CN107586272B - Polysubstituted benzo-bicyclo [2.2.2] octane derivative and preparation method thereof - Google Patents
Polysubstituted benzo-bicyclo [2.2.2] octane derivative and preparation method thereof Download PDFInfo
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Abstract
The invention provides a polysubstituted benzo-bicyclo [2.2.2]The octane derivative has a structural formula shown as a formula (I), and the preparation method comprises the following steps: dissolving the o-phenylenediene derivative and the compound containing the olefin structure in an organic solvent at room temperature in the air or nitrogen atmosphere, uniformly mixing, placing under an ultraviolet lamp for illumination until the reaction is complete, performing rotary evaporation on the solvent, and performing silica gel column chromatography separation and purification. The polysubstituted benzobicyclics [2.2.2] of the invention]The octane derivative has more biological activity and great research value, the preparation method can be carried out at normal temperature and normal pressure, the reaction condition is mild, transition metal catalysis is not needed, and the method has the advantages of simple operation, no pollution, safety, environmental protection, low cost and the like.Wherein R is1、R2Is an ester group, an acyl group or a nitrile group, R3Is hydrogen, alkoxy, halogen or alkyl; x is O, NH, N-CH3、N‑C2H5N-phenyl, N-tert-butyl or N-benzyl.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a polysubstituted benzo-bicyclo [2.2.2] octane derivative and a preparation method thereof.
Background
The bicyclo [2.2.2] octane carbon skeleton widely exists in natural products and non-natural products with bioactivity, and is an important raw material for synthesizing other natural products due to the inherent stereo structure of the bicyclo ring, for example, cis-1, 4-disubstituted cyclohexane can be obtained by cutting off any carbon-carbon bond on the bicyclo ring. According to the literature reports, a series of benzo-bicyclo [2.2.2] octane derivatives have various biological activities, and have the following structures shown as compounds 1-3, wherein the compound 1 is a calcium ion channel blocker, the compound 2 is a cannabinoid receptor ligand, and the compound 3 is a tumor necrosis factor-alpha inhibitor, so that the synthesis of the polysubstituted benzo-bicyclo [2.2.2] octane derivatives is widely concerned by chemists.
At present, few reports are reported for synthesizing polysubstituted benzo-bicyclo [2.2.2] octane derivatives, and most of the existing synthetic methods adopt Lewis acid or transition metal catalytic systems, so that the environment is inevitably polluted and damaged greatly, the yield is low, or the steps are complicated. Therefore, a method for synthesizing the benzo-bicyclo [2.2.2] octane derivative which is environment-friendly, simple in method, few in steps and high in yield is sought, and a problem to be solved is needed at present.
Disclosure of Invention
The first purpose of the invention is to provide a polysubstituted benzo bicyclo [2.2.2] octane derivative, the structural formula of which is shown in the formula (I):
wherein R is1、R2Is an ester group, an acyl group or a nitrile group, R3Is hydrogen, alkoxy, halogen or alkyl; x is O, NH, N-CH3、N-C2H5N-phenyl, N-tert-butyl or N-benzyl; the ester group is a methyl ester group, an ethyl ester group, a propyl ester group, a tert-butyl ester group, and the like, and the alkyl group generally includes, but is not limited to: methyl, ethyl, propyl, tert-butyl.
Preferably, the acyl group is a formyl group, an acetyl group or a benzoyl group.
It is a second object of the present invention to provide a process for preparing polysubstituted benzobicyclo [2.2.2] octane derivatives, comprising the steps of:
dissolving the o-phenylenediene derivative shown in the formula (II) and the compound containing the olefin structure shown in the formula (III) in an organic solvent at room temperature in the air or nitrogen atmosphere, uniformly mixing, placing under an ultraviolet lamp for illumination until the reaction is complete, performing rotary evaporation on the solvent, and performing silica gel column chromatography separation and purification to obtain the polysubstituted benzo-bicyclo [2.2.2] octane derivative;
wherein, R1 and R2 are ester group, acyl group or nitrile group, and R3 is hydrogen, alkoxy, halogen or alkyl; x is O, NH, N-CH3、N-C2H5N-phenyl, N-tert-butyl or N-benzyl. The reaction route is as follows:
preferably, the compound containing an olefin structure is maleic anhydride, maleimide, N-methylmaleimide, N-ethylmaleimide, N-phenylmaleimide, N-t-butylmaleimide or N-benzylmaleimide.
