CN111848637A - Method for synthesizing cis/trans spiro compound containing oxygen nitrogen heteroatom - Google Patents

Method for synthesizing cis/trans spiro compound containing oxygen nitrogen heteroatom Download PDF

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CN111848637A
CN111848637A CN202010639390.2A CN202010639390A CN111848637A CN 111848637 A CN111848637 A CN 111848637A CN 202010639390 A CN202010639390 A CN 202010639390A CN 111848637 A CN111848637 A CN 111848637A
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CN111848637B (en
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孙晶
刘旦
韩莹
颜朝国
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Yangzhou University
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Abstract

The invention discloses a method for synthesizing cis/trans [2, 4-dioxa-8-azaspiro [5.5] undec-9-alkene compounds. The method comprises the step of carrying out one-step reaction on a compound shown as a formula 1, a compound shown as a formula 2 and dimethyl butynedioate in the presence of anhydrous magnesium sulfate by taking dichloromethane as a solvent to obtain a cis/trans [2, 4-dioxa-8-azaspiro [5.5] undec-9-alkene compound. The target molecule has important application value in various fields of medicine, pesticide, life science and the like. The method has the advantages of easily obtained raw materials, no need of using a transition metal catalyst, simple and convenient operation, and provides an efficient, economical and applicable method for synthesizing cis/trans [2, 4-dioxa-8-azaspiro [5.5] undec-9-alkene compounds.

Description

Method for synthesizing cis/trans spiro compound containing oxygen nitrogen heteroatom
Technical Field
The invention belongs to the technical field of organic synthesis, and relates to a method for synthesizing a cis/trans spiro compound containing oxygen nitrogen heteroatom.
Background
The nitrogen-containing heterocyclic compound generally has unique biological activity, low toxicity and high systemic property, is often used as a structural unit of medicines and pesticides, and plays an important role in the aspects of medicine and pesticide application. The synthesis of nitrogen-containing heterocyclic compound derivatives has been a research hotspot in the field of organic synthesis. Wherein, the nitrogen heterocyclic compound containing pyridine ring has important medicinal value. Milrinone (1) inhibits phosphodiesterase of the heart, produces positive contraction and peripheral vascular dilation, and is suitable for short-term treatment of patients with severe congestive heart failure who are ineffective in conventional maintenance therapy. (Chenshuangwei, Yang Jian, Jinqingping, China journal of pharmaceutical chemistry, 2009,19, 261-. The non-Niramine (2) is used for treating skin mucosa and allergic diseases. (Hamid, M.; Haniti, S.A.; Allen, C.; et al. J Am Chem Soc.2009,131, 1766-1774). Blonanserin (3) is a highly selective antagonist of the 5-HT2 receptor and the D2 receptor, has low affinity for the D1 receptor and the adrenergic alpha 1, H1 histamine receptor and the M1 choline receptor, and is clinically used for treating atypical psychosis. (Ochi, T.; Sakamoto, M.; Minamida, A.; et al. BioorgMed Chem Lett.2005,15, 1055-.
Figure BDA0002570929540000011
In 2005, Nair et al synthesized a large number of unreported pyridine derivatives from isoquinoline, dimethyl butynedioate, and arylmethylenemalononitrile at room temperature in tetrahydrofuran as a solvent. (Nair, V.; Devi, B.R.; Varma, L.R.tetrahedron Lett.2005,46, 5333-; in 2012, Rajan et al synthesized pyridinispiroindolinone compounds from isoquinoline, dimethyl 2, 3-pentadienedioate and isatin malononitrile under nitrogen protection (Rajan, E.; Babu, B.P; Kumar, A.; Paul, R.R.; Sinu, C.R.; Suresh, E.; Nair, V.Synthesis.2012,44, 417-423.); in 2012, the sensitization group used 2- (1-benzyl-2-oxoindole-3-propylene) malononitrile, and pyridine and dimethyl butynedioate were reacted under reflux in tetrahydrofuran to obtain pyridine spiroindolone derivatives. (Yang, H.B.; Guan, X.Y; Wei, Y.; Shi M.Eur.J.org.chem.2012,2012,2792-2800.).
The analysis of published documents shows that the method for synthesizing pyridine spiro-derivative has some problems, such as the raw materials need to be prepared in advance, the reaction conditions are harsh, the reaction time is long, the substrate expansion range is small, and the spiro-compound containing oxygen nitrogen heteroatom cannot be synthesized. Therefore, the method for synthesizing the spiro compound containing the oxygen nitrogen heteroatom, which is efficient, economical and green, and has a wide substrate expansion range, has great significance.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the problems and provide a method for synthesizing the cis/trans spiro compound containing the oxygen nitrogen heteroatom in one step, which has the advantages of wide substrate expansion range, easily available raw materials, simple operation and no need of a transition metal catalyst.
The technical scheme for solving the technical problems is as follows:
a method of synthesizing a cis/trans oxygen-containing nitrogen heteroatom spirocyclic compound comprising: taking an organic solvent as a solvent, firstly adding anhydrous magnesium sulfate, and then carrying out multi-component reaction on a compound shown in a formula 1, a compound shown in a formula 2 and dimethyl butynedioate shown in a formula 3 according to a certain molar ratio to obtain a cis-form oxygen-containing nitrogen heteroatom spiro compound shown in a formula 4 and/or a trans-form oxygen-containing nitrogen heteroatom spiro compound shown in a formula 5;
the general reaction formula of the invention is:
Figure BDA0002570929540000021
in the formula Ar1Represents any one of phenyl and halogenated phenyl, preferably any one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl and 2-nitrophenyl; in the formula Ar2Represents any one of phenyl, halogenated phenyl and benzyl, preferably any one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-halogenated phenyl and 3-halogenated phenyl; in the formula Ar 3Represents a phenyl group, preferably any of a 4-methoxyphenyl group and a 4-tert-butylphenyl group.
Preferably, the cis/trans spiro compound containing oxygen nitrogen heteroatom is synthesized by reaction at 20-30 deg.c.
More preferably, the reaction is carried out at room temperature for 12-14 hours.
Preferably, the organic solvent for the reaction is any one or more of dichloromethane, trichloromethane, acetonitrile, tetrahydrofuran and toluene.
More preferably, the organic solvent of the reaction is dichloromethane.
Preferably, the addition amount of the anhydrous magnesium sulfate is 0.5-2 times of the molar weight of the compound shown in the formula 1.
More preferably, the anhydrous magnesium sulfate is added in an amount of 1.5 times the molar amount of the compound represented by formula 1.
Preferably, the mole ratio of the compound shown in formula 1, the compound shown in formula 2 and dimethyl butynedioate is (1-1.2): 0.7-0.9): 1.
More preferably, the molar ratio of the compound shown in the formula 1, the compound shown in the formula 2 and dimethyl butynedioate is 1.1:0.8: 1.
Preferably, the order of adding reactants in the synthesis of cis/trans spiro compounds containing oxygen nitrogen heteroatom is that organic solvent and anhydrous magnesium sulfate are added, then the compound shown in formula 1 and the compound shown in formula 2 are added, and finally dimethyl butynedioate is added.
The invention takes easily obtained alpha, beta-unsaturated N-aryl imine, 2-arylene Meldrum acid and dimethyl butynedioate as raw materials to obtain cis/trans spiro compound containing oxygen nitrogen heteroatom through one-step reaction. The synthesis method has the advantages of high efficiency, simple operation, high yield and environmental friendliness.
Detailed Description
The present invention will be described in further detail with reference to examples, but the scope of the present invention is not limited to these examples.
