CN109020814B - Polysubstituted 10-hydroxy phenanthrene and derivative thereof and synthesis method thereof - Google Patents

Polysubstituted 10-hydroxy phenanthrene and derivative thereof and synthesis method thereof Download PDF

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CN109020814B
CN109020814B CN201710433212.2A CN201710433212A CN109020814B CN 109020814 B CN109020814 B CN 109020814B CN 201710433212 A CN201710433212 A CN 201710433212A CN 109020814 B CN109020814 B CN 109020814B
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王彬
江雅婷
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Nankai University
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    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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    • C07C69/94—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings
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Abstract

The invention provides a polysubstituted 10-hydroxy phenanthrene and a derivative thereofAn organism and a method for its synthesis, the method comprising: the compound of formula (1) is reacted with bromine catalyst, additive, peroxide and organic solvent to obtain the compound of formula (2), which has the following general reaction formula:
Figure DDA0001317955320000011
wherein R is1Is hydrogen, halogen, aryl, alkyl or alkoxy, and the combination position is 3 position or 4 position or 5 position or 6 position; r2Is hydrogen, halogen, aryl, alkyl, alkoxy or ester group, and the combination position is 2' position, 3' position, 4' position, 5' position or 6 ' position; EWG is cyano, methoxyformyl, ethoxyformyl or N-phenylcarboxamido. The method has the advantages of short synthetic route, simple initial raw materials, mild reaction conditions, low cost and no pollution of the catalyst, wide substrate range and easy separation of products.

Description

Polysubstituted 10-hydroxy phenanthrene and derivative thereof and synthesis method thereof
Technical Field
The invention belongs to the technical field of pharmaceutical and chemical intermediates and related chemistry, and particularly relates to a polysubstituted 10-hydroxy phenanthrene and a derivative thereof and a green synthesis method thereof.
Background
Polycyclic aromatic hydrocarbons are the basic skeleton of organic molecules and are widely used in the chemical field. Organic photoelectric materials containing polycyclic aromatic hydrocarbon structures have received much attention. Materials containing phenanthrene or phenanthrene-based derivatives are receiving attention due to their high photo-thermal stability, and are widely used in the fields of pigments and photoelectric materials. Meanwhile, the polycyclic skeleton can stabilize the whole structure due to the pi-pi stacking effect and can be used for synthesizing ligands and combining with biomacromolecules such as DNA and the like for medicine. The basic skeleton of phenanthrene is also used for synthesizing natural active products, for example, the skeleton structure of phenanthrene ethyl formate is a key intermediate for synthesizing phenanthrene indole lizidine alkaloid. Therefore, the method for constructing the polycyclic aromatic hydrocarbon skeleton of phenanthrene and derivatives thereof has wide scientific research value and market prospect.
The phenanthrene skeleton has various production methods, four are common, firstly, diaryl vinyl nitrile is used for constructing phenanthrene ring through free radical cyclization under the illumination condition through elemental iodine; or diaryl vinyl nitrile is subjected to intramolecular oxidative coupling under the conditions that trifluoroacetic acid is used as a solvent and vanadium trifluoride oxide (VOF3) is used as an oxidant to obtain phenanthrene methyl nitrile; thirdly, bromine-substituted diaryl vinyl methyl formate on an aromatic ring is used as a substrate, an aryl free radical is generated under the induction of a free radical initiator, and then free radical cyclization is carried out to obtain polysubstituted phenanthrene methyl formate; and fourthly, 2- (bromoethynyl) -1,1' -biphenyl is used as a substrate, and the bromine-substituted phenanthrene ring is obtained through metal catalysis. However, the above methods have many reaction steps, difficult preparation of the substrate, and defects in the aspects of substrate range, selectivity and the like, and most of the methods need to use transition metals as catalysts, so that the methods have various defects of environmental pollution and the like. The use of transition metals in the last steps of drug synthesis is often avoided to prevent effects on product activity testing, and therefore its use is limited.
Therefore, research work on how to prepare multi-substituted phenanthrenes and their derivatives from simple starting materials, fewer reaction steps, mild reaction conditions, and the use of inexpensive and pollution-free catalysts is necessary.
Disclosure of Invention
The invention aims to provide a high-efficiency polysubstituted 10-hydroxy phenanthrene and a derivative thereof and a green synthesis method thereof.
In order to achieve the purpose, the technical scheme of the invention is realized as follows:
a method for synthesizing polysubstituted 10-hydroxy phenanthrene and derivatives thereof comprises the following steps: the compound of formula (1) is reacted with bromine catalyst, additive, peroxide and organic solvent to obtain the compound of formula (2), which has the following general reaction formula:
Figure BDA0001317955300000021
wherein R is1Is hydrogen, halogen, aryl, alkyl or alkoxy, and the combination position is 3 position or 4 position or 5 position or 6 position; r2Is hydrogen, halogen, aryl, alkyl, alkoxy or ester group, and the combination position is 2' position, 3' position, 4' position, 5' position or 6 ' position; EWG is cyano, methoxyformyl, ethoxyformyl or N-phenylcarboxamido.
Furthermore, the compound of formula (2) is synthesized by the method that the molar ratio of the compound of formula (1), the bromine-containing catalyst, the peroxide and the additive is 1 (0.05-0.8) to 1-5 to 0.4-3.
Further, the bromine-containing catalyst is one or a mixture of more than two of N-bromosuccinimide, N-bromophthalimide, tetrabutylammonium bromide, lithium bromide, sodium bromide, potassium bromide, hydrobromic acid, triphenyl phosphine hydrobromide, bromoethylamine hydrobromide, bromobenzene, bromodiphenylmethane, benzyl bromide, dibromoisocyanuric acid, N-bromoacetamide or N-bromocyclohexyllactam; preferably, the bromine-containing catalyst is one or a mixture of more than two of N-bromosuccinimide, N-bromophthalimide, N-bromocyclohexylamine, dibromoisocyanuric acid or bromoethylamine hydrobromide; more preferably, the bromine-containing catalyst is N-bromosuccinimide.
