CN109320481B - Carboxylic acid NHPI ester decarboxylation alkylation method and application thereof in synthesis of diaryl derivatives - Google Patents
Carboxylic acid NHPI ester decarboxylation alkylation method and application thereof in synthesis of diaryl derivatives Download PDFInfo
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Abstract
The application discloses a decarboxylation alkylation method of carboxylic acid NHPI ester, wherein an active pyridine-boron free radical generated by the reaction of ethyl isonicotinate and diboron pinacol ester is used for catalyzing and activating the carboxylic acid NHPI ester to generate a carbon free radical. The application also discloses an application of the method in synthesis of diaryl derivatives, wherein 1, 1-diaryl derivatives are obtained by reacting pinacol ester diboron and diaryl olefin serving as initiators, 1,3, 5-trimethyl-1, 4-cyclohexadiene serving as a hydrogen source and ethyl isonicotinate serving as a catalyst. The method for catalyzing and activating the alkyl or aromatic carboxylic acid activated ester by the pyridine-boron free radical can be applied to synthesis of 1, 1-diaryl derivatives, and has value in developing a new method for industrially synthesizing the 1, 1-diaryl compounds.
Description
Technical Field
The application relates to the technical field of organic synthesis, in particular to a decarboxylation alkylation method of carboxylic acid NHPI ester and application of the carboxylic acid NHPI ester in synthesis of diaryl derivatives.
Background
The carboxylic acid compounds have the advantages of stability, low price, easy acquisition and the like because of wide existence in nature, and have wide application in the fields of organic, medicine, natural product synthetic chemistry and the like. The method can effectively realize the catalytic conversion of carboxylic acid or carboxylic acid derivative (activated ester) in a transition metal compound catalysis or photocatalysis mode, and is widely applied to the addition reaction of unsaturated compounds. However, the transition metals used in these processes are often toxic, expensive, and heavy metal residues in the reaction products; therefore, the development of new methods for the catalysis and conversion of carboxylic acids and their derivatives based on non-transition metal catalytic systems has also attracted attention.
The prior known catalytic and conversion methods of carboxylic acid derivatives without the participation of transition metals are mainly limited to the organic photocatalysts to catalyze the reactions. The organic photocatalytic reaction has the problems of low catalytic efficiency, narrow substrate range and the like, and is difficult to be applied in a large quantity. In view of this, it is important to develop a novel, simple and convenient catalytic method for the catalysis and conversion of carboxylic acids and derivatives thereof.
1, 1-diaryl compounds are important structural units and widely exist in fine chemical raw materials and drug synthesis intermediates. Such as: the 1, 1-diaryl structure is an important structural unit of a drug molecule, is used as a mother nucleus structure in the pharmaceutical industry, and can be used for producing antihistamine drugs such as chlorpheniramine, topiramine, antianginal drug, and the like. The traditional method for preparing the 1, 1-diaryl compound has a Friedel-crafts reaction method or a coupling reaction catalyzed by transition metal, wherein the adoption of the Friedel-crafts reaction mode has the advantages of mature process, stable reaction, simple three-waste treatment and the like, but the yield is low, and the time and the labor are consumed; the transition metal method has the advantages of easy control of reaction, simple experimental operation and the like, but has the defects of expensive catalyst, heavy metal residue in products, generation of a large amount of waste liquid, too high production cost, no accordance with the requirements of development of modern green chemical industry and no large-scale application in industry. Based on the above, it is worth studying whether a novel method for synthesizing diaryl derivatives can be provided.
Disclosure of Invention
The carboxylic acid NHPI ester is a reaction product of carboxylic acid and NHPI, and the application mainly aims to provide a decarboxylation alkylation method of NHPI ester. Another objective of the present application is to provide a novel synthesis route for 1, 1-diaryl derivatives by applying the above-mentioned decarboxylation alkylation method of NHPI esters to the synthesis of diaryl derivatives.
Specifically, the research finds that pyridine-boron free radicals are generated by using ethyl isonicotinate and pinacol diboron, the free radicals are used as active intermediates, the induced activation and conversion of carboxylic acid derivatives can be effectively realized, and the method can be applied to the synthesis of 1, 1-diaryl derivatives.
Accordingly, the present invention provides a method for decarboxylation alkylation of NHPI esters: the active pyridine-boron free radical generated by the reaction of ethyl isonicotinate and pinacol ester diboron is used for catalyzing and activating NHPI ester carboxylate to generate a carbon free radical.
