CN107235900B - Synthetic method of 6-benzylphenanthridine compound - Google Patents
Synthetic method of 6-benzylphenanthridine compound Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/10—Aza-phenanthrenes
- C07D221/12—Phenanthridines
Abstract
The invention discloses a synthesis method of a 6-benzylphenanthridine compound, which has the following reaction equation:
Description
Technical Field
The invention relates to a synthetic method of an organic compound, in particular to a synthetic method of a 6-benzylphenanthridine compound, belonging to the technical field of chemistry.
Background
The 6-benzyl phenanthridine compound is a common structural unit in a natural product, and a plurality of natural products containing phenanthridine structural units show good pharmacological activity, wherein the natural products represent trimodamine, nitidine chloride (with anti-liver cancer activity) and zanthoxylum piperitum. Some benzophenanthridine compounds have anti-liver cancer, anti-nasopharyngeal cancer and anti-gastric cancer activities, and have strong interaction with calf thymus DNA. Benzophenanthridine compounds have been reported to act as topoisomerase i and topoisomerase ii inhibitors and thus have been shown to have anti-cancer activity.
It is because of such importance of 6-benzylphenanthridines that a great deal of research has been carried out on their synthesis, and several synthetic routes and methods have been explored, for example:
(1) grignard reagent method: taking 2-cyano-2' -bromobiphenyl and ethyl magnesium bromide as raw materials, and reacting under the condition of a copper catalyst to obtain 6-benzylphenanthridine;
(2) azidotrimethylsilane method: taking 2-acetylbiphenyl and azidotrimethylsilane as raw materials, adding equivalent weight of pivalic acid, and obtaining the 6-benzylphenanthridine in a trifluoroacetic acid solvent.
However, neither the grignard reagent method nor the azidotrimethylsilane method has certain drawbacks, such as:
(1) grignard reagent method: high temperature and high pressure are needed, and reaction conditions are harsh; metal catalysis is needed, and the synthesis cost is high; the environmental pollution is great;
(2) azidotrimethylsilane: the raw material azide used is very dangerous, and a large amount of acid needs to be added into a reaction system, so that the environmental pollution is serious.
It can be seen that although there are many methods for preparing 6-benzylphenanthridine compounds in the prior art, these methods all have serious defects, so that their application is limited.
At present, the synthesis method of phenanthridine is a research hotspot, a new phenanthridine mother nucleus synthesis method is researched, and particularly a metal-free synthesis method can greatly promote the research on drugs containing phenanthridine structural units.
Disclosure of Invention
The invention aims to provide a synthetic method of a 6-benzylphenanthridine compound, which is simple and convenient to operate, easy to carry out post-treatment, mild in reaction condition, free of a catalyst, green and economic.
In order to achieve the above object, the present invention adopts the following technical solutions:
the synthesis method of the 6-benzylphenanthridine compound is characterized in that toluene and 2-isocyano biphenyl with a structure shown in a formula (I) are used as raw materials, an oxidant and alkali are added, the 6-benzylphenanthridine compound with the structure shown in a formula (II) is obtained through a free radical reaction in a reaction solvent, and the reaction equation is as follows:
wherein R is hydrogen, fluoro, chloro, methyl, methoxy or a naphthalene ring.
The synthesis method of the 6-benzylphenanthridine compound is characterized by comprising the following steps:
step 1: adding a reaction solvent and a catalytic amount of alkali into a reaction container, and continuously performing 3 times of air suction-nitrogen filling operations on the reaction container;
step 2: continuously adding an oxidant, toluene with a structure shown in a formula (I) and 2-isocyano biphenyl into the reaction vessel, and reacting for a period of time in an oil bath;
step 3: after the reaction is finished, the mixture obtained by the reaction is separated and purified.
The synthesis method of the 6-benzylphenanthridine compound is characterized in that the molar ratio of the 2-isocyanobiphenyl to the toluene with the structure shown in the formula (I) is 1: 1-65.
The synthesis method of the 6-benzylphenanthridine compound is characterized in that the oxidant is at least one of chromic oxide, manganese dioxide, 2, 6, 6-tetramethylpiperidine oxide, 2, 3-dichloro-5, 6-dicyano-1, 4-benzoquinone, bis (trifluoroacetic acid) iodobenzene, di-tert-butyl hydroperoxide, silver carbonate, silver acetate, silver nitrate, silver sulfate, iodobenzene diacetate, ammonium persulfate, potassium persulfate and sodium persulfate.