Further, the peroxide is one or a mixture of more than two of tert-butyl hydroperoxide, hydrogen peroxide, di-tert-butyl peroxide, cumyl hydroperoxide, m-chloroperoxybenzoic acid, tert-butyl peroxybenzoate, potassium hydrogen persulfate composite salt, potassium persulfate or iodobenzene acetate; preferably, the peroxide is tert-butyl hydroperoxide.
Further, the additive in the synthesis method of the compound shown in the formula (2) is one or a mixture of more than two of sodium dihydrogen phosphate and hydrate thereof, acetic acid, triphenylphosphine, citric acid, pyridine, sodium acetate or DBU; preferably, the additive is one or a mixture of more than two of sodium dihydrogen phosphate, acetic acid or citric acid; more preferably, the additive is sodium dihydrogen phosphate.
Furthermore, the adding amount of the organic solvent in the synthesis method of the compound of the formula (2) is 4-100 times of the weight of the compound of the formula (1).
Further, the reaction temperature of the synthesis method of the compound of the formula (2) is 60-100 ℃, and the reaction time is 0.5-15 hours.
Further, the reaction temperature of the synthesis method of the compound of the formula (2) is 80-90 ℃, and the reaction time is 7-15 hours.
Further, when EWG is cyano, the compound of formula (1) can be synthesized as follows:
Figure BDA0001317955300000022
when EWG is methoxyformyl or ethoxyformyl, the compound of formula (1) is synthesized as follows:
Figure BDA0001317955300000023
when EWG is an N-phenylcarboxamido group, the compounds of formula (1) are synthesized as follows:
Figure BDA0001317955300000031
further, the organic solvent in the synthesis method of the compound of the formula (1) is one or a mixture of more than two of toluene, 1, 4-dioxane, N' -dimethylformamide, ethanol or methanol;
the organic solvent in the method for synthesizing the compound of the formula (2) by using the compound of the formula (1) is one or a mixture of more than two of ethanol, methanol, ethylene glycol dimethyl ether, 1, 4-dioxane, tetrahydrofuran, 1, 2-dichloromethane, carbon tetrachloride or N, N' -dimethylformamide; preferably, the organic solvent is tetrahydrofuran.
Further, the alkaline additive in the synthesis method of the compound in the formula (1) is one or a mixture of more than two of anhydrous sodium carbonate, anhydrous potassium phosphate or barium hydroxide; the palladium catalyst is one of tetrakis- (triphenylphosphine) palladium, 1' -bis (diphenylphosphino) ferrocene palladium dichloride (II) or bis (triphenylphosphine) palladium dichloride (II).
Further, when the EWG is cyano-group, methoxy-formyl group or ethoxy-formyl group, the reaction time of the first step of the synthesis reaction of the compound of the formula (1) is 8-12 hours, and the reaction temperature is 80-165 ℃; the reaction time of the second step is 1-5 hours, and the reaction temperature is 80 ℃.
Further, when the EWG is an N-phenylcarboxamido group, the reaction time of the synthesis reaction of the compound of formula (1) is 8 to 12 hours, and the reaction temperature is 165 ℃.
The invention also provides polysubstituted 10-hydroxy phenanthrene and a derivative thereof, wherein the compound has a chemical structure shown in a formula (2):
Figure BDA0001317955300000032
wherein R is1Is hydrogen, halogen, aryl, alkyl or alkoxy, and the combination position is 3 position or 4 position or 5 position or 6 position; r2Is hydrogen, halogen, aryl, alkyl, alkoxy or ester group, and the combination position is 2' position, 3' position, 4' position, 5' position or 6 ' position; EWG is cyano, methoxyformyl, ethoxyformyl or N-phenylcarboxamido.
Compared with the prior art, the polysubstituted 10-hydroxy phenanthrene and the derivative and the synthesis method thereof have the following advantages:
the method has the advantages of short synthetic route, simple initial raw materials, mild reaction conditions, low cost and no pollution of the catalyst, wide substrate range and easy separation of products.
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The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate an embodiment of the invention and, together with the description, serve to explain the invention and not to limit the invention. In the drawings:
FIG. 1 is a drawing of compound 1a of examples 1-41H nuclear magnetism,13C nuclear magnetic spectrum and high-resolution mass spectrum;
FIG. 2 is a photograph of Compound 2a of example 51H nuclear magnetism,13C nuclear magnetic spectrum;
FIG. 3 is a photograph of compound 3a of example 61H nuclear magnetism,13C nuclear magnetic spectrum;
FIG. 4 is a photograph of compound 4a of example 71H nuclear magnetism,13C nuclear magnetic spectrum;
FIG. 5 is a photograph of compound 5a of example 81H nuclear magnetism,13C nuclear magnetic spectrum;
FIG. 6 is a photograph of Compound 5b of example 81H nuclear magnetism,13C nuclear magnetic spectrum;
FIG. 7 is a photograph of compound 6a of example 91H nuclear magnetism,13C nuclear magnetic spectrum;
FIG. 8 is a photograph of Compound 7a of example 101H nuclear magnetism,13C nuclear magnetic spectrum;
FIG. 9 is a photograph of compound 8a of example 111H nuclear magnetism,13C nuclear magnetic spectrum;
FIG. 10 is a photograph of compound 9a of example 121H nuclear magnetism,13C nuclear magnetic spectrum;
FIG. 11 is a photograph of compound 10a of example 131H nuclear magnetism,13C nuclear magnetic spectrum;
FIG. 12 is a photograph of compound 11a of example 141H nuclear magnetism,13C nuclear magnetic spectrum;
FIG. 13 is a photograph of compound 12a of example 151H nuclear magnetism,13C nuclear magnetic spectrum;
FIG. 14 is a photograph of compound 13a of example 161H nuclear magnetism,13C nuclear magnetic spectrum.
Detailed Description
Unless defined otherwise, technical terms used in the following examples have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention belongs. The test reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the experimental methods are conventional methods unless otherwise specified.
The present invention will be described in detail with reference to examples.