Specifically, the reaction line of the decarboxylation alkylation method of the NHPI ester is shown as the following formula:
wherein R is1Is independent chain, ring alkyl or aromatic group.
The invention also provides an application of the decarboxylation alkylation method of the carboxylic acid NHPI ester, and particularly relates to an application of the decarboxylation alkylation method to synthesis of diaryl derivatives.
Specifically, the synthetic route of the diaryl derivative is as follows:
wherein R is1Is an independent chain, cyclic alkyl or aryl;
R2can be independently hydrogen, methyl, trifluoromethyl, alkoxy, dialkylamino, cyano, alkoxyformyl, alkylcarbamoyl or aryl;
R3can be independently hydrogen, methyl, trifluoromethyl, alkoxy, dialkylamino, cyano, alkoxyformyl, alkylcarbamoyl or aryl;
x may be independently a hydrocarbon (CH) or a nitrogen atom.
Further, the molar ratio of each substance in the synthesis line is as follows: diboron pinacol ester: diaryl olefins: hydrogen source: isonicotinic acid ethyl ester 1: 1: 2: 1.5: 0.2.
further, the hydrogen source is 1,3, 5-trimethyl-1, 4-cyclohexadiene, triethylsilylhydride, 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridinedicarboxylic acid diethyl ester. 1,3, 5-trimethyl-1, 4-cyclohexadiene is preferred.
Further, the reaction temperature is 110-130 ℃, and preferably 120 ℃; the reaction time is 18-24 h.
Specifically, the synthesis reaction is carried out by adopting the synthesis line, and the steps are as follows: dissolving pinacol diborate, diarylolefin and a hydrogen source in trifluoromethyl benzene, adding ethyl isonicotinate under the protection of nitrogen, reacting at 120 ℃ for 18-24 hours, cooling, filtering, recovering a solvent under reduced pressure, and performing column chromatography separation to obtain a product.
The invention also provides a synthetic method of the 1, 1-diaryl derivative, which comprises the following steps: the method comprises the following steps of reacting pinacol ester diboron and diarylolefin serving as initiators, 1,3, 5-trimethyl-1, 4-cyclohexadiene serving as a hydrogen source and ethyl isonicotinate serving as a catalyst to obtain the 1, 1-diaryl derivative.
Specifically, the synthetic route of the 1, 1-diaryl derivative is as follows:
wherein R is1Is an independent chain, cyclic alkyl or aryl;
R2can be independently hydrogen, methyl, trifluoromethyl, alkoxy, dialkylamino, cyano, alkoxyformyl, alkylcarbamoyl or aryl;
R3can be independently hydrogen, methyl, trifluoromethyl, alkoxy, dialkylamino, cyano, alkoxyformyl, alkylcarbamoyl or aryl;
x may be independently a hydrocarbon (CH) or a nitrogen atom.
Has the advantages that: the synthesis line provided by the invention has no heavy metal participation, and solves the problem of heavy metal residue in the product in the traditional synthesis line.
The invention utilizes active pyridine-boron free radicals generated by ethyl isonicotinate and pinacol diboron diboride to catalyze and activate carboxylic acid NHPI ester to generate carbon free radicals, uses diaryl olefin as a free radical acceptor, uses 1,3, 5-trimethyl-1, 4-cyclohexadiene as a hydrogen source, realizes the high-efficiency synthesis of 1, 1-diaryl compounds through a simple mode, and develops a new synthesis method of the 1, 1-diaryl derivatives.
Detailed Description
In order that those skilled in the art will better understand the technical solution of the present application, the technical solution of the present application will be clearly and completely described below with reference to specific embodiments, and it is obvious that the described embodiments are only a part of the embodiments of the present application, and not all embodiments.
Examples 1-10 are specific products synthesized using the methods provided herein.