The method for synthesizing the 6-benzylphenanthridine compound is characterized in that the ratio of the amount of the oxidant to the amount of the 2-isocyanobiphenyl is 1:1 to 3.
The method for synthesizing the 6-benzylphenanthridine compound is characterized in that the base is at least one of 1, 8-diazabicycloundecen-7-ene, 1, 4-diazabicyclo (2, 2, 2) octane, diethylamine, triethylamine, diethanolamine and triethanolamine, and the amount of the base is 1 to 10% of the amount of the 2-isocyanobiphenyl in terms of molar amount.
The synthesis method of the 6-benzylphenanthridine compound is characterized in that the base is at least one of potassium carbonate, sodium carbonate, potassium acetate and sodium acetate, and the amount of the base is 1-10% of that of the 2-isocyanobiphenyl in terms of molar weight.
The synthesis method of the 6-benzylphenanthridine compound is characterized in that the reaction solvent is at least one of toluene, 4-chlorotoluene, 4-methoxytoluene, 4-bromotoluene, 3-chlorotoluene o-xylene, m-xylene, p-xylene, 2,3,4,5, 6-pentafluorotoluene and mesitylene.
The synthesis method of the 6-benzylphenanthridine compound is characterized in that the reaction temperature is 0-120 ℃.
The synthesis method of the 6-benzylphenanthridine compound is characterized in that the reaction time is 12-24 hours.
It should be noted that:
(1) reaction temperature
In the synthesis process of the present invention, the reaction temperature is from 0 ℃ to 120 ℃, such as, but not limited to: 0 ℃, 20 ℃, 40 ℃, 60 ℃, 80 ℃, 100 ℃ or 120 ℃.
(2) Reaction time
In the synthesis method of the present invention, the reaction time is not particularly limited, and a suitable reaction time can be determined by detecting the residual percentage of the desired product or raw material by liquid chromatography, and is usually 12 to 24 hours, such as, but not limited to: 12h, 14h, 16h, 18h, 20h, 22h or 24 h.
(3) Separating and purifying
The mixture obtained after the reaction may be further separated and purified to obtain a purer final product, and separation and purification methods well known to those skilled in the art may be used, for example: extraction, column chromatography, distillation, recrystallization, decantation, filtration, centrifugation, washing, evaporation, stripping or adsorption, or a combination of at least two separation and purification methods, for example: a combination of extraction and column chromatography.
Of course, the obtained reaction mixture can be directly introduced into other processes for direct reaction to produce other products, if desired. Optionally, the reaction mixture may be pretreated, e.g., by one or more of concentration, extraction and distillation under reduced pressure, to obtain a crude or pure product prior to introduction to other processes.
The invention has the advantages that:
(1) the preparation process is simple and convenient to operate, and the obtained product is easy to post-treat;
(2) high temperature and high pressure are not needed, and the reaction condition is mild;
(3) no catalyst is needed, and the synthesis cost is reduced;
(4) the tolerance of the reaction substrate functional group is high, the substrate range is wide, and the preparation is easy;
(5) the oxidant is cheap and easy to obtain, and is more economical;
(6) the reaction is efficient and the yield is high;
(7) no environmental pollution and environmental protection.
Detailed Description
The synthesis method of the invention uses 2-isocyano biphenyl and toluene as raw materials, uses a method of activating a carbon-hydrogen bond at a methylbenzene benzylic position without metal, obtains the 6-benzyl phenanthridine compound through a free radical reaction, and has the advantages of simple experimental operation, no metal catalysis and no pollution to the environment.
In order to more clearly illustrate the synthesis of the present invention, the present invention is specifically described below with reference to specific preferred embodiments.