Example 1: synthesis of ethyl 10-hydroxyphenanthrene-9-carboxylate (1a)
Figure BDA0001317955300000041
A method of synthesizing a compound of formula (1) comprising the steps of:
the first step is as follows: tetrakis (triphenylphosphine) palladium (0.3mmol,346.7mg), anhydrous potassium carbonate (9mmol,1.24g) were added to a three-necked flask, and after sealing, the flask was evacuated of air and filled with nitrogen gas, and this was repeated once. Then, 2' -bromoacetophenone (3mmol, 405. mu.L) and a mixture of phenylboronic acid (3.6mmol,435mg) dissolved in 3mL of ethanol were sequentially added to a three-necked flask, and 12mL of toluene saturated with nitrogen was added. And carrying out reflux reaction on the reaction mixed solution at the temperature of 110 ℃ for 11 hours to obtain an intermediate product, namely the diphenoyl ketone. Almost complete conversion. And (4) separating and purifying by a silica gel column (petroleum ether: ethyl acetate: 100: 1).
The second step is that: in a three-necked flask, 10mL of anhydrous tetrahydrofuran was charged, and further added were sodium hydride (dispersed in kerosene, content: 60%, 8.4mmol,0.336g) and diethyl carbonate (8.4mmol,0.72 mL). Sealing, and heating in oil bath at 80 deg.C. The acetophenone was dissolved in 10mL of anhydrous tetrahydrofuran and added dropwise to the reaction mixture under reflux. The reaction was stopped until the acetophenone was completely consumed, almost completely converted. After separation and purification by silica gel column, the compound ethyl3- ([1,1' -biphenyl ] -2-yl) -3-oxypropanoate of the formula (1) can be obtained.
The reaction formula is as follows:
Figure BDA0001317955300000051
a method of synthesizing a compound of formula (2) comprising the steps of:
a reactor was charged with ethyl3- ([1,1' -biphenyl ] -2-yl) -3-oxopropanoate (compound of formula (1) (0.25mmol,67mg), N-bromosuccinimide (0.1mmol,17.8mg), t-butylhydroperoxide (0.875mmol,78.86mg), sodium dihydrogen phosphate dihydrate (0.25mmol,39mg), and 2mL of tetrahydrofuran, followed by sealing and stirring at 80 ℃ for 15 hours. After cooling to room temperature and removal of the solvent under reduced pressure, the compound of formula (2) ethyl 10-hydroxyphenanthrene-9-carboxylate (1a) was obtained in a yield of 96% by separation and purification by column chromatography (eluent petroleum ether) 63.7 mg.
1H NMR(400MHz,Chloroform-d)δ13.32(s,1H),8.77(d,J＝8.5Hz,1H),8.64–8.45(m,3H),7.73(t,J＝7.7Hz,1H),7.65–7.41(m,3H),4.58(q,J＝6.8Hz,2H),1.53(t,J＝7.0Hz,3H)；13C NMR(101MHz,CDCl3)δ172.96,162.75,133.67,130.44,129.47,127.61,126.88,126.08,126.00,125.26,124.98,124.23,122.87,122.45,101.56,62.09,14.39.[M+H]+:267.1016,found 267.1016.
Example 2: synthesis of ethyl 10-hydroxyphenanthrene-9-carboxylate (1a)
Figure BDA0001317955300000052
The method of synthesizing the compound of formula (1) is as described in example 1.
A method of synthesizing a compound of formula (2) comprising the steps of:
a reactor was charged with ethyl3- ([1,1' -biphenyl ] -2-yl) -3-oxopropanoate (compound of formula (1) (0.25mmol,67mg), N-bromosuccinimide (0.1mmol,17.8mg), t-butylhydroperoxide (0.875mmol,78.86mg), sodium dihydrogen phosphate dihydrate (0.25mmol,39mg), and 2mL of tetrahydrofuran, followed by sealing and stirring at 90 ℃ for 15 hours. After cooling to room temperature and removal of the solvent under reduced pressure, the compound of formula (2) ethyl 10-hydroxyphenanthrene-9-carboxylate (1a) was obtained in 57.2mg, 86% yield by column chromatography separation and purification (eluent petroleum ether).
Example 3: synthesis of ethyl 10-hydroxyphenanthrene-9-carboxylate (1a)
Figure BDA0001317955300000053
The method of synthesizing the compound of formula (1) is as described in example 1.
A method of synthesizing a compound of formula (2) comprising the steps of:
a reactor was charged with ethyl3- ([1,1' -biphenyl ] -2-yl) -3-oxopropanoate (compound of formula (1) (0.25mmol,67mg), N-bromosuccinimide (0.1mmol,17.8mg), bromoethylamine hydrobromide (0.1mmol,20.5mg), t-butyl hydroperoxide (0.875mmol,78.86mg), sodium dihydrogen phosphate dihydrate (0.25mmol,39mg), and tetrahydrofuran (2 mL), sealed, and the reaction was stirred at 80 ℃ for 15 hours. After cooling to room temperature and removal of the solvent under reduced pressure, the compound of formula (2) ethyl 10-hydroxyphenanthrene-9-carboxylate (1a) was obtained in 61.9mg (93% yield) by column chromatography separation and purification (eluent petroleum ether).
Example 4: synthesis of ethyl 10-hydroxyphenanthrene-9-carboxylate (1a)
Figure BDA0001317955300000061
The method of synthesizing the compound of formula (1) is as described in example 1.
A method of synthesizing a compound of formula (2) comprising the steps of:
a reaction vessel was charged with ethyl3- ([1,1' -biphenyl ] -2-yl) -3-oxopropanoate (compound of formula (1) (0.25mmol,67mg), dibromoisocyanuric acid (0.05mmol,14.8mg), t-butylhydroperoxide (0.875mmol,78.86mg), and 2mL of tetrahydrofuran, and the mixture was stirred at 90 ℃ for 15 hours. After cooling to room temperature and removal of the solvent under reduced pressure, the compound ethyl 10-hydroxyphenanthrene-9-carboxylate (1a) of the formula (2) was obtained in 49mg yield by column chromatography separation and purification (eluent petroleum ether).