Preferably, the feeding molar ratio of the o-phenylenediene derivative to the compound containing the olefin structure is 1: 1-3.
Preferably, the organic solvent is selected from acetonitrile, tetrahydrofuran, benzene, toluene, dimethyl sulfoxide or N, N-dimethylformamide.
Preferably, the organic solvent is fed in a volume of 30 to 90mL/mmol of the o-phenylenediene derivative.
Preferably, the reaction time of the ultraviolet irradiation is 4-10 h.
Preferably, the solvent used for silica gel column chromatography separation and purification is a mixed solvent of petroleum ether and ethyl acetate.
More preferably, the volume ratio of the petroleum ether to the ethyl acetate is 4-10: 1.
The invention has the beneficial effects that:
1. the invention provides a polysubstituted benzo-bicyclo [2.2.2] octane derivative which has potential biological activity and great research value. The derivative with the structure of the benzo-bicyclo [2.2.2] octane has more biological activity, so the derivative has higher research value and can be used for screening a medicine lead compound and used by scientific research units for biological activity research and the like. The invention can also be used as a raw material for synthesizing other benzo-bicyclo [2.2.2] octane derivatives.
2. The invention provides a simple one-step method for synthesizing polysubstituted benzo-bicyclo [2.2.2] octane derivatives, which solves the problems of complicated synthesis steps, low yield and poor environmental protection of the existing benzo-bicyclo [2.2.2] octane derivatives, can react at normal temperature and normal pressure, has mild reaction conditions, does not need transition metal catalysis, and has the advantages of simple operation, no pollution, safety, environmental protection, low cost and the like.
Detailed Description
In order to make the technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
100mg (0.41mmol) of dimethyl ester-substituted o-phenylenediene, 92mg (0.82mmol) of N-methylmaleimide and 20mL of acetonitrile are added into a 50mL quartz tube, stirred uniformly, introduced with nitrogen for 30 minutes, placed under an ultraviolet lamp, and irradiated at room temperature for reaction for 4 hours. After the reaction is finished, concentrating and spin-drying the reaction solvent by a rotary evaporator, and then mixing the reaction solvent with petroleum ether in a volume ratio of 4: 1: the mixed solution of ethyl acetate is used as eluent to carry out silica gel column chromatography purification and separation to obtain the corresponding polysubstituted benzo bicyclo [2.2.2] octane derivative, and the reaction formula is as follows:
the product purity was 99%, yield was 84%, and its nuclear magnetic data analysis was:1H NMR(400MHz,CDCl3)7.26–7.14(m,3H),7.14–6.99(m,1H),4.06(t,J=2.7Hz,1H),3.93(t,J=3.0Hz,1H),3.82(s,3H),3.59(s,3H),3.47(dd,J=5.5,2.2Hz,1H),3.23(dd,J=8.5,3.2Hz,1H),3.19(dd,J=5.5,2.9Hz,1H),3.11(dd,J=8.5,3.2Hz,1H),2.47(s,3H).