Example 1
4- (2, 2-diphenylethyl) tetrahydro-2H-pyran of the formula:
example 2
5- (1-phenyl-2- (tetrahydro-2H-pyran-4-yl) ethyl) benzo [ d ] [1,3] dioxazole of the formula:
example 3
4- (2- (4- (methylthio) phenyl) -2-phenylethyl) tetrahydro-2H-pyran of the formula:
example 4
4- (2-phenyl-2- (4- (trifluoromethoxy) phenyl) ethyl) tetrahydro-2H-pyran of the formula:
example 5
2- (1-phenyl-2- (tetrahydro-2H-pyran-4-yl) ethyl) pyridine, having the structural formula:
example 6
(Z) -2- (1-phenyl-nonadec-10-en-1-yl) pyridine having the formula:
example 7
N-Boc-4-diphenylmethyl-piperidine, having the formula:
example 8
2- (3, 3-dimethyl-1-phenylbutyl) pyridine, having the structural formula:
example 9
1- (2, 2-diphenylethyl) adamantane, of formula:
example 10
2-chloro-6- (2, 2-diphenylpropyl) pyridine having the structural formula:
example 11
2- (2, 2-diphenylethyl) -6- (trifluoromethyl) pyridine having the formula:
example 12
2-methyl-1- (4-chlorobenzoyl) -3- (3, 3-diphenylpropyl) -5-methoxy-1H-indole of the formula:
example 13
2-methyl-1- (4-chlorobenzoyl) -3- [ 3-phenyl-3- (pyridin-2-yl) propyl ] -5-methoxy-1H-indole, of the formula:
example 14
(4- (4-chlorobenzoyl) phenyl) [ 2-methyl-4- (4, 4-diphenyl) -butan-2-yl ] ether having the formula:
example 15
2- (6- (2, 5-dimethylphenoxy) -3, 3-dimethyl-1-phenylhexyl) pyridine, having the formula:
the following is a specific example of the method for synthesizing the 1, 1-diaryl derivatives.
First, the starting material-NHPI carboxylate ester as shown in formula I was prepared by esterification according to the methods of the literature (Fawcett, A., Pradelles, J., Wang, Y., Mutsuga, T., Myers, E.L., & Aggarwal, V.K.science,2017,357, 283-286).
Examples 16 to 30 are specific examples of the synthesis of 1, 1-diaryl derivatives.
Example 16
This example is an example of the preparation of the compound provided in example 1, the synthesis of which is:
55.0mg (0.2mmol) of NHPI ester tetrahydropyran-4-carboxylic acid, 50.8mg (0.2mmol) of pinacol diboron diborate, 72.1mg (0.4mmol) of 1, 1-stilbene, 45.0 mu L (0.3mmol) of 1,3, 5-trimethyl-1, 4-cyclohexadiene, 6.0 mu L (0.04mmol) of ethyl isonicotinate and 1.0mL of trifluoromethylbenzene are taken, sealed and reacted at 120 ℃ for 18h under the protection of nitrogen. Cooling, filtering, decompressing and recovering the solvent, and separating by column chromatography to obtain 40.5mg of the compound of example 1 with a yield of 76%.
The structure is confirmed by NMR detection;1H NMR(400MHz,CDCl3)δ7.34-7.25(m,8H), 7.24-7.17(m,2H),4.09(t,J＝8.0Hz,1H),3.97-3.91(m,2H),3.32-3.26(m,2H), 2.04-2.01(m,2H),1.67(d,J＝11.9Hz,2H),1.41-1.31(m,3H)；13C NMR(100 MHz,CDCl3)δ144.9,128.6,127.9,126.3,68.0,47.7,43.1,33.2,32.5。
example 17
This example is an example of the preparation of the compound provided in example 2, the synthesis of which is:
taking 55.0mg (0.2mmol) of tetrahydropyran-4-formic acid NHPI ester, 50.8mg (0.2mmol) of pinacol diboron diborate, 89.6mg (0.4mmol) of 5- (1-phenyl vinyl) benzo [ d ] [1,3] dioxazole, 45.0 mu L (0.3mmol) of 1,3, 5-trimethyl-1, 4-cyclohexadiene, 6.0 mu L (0.04mmol) of ethyl isonicotinate and 1.0mL of trifluoromethyl benzene, sealing and reacting for 18h at 120 ℃ under the protection of nitrogen. Cooling, filtering, recovering solvent under reduced pressure, and separating by column chromatography to give 39.1mg of the compound of example 2 in 63% yield.