Example 5: synthesis of ethyl 10-hydroxy-7-methoxyphenanthrene-9-carboxylate (2a)
Figure BDA0001317955300000062
A method of synthesizing a compound of formula (1) comprising the steps of:
the phenylboronic acid (3.6mmol,435mg) in example 1 was replaced with p-methoxyphenylboronic acid (3.6mmol,548mg), and the compound ethyl3- (4'-methoxy- [1,1' -biphenol ] -2-yl) -3-oxopropanoate of formula (1) was obtained by the same method and under the same conditions as in example 1.
A method of synthesizing a compound of formula (2) comprising the steps of:
a reactor was charged with ethyl3- (4'-methoxy- [1,1' -biphenyl ] -2-yl) -3-oxopropanoate (0.25mmol,75mg) compound of formula (1), N-bromosuccinimide (0.1mmol,17.8mg), t-butylhydroperoxide (0.875mmol,78.86mg), sodium dihydrogen phosphate dihydrate (0.25mmol,39mg) and 2mL tetrahydrofuran, and the reaction was stirred at 80 ℃ for 15 hours. After cooling to room temperature and removal of the solvent under reduced pressure, the compound of formula (2) was purified by column chromatography (eluent petroleum ether) to give 68.9mg of ethyl 10-hydroxy-7-methoxyphenylene-9-carboxylate (2a) as a compound of formula (2) in 92% yield.
1H NMR(400MHz,Chloroform-d)δ13.44(s,1H),8.49(d,J＝8.2Hz,1H),8.43(d,J＝8.9Hz,2H),8.30(d,J＝2.6Hz,1H),7.70(d,J＝7.7Hz,1H),7.54(t,J＝7.6Hz,1H),7.08(dd,J＝9.1,2.6Hz,1H),4.57(q,J＝7.1Hz,2H),3.92(s,3H),1.55(t,J＝7.1Hz,3H).；13C NMR(101MHz,CDCl3)δ173.00,163.69,159.05,133.84,131.02,130.55,125.79,125.02,124.29,124.16,121.93,120.20,113.58,108.03,101.15,77.37,77.05,76.73,61.97,55.15,14.35.
Example 6: synthesis of ethyl 7-fluoro-10-hydroxyphenylene-9-carboxylate (3a)
Figure BDA0001317955300000071
A method of synthesizing a compound of formula (1) comprising the steps of:
the phenylboronic acid (3.6mmol,435mg) in example 1 was replaced with p-fluorophenylboronic acid (3.6mmol,504mg), and the compound ethyl3- (4'-fluoro- [1,1' -biphenol ] -2-yl) -3-oxopropanoate of formula (1) was obtained by the same method and under the same conditions as in example 1.
A method of synthesizing a compound of formula (2) comprising the steps of:
the compound ethyl3- (4'-fluoro- [1,1' -biphenyl ] -2-yl) -3-oxopropanoate (0.25mmol,71.0mg), N-bromosuccinimide (0.1mmol,17.8mg), t-butylhydroperoxide (0.875mmol,78.86mg), sodium dihydrogen phosphate dihydrate (0.25mmol,39mg) and 2mL of tetrahydrofuran (formula 1) were charged into a reactor, and the reaction was stirred at 80 ℃ for 15 hours. After cooling to room temperature and removal of the solvent under reduced pressure, the compound (2) was purified by column chromatography (eluent: petroleum ether) to give 59.0mg of Ethyl 4- (4-bromophenyl) -1-hydroxy-2-naphthoate (3a) as a compound of formula (2) in 84% yield.
1H NMR(400MHz,Chloroform-d)δ13.50(s,1H),8.41(ddd,J＝23.3,15.5,8.2Hz,4H),7.70(t,J＝7.6Hz,1H),7.56(t,J＝7.6Hz,1H),7.14(t,J＝8.2Hz,1H),4.57(q,J＝7.1Hz,2H),1.54(t,J＝7.1Hz,3H)；13C NMR(101MHz,CDCl3)δ172.64,163.97,163.39,160.97,133.27,131.18,131.08,130.70,126.56,125.06,124.82,124.73,124.69,122.51,122.49,122.17,112.59,112.36,111.56,111.31,100.91,100.88,77.37,77.05,76.73,62.28,14.29
Example 7: synthesis of ethyl 10-hydroxy-7-methylphenanthrene-9-carboxylate (4a)
Figure BDA0001317955300000072
A method of synthesizing a compound of formula (1) comprising the steps of:
the phenylboronic acid (3.6mmol,435mg) in example 1 was replaced with p-methylphenylboronic acid (3.6mmol,490mg), and the compound ethyl3- (4'-methyl- [1,1' -biphenyl ] -2-yl) -3-oxopropanoate of formula (1) was obtained by the same method and under the same conditions as in example 1.
A method of synthesizing a compound of formula (2) comprising the steps of:
a reactor was charged with ethyl3- (4'-methyl- [1,1' -biphenyl ] -2-yl) -3-oxopropanoate (0.25mmol,70.0mg), N-bromosuccinimide (0.1mmol,17.8mg), t-butylhydroperoxide (0.875mmol,78.86mg), sodium dihydrogen phosphate dihydrate (0.25mmol,39mg) and 2mL of tetrahydrofuran (formula (1), which was then sealed and stirred at 80 ℃ for 15 hours. After cooling to room temperature and removal of the solvent under reduced pressure, the compound of formula (2) was purified by column chromatography (eluent petroleum ether) to give 65.5mg of ethyl 10-hydroxy-7-methylphenanthrene-9-carboxylate (4a) as a compound of formula (2) in 94% yield.