Example 1
Taking as an example the preparation of cis-dimethyl-8, 11-bis (4-methoxyphenyl) -7- ((E) -4-methoxystyryl) -3, 3-dimethyl-1, 5-dioxa-2, 4-dioxa-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylate of the formula:
Figure BDA0002570929540000041
adding 5mL of dichloromethane and 0.1800g (1.5mmol) of anhydrous magnesium sulfate into a 10mL Schenk tube, adding 0.2937g (1.1mmol) of (1E,2E) -N, 3-bis (4-methoxyphenyl) prop-2-ene-1-imine and 0.2096g (0.8mmol) of 5- (4-methoxybenzylidene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione, finally 0.1420g (1mmol) of dimethyl butynedioate, reacting at room temperature for 12 hours, removing the anhydrous magnesium sulfate by suction filtration after the reaction is finished, evaporating and concentrating the filtrate, purifying by silica gel column chromatography to obtain pure cis-dimethyl-8, 11-bis (4-methoxyphenyl) -7- ((E) -4-methoxystyryl) -3, 3-dimethyl-1, 5-dioxa-2, 4-dioxa-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylate with an isolation yield of 63%, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3):7.24-7.15(m,3H,ArH),7.02(d,J＝8.8Hz,2H,ArH),6.80(d,J＝8.0Hz,3H,ArH),6.73(d,J＝8.4Hz,4H,ArH),6.46(d,J＝15.6Hz,1H,CH),5.30(dd,J1＝16.0Hz,J2＝10.4Hz,1H,CH),4.85(t,J＝5.2Hz,2H,CH),3.75(s,9H,3OCH3),3.53(s,3H,OCH3),3.35(s,3H,OCH3),1.22(s,3H,CH3),0.68(s,3H,CH3)；13C NMR(100MHz,CDCl3):167.4,166.2,165.1,162.2,159.9,158.8,158.8,149.0,136.3,132.3,132.0,131.0,130.5,128.5,127.9,127.7,118.8,114.2,113.9,113.7,113.3,106.0,100.3,67.5,59.5,55.2,55.1,52.1,50.9,45.9,29.0,28.9；IR(KBr)υ:3004,2948,2839,1736,1696,1601,1510,1436,1395,1293,1252,1136,1063,1028,976,948,906,832,782,736cm-1；MS(m/z):HRMS(ESI)Calcd.For C37H37NNaO11([M+Na]+):694.2259,found:694.2243。
Example 2
Taking as an example the preparation of trans dimethyl-8, 11-bis (4-methoxyphenyl) -7- ((E) -4-methoxystyryl) -3, 3-dimethyl-1, 5-dioxa-2, 4-dioxa-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylate of the formula:
Figure BDA0002570929540000051
pure trans-dimethyl-8, 11-bis (4-methoxyphenyl) -7- ((E) -4-methoxystyryl) -3, 3-dimethyl-1, 5-dioxa-2, 4-dioxa-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylate was obtained in 30% isolation yield by column chromatography purification on silica gel in example 1, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3):7.28(d,J＝9.2Hz,2H,ArH),7.24(t,J＝8.4Hz,2H,ArH),7.04(d,J＝7.6Hz,2H,ArH),6.89(d,J＝8.4Hz,2H,ArH),6.79(d,J＝8.8Hz,2H,ArH),6.74(d,J＝8.4Hz,2H,ArH),6.36(d,J＝15.6Hz,1H,CH),5.74(dd,J1＝16.0Hz,J2＝9.2Hz,1H,CH),4.77(d,J＝8.8Hz,1H,CH),4.56(s,1H,CH),3.81(s,3H,OCH3),3.75(s,6H,2OCH3),3.55(s,3H,OCH3),3.50(s,3H,OCH3),1.72(s,3H,CH3),1.52(s,3H,CH3)；13C NMR(100MHz,CDCl3):166.1,164.7,164.6,159.7,159.1,158.9,148.4,136.8,130.8,130.6,129.7,128.3,127.8,119.5,113.9,113.8,113.7,105.7,55.2,55.2,55.1,52.2,51.3,29.9,28.4；IR(KBr)υ:3621,2949,2840,1749,1694,1603,1511,1438,1295,1248,1181,1124,1070,1032,982,905,828cm-1；MS(m/z):HRMS(ESI)Calcd.For C37H37NNaO11([M+Na]+)：694.2259,found:694.2247。
example 3
To illustrate the preparation of cis-dimethyl-11- (4-methoxyphenyl) -7- ((E) -4-methoxystyryl) -3, 3-dimethyl-1, 5-dioxa-8- (p-tolyl) -2, 4-dioxa-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylate of the formula:
Figure BDA0002570929540000061
5mL of methylene chloride and 0.1203g (1.0mmol) of anhydrous magnesium sulfate were put into a 10mL Schenk tube, 0.3012g (1.2mmol) of (1E,2E) -3- (4-methoxyphenyl) -N- (p-tolyl) prop-2-ene-1-imine and 0.2620g (1.0mmol) of 5- (4-methoxybenzylidene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione were added, and 0.1420g (1mmol) of dimethyl butynedioate was added to the tube to react at room temperature for 12 hours, and after completion of the reaction, the anhydrous magnesium sulfate was removed by suction filtration Magnesium sulfate, evaporating and concentrating the filtrate, and purifying by silica gel column chromatography to obtain cis-dimethyl-11- (4-methoxyphenyl) -7- ((E) -4-methoxystyryl) -3, 3-dimethyl-1, 5-dioxa-8- (p-tolyl) -2, 4-dioxa-8-azaspiro [5.5]Undec-9-ene-9, 10-dicarboxylate with an isolated yield of 43%, and the following structural characterization data:1H NMR(400MHz,CDCl3):7.23(s,1H,ArH),7.16(s,2H,ArH),7.02(t,J＝8.8Hz,5H,ArH),6.80(d,J＝7.2Hz,2H,ArH),6.73(d,J＝8.4Hz,2H,ArH),6.46(d,J＝16.0Hz,1H,CH),5.30(dd,J1＝15.6Hz,J2＝10.4Hz,1H,CH),4.87(d,J＝10.8Hz,1H,CH),4.86(s,1H,CH),3.75(s,6H,2OCH3),3.52(s,3H,OCH3),3.35(s,3H,OCH3),2.27(s,3H,CH3),1.22(s,3H,CH3),0.68(s,3H,CH3)；13C NMR(100MHz,CDCl3):167.4,166.2,165.1,162.2,159.9,158.8,148.9,137.8,137.0,136.3,130.9,130.5,130.4,128.9,128.6,127.9,127.7,118.9,114.2,113.9,113.7,106.0,100.5,67.4,59.5,55.1,52.1,50.9,45.9,29.0,28.9,21.0；IR(KBr)υ:3474,2997,2946,2840,1745,1695,1606,1512,1438,1386,1270,1130,1101,1031,982,908,824,784,743cm-1；MS(m/z):HRMS(ESI)Calcd.For C37H37NNaO10([M+Na]+)：678.2310,found:678.2292。
example 4
In an example of the preparation of trans dimethyl-11- (4-methoxyphenyl) -7- ((E) -4-methoxystyryl) -3, 3-dimethyl-1, 5-dioxa-8- (p-tolyl) -2, 4-dioxa-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylate of the formula:
Figure BDA0002570929540000071
pure trans-dimethyl-11- (4-methoxyphenyl) -7- ((E) -4-methoxystyryl) -3, 3-dimethyl-1, 5-dioxa-8- (p-tolyl) -2, 4-dioxa-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylate was obtained in 18% isolated yield by column chromatography purification on silica gel in example 3, and the structural characterization data were as follows:
1H NMR(400MHz,CDCl3):7.25-7.23(m,4H,ArH),7.09-7.04(m,4H,ArH),6.89(d,J＝8.4Hz,2H,ArH),6.74(d,J＝8.8Hz,2H,ArH),6.39(d,J＝16.0Hz,1H,CH),5.77(dd,J1＝15.2Hz,J2＝9.2Hz,1H,CH),4.79(d,J＝8.4Hz,1H,CH),4.57(s,1H,CH),3.80(s,3H,OCH3),3.75(s,3H,OCH3),3.56(s,3H,OCH3),3.49(s,3H,OCH3),2.28(s,3H,CH3),1.68(s,3H,CH3),1.52(s,3H,CH3)；13C NMR(100MHz,CDCl3):166.2,164.6,159.7,159.1,138.5,137.9,136.7,130.7,129.8,129.3,128.8,128.3,127.8,119.5,113.9,113.8,105.6,55.2,55.1,52.2,51.3,29.8,28.5,21.1；IR(KBr)υ:3625,3007,2957,1752,1695,1586,1512,1437,1296,1252,1183,1125,1071,1029,982,905,821,760cm-1；MS(m/z):HRMS(ESI)Calcd.ForC37H37NNaO10([M+Na]+)：678.2310,found:678.2302。
example 5
Taking as an example the preparation of cis-dimethyl-11- (4-methoxyphenyl) -7- ((E) -4-methoxystyryl) -3, 3-dimethyl-1, 5-dioxa-8-phenyl-2, 4-dioxa-8-azaspiro [5.5] undecene-9, 10-dicarboxylic acid of the formula:
Figure BDA0002570929540000081
Adding 5mL of dichloromethane and 0.1800g (1.5mmol) of anhydrous magnesium sulfate into a 10mL Schenk tube, adding 0.2371g (1.0mmol) of (1E,2E) -3- (4-methoxyphenyl) -N-phenylpropan-2-ene-1-imine, 0.2096g (0.9mmol) of 5- (4-methoxybenzylidene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione, and finally 0.1420g (1mmol) of dimethyl butynedioate, reacting at room temperature for 12 hours, removing the anhydrous magnesium sulfate by suction filtration after the reaction is finished, evaporating and concentrating the filtrate, purifying by silica gel column chromatography to obtain pure cis-dimethyl-11- (4-methoxyphenyl) -7- ((E) -4-methoxystyryl) -3, 3-dimethyl-1, 5-dioxa-8-phenyl-2, 4-dioxa-8-azaspiro [5.5]Undecene-9, 10-dicarboxylic acid, isolation thereofThe yield was 30%, and the structural characterization data were as follows:1H NMR(400MHz,CDCl3):7.33-7.30(m,2H,ArH),7.24-7.16(m,5H,ArH),6.99(d,J＝7.6Hz,2H,ArH),6.81(s,2H,ArH),6.72(d,J＝7.6Hz,2H,ArH),6.48(d,J＝16.0Hz,1H,CH),5.27(dd,J1＝14.8Hz,J2＝9.6Hz,1H,CH),4.91(d,J＝10.4Hz,1H,CH),4.87(s,1H,CH),3.76(s,3H,OCH3),3.75(s,3H,OCH3),3.50(s,3H,OCH3),3.36(s,3H,OCH3),1.22(s,3H,CH3),0.69(s,3H,CH3)；13C NMR(100MHz,CDCl3):167.4,166.3,165.1,162.3,160.0,158.9,148.7,139.7,136.5,130.9,130.5,128.3,128.0,127.9,127.7,118.9,114.2,114.0,106.2,100.9,67.4,59.6,55.2,52.2,51.0,46.0,29.1,28.9；IR(KBr)υ:3460,3009,2953,2845,1737,1692,1578,1508,1434,1383,1296,1258,1182,1141,1067,1035,974,917,840,754cm-1；MS(m/z):HRMS(ESI)Calcd.For C36H35NNaO10([M+Na]+):664.2135,found:664.2141.
example 6
Taking as an example the preparation of trans-dimethyl-11- (4-methoxyphenyl) -7- ((E) -4-methoxystyryl) -3, 3-dimethyl-1, 5-dioxa-8-phenyl-2, 4-dioxa-8-azaspiro [5.5] undecene-9, 10-dicarboxylic acid of the formula:
Figure BDA0002570929540000091
in example 5, pure trans-dimethyl-11- (4-methoxyphenyl) -7- ((E) -4-methoxystyryl) -3, 3-dimethyl-1, 5-dioxa-8-phenyl-2, 4-dioxa-8-azaspiro [5.5] was obtained by column chromatography purification using a silica gel column ]Undecene-9, 10-dicarboxylic acid in an isolated yield of 10% and the structural characterization data below:1H NMR(400MHz,CDCl3):7.36(d,J＝7.6Hz,2H,ArH),7.30(t,J＝7.6Hz,3H,ArH),7.24-7.20(m,2H,ArH),7.03(d,J＝8.8Hz,2H,ArH),6.89(d,J＝8.4Hz,2H,ArH),6.73(d,J＝8.8Hz,2H,ArH),6.41(d,J＝15.6Hz,1H,CH),5.75(dd,J1＝15.2Hz,J2＝8.4Hz,1H,CH),4.82(d,J＝9.2Hz,1H,CH),4.59(s,1H,CH),3.81(s,3H,OCH3),3.75(s,3H,OCH3),3.54(s,3H,OCH3),3.50(s,3H,OCH3),1.67(s,3H,CH3),1.52(s,3H,CH3)；13C NMR(100MHz,CDCl3):166.2,164.8,164.6,159.8,159.2,147.8,136.9,130.7,129.9,128.8,128.3,128.1,127.9,119.4,114.0,113.9,105.8,55.2,55.2,52.3,51.4,29.9,28.5；IR(KBr)υ:3270,3034,2910,1708,1595,1522,1497,1449,1406,1368,1339,1310,1205,1158,1128,1094,990,893,848,819,753cm-1；MS(m/z):HRMS(ESI)Calcd.For C36H35NNaO10([M+Na]+):664.2135,found:664.2153.
example 7
To illustrate the preparation of cis-dimethyl-8, 11-bis (4-methoxyphenyl) -3, 3-dimethyl-7- ((E) -4-methylstyryl) -1, 5-dioxa-2, 4-dioxa-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylate of the formula:
Figure BDA0002570929540000092
adding 5mL of trichloromethane and 0.1800g (1.5mmol) of anhydrous magnesium sulfate into a 10mL Schenk tube, adding 0.2762g (1.1mmol) of (1E,2E) -N- (4-methoxyphenyl) -3- (p-tolyl) prop-2-ene-1-imine, 0.2096g (0.8mmol) of 5- (4-methoxybenzylidene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione, finally 0.1420g (1mmol) of dimethyl butynedioate, reacting at room temperature for 12 hours, removing anhydrous magnesium sulfate by suction filtration after the reaction is finished, evaporating and concentrating the filtrate, and purifying by using a silica gel column chromatography to obtain pure cis-dimethyl-8, 11-bis (4-methoxyphenyl) -3, 3-dimethyl-7- ((E) -4-methylstyrene-1 5-dioxa-2, 4-dioxa-8-azaspiro [5.5]Undec-9-ene-9, 10-dicarboxylate with an isolated yield of 30% and the following structural characterization data:1H NMR(400MHz,CDCl3):7.22(s,1H,ArH),7.16(s,1H,ArH),7.03-6.96(m,5H,ArH),6.81-6.74(m,5H,ArH),6.48(d,J＝16.0Hz,1H,CH),5.40(dd,J1＝16.0Hz,J2＝10.4Hz,1H,CH),4.87(d,J＝9.6Hz,1H,CH),4.85(s,1H,CH),3.75(s,3H,OCH3),3.74(s,3H,OCH3),3.53(s,3H,OCH3),3.50(s,3H,OCH3),2.27(s,3H,CH3),1.23(s,3H,CH3),0.68(s,3H,CH3)；13C NMR(100MHz,CDCl3):167.4,166.2,165.1,162.2,158.9,158.8,149.0,138.7,136.8,132.3,132.2,132.0,131.0,130.5,129.2,128.6,126.5,120.0,113.4,113.4,109.9,106.1,100.3,67.5,59.4,55.2,55.1,52.1,50.9,45.9,29.0,28.9,21.1；IR(KBr)υ:3479,2999,2949,2839,1737,1695,1585,1509,1435,1388,1294,1245,1136,1105,1025,978,907,813,736cm-1；MS(m/z):HRMS(ESI)Calcd.For C37H37NNaO10([M+Na]+):678.2310,found:678.2300.