Example 1
Synthesis of 6-benzylphenanthridine:
at room temperature (25 ℃), adding a reaction solvent toluene (2mL) and a catalytic amount of organic base 1, 4-diazabicyclo (2, 2, 2) octane (DABCO, 0.03mmol, 0.1equiv) into a reaction tube, continuously performing 3 times of air extraction-nitrogen filling operation on the reaction tube, then continuously adding an oxidant di-tert-butyl hydroperoxide (DTBP, 0.75mmol, 2.5equiv), a raw material toluene (2mL) and a raw material 2-isocyanobiphenyl (0.3mmol, 1equiv) into the reaction tube, stirring for 24 hours at a reaction temperature of 120 ℃ in an oil bath, directly spinning off the reaction solvent after the reaction is finished, and separating by column chromatography (filling 300-mesh silica gel in the column, and taking petroleum ether and ethyl acetate in a volume ratio of 40: 1 as an eluent) to obtain a product, wherein the product is a yellow solid and the yield is 80%.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz,CDCl3)δ8.59(1H,d),8.53(1H,d),8.19(2H,t),7.71-7.77(2H,m),7.63(1H,t),7.55(1H,t),7.30-7.32(2H,m),7.21-7.25(2H,m),7.16(1H,d),4.75(2H,s)。
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz,CDCl3)δ160.2,143.6,139.0,133.2,130.3,129.8,128.6,128.5,127.2,127.0,126.6,125.3,123.9,122.3,121.9,43.0。
theoretical calculations and experimental results for the analysis of the product are as follows:
Anal.Calcd.For C20H15N：C,89.19；H,5.61；N,5.20；
Found：C,89.20；H,5.72；N,5.21。
example 2
Synthesis of 6- (4-methylbenzyl) phenanthridine:
at room temperature (25 ℃), adding a reaction solvent p-xylene (2mL) and a catalytic amount of organic base 1, 4-diazabicyclo (2, 2, 2) octane (DABCO, 0.03mmol, 0.1equiv) into a reaction tube, continuously performing extraction-nitrogen filling operation for 3 times, then continuously adding an oxidant di-tert-butyl hydroperoxide (DTBP, 0.75mmol, 2.5equiv), a raw material p-xylene (2mL) and a raw material 2-isocyanobiphenyl (0.3mmol, 1equiv) into the reaction tube, stirring for 24 hours at a reaction temperature of 120 ℃ in an oil bath, directly spinning off the reaction solvent after the reaction is finished, and separating by column chromatography (filling 300-mesh silica gel in the column, and taking petroleum ether and ethyl acetate in a volume ratio of 40: 1 as an eluent) to obtain a product, wherein the product is a yellow solid and the yield is 78%.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz,CDCl3)δ8.58(1H,d),8.52(1H,d),8.18-8.20(m,2H),7.71-7.76(m,2H),7.61-7.64(m,1H),7.53-7.57(m,1H),7.19-7.23(m,2H),7.02-7.04(m,2H),4.70(s,2H),2.25(s,3H)。
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz,CDCl3)δ160.3,143.7,136.0,135.7,133.2,130.2,129.8,129.6,129.2,128.6,128.3,127.2,127.0,126.5,125.3,123.9,122.3,121.9,42.6,20.9。
theoretical calculations and experimental results for the analysis of the product are as follows:
Anal.Calcd.For C21H17N：C,89.01；H,6.05；N,4.94；
Found：C,89.02；H,6.06；N,4.95。
example 3
Synthesis of 6- (3-methylbenzyl) phenanthridine:
at room temperature (25 ℃), adding a reaction solvent m-xylene (2mL) and a catalytic amount of organic base 1, 4-diazabicyclo (2, 2, 2) octane (DABCO, 0.03mmol, 0.1equiv) into a reaction tube, continuously performing extraction-nitrogen filling operation for 3 times, then continuously adding an oxidant di-tert-butyl hydroperoxide (DTBP, 0.75mmol, 2.5equiv), a raw material m-xylene (2mL) and a raw material 2-isocyanobiphenyl (0.3mmol, 1equiv) into the reaction tube, stirring for 24 hours at a reaction temperature of 120 ℃ in an oil bath, directly spinning off the reaction solvent after the reaction is finished, and separating by column chromatography (column chromatography is filled with 300-mesh silica gel, and the volume ratio of petroleum ether to ethyl acetate is 40: 1 to obtain a product, wherein the product is a yellow solid, and the yield is 73%.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz,CDCl3)δ:8.59(d,1H),8.54(d,1H),8.18-8.22(m,2H),7.72-7.77(m,2H),7.62-7.66(m,1H),7.54-7.58(m,1H),7.11-7.12(m,3H),6.97(d,1H),4.71(s,2H),2.24(s,3H)。