The structure is confirmed by NMR detection;1H NMR(400MHz,CDCl3)δ7.31-7.24(m,2H), 7.24-7.11(m,3H),6.73-6.68(m,3H),5.92-5.85(m,2H),3.97(t,J＝8.0Hz,1H), 3.90(dd,J＝11.4,3.2Hz,2H),3.29-3.23(m,2H),1.96-1.89(m,2H),1.65-1.58 (m,2H),1.39-1.26(m,3H)；13C NMR(100MHz,CDCl3)δ147.9,145.9,145.1, 139.0,128.6,127.7,126.3,120.8,108.3,101.0,68.0,47.3,43.2,33.2,32.5。
example 18
This example is an example of the preparation of the compound provided in example 3, the synthesis of which is:
55.0mg (0.2mmol) of NHPI ester tetrahydropyran-4-carboxylic acid, 50.8mg (0.2mmol) of pinacol diboron diborate, 90.5mg (0.4mmol) of 1-phenyl-1- (4-methylthiophenyl) -ethylene, 45.0 muL (0.3mmol) of 1,3, 5-trimethyl-1, 4-cyclohexadiene, 6.0 muL (0.04mmol) of ethyl isonicotinate and 1.0mL of trifluoromethylbenzene are taken, sealed and reacted at 120 ℃ for 18h under the protection of nitrogen. Cooling, filtering, recovering solvent under reduced pressure, and separating by column chromatography to give 51.7mg of the compound of example 3 in 83% yield.
The structure is confirmed by NMR detection;1H NMR(400MHz,CDCl3)δ7.23(d,J＝7.3Hz, 2H),7.18(d,J＝6.7Hz,2H),7.16-7.11(m,5H),3.98(t,J＝8.0Hz,1H),3.87(dd, J＝10.7,3.5Hz,2H),3.22(t,J＝11.0Hz,2H),2.41(s,3H),1.97-1.90(m,2H), 1.59(d,J＝11.2Hz,2H),1.37-1.25(m,3H)；13C NMR(100MHz,CDCl3)δ144.9, 142.0,135.9,128.6,128.4,127.8,127.1,126.3,68.0,47.1,43.0,33.3 and 33.2, 32.5,16.1。
example 19
This example is an example of the preparation of the compound provided in example 4, the synthesis of which is:
55.0mg (0.2mmol) of NHPI ester tetrahydropyran-4-carboxylic acid, 50.8mg (0.2mmol) of pinacol diboron diborate, 105.7mg (0.4mmol) of 1-phenyl-1- (4-trifluoromethoxyphenyl) -ethene, 45.0 muL (0.3mmol) of 1,3, 5-trimethyl-1, 4-cyclohexadiene, 6.0 muL (0.04mmol) of ethyl isonicotinate and 1.0mL of trifluoromethyl benzene are taken, sealed and reacted for 18h at 120 ℃ under the protection of nitrogen. Cooling, filtering, decompressing and recovering the solvent, and separating by column chromatography to obtain 54.5mg of the compound of example 4 with 78% yield.
The structure is confirmed by NMR detection;1H NMR(400MHz,CDCl3)δ7.31-7.23(m,2H), 7.23-7.13(m,5H),7.08(d,J＝8.2Hz,2H),4.07(t,J＝8.0Hz,1H),3.90-3.83(m, 2H),3.26-3.20(m,2H),1.99-1.88(m,2H),1.59(t,J＝12.3Hz,2H),1.33-1.22(m, 3H)；13C NMR(100MHz,CDCl3)δ147.6,144.3,143.8,129.1,128.8,127.9, 126.6,121.1,120.6(d,JC-F＝256.8Hz),67.9,47.1,43.1,33.3 and 33.2,32.5；19F NMR(376MHz,CDCl3)δ-57.85。
example 20
This example is an example of the preparation of the compound provided in example 5, the synthesis of which is:
55.0mg (0.2mmol) of NHPI ester tetrahydropyran-4-carboxylic acid, 50.8mg (0.2mmol) of pinacol diboron diborate, 72.5mg (0.4mmol) of 1-phenyl-1- (2-pyridyl) -ethylene, 45.0 mu L (0.3mmol) of 1,3, 5-trimethyl-1, 4-cyclohexadiene, 6.0 mu L (0.04mmol) of ethyl isonicotinate and 1.0mL of trifluoromethylbenzene are taken, sealed and reacted at 120 ℃ for 18h under the protection of nitrogen. Cooling, filtering, decompressing and recovering solvent, and separating by column chromatography to obtain 45.0mg of the compound of example 5 with 84% yield.