13C NMR(151MHz,CDCl3)177.43,176.94,173.26,172.24,136.34,134.59,128.21,128.20,126.13,125.16,52.83,52.45,44.61,44.43,43.88,40.66,38.75,38.53,24.29.
example 2
To a 50mL quartz tube, 90mg (0.37mmol) of dimethyl ester-substituted o-phenylenediene, 137mg (0.78mmol) of N-benzylmaleimide and 20mL of acetonitrile were added, and after stirring uniformly, nitrogen gas was introduced thereinto for 30 minutes, and the mixture was placed under an ultraviolet lamp and reacted at room temperature for 6 hours by irradiation. After the reaction is finished, concentrating and spin-drying the reaction solution by a rotary evaporator, and then mixing the reaction solution with petroleum ether in a volume ratio of 6: 1: the mixed solution of ethyl acetate is used as eluent to carry out silica gel column chromatography purification and separation to obtain the corresponding polysubstituted benzo bicyclo [2.2.2] octane derivative, and the reaction formula is as follows:
the product purity was 99.2% and yield was 83%. The nuclear magnetic data analysis is as follows:1H NMR(400MHz,CDCl3)7.25–7.01(m,7H),6.57(d,J=7.1Hz,2H),4.27(s,2H),4.09(t,J=2.7Hz,1H),3.96(t,J=3.0Hz,1H),3.83(s,3H),3.60(s,3H),3.49(dd,J=5.4,2.2Hz,1H),3.26(dd,J=8.6,3.2Hz,1H),3.18(dd,J=5.4,2.9Hz,1H),3.15(dd,J=8.7,3.2Hz,1H).
13C NMR(151MHz,CDCl3)177.05,176.58,173.26,172.21,136.33,134.76,134.54,128.37,128.34,128.32,127.35,127.24,126.17,125.20,,52.86,52.46,44.81,44.66,43.80,42.00,40.59,38.67,38.46.
example 3
To a 50mL quartz tube, 60mg (0.22mmol) of diethyl ester-substituted o-phenylenediene, 48mg (0.43mmol) of N-methylmaleimide and 15mL of acetonitrile were added, and after stirring uniformly, the mixture was placed under an ultraviolet lamp and reacted at room temperature with light for 7 hours. After the reaction is finished, concentrating and spin-drying the reaction solution by a rotary evaporator, and then mixing the reaction solution with petroleum ether in a volume ratio of 8: 1: using the mixed solution of ethyl acetate as an eluent to carry out silica gel column chromatography purification and separation to obtain the corresponding polysubstituted benzo bicyclo [2.2.2] octane derivative, wherein the chemical reaction formula is as follows:
the product purity was 99% and the yield was 71%. The nuclear magnetic data analysis is as follows:1H NMR(400MHz,CDCl3)7.28–7.15(m,3H),7.14–7.03(m,1H),4.34–4.17(m,2H),4.12–3.98(m,3H),3.94(t,J=3.1Hz,1H),3.46(dd,J=5.4,2.4Hz,1H),3.24(dd,J=8.5,3.2Hz,1H),3.20(dd,J=5.4,2.9Hz,1H),3.12(dd,J=8.5,3.3Hz,1H),2.48(d,J=4.1Hz,3H),1.36(t,J=7.1Hz,3H),1.19(t,J=7.1Hz,3H).
13C NMR(151MHz,CDCl3)177.48,177.08,172.89,171.78,136.47,134.61,128.17,128.10,126.08,125.20,61.80,61.29,44.56,44.43,43.89,40.73,38.77,38.72,24.30,14.26,14.18.
example 4
To a 50mL quartz tube, 65mg (0.22mmol) of dimethyl fluoroaluminate-substituted o-phenylenediene, 96mg (0.88mmol) of N-methylmaleimide and 20mL of acetonitrile were added, and after stirring, the mixture was placed under an ultraviolet lamp and reacted with light at room temperature for 7 hours. After the reaction is finished, concentrating and spin-drying the reaction solution by a rotary evaporator, and then mixing the reaction solution with petroleum ether in a volume ratio of 4: 1: using the mixed solution of ethyl acetate as eluent to carry out silica gel column chromatography purification and separation,
to obtain the corresponding polysubstituted benzo-bicyclo [2.2.2] octane derivative, wherein the chemical reaction formula is shown as follows:
the product purity was 99% and the yield was 67%. The nuclear magnetic data analysis is as follows:1H NMR(400MHz,CDCl3)7.22–7.03(m,1H),6.96–6.79(m,2H),4.37–4.18(m,2H),4.11–4.01(m,3H),3.94(dd,J=7.6,3.2Hz,1H),3.45(td,J=5.7,2.4Hz,1H),3.24(ddd,J=8.5,3.0,1.9Hz,1H),3.17(ddd,J=8.1,5.4,2.9Hz,1H),3.11(ddd,J=8.4,4.9,3.4Hz,1H),2.53(s,3H),1.36(t,J=7.1Hz,3H),1.23–1.16(m,3H).
