum ether ═ 1:10, v/v) to give 46.2mg of 3-p-toluenesulfonylimino-2 ' -phenyl-5 ' - (buten-2-yl) -3H-spiro [ benzofuran-2, 1' -cyclopentane ] yl-3 ',3' -dicarboxylic acid ethyl ester (iiiac) as a white solid, with a yield of 75%.
The characterization data of the product (IIIac) obtained are as follows:
white solid (46.2mg, 75%); 126-;
1H NMR(400MHz,CDCl3)δ8.38(d,J＝8.1Hz,1H),7.99(d,J＝8.1Hz,2H),7.50–7.44(m,1H),7.38(d,J＝8.0Hz,2H),7.18–7.11(m,2H),7.09–7.02(m,3H),7.00(d,J＝8.4Hz,1H),6.93(t,J＝7.8Hz,1H),5.04(s,1H),4.81(s,2H),4.30–4.22(m,1H),4.20–4.10(m,1H),3.92–3.84(m,1H),3.60(t,J＝14.0Hz,1H),3.54–3.41(m,1H),3.06(dd,J＝14.3,6.3Hz,1H),2.47(s,3H),2.41(dd,J＝13.7,6.3Hz,1H),1.85(q,J＝7.4Hz,2H),1.20(t,J＝7.1Hz,3H),0.82(d,J＝7.3Hz,3H),0.70(d,J＝7.1Hz,3H)；
13C NMR(100MHz,CDCl3)δ180.2,171.8,170.3,169.8,144.7,143.3,139.0,138.8,133.7,130.5,130.3,129.5,127.8,127.6,126.9,121.9,118.5,112.9,112.3,100.7,62.6,62.0,61.4,60.6,53.8,37.9,28.8,21.6,13.9,13.2,12.4；
HRMS(ESI):m/z calcd for C35H38NO7S:616.2363[M+C2H5]+,found:616.2363。
example 4
Synthesis of 3-p-toluenesulfonylimino-2 '- (4-methoxy) -phenyl-5' -vinyl-3H-spiro [ benzofuran-2, 1 '-cyclopentane ] yl-3', 2 "-indandione (IIIbd)
The reaction route is as follows:
PMP is p-methoxyphenyl.
The preparation method comprises the following specific steps: in a glove box under nitrogen atmosphere, N- ((E) -2- ((Z) -p-methoxybenzylidene) benzofuran-3 (2H) -methylene) -4-methylbenzenesulfonylimide (Ib) (37.5mg, 0.1mmol), vinylcyclopropanyl-1, 1-indanedione (IId) (19.8mg,0.1mmol) and lithium iodide (6.7mg,0.05mmol) were added in this order to a 5mL round-bottomed flask, and then chromatographic grade ethyl acetate (1.0mL) was added to the reaction, followed by stirring the reaction for 16H at 60 ℃ in an oil bath. After the reaction was complete, the reaction was cooled to room temperature, then quenched with water (1.0mL), extracted with dichloromethane (3 × 4mL), the organic phase was dried over anhydrous sodium sulfate and the solvent was evaporated to dryness using a rotary evaporator and the resulting crude product was separated and purified by column chromatography (eluent ethyl acetate: dichloromethane: petroleum ether: 2:5:20, v/v/v) to give 3-p-toluenesulfonylimino-2 '- (4-methoxy) -phenyl-5' -vinyl-3H-spiro [ benzofuran-2, 1 '-cyclopentane ] yl-3', 2 "-indandione (iii bd)26.6mg, 48% yield as a white solid.