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13CNMR(125MHz,CDCl3)δ：160.2,143.6,139.0,138.1,133.2,130.3,129.8,128.6,128.3,127.3,127.1,126.6,125.5,125.4,123.9,121.9,43.0,21.3。
theoretical calculations and experimental results for the analysis of the product are as follows:
Anal.Calcd.For C21H17N：C,89.01；H,6.05；N,4.94；
Found：C,89.02；H,6.06；N,4.95。
example 4
Synthesis of 6- (2-methylbenzyl) phenanthridine:
at room temperature (25 ℃), adding a reaction solvent o-xylene (2mL) and a catalytic amount of organic base 1, 4-diazabicyclo (2, 2, 2) octane (DABCO, 0.03mmol, 0.1equiv) into a reaction tube, continuously performing extraction-nitrogen filling operation for 3 times, then continuously adding an oxidant di-tert-butyl hydroperoxide (DTBP, 0.75mmol, 2.5equiv), a raw material o-xylene (2mL) and a raw material 2-isocyanobiphenyl (0.3mmol, 1equiv) into the reaction tube, stirring for 24 hours at a reaction temperature of 120 ℃ in an oil bath, directly spinning off the reaction solvent after the reaction is finished, and separating by column chromatography (column chromatography is filled with 300-mesh silica gel, and the volume ratio of petroleum ether to ethyl acetate is 40: 1 to obtain a product, wherein the product is a yellow solid, and the yield is 70%.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz,CDCl3)δ8.62(1H,d),8.55(1H,d),8.15(1H,d),8.01(1H,d),7.70-7.78(2H,m),7.61-7.65(1H,m),7.54(1H,t),7.20-7.22(2H,m),7.08(t,1H),6.91-6.95(m,1H),6.74(1H,d),4.68(2H,s),2.49(3H,s)。
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz,CDCl3)δ:160.1,143.8,137.6,136.0,133.0,130.3,130.0,129.8,128.6,128.4,127.3,126.9,126.2,125.9,125.6,123.8,122.4,121.9,40.2,20.0。
theoretical calculations and experimental results for the analysis of the product are as follows:
Anal.Calcd.For C21H17N：C,89.01；H,6.05；N,4.94；
Found：C,89.02；H,6.06；N,4.95。
example 5
Synthesis of 6- (4-methoxybenzyl) phenanthridine:
at room temperature (25 ℃), adding a reaction solvent 4-methoxytoluene (2mL) and a catalytic amount of organic base 1, 4-diazabicyclo (2, 2, 2) octane (DABCO, 0.03mmol, 0.1equiv) into a reaction tube, continuously performing air extraction-nitrogen filling operation for 3 times on the reaction tube, then continuously adding an oxidant di-tert-butyl hydroperoxide (DTBP, 0.75mmol, 2.5equiv), a raw material 4-methoxytoluene (2mL) and a raw material 2-isocyanobenzene (0.3mmol, 1equiv) into the reaction tube, stirring for 24 hours at the reaction temperature of 120 ℃ in an oil bath, directly spinning off the reaction solvent after the reaction is finished, and separating by column chromatography (filling a 300-mesh silica gel into the column, and taking petroleum ether and ethyl acetate in a volume ratio of 40: 1 as an eluent) to obtain a product which is a yellow solid with a yield of 68%.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz,CDCl3)δ：8.53(1H,d),8.46(1H,d),8.12(2H,2H),7.64-7.70(2H,m),7.55-7.58(1H,m),7.48-7.51(1H,m),7.14-7.16(2H,m),6.70(2H,d),6.70(2H,d),4.61(2H,s),3.64(3H,s)。
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz,CDCl3)δ：160.5,158.1,133.3,131.2,130.4,129.8,129.5,128.7,127.3,126.7,125.4,124.0,122.4,122.0,114.0,55.2,42.2。
theoretical calculations and experimental results for the analysis of the product are as follows:
Anal.Calcd.For C21H17NO：C,84.25；H,5.72；N,4.68；O,5.34；
Found：C,84.26；H,5.73；N,4.69；O,5.35。
example 6
Synthesis of 6- (4-chlorobenzyl) phenanthridine:
at room temperature (25 ℃), adding a reaction solvent 4-chlorotoluene (2mL) and a catalytic amount of organic base 1, 4-diazabicyclo (2, 2, 2) octane (DABCO, 0.03mmol, 0.1equiv) into a reaction tube, continuously performing air extraction-nitrogen filling operation for 3 times on the reaction tube, then continuously adding an oxidant di-tert-butyl hydroperoxide (DTBP, 0.75mmol, 2.5equiv), a raw material 4-chlorotoluene (2mL) and a raw material 2-isocyanobenzene (0.3mmol, 1equiv) into the reaction tube, stirring for 24 hours at a reaction temperature of 120 ℃ in an oil bath, directly spinning off the reaction solvent after the reaction is finished, and separating by column chromatography (filling a 300-mesh silica gel in the column, taking petroleum ether and ethyl acetate in a volume ratio of 40: 1 as an eluent) to obtain a product which is a yellow solid with a yield of 70%.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz,d6-DMSO)δ:8.61(1H,d),8.54(1H,d),8.18(1H,d),8.10(1H,d),7.72-7.79(2H,m),7.65(1H,t),7.58(1H,t),7.19-7.24(4H,m),4.70(2H,s)。
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13CNMR(100MHz,d6-DMSO)δ:159.5,137.5,133.2,132.0,130.4,129.8,129.8,128.7,127.3,126.7,125.1,123.8,122.4,121.9,42.2。
theoretical calculations and experimental results for the analysis of the product are as follows:
Anal.Calcd.For C20H14ClN：C,79.07；H,4.65；Cl,11.67；N,4.61；
Found：C,79.08；H,4.66；Cl,11.68；N,4.62。
example 7
Synthesis of 6- (2,3,4,5, 6-pentafluorobenzyl) phenanthridine:
adding a reaction solvent 2,3,4,5, 6-pentafluorotoluene (2mL) and a catalytic amount of organic base 1, 4-diazabicyclo (2, 2, 2) octane (DABCO, 0.03mmol, 0.1equiv) into a reaction tube at room temperature (25 ℃), continuously performing air extraction-nitrogen filling operation on the reaction tube for 3 times, then continuously adding an oxidant di-tert-butyl hydroperoxide (DTBP, 0.75mmol, 2.5equiv), a raw material 2,3,4,5, 6-pentafluorotoluene (2mL) and a raw material 2-isocyanobiphenyl (0.3mmol, 1equiv) into the reaction tube, stirring for 24 hours at the reaction temperature of 120 ℃ in an oil bath, directly spinning off the reaction solvent after the reaction is finished, separating by filling silica gel with 300-mesh column chromatography by taking the volume ratio of petroleum ether to ethyl acetate as 40: 1 to obtain a product, wherein the product is an eluent and is yellow solid, the yield thereof was found to be 75%.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz,CDCl3)δ：8.66(1H,d),8.51-8.54(1H,m),8.28(1H,d),7.92(1H,d),7.87(1H,t),7.74(1H,t),7.60-7.67(2H,m),4.76(2H,s)。
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(1120MHz,CDCl3)δ：155.4,143.7,133.2,130.8,130.4,128.9,127.8,127.3,127.1,125.3,125.2,124.0,122.9,122.1,29.1。
theoretical calculations and experimental results for the analysis of the product are as follows:
Anal.Calcd.For C20H10F5N：C,66.86；H,2.81；F,26.44；N,3.90；
Found：C,66.87；H,2.82；F,26.45；N,3.91。
example 8
Synthesis of 6- (2-naphthylmethyl) phenanthridine:
at room temperature (25 ℃), adding a reaction solvent 2-methylnaphthalene (2mL) and a catalytic amount of organic base 1, 4-diazabicyclo (2, 2, 2) octane (DABCO, 0.03mmol, 0.1equiv) into a reaction tube, continuously performing air extraction-nitrogen filling operation for 3 times on the reaction tube, then continuously adding an oxidant di-tert-butyl hydroperoxide (DTBP, 0.75mmol, 2.5equiv), a raw material 2-methylnaphthalene (2mL) and a raw material 2-isocyanobenzene (0.3mmol, 1equiv) into the reaction tube, stirring for 24 hours at the reaction temperature of 120 ℃ in an oil bath, directly spinning off the reaction solvent after the reaction is finished, and separating by column chromatography (filling a 300-mesh silica gel in the column, taking petroleum ether and ethyl acetate in a volume ratio of 40: 1 as an eluent) to obtain a product, wherein the product is a yellow solid and the yield is 83%.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz,CDCl3)δ:8.61(1H,d),8.56(1H,d),8.22-8.25(2H,m),7.64-7.78(7H,m),7.53(1H,t),7.48(1H,d),7.37-7.39(2H,m),4.92(2H,s)。