example 8
To illustrate the preparation of trans-dimethyl-8, 11-bis (4-methoxyphenyl) -3, 3-dimethyl-7- ((E) -4-methylstyryl) -1, 5-dioxa-2, 4-dioxa-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylate of the formula:
Figure BDA0002570929540000101
In example 7, pure trans-dimethyl-8, 11-bis (4-methoxyphenyl) -3, 3-dimethyl-7- ((E) -4-methylstyryl) -1, 5-dioxa-2, 4-dioxa-8-azaspiro [5.5] was obtained by column chromatography purification using a silica gel column]Undec-9-ene-9, 10-dicarboxylate with an isolation yield of 18% and the following structural characterization data:1H NMR(400MHz,CDCl3):7.29(d,J＝8.8Hz,2H,ArH),7.23(t,J＝8.4Hz,2H,ArH),7.03-6.98(m,4H,ArH),6.89(d,J＝8.8Hz,2H,ArH),6.78(d,J＝8.8Hz,2H,ArH),6.39(d,J＝15.6Hz,1H,CH),5.84(dd,J1＝15.6Hz,J2＝9.6Hz,1H,CH),4.79(d,J＝9.2Hz,1H,CH),4.56(s,1H,CH),3.81(s,3H,OCH3),3.75(s,3H,OCH3),3.55(s,3H,OCH3),3.50(s,3H,OCH3),2.27(s,3H,CH3),1.73(s,3H,CH3),1.52(s,3H,CH3)；13C NMR(100MHz,CDCl3):166.1,164.7,164.6,159.1,159.0,138.3,137.3,132.7,130.7,130.6,129.7,129.1,126.5,120.8,113.9,113.7,105.7,55.2,55.1,52.2,51.3,30.0,28.4,21.1；IR(KBr)υ:3001,2949,2840,1749,1695,1586,1510,1439,1393,1242,1125,1070,1033,982,907,809,728cm-1；MS(m/z):HRMS(ESI)Calcd.For C37H37NNaO10([M+Na]+):678.2310,found:678.2304.
example 9
Taking as an example the preparation of cis-dimethyl-8, 11-bis (4-methoxyphenyl) -3, 3-dimethyl-1, 5-dioxo-7- ((E) -styryl) -2, 4-dioxa-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylic acid ester of the formula:
Figure BDA0002570929540000111
adding 5mL of acetonitrile and 0.1800g (1.5mmol) of anhydrous magnesium sulfate into a 10mL Schenk tube, adding 0.2608g (1.1mmol) of (1E,2E) -N- (4-methoxyphenyl) -3-phenylpropan-2-ene-1-imine, 0.2096g (0.8mmol) of 5- (4-methoxybenzylidene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione, finally 0.1420g (1mmol) of dimethyl butynedioate, reacting at room temperature for 12 hours, removing the anhydrous magnesium sulfate by suction filtration after the reaction is finished, evaporating and concentrating the filtrate, purifying by silica gel column chromatography to obtain pure cis-dimethyl-8, 11-bis (4-methoxyphenyl) -3, 3-dimethyl-1, 5-dioxo-7- ((E) -styryl) -2, 4-dioxa-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylate in an isolated yield of 14%, with the following structural characterization data:
1H NMR(400MHz,CDCl3):7.22-7.16(m,6H,ArH),7.09-7.07(m,2H,ArH),6.80(d,J＝8.0Hz,3H,ArH),6.76(s,2H,ArH),6.53(d,J＝15.6Hz,1H,CH),5.47(dd,J1＝16.0Hz,J2＝10.4Hz,1H,CH),4.89(d,J＝8.8Hz,1H,CH),4.86(s,1H,CH),3.75(s,6H,2OCH3),3.53(s,3H,OCH3),3.35(s,3H,OCH3),1.21(s,3H,CH3),0.68(s,3H,CH3)；13C NMR(100MHz,CDCl3):167.3,166.2,165.1,162.2,158.9,148.9,136.9,134.9,132.3,130.4,128.6,128.6,126.5,121.2,113.4,113.4,106.1,100.4,67.4,59.4,55.2,55.1,52.1,50.9,45.9,28.9,28.9；IR(KBr)υ:3472,2947,2839,1737,1696,1583,1509,1438,1396,1295,1241,1137,1064,1026,979,946,906,843,798,757,729cm-1；MS(m/z):HRMS(ESI)Calcd.ForC36H35NNaO10([M+Na]+):664.2153,found:664.2143.
Example 10
Taking as an example the preparation of trans dimethyl-8, 11-bis (4-methoxyphenyl) -3, 3-dimethyl-1, 5-dioxo-7- ((E) -styryl) -2, 4-dioxa-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylic acid ester of the formula:
Figure BDA0002570929540000121
pure trans-dimethyl-8, 11-bis (4-methoxyphenyl) -3, 3-dimethyl-1, 5-dioxo-7- ((E) -styryl) -2, 4-dioxa-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylate was obtained by column chromatography purification treatment using a silica gel column in example 9, with an isolation yield of 8%, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3):7.29(d,J＝8.4Hz,2H,ArH),7.25-7.20(m,5H,ArH),7.10(d,J＝5.6Hz,2H,ArH),6.90(d,J＝8.8Hz,2H,ArH),6.79(d,J＝8.8Hz,2H,ArH),6.43(d,J＝15.6Hz,1H,CH),5.91(dd,J1＝15.2Hz,J2＝8.4Hz,1H,CH),4.80(d,J＝8.8Hz,1H,CH),4.57(s,1H,CH),3.81(s,3H,OCH3),3.75(s,3H,OCH3),3.56(s,3H,OCH3),3.50(s,3H,OCH3),1.73(s,3H,CH3),1.53(s,3H,CH3)；13C NMR(100MHz,CDCl3):166.1,164.7,164.5,159.1,159.0,137.4,135.5,130.7,130.6,129.8,128.4,128.2,126.5,121.9,114.0,113.8,105.7,55.2,55.1,52.2,51.3,29.9,28.4；IR(KBr)υ:3469,3001,2951,2843,1749,1691,1584,1510,1440,1290,1245,1188,1127,1034,982,907,842,769cm-1；MS(m/z):HRMS(ESI)Calcd.For C36H35NNaO10([M+Na]+):664.2153,found:664.2144.