The characterization data of the product (III bd) obtained are as follows:
white foamy solid (26.6mg, 48%);
1H NMR(400MHz,CDCl3)δ8.46(d,J＝8.1Hz,1H),8.08(d,J＝8.2Hz,2H),7.90(d,J＝7.0Hz,1H),7.81(d,J＝7.0Hz,1H),7.76–7.68(m,2H),7.50(t,J＝7.8Hz,1H),7.44(d,J＝8.1Hz,2H),7.08–6.99(m,2H),6.98(d,J＝8.6Hz,2H),6.45(d,J＝8.8Hz,2H),6.03–5.76(m,1H),5.11–4.96(m,2H),4.26(s,1H),4.20–4.08(m,1H),3.55(s,3H),2.50(s,3H),2.27(d,J＝11.5Hz,1H),2.19(dd,J＝12.8,7.2Hz,1H)；
13C NMR(100MHz,CDCl3)δ202.3,201.1,182.0,170.6,158.9,143.4,142.1,141.5,139.1,138.9,136.0,135.6,134.7,131.7,130.5,129.5,126.9,124.0,123.3,123.1,122.1,118.2,117.5,113.3,112.4,99.9,64.5,54.9,54.1,38.2,21.7；
HRMS(ESI):m/z calcd for C36H30NO6S:604.1584[M+H]+,found:604.1582。
example 5
Synthesis of 3-p-toluenesulfonylimino-2 '-methyl-5' phenyl-2 '-vinyl-3H-spiro [ benzofuran-2, 1' -cyclopentane ] yl-4 ',4' -dicarboxylic acid ethyl ester (IIIaf)
The reaction route is as follows:
the preparation method comprises the following specific steps: in a glove box under nitrogen atmosphere, N- ((E) -2- ((Z) -benzylidene) benzofuran-3 (2H) -methylidene) -4-methylbenzenesulfonylimide (Ia) (37.5mg, 0.1mmol), 2-methyl-2 vinylcyclopropanyl-1, 1-dicarboxylate (IIf) (26.2mg,0.1mmol) and lithium iodide (4.0mg,0.03mmol) were added sequentially to a 5mL round bottom flask, and then chromatographic grade ethyl acetate (1.0mL) was added to the reaction, followed by stirring the reaction at 60 ℃ in an oil bath for 16H. After the reaction was completed, the reaction was cooled to room temperature, then quenched with water (1.0mL), extracted with dichloromethane (3 × 4mL), the organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness with a rotary evaporator, and the obtained crude product was separated and purified by column chromatography (eluent ethyl acetate: dichloromethane: petroleum ether: 1:16, v/v/v) to give 56.0mg of ethyl 3-p-toluenesulfonylimino-2 '-methyl-5' phenyl-2 '-vinyl-3H-spiro [ benzofuran-2, 1' -cyclopentane ] yl-4 ',4' -dicarboxylate (iiiaf) as a white solid in 93% yield.
The characterization data of the product (IIIaf) obtained are as follows:
white foamy solid (56.0mg, yield 93%);
1H NMR(400MHz,CDCl3)δ8.32(d,J＝8.0Hz,1H),7.80(d,J＝8.2Hz,2H),7.50(t,J＝7.3Hz,1H),7.28(d,J＝8.1Hz,2H),7.12–7.05(m,3H),6.99–6.96(m,3H),6.92(t,J＝8.0Hz,1H),6.18(dd,J＝17.4,10.9Hz,1H),4.99–4.87(m,2H),4.67(s,1H),4.16–4.03(m,2H),3.87–3.77(m,1H),3.48–3.35(m,2H),2.47(d,J＝14.1Hz,1H),2.41(s,3H),1.13(t,J＝7.1Hz,3H),0.94(s,3H),0.62(t,J＝7.1Hz,3H)；
13C NMR(100MHz,CDCl3)δ176.8,172.2,169.8,169.6,143.3,139.0,138.9,138.8,134.0,130.5,130.3,129.4,127.9,127.6,126.8,122.0,118.8,114.1,112.1,102.7,62.6,61.9,61.6,57.7,53.8,44.7,21.6,18.9,13.9,13.2；
HRMS(ESI):m/z calcd for C34H36NO7S:602.2207[M+H]+,found:602.2203。
comparative example 1
Synthesis of methyl 3-p-toluenesulfonylimino-2 ' -phenyl-5 ' - (2-methylpropen-1-yl) -3H-spiro [ benzofuran-2, 1' -cyclopentane ] yl-3 ',3' -dicarboxylate (IIIab) as described in example 2, except that: no catalyst is added, the target product is not obtained, and the raw materials hardly react.
Comparative example 2
Synthesis of methyl 3-p-toluenesulfonylimino-2 ' -phenyl-5 ' - (E) -styryl-3H-spiro [ benzofuran-2, 1' -cyclopentane ] yl-3 ',3' -dicarboxylate (IIIaa) As described in the examples, except that: the reaction temperature was room temperature and the product yield was 4.7%.
In the comparative example, the reaction temperature is room temperature, and the yield of the obtained target product is low.
The above embodiments are only some examples of the present invention, and the present invention is not limited thereto in any way, and any simple modification, equivalent change and modification to the above embodiments according to the technical spirit of the present invention are within the technical scope of the present invention.