The structure is confirmed by NMR detection;1H NMR(400MHz,CDCl3)δ8.62(d,J＝4.2Hz, 1H),7.62-7.58(m,1H),7.40(d,J＝7.1Hz,2H),7.34(t,J＝7.5Hz,2H),7.23(d,J ＝7.3Hz,1H),7.20(d,J＝7.8Hz,1H),7.13(dd,J＝7.5,4.9Hz,1H),4.28(t,J＝ 7.9Hz,1H),3.95(d,J＝11.4Hz,2H),3.34-3.27(m,2H),2.29-2.22(m,1H), 2.14-2.07(m,1H),1.73-1.65(m,2H),1.45-1.36(m,3H)；13C NMR(100MHz, CDCl3)δ163.9,149.3,143.7,136.6,128.6,128.1,126.5,122.7,121.4,68.0,50.2, 42.2,33.3 and 33.1,32.6。
example 21
This example is an example of the preparation of the compound provided in example 6, the synthesis of which is:
85.5mg (0.2mmol) of oleic acid NHPI ester, 50.8mg (0.2mmol) of pinacol diboron diborate, 72.5mg (0.4mmol) of 1-phenyl-1- (2-pyridyl) -ethylene, 45.0. mu.L (0.3mmol) of 1,3, 5-trimethyl-1, 4-cyclohexadiene, 6.0. mu.L (0.04mmol) of ethyl isonicotinate and 1.0mL of trifluoromethylbenzene were taken, sealed and reacted at 120 ℃ for 18h under the protection of nitrogen. Cooling, filtering, decompressing and recovering the solvent, and separating by column chromatography to obtain 60.5mg of the compound of example 6 with a yield of 72%.
The structure is confirmed by NMR detection;1H NMR(400MHz,CDCl3)δ8.60-8.54(m,1H), 7.58-7.50(m,1H),7.34(d,J＝7.2,2H),7.31-7.25(m,2H),7.22-7.13(m,2H), 7.10-7.02(m,1H),5.43-5.31(m,2H),4.05(t,J＝7.8Hz,1H),2.28-2.18(m,1H), 2.12-2.05(m,1H),2.04-1.96(m,4H),1.34-1.20(m,24H),0.93-0.85(m,3H)；13C NMR(100MHz,CDCl3)δ164.3,149.3,144.1,136.4,130.0,129.9,128.5,128.1, 126.4,122.7,121.3,53.9,35.2,32.0,29.9,29.8,29.7,29.7,29.6,29.6,29.5,29.4, 29.3,29.1,28.0,27.3,22.8,14.2。
example 22
This example is an example of the preparation of the compound provided in example 7, the synthesis of which is:
74.8mg (0.2mmol) of NHPI 1-Boc-4-piperidinecarboxylate, 50.8mg (0.2mmol) of pinacol diborate, 70.2. mu.L (0.4mmol) of 1, 1-diphenylethylene, 45.0. mu.L (0.3mmol) of 1,3, 5-trimethyl-1, 4-cyclohexadiene, 6.0. mu.L (0.04mmol) of ethyl isonicotinate and 1.0mL of trifluoromethylbenzene were taken, sealed and reacted at 120 ℃ for 18h under the protection of nitrogen. Cooling, filtering, recovering solvent under reduced pressure, and separating by column chromatography to give 44.5mg of the compound of example 7 in 61% yield.
The structure is confirmed by NMR detection;1H NMR(400MHz,CDCl3)δ7.34-7.26(m,8H), 7.25-7.16(m,2H),4.15-4.07(m,3H),2.62(d,J＝13.3Hz,2H),2.03-2.00(m,2H), 1.73(d,J＝12.0Hz,2H),1.48(s,9H),1.36-1.30(m,1H),1.23-1.13(m,2H)；13C NMR(100MHz,CDCl3)δ154.9,144.9,128.6,127.9,126.3,79.3,47.9,43.7, 42.7,33.5,32.3,28.6。
example 23
This example is an example of the preparation of the compound provided in example 8, the synthesis of which is:
take NHPI pivalate 55.1mg (0.2mmol), pinacol diboron 50.8mg (0.2mmol), 1-phenyl-1- (2-pyridyl) -ethene 72.5mg (0.4mmol), 1,3, 5-trimethyl-1, 4-cyclohexadiene 45.0. mu.L (0.3mmol), isonicotinic acid ethyl ester 6.0. mu.L (0.04mmol), trifluoromethylbenzene 1.0mL, seal under nitrogen protection, react for 18h at 120 ℃. Cooling, filtering, recovering solvent under reduced pressure, and separating by column chromatography to give 43.5mg of the compound of example 8 in 91% yield.