example 11
To illustrate the preparation of cis-dimethyl-11- (4-methoxyphenyl) -3, 3-dimethyl-1, 5-dioxa-7- ((E) -styryl) -8- (p-tolyl) -2, 4-dioxa-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylic acid ester of the formula:
Figure BDA0002570929540000131
5mL of tetrahydrofuran and 0.1800g (1.5mmol) of anhydrous magnesium sulfate were added to a 10mL Schenk tube, 0.2434g (1.1mmol) of (1E,2E) -3-phenyl-N- (p-tolyl) propan-2-ene-1-imine and 0.2096g (0.8mmol) of 5- (4-methoxybenzylidene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione were added, 0.1420g (1mmol) of dimethyl butynedioate were added, the mixture was reacted at room temperature for 12 hours, anhydrous magnesium sulfate was removed by suction filtration after the reaction was completed, the filtrate was evaporated and concentrated, and purification by column chromatography using a silica gel column was carried out to obtain pure cis-dimethyl-11- (4-methoxyphenyl) -3, 3-dimethyl-1, 5-dioxa-7- ((E) -styryl) -8- (p-toluene 2, 4-dioxa-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylate in an isolated yield of 12%, with the following structural characterization data:
1H NMR(400MHz,CDCl3):7.21-7.16(m,6H,ArH),7.08-7.04(m,5H,ArH),6.80(d,J＝7.6Hz,2H,ArH),6.52(d,J＝16.0Hz,1H,CH),5.46(dd,J1＝15.6Hz,J2＝10.0Hz,1H,CH),4.91(d,J＝10.0Hz,1H,CH),4.87(s,1H,CH),3.75(s,3H,OCH3),3.36(s,3H,OCH3),2.27(s,3H,CH3),1.20(s,3H,CH3),0.67(s,3H,CH3)；13C NMR(100MHz,CDCl3):167.4,166.2,165.1,162.1,158.9,148.8,137.9,137.0,136.8,135.0,130.4,130.4,129.0,128.6,128.5,126.5,121.3,106.1,100.6,67.3,59.4,55.1,52.1,50.9,45.9,28.9,28.9,21.1；IR(KBr)υ:3473,2997,2947,2841,1737,1696,1583,1509,1436,1391,1265,1137,1063,1025,979,905,844,757,724cm-1；MS(m/z):HRMS(ESI)Calcd.For C36H35NNaO9([M+Na]+):648.2204,found:648.2201.
Example 12
Taking as an example the preparation of trans dimethyl-11- (4-methoxyphenyl) -3, 3-dimethyl-1, 5-dioxa-7- ((E) -styryl) -8- (p-tolyl) -2, 4-dioxa-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylic acid ester of the formula:
Figure BDA0002570929540000141
in example 11, pure trans-dimethyl-11- (4-methoxyphenyl) -3, 3-dimethyl-1, 5-dioxa-7- ((E) -styryl) -8- (p-tolyl) -2, 4-dioxa-8-azaspiro [5.5] was obtained by column chromatography purification using a silica gel column]Undec-9-ene-9, 10-dicarboxylate with an isolation yield of 6% and the following structural characterization data:1H NMR(400MHz,CDCl3):7.25-7.20(m,7H,ArH),7.10(t,J＝8.4Hz,4H,ArH),6.89(d,J＝8.4Hz,2H,ArH),6.46(d,J＝16.0Hz,1H,CH),5.93(dd,J1＝16.4Hz,J2＝9.2Hz,1H,CH),4.82(d,J＝8.4Hz,1H,CH),4.58(s,1H,CH),3.81(s,3H,OCH3),3.56(s,3H,OCH3),3.50(s,3H,OCH3),2.28(s,3H,CH3),1.68(s,3H,CH3),1.52(s,3H,CH3)；13C NMR(100MHz,CDCl3):166.1,164.7,164.5,164.5,159.1,138.0,137.2,135.6,130.6,129.8,129.4,128.7,128.4,128.2,126.6,121.9,113.9,105.7,55.1,52.2,51.3,29.8,28.5,21.1；IR(KBr)υ:3465,3002,2951,2842,1749,1694,1587,1509,1439,1389,1242,1129,1037,980,907,848,767,728cm-1；MS(m/z):HRMS(ESI)Calcd.For C36H35NNaO9([M+Na]+):648.2204,found:648.2192.
example 13
Exemplified is the preparation of cis-dimethyl-11- (4-methoxyphenyl) -3, 3-dimethyl-1, 5-dioxa-8-phenyl-7- (((E) -styryl) -2, 4-dioxa-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylate of the formula:
Figure BDA0002570929540000151
5mL of toluene and 0.1800g (1.5mmol) of anhydrous magnesium sulfate were put into a 10mL Schenk tube, and 0.2277g (1.1mmol) of (1E,2E) -N, 3-bis (tert-butyl-phenyl) was addedPhenylpropyl-2-ene-1-imine, 0.2096g (0.8mmol)5- (4-methoxybenzylidene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione, 0.1420g (1mmol) dimethyl butynedioate, reaction at room temperature for 12 hours, suction filtration to remove anhydrous magnesium sulfate after the reaction is finished, evaporation concentration of the filtrate, and purification by silica gel column chromatography to obtain pure cis-dimethyl-11- (4-methoxyphenyl) -3, 3-dimethyl-1, 5-dioxa-8-phenyl-7- (((E) -styryl) -2, 4-dioxa-8-azaspiro [ 5.5.5 ] ]Undec-9-ene-9, 10-dicarboxylate with an isolation yield of 15% and the following structural characterization data:1H NMR(400MHz,CDCl3):7.28(s,2H,ArH),7.24(d,J＝8.0Hz,3H,ArH),7.21-7.19(m,5H,ArH),7.05-7.03(m,2H,ArH),6.81(d,J＝7.6Hz,2H,ArH),6.54(d,J＝16.0Hz,1H,CH),5.42(dd,J1＝16.0Hz,J2＝10.4Hz,1H,CH),4.94(d,J＝10.4Hz,1H,CH),4.88(s,1H,CH),3.76(s,3H,OCH3),3.50(s,3H,OCH3),3.36(s,3H,OCH3),1.20(s,3H,CH3),0.68(s,3H,CH3)；13C NMR(100MHz,CDCl3):167.3,166.2,165.0,162.1,158.9,148.6,139.6,137.0,134.9,131.0,130.8,130.4,128.6,128.5,128.4,128.1,126.5,121.3,106.1,100.9,67.2,59.4,55.2,52.1,51.0,45.9,29.0,28.9；IR(KBr)υ:3449,2998,2948,2843,1736,1700,1612,1505,1443,1386,1291,1142,1104,1060,1024,979,948,909,854,812,761.cm-1；MS(m/z):HRMS(ESI)Calcd.For C35H33NNaO9([M+Na]+):634.2048,found:634.2049.
example 14
Taking as an example the preparation of trans dimethyl-11- (4-methoxyphenyl) -3, 3-dimethyl-1, 5-dioxa-8-phenyl-7- (((E) -styryl) -2, 4-dioxa-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylate of the formula:
Figure BDA0002570929540000161
in example 13, pure trans-dimethyl-11- (4-methoxyphenyl) -3, 3-dimethyl-1, 5-dioxa-8-phenyl-7- (((4-methoxyphenyl) can be obtained by column chromatography purification using a silica gel columnE) -styryl) -2, 4-dioxa-8-azaspiro [5.5]Undec-9-ene-9, 10-dicarboxylate with an isolation yield of 20% and the following structural characterization data:1H NMR(400MHz,CDCl3):7.37(d,J＝7.2Hz,2H,ArH),7.31(t,J＝7.2Hz,2H,ArH),7.24-7.20(m,6H,ArH),7.09(d,J＝6.0Hz,2H,ArH),6.89(d,J＝8.4Hz,2H,ArH),6.49(d,J＝16.0Hz,1H,CH),5.91(dd,J1＝15.6Hz,J2＝8.4Hz,1H,CH),4.85(d,J＝8.8Hz,1H,CH),4.60(s,1H,CH),3.81(s,3H,OCH3),3.55(s,3H,OCH3),3.50(s,3H,OCH3),1.68(s,3H,CH3),1.53(s,3H,CH3)；13C NMR(100MHz,CDCl3):166.1,164.7,164.6,164.4,159.1,147.7,137.4,135.5,130.5,129.9,129.0,129.0,129.0,128.9,128.8,128.8,128.4,128.3,128.1,126.6,121.7,113.9,105.8,57.8,57.8,55.1,52.2,51.3,44.4,29.8,28.5；IR(KBr)υ:3462,3066,2998,2949,2838,1748,1694,1580,1505,1441,1404,1247,1121,1069,1033,980,905,845,755cm-1；MS(m/z):HRMS(ESI)Calcd.For C35H33NNaO9([M+Na]+):634.2048,found:634.2046.