1H NMR(400MHz,Chloroform-d)δ13.26(s,1H),8.55(s,1H),8.49(t,J＝8.4Hz,2H),8.39(d,J＝8.3Hz,1H),7.70(t,J＝7.6Hz,1H),7.57(t,J＝7.6Hz,1H),7.26(d,J＝8.4Hz,1H),4.57(q,J＝7.1Hz,2H),2.50(s,3H),1.53(t,J＝7.1Hz,3H).；13C NMR(101MHz,CDCl3)δ172.93,162.74,137.25,133.73,130.34,129.53,126.38,125.98,125.71,124.94,124.86,123.88,122.73,122.23,101.37,77.41,77.09,76.77,61.98,22.19,14.30
Example 8: synthesis of ethyl 10-hydroxy-8-methylphenanthrene-9-carboxylate (5a) and ethyl 10-hydroxy-6-methylphenanthrene-9-carboxylate (5b)
Figure BDA0001317955300000081
A method of synthesizing a compound of formula (1) comprising the steps of:
the phenylboronic acid (3.6mmol,435mg) in example 1 was replaced with 3-methylphenylboronic acid (3.6mmol,490mg), and the compound ethyl3- (3'-methyl- [1,1' -biphenol ] -2-yl) -3-oxopropanoate of formula (1) was obtained by the same method and under the same conditions as in example 1.
A method of synthesizing a compound of formula (2) comprising the steps of:
a reactor was charged with ethyl3- (3'-methyl- [1,1' -biphenyl ] -2-yl) -3-oxopropanoate (0.25mmol,70.5mg), N-bromosuccinimide (0.1mmol,17.8mg), t-butylhydroperoxide (0.875mmol,78.86mg), sodium dihydrogen phosphate dihydrate (0.25mmol,39mg) and 2mL of tetrahydrofuran (formula (1), which was then sealed and stirred at 80 ℃ for 15 hours. After cooling to room temperature and removal of the solvent under reduced pressure, the product was purified by column chromatography (eluent petroleum ether) to yield 37mg of ethyl 10-hydroxy-8-methylphenanthrene-9-carboxylate (5a) in 53% yield and 27.9mg of ethyl 10-hydroxy-6-methylphenanthrene-9-carboxylate (5b) in 40% yield and 93% overall yield.
(5a)1H NMR(400MHz,Chloroform-d)δ13.23(s,1H),8.68(d,J＝8.6Hz,1H),8.62–8.50(m,2H),8.36(s,1H),7.75(t,J＝7.8Hz,1H),7.63(t,J＝7.5Hz,1H),7.40(d,J＝8.6Hz,1H),4.61(q,J＝7.1Hz,2H),2.56(s,3H),1.55(t,J＝7.1Hz,3H)；13C NMR(101MHz,CDCl3)δ172.94,162.07,133.60,133.44,130.21,129.16,127.12,126.70,126.15,125.88,125.35,124.93,122.73,122.40,101.54,77.36,77.05,76.73,61.95,21.49,14.37.
(5b)1H NMR(600MHz,Chloroform-d)δ10.89(s,1H),8.57(d,J＝8.3Hz,1H),8.44(dd,J＝17.8,8.0Hz,2H),7.74(t,J＝8.3Hz,1H),7.63(t,J＝8.0Hz,1H),7.43(dt,J＝14.6,7.0Hz,2H),4.45(q,J＝7.1Hz,2H),2.53(s,3H),1.37(t,J＝7.2Hz,3H)；13C NMR(151MHz,CDCl3)δ171.70,158.24,134.18,133.75,130.44,130.02,128.78,127.21,126.85,124.55,124.53,122.76,120.28,103.63,77.25,77.03,76.82,61.78,22.96,14.14.
Example 9: synthesis of ethyl7- (tert-butyl) -10-hydroxyphenylene-9-carboxylate (6a)
Figure BDA0001317955300000091
A method of synthesizing a compound of formula (1) comprising the steps of:
the phenylboronic acid (3.6mmol,435mg) in example 1 was replaced with p-tert-butylboronic acid (3.6mmol,642mg), and the compound ethyl7- (tert-butyl) -10-hydroxyphenanthrene-9-carboxylate of formula (1) was obtained by the same method and under the same conditions as in example 1.
A method of synthesizing a compound of formula (2) comprising the steps of:
a reactor was charged with ethyl7- (tert-butyl) -10-hydroxyphenylene-9-carboxlate (0.25mmol,83.0mg) which is a compound of formula (1), N-bromosuccinimide (0.1mmol,17.8mg), t-butylhydroperoxide (0.875mmol,78.86mg), sodium dihydrogen phosphate dihydrate (0.25mmol,39mg) and 2mL of tetrahydrofuran, and the reaction was stirred at 80 ℃ for 15 hours. After cooling to room temperature and removal of the solvent under reduced pressure, the compound ethyl7- (tert-butyl) -10-hydroxyphenylene-9-carboxylate (6a) of the formula (2) was obtained by separation and purification by column chromatography (eluent petroleum ether) in 76.7mg, 95% yield.
1H NMR(400MHz,Chloroform-d)δ13.39(s,1H),8.86(s,1H),8.62–8.41(m,3H),7.73(t,J＝7.6Hz,1H),7.64–7.51(m,2H),4.59(q,J＝7.1Hz,2H),1.57(t,J＝7.1Hz,3H),1.44(s,9H)；13C NMR(101MHz,CDCl3)δ173.20,162.99,150.28,133.62,130.41,129.24,126.46,125.00,124.96,123.85,122.59,122.33,122.30,101.68,77.38,77.07,76.75,62.00,35.25,31.51,14.46.
Example 10: synthesis of diethyl 9-hydroxyphenanthrene-2, 10-dicarboylate (7a)
Figure BDA0001317955300000092
A method of synthesizing a compound of formula (1) comprising the steps of:
the phenylboronic acid (3.6mmol,435mg) in example 1 was replaced with p-ethoxyformylphenylboronic acid (3.6mmol,699mg), and the compound ethyl2'- (3-ethoxy-3-oxopropanoyl) - [1,1' -biphenol ] -4-carboxylate of formula (1) was obtained by the same method and under the same conditions as in example 1.
A method of synthesizing a compound of formula (2) comprising the steps of:
a reactor was charged with ethyl2'- (3-ethoxy-3-oxopropanoyl) - [1,1' -biphenol ] -4-carboxylate (0.25mmol,85.0mg), N-bromosuccinimide (0.1mmol,17.8mg), t-butylhydroperoxide (0.875mmol,78.86mg), sodium dihydrogen phosphate dihydrate (0.25mmol,39mg), and tetrahydrofuran (2 mL), and the mixture was sealed, and stirred at 80 ℃ for 15 hours. After cooling to room temperature and removal of the solvent under reduced pressure, the compound of formula (2) was isolated and purified by column chromatography (eluent petroleum ether to ethyl acetate 200:1) to give diethyl 9-hydroxyphenylene-2, 10-dicarboxylate (7a)76. 0mg, 90% yield.