13C NMR(151MHz,CDCl3)177.25,176.72,172.64,171.55,162.27(d,J=252.0Hz),136.79(d,J=7.8Hz),132.19,126.85(d,J=8.6Hz),115.04(d,J=9.0Hz),113.61(d,J=22.3Hz),44.67,44.19,43.57,40.66,38.82,38.14,24.41,14.24,14.17.
example 5
80mg (0.33mmol) of dimethyl ester-substituted o-phenylenediene, 32mg (0.33mmol) of maleic anhydride and 25mL of dimethyl sulfoxide are added into a 50mL quartz tube, stirred uniformly, placed under an ultraviolet lamp, and subjected to light reaction at room temperature for 8 hours. After the reaction is finished, concentrating and spin-drying the reaction solution by a rotary evaporator, and then mixing the reaction solution with petroleum ether in a volume ratio of 10: 1: using the mixed solution of ethyl acetate as eluent to carry out silica gel column chromatography purification and separation,
to obtain the corresponding polysubstituted benzo-bicyclo [2.2.2] octane derivative, the chemical reaction formula of which is as follows:
the product purity was 99% and the yield was 55%. The nuclear magnetic data analysis is as follows:1H NMR(400MHz,CDCl3)7.39–7.06(m,4H),4.11(t,J=2.7Hz,1H),3.97(t,J=3.0Hz,1H),3.82(s,3H),3.61(s,3H),3.55–3.49(m,1H),3.47–3.39(m,2H),3.21(dd,J=5.4,2.9Hz,1H).
13C NMR(151MHz,CDCl3)172.98,171.68,171.39,170.87,135.86,134.04,128.98,126.47,125.51,53.03,52.67,44.61,44.17,44.11,41.55,38.54,38.32.
example 6
To a 50mL quartz tube, 100mg (0.3mmol) of dibenzoyl-substituted o-phenylenediene was added,
65mg (0.59mmol) of N-methylmaleimide and 25mL of N, N-dimethylformamide are uniformly stirred and placed under an ultraviolet lamp to perform a light reaction for 10 hours at room temperature. After the reaction is finished, concentrating and spin-drying the reaction solution by a rotary evaporator, and then mixing the reaction solution with petroleum ether in a volume ratio of 4: 1: the mixed solution of ethyl acetate is used as eluent to carry out silica gel column chromatography purification and separation to obtain the corresponding polysubstituted benzo bicyclo [2.2.2] octane derivative, and the chemical reaction formula is as follows:
the purity of the product was 98.5% with a yield of 62%. The nuclear magnetic data analysis is as follows:1H NMR(400MHz,CDCl3)8.08(d,J=7.3Hz,2H),7.90(d,J=7.3Hz,2H),7.67–7.48(m,6H),7.28–7.25(m,2H),7.18(td,J=6.9,2.4Hz,1H),6.88(d,J=7.3Hz,1H),4.66(dd,J=5.2,1.9Hz,1H),4.55(dd,J=5.2,2.5Hz,1H),4.06–3.97(m,1H),3.91(t,J=2.8Hz,1H),3.54(dd,J=8.4,3.2Hz,1H),3.18(dd,J=8.4,3.3Hz,1H),2.46(s,3H).