example 15
To illustrate the preparation of cis-dimethyl-8- (3-chlorophenyl) -11- (4-methoxyphenyl) -3, 3-dimethyl-1, 5-dioxa-7- ((E) -styryl) -2, 4-dioxa-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylate of the formula:
Figure BDA0002570929540000162
5mL of methylene chloride and 0.1203g (1.0mmol) of anhydrous magnesium sulfate are added into a 10mL Schenk tube, 0.2653g (1.1mmol) of (1E,2E) -N- (3-chlorophenyl) -3-phenylpropan-2-ene-1-imine and 0.2096g (0.8mmol) of 5- (4-methoxybenzylidene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione are added, 0.1420g (1mmol) of dimethyl butynedioate is added finally, the mixture is reacted for 12 hours at room temperature, after the reaction is finished, the anhydrous magnesium sulfate is removed by suction filtration, the filtrate is evaporated and concentrated, the pure cis-dimethyl-8- (3-chlorophenyl) -11- (4-methoxyphenyl) -3 is obtained by column chromatography purification treatment of a silica gel column, 3-dimethyl-1, 5-dioxa-7- ((E) -styryl) -2, 4-dioxa-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylate with an isolation yield of 18%, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3):7.22-7.17(m,9H,ArH),7.10-7.08(m,2H,ArH),6.81(d,J＝7.6Hz,2H,ArH),6.59(d,J＝15.6Hz,1H,CH),5.42(dd,J1＝15.6Hz,J2＝10.0Hz,1H,CH),4.91(d,J＝10.4Hz,1H,CH),4.86(s,1H,CH),3.76(s,3H,OCH3),3.57(s,3H,OCH3),3.37(s,3H,OCH3),1.22(s,3H,CH3),0.69(s,3H,CH3)；13C NMR(100MHz,CDCl3):167.3,166.1,164.9,162.3,159.0,147.9,140.9,137.7,134.7,133.9,130.9,130.1,129.2,129.0,128.9,128.7,128.3,126.6,120.8,106.3,102.3,67.2,59.3,55.2,52.3,51.2,46.0,29.0,28.9；IR(KBr)υ:3449,2998,2948,2843,1746,1700,1612,1505,1443,1386,1291,1142,1130,1104,1060,1024,979,948,910,864,832,758.cm-1；MS(m/z):HRMS(ESI)Calcd.ForC35H32ClNNaO9([M+Na]+):668.1658,found:668.1650.
Example 16
Taking as an example the preparation of trans-dimethyl-8- (3-chlorophenyl) -11- (4-methoxyphenyl) -3, 3-dimethyl-1, 5-dioxa-7- ((E) -styryl) -2, 4-dioxa-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylate of the formula:
Figure BDA0002570929540000171
in example 15, pure trans-dimethyl-8- (3-chlorophenyl) -11- (4-methoxyphenyl) -3, 3-dimethyl-1, 5-dioxa-7- ((E) -styryl) -2, 4-dioxa-8-azaspiro [5.5] can be obtained by column chromatography purification using a silica gel column]Undec-9-ene-9, 10-dicarboxylate with an isolation yield of 10% and the following structural characterization data:1H NMR(400MHz,CDCl3):7.40(s,1H,ArH),7.24(s,8H,ArH),7.16(s,2H,ArH),6.88(d,J＝7.2Hz,2H,ArH),6.57(d,J＝16.8Hz,1H,CH),5.90(dd,J1＝16.8Hz,J2＝10.0Hz,1H,CH),4.81(d,J＝7.6Hz,1H,CH),4.60(s,1H,CH),3.80(s,3H,OCH3),3.63(s,3H,OCH3),3.50(s,3H,OCH3),1.61(s,3H,CH3),1.54(s,3H,CH3)；13C NMR(100MHz,CDCl3):166.0,164.8,164.7,164.3,159.2,135.4,134.4,130.2,130.0,129.7,128.7,128.6,128.5,128.2,126.7,121.2,114.0,105.9,55.2,52.5,51.5,29.7,28.6；IR(KBr)υ:3485,2999,2950,2839,1740,1702,1582,1512,1475,1435,1380,1291,1265,1221,1139,1100,1062,1026,978,948,910,865,815,781cm-1；MS(m/z):HRMS(ESI)Calcd.For C35H32ClNNaO9([M+Na]+):668.1658,found:668.1658.
example 17
To illustrate the preparation of cis-dimethyl-8- (4-bromophenyl) -11- (4-methoxyphenyl) -3, 3-dimethyl-1, 5-dioxa-7- ((E) -styryl) -2, 4-dioxa-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylate of the formula:
Figure BDA0002570929540000181
5mL of methylene chloride and 0.2406g (2.0mmol) of anhydrous magnesium sulfate are added into a 10mL Schenk tube, 0.3139g (1.1mmol) of (1E,2E) -N- (4-bromophenyl) -3-phenylpropan-2-ene-1-imine and 0.2096g (0.8mmol) of 5- (4-methoxybenzylidene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione are added, 0.1420g (1mmol) of dimethyl butynedioate is finally added, the mixture is reacted for 12 hours at room temperature, after the reaction is finished, the anhydrous magnesium sulfate is removed by suction filtration, the filtrate is evaporated and concentrated, and the pure cis-dimethyl-8- (4-bromophenyl) -11- (4-methoxyphenyl) -3 is obtained by column chromatography purification treatment of a silica gel column, 3-dimethyl-1, 5-dioxa-7- ((E) -styryl) -2, 4-dioxa-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylate with an isolation yield of 21%, and the structural characterization data are as follows:
1H NMR(400MHz,CDCl3):7.39(d,J＝7.6Hz,2H,ArH),7.24-7.17(m,8H,ArH),7.09(d,J＝3.2Hz,3H,ArH),6.80(d,J＝7.6Hz,2H,ArH),6.58(d,J＝15.6Hz,1H,CH),5.41(dd,J1＝15.6Hz,J2＝10.0Hz,1H,CH),4.90(d,J＝10.4Hz,1H,CH),4.86(s,1H,CH),3.76(s,3H,OCH3),3.55(s,3H,OCH3),3.37(s,3H,OCH3),1.22(s,3H,CH3),0.67(s,3H,CH3)；13C NMR(100MHz,CDCl3):167.2,166.0,164.9,162.3,159.0,148.0,138.7,137.6,134.6,132.3,131.5,130.1,128.9,128.7,126.6,122.0,120.6,106.2,102.2,67.2,59.3,55.2,52.3,51.1,46.0,29.0,28.9；IR(KBr)υ:3468,2948,1736,1697,1598,1509,1435,1388,1294,1264,1234,1138,1063,1023,979,905,847,767cm-1；MS(m/z):HRMS(ESI)Calcd.ForC35H32BrNNaO9([M+Na]+):712.1153,found:712.1144.