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz,CDCl3)δ:160.3,143.9,136.9,133.8,133.6,132.4,130.7,129.0,128.4,127.8,127.6,127.4,127.3,127.1,127.0,126.2,125.7,124.3,122.7,122.2,43.4。
theoretical calculations and experimental results for the analysis of the product are as follows:
Anal.Calcd.For C24H17N：C,90.25；H,5.36；N,4.39；
Found：C,90.26；H,5.37；N,4.40。
example 9
Synthesis of 6- (3, 5-dimethylbenzyl) phenanthridine:
at room temperature (25 ℃), adding a reaction solvent mesitylene (2mL) and a catalytic amount of organic base 1, 4-diazabicyclo (2, 2, 2) octane (DABCO, 0.03mmol, 0.1equiv) into a reaction tube, continuously performing air extraction-nitrogen filling operation for 3 times, then continuously adding an oxidant di-tert-butyl hydroperoxide (DTBP, 0.75mmol, 2.5equiv), a raw material mesitylene (2mL) and a raw material 2-isocyanobenzene (0.3mmol, 1equiv), stirring for 24 hours at a reaction temperature of 120 ℃ in an oil bath, directly screwing off the reaction solvent after the reaction is finished, and separating by column chromatography (filling a 300-mesh silica gel in the column, taking petroleum ether and ethyl acetate in a volume ratio of 40: 1 as an eluent) to obtain a product, wherein the product is a yellow solid and the yield is 87%.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1H NMR(500MHz,d6-DMSO)δ8.79(1H,dd),8.73(1H,dd),8.31(1H,d)；8.12(1H,d),7.85(1H,t),7,77(1H,t),7.68(2H,m),6.92(2H,s),6.74(1H,s),4.62(2H,s),2.12(6H,s)。
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13C NMR(125MHz,DMSO-d6)δ160.1,143.2,139.0,137.3,132.6,130.7,128.8,127.7,126.9,126.7,126.1,124.7,123.3,122.7,122.5,41.8,20.8。
theoretical calculations and experimental results for the analysis of the product are as follows:
Anal.Calcd.For C22H19N：C,88.85；H,6.44；N,4.71；
Found：C,88.86；H,6.45；N,4.72。
examples 10 to 20
Examples 10 to 20 were each carried out in the same manner as in example 1 with the highest product yield, except that the organic base DABCO was replaced with the following bases, respectively, and the yields of the bases and the corresponding products used are shown in the following table:
as can be seen from the above table, when other bases are used, such as: organic bases 1, 8-diazabicycloundecen-7-ene (DBU), triethylamine, diethylamine, triethanolamine, diethanolamine, and the strong bases potassium carbonate, sodium carbonate, potassium acetate and sodium acetate in inorganic bases all reacted, but the yield was significantly reduced compared to DABCO, which indicates that the yield of the reaction is significantly affected by the appropriate choice of base.
In addition, tests show that when the reaction solvent is 3-chlorotoluene, 4-bromotoluene or 3-bromotoluene, the reaction can also occur, and the yield of the product is high and can at least reach more than 70 percent or even higher.
It is apparent from all the above examples that 6-benzylphenanthridine compounds are obtained in high yield and high purity by radical reaction in a reaction solvent using toluene and 2-isocyano biphenyl as raw materials, adding an oxidant and an alkali, which provides a brand new synthetic route for efficient and rapid synthesis of the compounds.
It should be noted that the above-mentioned embodiments do not limit the present invention in any way, and all technical solutions obtained by using equivalent alternatives or equivalent variations fall within the protection scope of the present invention.