13C NMR(151MHz,CDCl3)199.86,198.53,177.67,177.16,136.38,135.87,135.59,134.25,134.10,133.43,129.13,129.00,128.81,128.41,128.34,128.16,126.25,124.96,45.94,45.08,44.26,40.58,40.31,39.65,24.33.
example 7
100mg (0.3mmol) of dibenzoyl-substituted o-phenylenediene, 58mg (0.59mmol) of maleic anhydride and 15mL of benzene were added into a 50mL quartz tube, stirred uniformly, placed under an ultraviolet lamp, and reacted at room temperature for 4 hours by illumination. After the reaction is finished, concentrating and spin-drying the reaction solution by a rotary evaporator, and then mixing the reaction solution with petroleum ether in a volume ratio of 4: 1: the mixed solution of ethyl acetate is used as eluent to carry out silica gel column chromatography purification and separation to obtain the corresponding polysubstituted benzo bicyclo [2.2.2] octane derivative, and the chemical reaction formula is as follows:
the product purity was 99% and the yield was 51%. The nuclear magnetic data analysis is as follows:1H NMR(400MHz,CDCl3)8.07(d,J=7.4Hz,2H),7.87(d,J=7.3Hz,2H),7.60(m,5H),7.42–7.18(m,4H),6.97(d,J=7.3Hz,1H),4.57(qd,J=5.2,2.2Hz,2H),4.17–3.99(m,1H),3.94(t,J=2.8Hz,1H),3.84(dd,J=9.3,3.3Hz,1H),3.53(dd,J=9.4,3.4Hz,1H).
13C NMR(151MHz,CDCl3)199.80,197.85,171.56,171.11,135.83,135.60,135.31,134.42,133.67,133.65,129.25,129.10,129.10,128.91,128.80,128.35,126.60,125.31,45.79,44.91,44.46,41.53,40.02,39.40.
example 8
To a 150mL quartz tube, 1.00g (4mmol) of the corresponding dimethyl ester-substituted o-phenylenediene, 0.80g (7.2mmol) of N-methylmaleimide and 150mL of toluene were added, stirred well, placed under an ultraviolet lamp, and reacted at room temperature with light for 6 hours. After the reaction is finished, concentrating and spin-drying the reaction solvent by a rotary evaporator, and then mixing the reaction solvent with petroleum ether in a volume ratio of 4: 1: purifying by silica gel column chromatography using ethyl acetate mixture as eluent
Separating to obtain the corresponding polysubstituted benzo bicyclo [2.2.2] octane derivative, wherein the chemical reaction formula is as follows:
the product purity was 98.9% and the yield was 82%. The nuclear magnetic data analysis is as follows:1H NMR(400MHz,CDCl3)7.26–7.14(m,3H),7.14–6.99(m,1H),4.06(t,J=2.7Hz,1H),3.93(t,J=3.0Hz,1H),3.82(s,3H),3.59(s,3H),3.47(dd,J=5.5,2.2Hz,1H),3.23(dd,J=8.5,3.2Hz,1H),3.19(dd,J=5.5,2.9Hz,1H),3.11(dd,J=8.5,3.2Hz,1H),2.47(s,3H).
13C NMR(151MHz,CDCl3)177.43,176.94,173.26,172.24,136.34,134.59,128.21,128.20,126.13,125.16,52.83,52.45,44.61,44.43,43.88,40.66,38.75,38.53,24.29.