Example 18
To illustrate the preparation of trans-dimethyl-8- (4-bromophenyl) -11- (4-methoxyphenyl) -3, 3-dimethyl-1, 5-dioxa-7- ((E) -styryl) -2, 4-dioxa-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylate of the formula:
Figure BDA0002570929540000191
in example 17, pure trans-dimethyl-8- (4-bromophenyl) -11- (4-methoxyphenyl) -3, 3-dimethyl-1, 5-dioxa-7- ((E) -styryl) -2, 4-dioxa-8-azaspiro [5.5] was obtained by column chromatography purification using a silica gel column]Undec-9-ene-9, 10-dicarboxylate with an isolation yield of 12% and the following structural characterization data:1H NMR(400MHz,CDCl3):7.43(d,J＝8.4Hz,2H,ArH),7.22(d,J＝8.8Hz,6H,ArH),7.15-7.13(m,2H,ArH),6.88(d,J＝8.4Hz,2H,ArH),6.53(d,J＝15.2Hz,1H,CH),5.89(dd,J1＝16.0Hz,J2＝8.4Hz,1H,CH),4.79(d,J＝8.4Hz,1H,CH),4.59(s,1H,CH),3.80(s,3H,OCH3),3.60(s,3H,OCH3),3.49(s,3H,OCH3),1.63(s,3H,CH3),1.53(s,3H,CH3)；13C NMR(100MHz,CDCl3):166.0,164.7,164.4,159.2,137.7,135.3,132.0,130.3,129.9,128.6,128.6,126.7,121.2,114.0,105.9,55.2,52.5,51.5,29.7,29.7,29.7,28.6；IR(KBr)υ:3000,2947,1744,1693,1587,1485,1438,1301,1243,1120,1062,1016,977,907,838,771cm-1；MS(m/z):HRMS(ESI)Calcd.For C35H32BrNNaO9([M+Na]+):712.1153,found:712.1141.
example 19
To illustrate the preparation of cis-dimethyl-8, 11-bis (4-methoxyphenyl) -3, 3-dimethyl-7- ((E) -2-nitrostyryl) -1, 5-dioxa-2-, 4-dioxa-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylate of the formula:
Figure BDA0002570929540000201
adding 5mL of dichloromethane and 0.1800g (1.5mmol) of anhydrous magnesium sulfate into a 10mL Schenk tube, adding 0.3092g (1.1mmol) of (1E,2E) -N- (4-methoxyphenyl) -3- (2-nitrophenyl) prop-2-ene-1-imine, 0.2096g (0.8mmol) of 5- (4-methoxybenzylidene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione, finally adding 0.1420g (1mmol) of dimethyl butynedioate, reacting at 30 ℃ for 24 hours, removing the anhydrous magnesium sulfate by suction filtration after the reaction is finished, evaporating and concentrating the filtrate by column chromatography, purifying by a silica gel column to obtain pure cis-dimethyl-8, 11-bis (4-methoxyphenyl) -3, 3-dimethyl-7- ((E) -2-nitrostyryl) -1, 5-dioxa-2-, 4-dioxa-8-azaspiro [5.5 ]Undec-9-ene-9, 10-dicarboxylate with an isolation yield of 17% and the following structural characterization data:1H NMR(400MHz,CDCl3):7.94(d,J＝7.6Hz,1H,ArH),7.44-7.36(m,3H,ArH),7.20(d,J＝6.4Hz,3H,ArH),7.05(d,J＝15.6Hz,1H,ArH),6.84-6.79(m,5H,ArH),5.38(dd,J1＝15.6Hz,J2＝10.0Hz,1H,CH),4.97(d,J＝10.0Hz,1H,CH),4.87(s,1H,CH),3.78(s,3H,OCH3),3.54(s,3H,OCH3),3.35(s,3H,OCH3),1.27(s,3H,CH3),0.67(s,3H,CH3)；13C NMR(100MHz,CDCl3):166.9,166.1,164.9,162.2,159.0,159.0,148.7,147.3,133.5,133.2,132.2,132.2,131.3,130.3,129.1,128.8,126.4,124.6,113.5,106.0,100.5,67.0,58.9,55.4,55.2,52.2,50.9,46.1,29.1,28.7；IR(KBr)υ:3466,3004,2952,2843,1743,1682,1598,1516,1436,1388,1346,1295,1233,1141,1104,1028,965,912,841,790,743.cm-1；MS(m/z):HRMS(ESI)Calcd.For C36H34N2NaO12([M+Na]+):709.2004,found:709.1997.
example 20
By way of example for the preparation of trans dimethyl-8, 11-bis (4-methoxyphenyl) -3, 3-dimethyl-7- ((E) -2-nitrostyryl) -1, 5-dioxa-2-, 4-dioxa-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylate of the formula:
Figure BDA0002570929540000211
pure trans-dimethyl-8, 11-bis (4-methoxyphenyl) -3, 3-dimethyl-7- ((E) -2-nitrostyryl) -1, 5-dioxa-2-, 4-dioxa-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylate was obtained in 15% isolation yield by column chromatography purification on silica gel in example 19, and the structural characterization data were as follows:
1H NMR(400MHz,CDCl3):7.92(d,J＝8.0Hz,1H,ArH),7.51(t,J＝7.2Hz,1H,ArH),7.42-7.35(m,4H,ArH),7.24(s,1H,ArH),7.15(s,1H,ArH),6.94(d,J＝15.6Hz,2H,CH),6.88-6.85(m,4H,ArH),5.94(dd,J1＝14.4Hz,J2＝7.6Hz,1H,CH),4.77(d,J＝7.6Hz,1H,CH),4.67(s,1H,CH),3.80(s,6H,2OCH3),3.57(s,3H,OCH3),3.49(s,3H,OCH3),1.57(s,6H,2CH3)；13C NMR(100MHz,CDCl3):166.1,164.7,163.9,159.2,159.1,147.4,133.4,133.1,132.1,130.3,130.2,130.0,129.5,128.9,127.2,124.5,114.0,114.0,113.9,105.9,55.4,55.2,52.4,51.4,29.6,28.7；IR(KBr)υ:3635,3003,2952,1746,1691,1604,1515,1437,1347,1290,1245,1132,1033,980,907,838,767cm-1；MS(m/z):HRMS(ESI)Calcd.ForC36H34N2NaO12([M+Na]+):709.2004,found:709.1999.
example 21
As an example of the preparation of cis-dimethyl-11- (4- (tert-butyl) phenyl) -7- ((E) -4-fluorostyryl) -8- (4-methoxyphenyl) -3, 3-dimethyl-1, 5-dioxa-2, 4-dioxine-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylic acid ester of the formula:
Figure BDA0002570929540000212
adding 5mL of dichloromethane and 0.1800g (1.5mmol) of anhydrous magnesium sulfate into a 10mL Schenk tube, adding 0.2795g (1.1mmol) of (1E,2E) -3- (4-fluorophenyl) -N- (4-methoxyphenyl) prop-2-ene-1-imine and 0.2305g (0.8mmol) of 5- (4- (tert-butyl) benzylidene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione, finally adding 0.1420g (1mmol) of dimethyl butynedioate, reacting at room temperature for 14 hours, removing anhydrous magnesium sulfate by suction filtration after the reaction is finished, evaporating and concentrating the filtrate, and purifying by using a silica gel column chromatography to obtain pure cis-dimethyl-11- (4- (tert-butyl) phenyl) -7- ((E) -4-fluorostyryl) -8- (4-methoxylphenyl) -7 Phenylphenyl) -3, 3-dimethyl-1, 5-dioxa-2, 4-dioxine-8-azaspiro [ 5.5% ]Undec-9-ene-9, 10-dicarboxylate with an isolation yield of 34% and the following structural characterization data:1H NMR(400MHz,CDCl3):7.28(s,2H,ArH),7.18(s,3H,ArH),7.06-7.03(m,3H,ArH),6.90(t,J＝8.4Hz,2H,ArH),6.76(s,2H,ArH),6.48(d,J＝16.0Hz,1H,CH),5.37(dd,J1＝15.6Hz,J2＝9.6Hz,1H,CH),4.87(d,J＝10.0Hz,1H,CH),4.85(s,1H,CH),3.76(s,3H,OCH3),3.54(s,3H,OCH3),3.33(s,3H,OCH3),1.24(s,9H,3CH3),1.18(s,3H,CH3),0.52(s,3H,CH3)；13C NMR(100MHz,CDCl3):167.3,166.1,165.1,164.0,162.0,161.5,158.9,150.6,148.8,135.6,135.3,132.4,131.2,131.2,128.2,128.1,121.2,121.2,115.7,115.5,113.4,106.1,100.2,67.2,59.3,55.3,52.1,50.8,46.3,34.3,31.1,29.0,28.3；IR(KBr)υ:3475,2959,1725,1605,1510,1439,1389,1292,1232,1137,1101,1063,1027,991,907,836,735cm-1；MS(m/z):HRMS(ESI)Calcd.For C39H40FNNaO9([M+Na]+):708.2579,found:708.2569.