The structure is confirmed by NMR detection;1H NMR(400MHz,CDCl3)δ8.42(d,J＝4.0Hz, 1H),7.41-7.36(m,1H),7.27(d,J＝7.7Hz,2H),7.15-7.08(m,3H),7.06-6.97(m, 1H),6.92-6.88(m,1H),4.11-4.08(m,1H),2.32(dd,J＝14.0,7.7Hz,1H),1.89 (dd,J＝14.0,5.6Hz,1H),0.7(s,9H)；13C NMR(100MHz,CDCl3)δ165.0,149.2, 145.8,136.5,128.5,128.0,126.2,122.9,121.2,50.8,48.7,31.5,30.2。
example 24
This example is an example of the preparation of the compound provided in example 9, the synthesis of which is:
taking 65.1mg (0.2mmol) of NHPI 1-adamantanecarboxylic acid ester, 50.8mg (0.2mmol) of pinacol diboron diborate, 70.2 mu L (0.4mmol) of 1, 1-diphenylethylene, 45.0 mu L (0.3mmol) of 1,3, 5-trimethyl-1, 4-cyclohexadiene, 6.0 mu L (0.04mmol) of ethyl isonicotinate and 1.0mL of trifluoromethylbenzene, sealing and reacting at 120 ℃ for 18h under the protection of nitrogen. Cooling, filtering, recovering solvent under reduced pressure, and separating by column chromatography to give 51.2mg of the compound of example 9 in 81% yield.
The structure is confirmed by NMR detection;1H NMR(400MHz,CDCl3)δ7.34-7.26(m,8H), 7.18-7.12(m,2H),4.17(t,J＝6.6Hz,1H),2.01(d,J＝6.6Hz,2H),1.93-1.89(m, 3H),1.72-1.56(m,6H),1.47(d,J＝2.6Hz,6H)；13C NMR(100MHz,CDCl3)δ 147.1,128.5,127.9,125.9,50.7,46.5,43.2,37.2,33.7,28.9。
example 25
This example is an example of the preparation of the compound provided in example 10, the synthesis of which is:
63.3mg (0.2mmol) of NHPI 6-chloro-pyridine-2-carboxylate, 50.8mg (0.2mmol) of pinacol diboron diborate, 70.2. mu.L (0.4mmol) of 1, 1-stilbene, 45.0. mu.L (0.3mmol) of 1,3, 5-trimethyl-1, 4-cyclohexadiene, 6.0. mu.L (0.04mmol) of ethyl isonicotinate and 1.0mL of trifluoromethylbenzene are taken, sealed and reacted at 120 ℃ for 18h under the protection of nitrogen. Cooling, filtering, decompressing and recovering the solvent, and separating by column chromatography to obtain 38.4mg of the compound of example 10 with a yield of 62%.
The structure is confirmed by NMR detection;1H NMR(400MHz,CDCl3)δ8.13(d,J＝2.4Hz, 1H),7.39(dd,J＝8.2,2.5Hz,1H),7.30-7.26(m,4H),7.25-7.14(m,7H),3.86(t,J ＝7.8Hz,1H),2.54(dd,J＝9.0,6.5Hz,2H),2.35(q,J＝7.7Hz,2H)；13C NMR (100MHz,CDCl3)δ149.7,149.2,144.2,138.9,136.3,128.8,127.9,126.6,124.0, 50.6,36.8,30.6。
example 26
This example is an example of the preparation of the compound provided in example 11, the synthesis of which is:
67.2mg (0.2mmol) of NHPI 6-trifluoromethyl-pyridine-2-carboxylate, 50.8mg (0.2mmol) of pinacol diboron diborate, 70.2. mu.L (0.4mmol) of 1, 1-stilbene, 45.0. mu.L (0.3mmol) of 1,3, 5-trimethyl-1, 4-cyclohexadiene, 6.0. mu.L (0.04mmol) of ethyl isonicotinate and 1.0mL of trifluoromethylbenzene are taken, sealed and reacted at 120 ℃ for 18h under the protection of nitrogen. Cooling, filtering, recovering solvent under reduced pressure, and separating by column chromatography to give 47.2mg of the compound of example 11 in 72% yield.