1H NMR(400MHz,Chloroform-d)δ13.45(s,1H),9.49(s,1H),8.48(t,J＝8.5Hz,3H),7.75(t,J＝7.7Hz,1H),7.65(t,J＝7.5Hz,1H),4.58(q,J＝7.1Hz,2H),4.44(q,J＝7.1Hz,2H),1.60(t,J＝7.1Hz,3H),1.46(t,J＝7.1Hz,3H)；13C NMR(101MHz,CDCl3)δ172.65,166.94,163.25,132.78,130.61,128.94,128.85,128.18,127.78,126.00,125.04,124.23,122.97,122.78,101.31,77.38,77.07,76.75,62.32,61.06,14.48,14.18.
Example 11: synthesis of ethyl 10-hydroxy-6, 8-methylenephenanthrene-9-carboxylate (8a)
Figure BDA0001317955300000101
A method of synthesizing a compound of formula (1) comprising the steps of:
the phenylboronic acid (3.6mmol,435mg) in example 1 was replaced with 3, 5-dimethylphenylboronic acid (3.6mmol,540mg), and the compound ethyl3- (3',5' -dimethyl- [1,1' -biphenyl ] -2-yl) -3-oxopropanoate of formula (1) was obtained by the same method and under the same conditions as in example 1.
A method of synthesizing a compound of formula (2) comprising the steps of:
a reactor was charged with ethyl3- (3',5' -dimethyl- [1,1' -biphenyl ] -2-yl) -3-oxopropanoate (0.25mmol,75.0mg), N-bromosuccinimide (0.1mmol,17.8mg), t-butylhydroperoxide (0.875mmol,78.86mg), sodium dihydrogen phosphate dihydrate (0.25mmol,39mg) and 2mL of tetrahydrofuran (formula (1), which was then sealed and stirred at 80 ℃ for 15 hours. After cooling to room temperature and removal of the solvent under reduced pressure, the compound of formula (2) was isolated and purified by column chromatography (eluent petroleum ether to ethyl acetate 200:1) to give 41.4mg of ethyl 10-hydroxy-6, 8-methyleneanthrene-9-carboxylate (8a) as a 56% yield.
1H NMR(400MHz,Chloroform-d)δ10.82(s,1H),8.54(d,J＝8.1Hz,1H),8.42(d,J＝7.8Hz,1H),8.19(s,1H),7.70(t,J＝7.3Hz,1H),7.59(t,J＝7.1Hz,1H),7.23(s,1H),4.42(q,J＝7.4Hz,2H),2.51(s,3H),2.47(s,3H),1.34(t,J＝6.9Hz,3H)；13C NMR(101MHz,CDCl3)δ171.80,157.68,133.98,133.55,132.09,129.88,127.31,126.76,126.53,124.66,124.52,122.77,120.36,103.62,77.41,77.09,76.77,61.77,22.86,21.52,14.19.
Example 12: synthesis of ethyl 5-fluoro-10-hydroxyphenylene-9-carboxylate (9a)
Figure BDA0001317955300000102
A method of synthesizing a compound of formula (1) comprising the steps of:
the phenylboronic acid (3.6mmol,435mg) in example 1 was replaced with 2-fluorophenylboronic acid (3.6mmol,504mg), and the compound ethyl3- (2'-fluoro- [1,1' -biphenol ] -2-yl) -3-oxopropanoate of formula (1) was obtained by the same method and under the same conditions as in example 1.
A method of synthesizing a compound of formula (2) comprising the steps of:
a reactor was charged with ethyl3- (2'-fluoro- [1,1' -biphenyl ] -2-yl) -3-oxopropanoate (0.25mmol,71.0mg) compound of formula (1), N-bromosuccinimide (0.1mmol,17.8mg), t-butylhydroperoxide (0.875mmol,78.86mg), sodium dihydrogen phosphate dihydrate (0.25mmol,39mg), and tetrahydrofuran (2 mL), and the reaction was stirred at 80 ℃ for 15 hours. After cooling to room temperature and removal of the solvent under reduced pressure, the compound ethyl 5-fluoro-10-hydroxyphenylene-9-carboxylate (9a) of the formula (2) was obtained in 64.0mg, 91% yield by column chromatography separation and purification (eluent petroleum ether).
1H NMR(400MHz,Chloroform-d)δ13.21(s,1H),9.02(d,J＝5.5Hz,1H),8.57(t,J＝8.6Hz,2H),7.77(t,J＝7.4Hz,1H),7.66(t,J＝7.4Hz,1H),7.46(q,J＝7.8Hz,1H),7.19(dd,J＝14.2,7.9Hz,1H),4.59(q,J＝6.9Hz,2H),1.53(t,J＝7.0Hz,3H)；13C NMR(101MHz,CDCl3)δ172.52,162.82,160.29,132.01,131.97,131.37,131.33,130.78,130.76,127.62,127.42,127.34,127.31,127.07,127.05,125.66,124.63,101.52,77.35,77.03,76.71,62.25,14.33.
Example 13: synthesis of ethyl 2-fluoro-10-hydroxyphenylene-9-carboxylate (10a)
Figure BDA0001317955300000111
A method of synthesizing a compound of formula (1) comprising the steps of:
the compound ethyl3- (4-fluoro- [1,1 '-biphenol ] -2-yl) -3-oxopropanoate of formula (1) was obtained by substituting 2' -bromoacetophenone (3mmol, 405. mu.L) in example 1 with 5 '-fluoro-2' -bromoacetophenone (3mmol,648mg) and the same procedures and conditions as in example 1.