Claims (9)
- The synthesis method of 1.6-benzylphenanthridine is characterized in that 2mL of reaction solvent toluene and 0.03mmol of 1, 4-diazabicyclo (2, 2, 2) octane are added into a reaction tube at 25 ℃, the reaction tube is continuously subjected to 3 times of air exhaust-nitrogen filling operation, then 0.75mmol of di-tert-butyl hydroperoxide, 2mL of raw material toluene and 0.3mmol of raw material 2-isocyanobiphenyl are continuously added into the reaction tube, then the reaction tube is stirred in an oil bath at 120 ℃ for 24 hours, after the reaction is finished, the reaction solvent is directly screwed off, and the 6-benzylphenanthridine is obtained after column chromatography separation, wherein the reaction equation is as follows:,
wherein:during column chromatography, 300-mesh silica gel is filled in the column, and the volume ratio of petroleum ether to ethyl acetate is 40: and 1 is an eluent. - The synthesis method of 6- (4-methylbenzyl) phenanthridine is characterized in that 2mL of reaction solvent p-xylene and 0.03mmol of 1, 4-diazabicyclo (2, 2, 2) octane are added into a reaction tube at 25 ℃, the reaction tube is continuously subjected to 3 times of air exhaust and nitrogen filling operations, then 0.75mmol of di-tert-butyl hydroperoxide, 2mL of raw material p-xylene and 0.3mmol of raw material 2-isocyanobiphenyl are continuously added into the reaction tube, the mixture is stirred and reacted for 24 hours at 120 ℃ in an oil bath, after the reaction is finished, the reaction solvent is directly screwed off, and the 6- (4-methylbenzyl) phenanthridine is obtained after column chromatography separation, wherein the reaction equation is as follows:,
wherein:during column chromatography, 300-mesh silica gel is filled in the column, and the volume ratio of petroleum ether to ethyl acetate is 40: and 1 is an eluent. - The synthesis method of 6- (3-methylbenzyl) phenanthridine is characterized in that 2mL of reaction solvent m-xylene and 0.03mmol of 1, 4-diazabicyclo (2, 2, 2) octane are added into a reaction tube at 25 ℃, the reaction tube is continuously subjected to 3 times of air extraction and nitrogen filling operations, then 0.75mmol of di-tert-butyl hydroperoxide, 2mL of raw material m-xylene and 0.3mmol of raw material 2-isocyanobiphenyl are continuously added into the reaction tube, then stirring reaction is carried out for 24 hours in an oil bath at the reaction temperature of 120 ℃, the reaction solvent is directly screwed off after the reaction is finished, and the 6- (3-methylbenzyl) phenanthridine is obtained after column chromatography separation, wherein the reaction equation is as follows:
wherein:during column chromatography, 300-mesh silica gel is filled in the column, and the volume ratio of petroleum ether to ethyl acetate is 40: and 1 is an eluent. - The synthesis method of 6- (2-methylbenzyl) phenanthridine is characterized in that 2mL of reaction solvent o-xylene and 0.03mmol of 1, 4-diazabicyclo (2, 2, 2) octane are added into a reaction tube at 25 ℃, the reaction tube is continuously subjected to 3 times of air extraction and nitrogen filling operations, then 0.75mmol of di-tert-butyl hydroperoxide, 2mL of raw material o-xylene and 0.3mmol of raw material 2-isocyanobiphenyl are continuously added into the reaction tube, stirring and reaction are carried out for 24 hours in an oil bath at 120 ℃, after the reaction is finished, the reaction solvent is directly screwed off, and 6- (2-methylbenzyl) phenanthridine is obtained after column chromatography separation, wherein the reaction equation is as follows:,
wherein:during column chromatography, 300-mesh silica gel is filled in the column, and the volume ratio of petroleum ether to ethyl acetate is 40: and 1 is an eluent. - The synthesis method of 6- (4-methoxybenzyl) phenanthridine is characterized in that 2mL of reaction solvent 4-methoxytoluene and 0.03mmol of 1, 4-diazabicyclo (2, 2, 2) octane are added into a reaction tube at 25 ℃, the reaction tube is continuously subjected to 3 times of air extraction and nitrogen filling operations, then 0.75mmol of di-tert-butyl hydroperoxide, 2mL of raw material 4-methoxytoluene and 0.3mmol of raw material 2-isocyanobiphenyl are continuously added into the reaction tube, then the mixture is stirred and reacted for 24 hours in an oil bath at 120 ℃, after the reaction is finished, the reaction solvent is directly screwed off, and 6- (4-methoxybenzyl) phenanthridine is obtained after column chromatography separation, wherein the reaction equation is as follows:
during column chromatography, 300-mesh silica gel is filled in the column, and the volume ratio of petroleum ether to ethyl acetate is 40: and 1 is an eluent. - The synthesis method of 6.6- (4-chlorobenzyl) phenanthridine is characterized in that 2mL of reaction solvent 4-chlorotoluene and 0.03mmol of 1, 4-diazabicyclo (2, 2, 2) octane are added into a reaction tube at 25 ℃, the reaction tube is continuously subjected to 3 times of air extraction and nitrogen filling operations, then 0.75mmol of di-tert-butyl hydroperoxide, 2mL of raw material 4-chlorotoluene and 0.3mmol of raw material 2-isocyanobiphenyl are continuously added into the reaction tube, the mixture is stirred and reacted for 24 hours at 120 ℃ in an oil bath, after the reaction is finished, the reaction solvent is directly screwed off, and 6- (4-chlorobenzyl) phenanthridine is obtained after column chromatography separation, wherein the reaction equation is as follows:
wherein:during column chromatography, 300-mesh silica gel is filled in the column, and the volume ratio of petroleum ether to ethyl acetate is 40: and 1 is an eluent. - The synthesis method of 6- (2,3,4,5, 6-pentafluorobenzyl) phenanthridine is characterized in that 2mL of reaction solvent 2,3,4,5, 6-pentafluorotoluene and 0.03mmol of 1, 4-diazabicyclo (2, 2, 2) octane are added into a reaction tube at 25 ℃, the reaction tube is continuously subjected to 3 times of air extraction-nitrogen filling operations, then 0.75mmol of di-tert-butyl hydroperoxide, 2mL of raw material 2,3,4,5, 6-pentafluorotoluene and 0.3mmol of raw material 2-isocyanobiphenyl are continuously added into the reaction tube, and then the mixture is stirred and reacted for 24 hours at 120 ℃ in an oil bath, after the reaction is finished, the reaction solvent is directly screwed off, and the 6- (2,3,4,5, 6-pentafluorobenzyl) phenanthridine is obtained after column chromatography separation, and the reaction equation is as follows:
wherein:during column chromatography, 300-mesh silica gel is filled in the column, and the volume ratio of petroleum ether to ethyl acetate is 40: and 1 is an eluent. - The synthesis method of 6- (2-naphthylmethyl) phenanthridine is characterized in that 2mL of reaction solvent 2-methylnaphthalene and 0.03mmol of 1, 4-diazabicyclo (2, 2, 2) octane are added into a reaction tube at 25 ℃, the reaction tube is continuously subjected to 3 times of air extraction and nitrogen filling operations, then 0.75mmol of di-tert-butyl hydroperoxide, 2mL of raw material 2-methylnaphthalene and 0.3mmol of raw material 2-isocyanobiphenyl are continuously added into the reaction tube, then the mixture is stirred and reacted for 24 hours in an oil bath at 120 ℃, after the reaction is finished, the reaction solvent is directly screwed off, and 6- (2-naphthylmethyl) phenanthridine is obtained after column chromatography separation, wherein the reaction equation is as follows:
wherein:during column chromatography, 300-mesh silica gel is filled in the column, and the volume ratio of petroleum ether to ethyl acetate is 40: and 1 is an eluent. - The synthesis method of 6- (3, 5-dimethylbenzyl) phenanthridine is characterized in that 2mL of reaction solvent mesitylene and 0.03mmol of 1, 4-diazabicyclo (2, 2, 2) octane are added into a reaction tube at 25 ℃, the reaction tube is continuously subjected to 3 times of air extraction and nitrogen filling operations, then 0.75mmol of di-tert-butyl hydroperoxide, 2mL of raw mesitylene and 0.3mmol of raw material 2-isocyanobiphenyl are continuously added into the reaction tube, the mixture is stirred and reacted for 24 hours in an oil bath at 120 ℃, the reaction solvent is directly screwed off after the reaction is finished, and a product is obtained after column chromatography separation, wherein the reaction equation is as follows:wherein:
during column chromatography, 300-mesh silica gel is filled in the column, and the volume ratio of petroleum ether to ethyl acetate is 40: and 1 is an eluent.
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