example 9
To a 150mL quartz tube, 1.00g (3.6mmol) of diethyl ester-substituted o-phenylenediene, 0.91g (7.3mmol) of N-ethylmaleimide and 145mL of acetonitrile were added, and after stirring, the mixture was placed under an ultraviolet lamp and reacted at room temperature with light for 6 hours. After the reaction is finished, concentrating and spin-drying the reaction solvent by a rotary evaporator, and then mixing the reaction solvent with petroleum ether in a volume ratio of 4: 1: the mixed solution of ethyl acetate is used as eluent to carry out silica gel column chromatography purification and separation to obtain the corresponding polysubstituted benzo bicyclo [2.2.2] octane derivative, and the chemical reaction formula is as follows:
the product purity was 98.2% and the yield was 70%. The nuclear magnetic data are:1H NMR(400MHz,CDCl3)7.17–7.10(m,3H),7.06(d,J=6.0Hz,1H),4.27–4.16(m,2H),4.05–3.93(m,3H),3.88(s,1H),3.46–3.37(m,1H),3.15(dd,J=7.8,3.2Hz,2H),3.04(dd,J=12.9,7.6Hz,3H),1.30(t,J=7.1Hz,3H),1.13(t,J=7.1Hz,3H),0.29(t,J=7.1Hz,3H).
13C NMR(150MHz,CDCl3)177.21,176.83,172.80,171.76,136.61,134.78,127.96,127.90,126.12,125.27,61.70,61.19,44.48,44.32,43.59,40.42,38.84,38.81,33.00,14.21,14.13,11.86.
example 10
To a 50mL quartz tube, 90mg (0.37mmol) of dimethyl ester-substituted o-phenylenediene, 112mg (0.73mmol) of N-t-butylmaleimide and 20mL of acetonitrile were added, and after stirring, nitrogen gas was introduced thereinto for 30 minutes, and the mixture was placed under an ultraviolet lamp and reacted with light at room temperature for 6 hours. After the reaction is finished, concentrating and spin-drying the reaction solution by a rotary evaporator, and then mixing the reaction solution with petroleum ether in a volume ratio of 6: 1: the mixed solution of ethyl acetate is used as eluent to carry out silica gel column chromatography purification and separation to obtain the corresponding polysubstituted benzo bicyclo [2.2.2] octane derivative, and the reaction formula is as follows:
the product purity was 99.2% with a yield of 73%. The nuclear magnetic data analysis is as follows:1H NMR(400MHz,CDCl3)7.25–7.07(m,4H),4.01(t,1H),3.89(t,J=3.1Hz,1H),3.82(s,3H),3.60(s,3H),3.46(dd,J=5.5,2.3Hz,1H),3.18(dd,J=5.5,2.9Hz,1H),3.06(dd,J=8.8,3.3Hz,1H),2.94(dd,J=8.8,3.3Hz,1H),1.08(s,9H).
13C NMR(150MHz,CDCl3)178.54,178.09,173.31,172.44,136.78,135.05,127.96,127.94,126.27,125.34,58.07,52.77,52.40,44.65,44.37,43.34,40.15,39.17,38.93,27.68.
example 11
To a 50mL quartz tube, 90mg (0.37mmol) of dimethyl ester-substituted o-phenylenediene, 71mg (0.73mmol) of maleimide and 20mL of acetonitrile were added, stirred uniformly, introduced with nitrogen for 30 minutes, placed under an ultraviolet lamp, and subjected to a light reaction at room temperature for 6 hours. After the reaction is finished, concentrating and spin-drying the reaction solution by a rotary evaporator, and then mixing the reaction solution with petroleum ether in a volume ratio of 6: 1: the mixed solution of ethyl acetate is used as eluent to carry out silica gel column chromatography purification and separation to obtain the corresponding polysubstituted benzo bicyclo [2.2.2] octane derivative, and the reaction formula is as follows:
the product purity was 99.2% and the yield was 70%. The nuclear magnetic data analysis is as follows:1H NMR(400MHz,CDCl3)7.67(s,1H),7.29–7.02(m,4H),4.06(t,J=2.7Hz,1H),3.93(t,J=3.0Hz,1H),3.83(s,3H),3.62(s,3H),3.45(dd,J=5.4,2.2Hz,1H),3.27(dd,J=8.7,3.2Hz,1H),3.20(dd,J=5.4,2.9Hz,1H),3.16(dd,J=8.7,3.2Hz,1H).