A method of synthesizing a compound of formula (2) comprising the steps of:
a reactor was charged with ethyl3- (4-fluoro- [1,1' -biphenyl ] -2-yl) -3-oxopropanoate (0.25mmol,74.0mg), N-bromosuccinimide (0.1mmol,17.8mg), t-butylhydroperoxide (0.875mmol,78.86mg), sodium dihydrogen phosphate dihydrate (0.25mmol,39mg), and tetrahydrofuran (2 mL), which was sealed, and the reaction was stirred at 80 ℃ for 15 hours. After cooling to room temperature and removal of the solvent under reduced pressure, the compound ethyl 5-fluoro-10-hydroxyphenylene-9-carboxylate (10a) of the formula (2) was obtained in a yield of 93% by separation and purification by column chromatography (eluent petroleum ether).
1H NMR(400MHz,Chloroform-d)δ13.18(s,1H),8.75(d,J＝8.4Hz,1H),8.56–8.35(m,2H),8.11(d,J＝9.8Hz,1H),7.50(dt,J＝28.2,6.7Hz,3H),4.60(q,J＝7.1Hz,2H),1.54(t,J＝7.1Hz,3H)；13C NMR(101MHz,CDCl3)δ172.69,162.78,161.51,161.47,160.32,130.14,130.12,128.89,127.38,126.04,125.70,124.92,124.84,124.48,122.62,119.24,119.00,109.83,109.61,102.45,77.36,77.04,76.72,62.22,14.34.
Example 14: synthesis of ethyl 10-hydroxy-2-methoxyphenylene-9-carboxylate (11a)
Figure BDA0001317955300000121
A method of synthesizing a compound of formula (1) comprising the steps of:
the compound ethyl3- (4-methoxy- [1,1 '-biphenol ] -2-yl) -3-oxypropanoate of formula (1) was obtained by replacing 2' -bromoacetophenone (3mmol, 405. mu.L) in example 1 with 5 '-methoxy-2' -bromoacetophenone (3mmol,684mg) and by the same method and conditions as in example 1.
A method of synthesizing a compound of formula (2) comprising the steps of:
a reactor was charged with ethyl3- (4-methoxy- [1,1' -biphenyl ] -2-yl) -3-oxopropanoate (0.25mmol,77.5mg), N-bromosuccinimide (0.1mmol,17.8mg), t-butylhydroperoxide (0.875mmol,78.86mg), sodium dihydrogen phosphate dihydrate (0.25mmol,39mg) and 2mL of tetrahydrofuran (formula (1), which was then sealed and stirred at 80 ℃ for 15 hours. After cooling to room temperature and removal of the solvent under reduced pressure, the compound of formula (2) ethyl 10-hydroxy-2-methoxyphenylene-9-carboxylate (11a) was obtained in 68.7mg (89% yield) by column chromatography separation purification (eluent petroleum ether).
1H NMR(400MHz,Chloroform-d)δ13.31(s,1H),8.70(d,J＝8.5Hz,1H),8.35(d,J＝9.1Hz,2H),7.79(s,1H),7.45(t,J＝7.7Hz,1H),7.35(t,J＝7.5Hz,1H),7.18–7.09(m,1H),4.49(q,J＝7.1Hz,2H),3.91(s,3H),1.44(t,J＝7.1Hz,3H)；13C NMR(101MHz,CDCl3)δ173.03，163.13,161.54,135.73,130.18,127.73,126.96,126.08,125.53,123.83,122.85,119.47,116.31,104.18,99.72,77.36,77.04,76.73,61.85,55.47,14.40.
Example 15: synthesis of ethyl 2-chloro-10-hydroxyphenylene-9-carboxylate (12a)
Figure BDA0001317955300000122
A method of synthesizing a compound of formula (1) comprising the steps of:
the compound ethyl3- (4-chloro- [1,1 '-biphenol ] -2-yl) -3-oxopropanoate of formula (1) was obtained by substituting 2' -bromoacetophenone (3mmol, 405. mu.L) in example 1 with 5 '-chloro-2' -bromoacetophenone (3mmol,696mg) and the other procedures and conditions were the same as in example 1.
A method of synthesizing a compound of formula (2) comprising the steps of:
a reactor was charged with ethyl3- (4-chloro- [1,1' -biphenyl ] -2-yl) -3-oxopropanoate (0.25mmol,78.0mg), N-bromosuccinimide (0.1mmol,17.8mg), t-butylhydroperoxide (0.875mmol,78.86mg), sodium dihydrogen phosphate dihydrate (0.25mmol,39mg) and 2mL of tetrahydrofuran (formula (1), which was then sealed and stirred at 80 ℃ for 15 hours. After cooling to room temperature and removal of the solvent under reduced pressure, the compound of formula (2) ethyl 10-hydroxy-2-methoxyphenylene-9-carboxylate (11a) was purified by column chromatography (eluent petroleum ether) in 73mg, 94% yield.
1H NMR(400MHz,Chloroform-d)δ13.28(s,1H),8.75(d,J＝8.4Hz,1H),8.41(dd,J＝16.1,8.3Hz,3H),7.64–7.37(m,3H),4.61(q,J＝6.8Hz,2H),1.56(t,J＝6.9Hz,3H)；13C NMR(101MHz,CDCl3)δ172.70,162.10,136.88,134.76,129.89,128.17,127.27,126.63,126.01,124.92,124.38,123.52,122.86,122.15,101.69,77.36,77.04,76.72,62.17,14.35.
Example 16: synthesis of ethyl 5-hydroxypyroro [1,2-a ] quinoline-4-carboxylate (13a)
Figure BDA0001317955300000131
A method of synthesizing a compound of formula (1) comprising the steps of:
the first step is as follows: cuprous iodide (0.25mmol, 49mg), anhydrous potassium phosphate (10.5mmol,2.3g), and 2-acetylpyrrole were charged into a three-necked flask, and then vacuum nitrogen gas was applied, and after repeating the operation once, the reactant iodobenzene (6mmol, 1.3mL), ligand N, N' -dimethylethylenediamine, and solvent toluene 5mL were added. The reaction mixture is refluxed and reacted for 24 hours at the temperature of 110 ℃, and an intermediate product N-phenyl-2-acetyl pyrrole can be obtained. Almost complete conversion. Separating and purifying by silica gel column.