example 22
As an example of the preparation of trans-dimethyl-11- (4- (tert-butyl) phenyl) -7- ((E) -4-fluorostyryl) -8- (4-methoxyphenyl) -3, 3-dimethyl-1, 5-dioxa-2, 4-dioxine-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylic acid ester of the formula:
Figure BDA0002570929540000221
in example 21, pure trans-dimethyl-11- (4- (tert-butyl) phenyl) -7- ((E) -4-fluorostyryl) -8- (4-methoxyphenyl) -3, 3-dimethyl-1, 5-dioxa-2, 4-dioxine-8-azaspiro [5.5] was obtained by column chromatography purification using a silica gel column]Undec-9-ene-9, 10-dicarboxylate with an isolation yield of 49% and the following structural characterization data:1H NMR(400MHz,CDCl3):7.35(d,J＝8.0Hz,2H,ArH),7.30(d,J＝9.2Hz,2H,ArH),7.22(d,J＝8.0Hz,2H,ArH),7.08(s,2H,ArH),6.90(t,J＝8.4Hz,2H,ArH),6.81(d,J＝8.8Hz,2H,ArH),6.40(d,J＝15.6Hz,1H,CH),5.85(dd,J1＝16.0Hz,J2＝8.4Hz,1H,CH),4.79(d,J＝8.8Hz,1H,CH),4.58(s,1H,CH),3.76(s,3H,OCH3),3.56(s,3H,OCH3),3.50(s,3H,OCH3),1.55(s,3H,CH3),1.51(s,3H,CH3),1.31(s,9H,3CH3)；13C NMR(100MHz,CDCl3):166.2,164.7,164.5,159.0,150.7,135.6,130.7,130.7,128.5,128.4,128.3,128.3,126.6,125.5,125.5,122.2,113.8,105.8,55.3,52.3,51.4,34.5,31.3,30.0,28.3；IR(KBr)υ:3519,29554,1750,1690,1580,1509,1439,1293,1233,1128,1061,980,948,904,827cm-1；MS(m/z):HRMS(ESI)Calcd.For C39H40FNNaO9([M+Na]+) 708.2579, found:708.2574. comparative example 23 (compare with example 1-2) the order of addition of the reactants has an effect on the reaction results:
adding 5mL of dichloromethane and 0.1800g (1.5mmol) of anhydrous magnesium sulfate into a 10mL Schenk tube, adding 0.1420g (1mmol) of butynedioic acid dimethyl ester, then adding 0.2937g (1.1mmol) of (1E,2E) -N, 3-bis (4-methoxyphenyl) prop-2-ene-1-imine, finally adding 0.2096g (0.8mmol) of 5- (4-methoxybenzylidene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione, reacting at room temperature for 12 hours, removing the anhydrous magnesium sulfate by suction filtration after the reaction is finished, evaporating and concentrating the filtrate, purifying by silica gel column chromatography, and confirming the structure, wherein the target product cis-dimethyl-8, 11-bis (4-methoxyphenyl) -7- ((E) -4-methoxystyryl) -3 in the reaction product, 3-dimethyl-1, 5-dioxa-2, 4-dioxa-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylate and/or trans-dimethyl-8, 11-bis (4-methoxyphenyl) -7- ((E) -4-methoxystyryl) -3, 3-dimethyl-1, 5-dioxa-2, 4-dioxa-8-azaspiro [5.5] undec-9-ene-9, 10-dicarboxylate are present in very small amounts.
It can be seen from this that: the order of addition of the reactants has a great influence on the reaction, which directly influences that the target product cannot be obtained.
The embodiment provided by the invention shows that the method for obtaining the cis/trans spiro compound containing the oxygen nitrogen heteroatom in one step through multi-component reaction has the advantages of easily obtained raw materials, no need of a catalyst, simple operation, high yield and large substrate expansion range.
The present invention has been disclosed in terms of the preferred embodiment, but it is not intended to be limited to the embodiment, and all technical solutions obtained by substituting or converting the equivalent embodiments fall within the scope of the present invention.

Claims (10)

1. A method for synthesizing a cis/trans spiro compound containing an oxygen nitrogen heteroatom, comprising: taking an organic solvent as a solvent, firstly adding anhydrous magnesium sulfate, and then carrying out multi-component reaction on a compound shown in a formula 1, a compound shown in a formula 2 and dimethyl butynedioate shown in a formula 3 according to a certain molar ratio to obtain a cis-form oxygen-containing nitrogen heteroatom spiro compound shown in a formula 4 and/or a trans-form oxygen-containing nitrogen heteroatom spiro compound shown in a formula 5;
Figure FDA0002570929530000011
in the formula Ar1Represents any one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl and 2-nitrophenyl, wherein Ar is 2Represents phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-halophenyl or 3-halophenylAny one of (1), wherein Ar is3Represents any one of 4-methoxyphenyl and 4-tert-butylphenyl.
2. The method of claim 1, wherein: in the formula Ar1Represents any one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl and 2-nitrophenyl, wherein Ar is2Represents any one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-halophenyl and 3-halophenyl, wherein Ar is3Represents any one of 4-methoxyphenyl and 4-tert-butylphenyl.
3. The method of claim 1, wherein: the reaction condition is that the reaction is carried out at 20-30 ℃.
4. The method of claim 1, wherein: the reaction condition is that the reaction is carried out for 12 to 14 hours at room temperature.
5. The method of claim 1, wherein: two configuration products can be obtained by one-step reaction: a cis-form spiro compound containing an oxygen nitrogen heteroatom represented by formula 4 and a trans-form spiro compound containing an oxygen nitrogen heteroatom represented by formula 5.
6. The method of claim 1, wherein: the addition amount of the anhydrous magnesium sulfate is 0.5-2 times of that of the compound shown in the formula 1, and preferably, the addition amount of the anhydrous magnesium sulfate is 1.5 times of the molar amount of the compound shown in the formula 1.
7. The method of claim 1, wherein: the organic solvent for reaction is any one or more of dichloromethane, trichloromethane, acetonitrile, tetrahydrofuran and toluene, and dichloromethane is preferred.
8. The method of claim 1, wherein: the molar ratio of the compound shown in the formula 1 to the compound shown in the formula 2 to the dimethyl butynedioate is (1-1.2): 0.7-0.9): 1.
9. The method of claim 8, wherein: the molar ratio of the compound shown in the formula 1 to the compound shown in the formula 2 to the dimethyl butynedioate is 1.1:0.8: 1.
10. The method according to any one of claims 1-9, wherein: the order of adding reactants in the reaction is that organic solvent and anhydrous magnesium sulfate are added firstly, then the compound shown in the formula 1 and the compound shown in the formula 2 are added, and finally dimethyl butynedioate is added.
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