13C NMR(150MHz,CDCl3)177.36,176.83,173.25,172.18,136.35,134.60,128.36,126.32,125.36,52.89,52.51,45.06,44.54,44.44,41.86,38.56,38.33.
example 12
To a 50mL quartz tube, 60mg (0.22mmol) of diethyl ester-substituted o-phenylenediene, 76mg (0.44mmol) of N-phenylmaleimide and 15mL of acetonitrile were added, and after stirring uniformly, the mixture was placed under an ultraviolet lamp and reacted at room temperature with light for 7 hours. After the reaction is finished, concentrating and spin-drying the reaction solution by a rotary evaporator, and then mixing the reaction solution with petroleum ether in a volume ratio of 8: 1: using the mixed solution of ethyl acetate as an eluent to carry out silica gel column chromatography purification and separation to obtain the corresponding polysubstituted benzo bicyclo [2.2.2] octane derivative, wherein the chemical reaction formula is as follows:
the product purity was 99.2% and the yield was 60%. The nuclear magnetic data analysis is as follows:1H NMR(600MHz,CDCl3)7.36–7.23(m,6H),7.19(d,J=6.5Hz,1H),6.46(dd,J=6.7,2.9Hz,2H),4.37–4.24(m,2H),4.18(t,J=2.7Hz,1H),4.13–4.04(m,2H),4.04–4.01(m,1H),3.52(dd,J=5.3,2.3Hz,1H),3.42(dd,J=8.5,3.3Hz,1H),3.31(dd,J=8.5,3.3Hz,1H),3.27(dd,J=5.3,2.9Hz,1H),1.38(t,J=7.1Hz,3H),1.21(t,J=7.1Hz,3H).
13C NMR(150MHz,CDCl3)176.69,176.32,172.91,171.81,136.74,134.91,131.30,129.09,128.78,128.31,128.25,126.40,126.35,125.51,61.89,61.38,44.49,44.38,44.03,40.88,39.14,39.10,14.29,14.22。
the above-described embodiments are only preferred embodiments of the present invention, and are not intended to limit the present invention in any way, and other variations and modifications may be made without departing from the spirit of the invention as set forth in the claims.
Claims (7)
1. A process for the preparation of a polysubstituted benzocyclo [2.2.2] octane derivative, characterized in that it comprises the following steps:
dissolving the o-phenylenediene derivative shown in the formula (II) and the compound containing the olefin structure shown in the formula (III) in an acetonitrile solvent at room temperature in the air or nitrogen atmosphere, uniformly mixing, placing under an ultraviolet lamp for illumination for several hours, after the reaction is completed, evaporating the solvent in a rotary manner, and then separating and purifying by silica gel column chromatography to obtain the polysubstituted benzo bicyclo [2.2.2] octane derivative shown in the formula (I);
wherein R is1、R2Is an ester group, an acyl group or a nitrile group, R3Is hydrogen, alkoxy, halogen or alkyl; x is O, NH, N-CH3、N-C2H5N-benzeneA group, N-tert-butyl or N-benzyl.
2. The method according to claim 1, wherein the compound having an olefin structure is maleic anhydride, maleimide, N-methylmaleimide, N-ethylmaleimide, N-phenylmaleimide, N-t-butylmaleimide, or N-benzylmaleimide.
3. The production method according to claim 1, wherein the molar ratio of the ortho-phenylene diene derivative to the compound having an olefin structure is 1:1 to 3.
4. The production method according to claim 1, wherein the acetonitrile solvent is fed in a volume of 30 to 90mL/mmol of the o-phenylenediene derivative.
5. The preparation method according to claim 1, wherein the ultraviolet irradiation reaction time is 4 to 10 hours.
6. The preparation method according to claim 1, wherein the solvent used for the silica gel column chromatography separation and purification is a mixed solvent of petroleum ether and ethyl acetate.
7. The method according to claim 6, wherein the volume ratio of the petroleum ether to the ethyl acetate is 4-10: 1.
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