The second step is that: in a three-necked flask, 10mL of anhydrous tetrahydrofuran was charged, and further added were sodium hydride (dispersed in kerosene, content: 60%, 8.4mmol,0.336g) and diethyl carbonate (8.4mmol,0.72 mL). Sealing, and heating in oil bath at 80 deg.C. N-phenyl-2-acetylpyrrole (3mmol,556mg) was dissolved in 10mL of anhydrous tetrahydrofuran and added dropwise to the reaction mixture under reflux. The reaction was stopped until the N-phenyl-2-acetylpyrrole was completely consumed, almost complete conversion. After separation and purification by silica gel column, the compound ethyl 3-oxo-3- (1-phenyl-1H-pyrro-2-yl) propanoate of the formula (1) can be obtained.
A method of synthesizing a compound of formula (2) comprising the steps of:
a reaction vessel was charged with ethyl 3-oxo-3- (1-phenyl-1H-pyrro-2-yl) propanoate (0.25mmol,63mg), N-bromosuccinimide (0.1mmol,17.8mg), t-butylhydroperoxide (0.875mmol,78.86mg), sodium dihydrogen phosphate dihydrate (0.25mmol,39mg) and 2mL of tetrahydrofuran (formula (1), which was then sealed and stirred at 90 ℃ for 15 hours. After cooling to room temperature and removal of the solvent under reduced pressure, the compound of formula (2) ethyl 5-hydroxypyroro [1,2-a ] quinoline-4-carboxylate (13a) was obtained in 42.2mg, 72% yield by column chromatography separation and purification (eluent petroleum ether).
1H NMR(400MHz,Chloroform-d)δ13.44(s,1H),8.62(d,J＝7.9Hz,1H),7.85(s,1H),7.76(d,J＝8.0Hz,1H),7.38–7.26(m,2H),7.08(d,J＝3.6Hz,1H),6.89–6.66(m,1H),4.52(q,J＝7.1Hz,2H),1.51(t,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ172.37,159.64,129.26,126.82,125.11,124.62,124.46,121.32,116.16,114.26,113.62,107.48,94.22,77.40,77.08,76.76,61.74,14.41.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included in the scope of the present invention.

Claims (9)

1. A method for synthesizing polysubstituted 10-hydroxy phenanthrene and derivatives thereof is characterized in that: the method comprises the following steps: the compound of formula (1) is reacted with bromine catalyst, additive, peroxide and organic solvent to obtain the compound of formula (2), which has the following general reaction formula:
Figure FDA0003064552660000011
wherein R is1Is hydrogen, halogen, aryl, alkyl or alkoxy, and the combination position is 3 position or 4 position or 5 position or 6 position; r2Is hydrogen, halogen, aryl, alkyl, alkoxy or ester group, and the combination position is 2' position, 3' position, 4' position, 5' position or 6 ' position; EWG is cyano, methoxyformyl, ethoxyformyl or N-phenylcarboxamido;
the bromine-containing catalyst is one or a mixture of more than two of N-bromosuccinimide, N-bromophthalimide, N-bromocyclohexylamine, dibromoisocyanuric acid or bromoethylamine hydrobromide;
the peroxide is one or a mixture of more than two of tert-butyl hydroperoxide, hydrogen peroxide, di-tert-butyl peroxide, cumyl hydroperoxide, m-chloroperoxybenzoic acid, tert-butyl peroxybenzoate, potassium hydrogen persulfate composite salt, potassium persulfate or iodobenzene acetate;
the additive is one or a mixture of more than two of sodium dihydrogen phosphate, acetic acid or citric acid.
2. The method for synthesizing polysubstituted 10-hydroxy phenanthrene and the derivatives thereof according to claim 1, characterized in that: the molar ratio of the compound of the formula (1), the bromine-containing catalyst, the peroxide and the additive is 1: 0.05-0.8: 1-5: 0.4-3.
3. The method for synthesizing polysubstituted 10-hydroxy phenanthrene and the derivatives thereof according to claim 1, characterized in that: the bromine-containing catalyst is N-bromosuccinimide.
4. The method for synthesizing polysubstituted 10-hydroxy phenanthrene and the derivatives thereof according to claim 1, characterized in that: the peroxide is tert-butyl hydroperoxide.
5. The method for synthesizing polysubstituted 10-hydroxy phenanthrene and the derivatives thereof according to claim 1, characterized in that: the adding amount of the organic solvent is 4-100 times of the weight of the compound in the formula (1).
6. The method for synthesizing polysubstituted 10-hydroxy phenanthrene and the derivatives thereof according to claim 1, characterized in that: the reaction temperature of the method is 60-100 ℃, and the reaction time is 0.5-15 hours.
7. The method for synthesizing polysubstituted 10-hydroxy phenanthrene and the derivatives thereof according to claim 1, characterized in that: when EWG is cyano, the compound of formula (1) is synthesized as follows:
Figure FDA0003064552660000012
when EWG is methoxyformyl or ethoxyformyl, the compound of formula (1) is synthesized as follows:
Figure FDA0003064552660000021
when EWG is an N-phenylcarboxamido group, the compounds of formula (1) are synthesized as follows:
Figure FDA0003064552660000022
8. the method for synthesizing polysubstituted 10-hydroxy phenanthrene and the derivatives thereof according to claim 7, characterized in that: the organic solvent in the synthesis method of the compound shown in the formula (1) is one or a mixture of more than two of toluene, 1, 4-dioxane, N' -dimethylformamide, ethanol or methanol;
the organic solvent in the method for synthesizing the compound of the formula (2) by using the compound of the formula (1) is one or a mixture of more than two of ethanol, methanol, ethylene glycol dimethyl ether, 1, 4-dioxane, tetrahydrofuran, 1, 2-dichloroethane, carbon tetrachloride or N, N' -dimethylformamide.
9. The method for synthesizing polysubstituted 10-hydroxy phenanthrene and the derivatives thereof according to claim 8, characterized in that:
the organic solvent in the process for synthesizing the compound of formula (2) from the compound of formula (1) is tetrahydrofuran.
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