The structure is confirmed by NMR detection;1H NMR(400MHz,CDCl3)δ7.57(t,J＝7.8Hz, 1H),7.43(d,J＝7.6Hz,1H),7.28-7.23(m,8H),7.22-7.14(m,2H),7.01(d,J＝ 7.8Hz,1H),4.65(t,J＝8.0Hz,1H),3.63(d,J＝8.0Hz,2H)；13C NMR(100MHz, CDCl3)δ161.1,147.8(q,JC-F＝34.3Hz),144.0,137.2,128.5,128.1,126.5,126.4, 121.7(q,JC-F＝274.2Hz),117.8(q,JC-F＝3.0Hz),50.8,44.0；19F NMR(376MHz, CDCl3)δ-68.04。
example 27
This example is an example of the preparation of the compound provided in example 12, the synthesis of which is:
104.0mg (0.2mmol) of 2-methyl-1- (4-chlorobenzoyl) -5-methoxy-1H-indole-3-acetic acid NHPI ester, 50.8mg (0.2mmol) of diboron acid pinacol ester, 70.2 muL (0.4mmol) of 1, 1-stilbene, 45.0 muL (0.3mmol) of 1,3, 5-trimethyl-1, 4-cyclohexadiene, 6.0 muL (0.04mmol) of ethyl isonicotinate, 1.0mL of trifluoromethylbenzene, sealing under the protection of nitrogen, and reacting at 120 ℃ for 18H. Cooling, filtering, decompressing and recovering the solvent, and separating by column chromatography to obtain 80.2mg of the compound of example 12 with 81% yield.
The structure is confirmed by NMR detection;1H NMR(400MHz,CDCl3)δ7.65(d,J＝8.2Hz, 2H),7.47(d,J＝8.5Hz,2H),7.35-7.30(m,8H),7.25-7.18(m,2H),6.94(d,J＝ 8.9Hz,1H),6.75(s,1H),6.68(d,J＝9.0Hz,1H),4.02(t,J＝7.6Hz,1H),3.81(s, 3H),2.65(t,J＝7.6Hz,2H),2.40(q,J＝7.6Hz,2H),2.20(s,3H)；13C NMR(100 MHz,CDCl3)δ168.4,155.9,144.8,139.0,134.4,134.0,131.2,131.1,131.0, 129.1,128.7,127.9,126.4,119.7,115.1,111.3,101.2,55.8,51.2,35.6,22.5,13.4。
example 28
This example is an example of the preparation of the compound provided in example 13, the synthesis of which is:
104.0mg (0.2mmol) of 2-methyl-1- (4-chlorobenzoyl) -5-methoxy-1H-indole-3-acetic acid NHPI ester, 50.8mg (0.2mmol) of diboron acid pinacol ester, 72.5mg (0.4mmol) of 1-phenyl-1- (2-pyridyl) -ethylene, 45.0 muL (0.3mmol) of 1,3, 5-trimethyl-1, 4-cyclohexadiene, 6.0 muL (0.04mmol) of ethyl isonicotinate, 1.0mL of trifluoromethylbenzene, sealing under the protection of nitrogen, and reacting at 120 ℃ for 18H. Cooling, filtering, recovering solvent under reduced pressure, and separating by column chromatography to give 82.0 mg of the compound of example 13 in 84% yield.
The structure is confirmed by NMR detection;1H NMR(400MHz,CDCl3)δ8.61-8.59(m,1H), 7.67-7.61(m,2H),7.59-7.55(m,1H),7.49-7.43(m,2H),7.42-7.38(m,2H), 7.34-7.30(m,2H),7.25-7.17(m,2H),7.13-7.08(m,1H),6.91(d,J＝9.0Hz,1H), 6.83(d,J＝2.5Hz,1H),6.67-6.64(m,1H),4.17(t,J＝7.0Hz,1H),3.81(s,3H), 2.70-2.60(m,3H),2.45-2.34(m,1H),2.20(s,3H)；13C NMR(100MHz,CDCl3)δ 168.3,163.6,155.9,149.3,143.7,138.9,136.5,134.4,133.9,131.3,131.1,131.0, 129.1,128.7,128.1,126.7,123.0,121.5,119.8,115.0,111.2,101.4,55.7,53.4, 34.8,22.4,13.3。
example 29
This example is an example of the preparation of the compound provided in example 14, the synthesis of which is:
92.8mg (0.2mmol) of NHPI 2-methyl-2- [4- (4-chlorobenzoyl) -phenoxy ] propionate, 50.8mg (0.2mmol) of pinacol diboron, 70.2. mu.L (0.4mmol) of 1, 1-stilbene, 45.0. mu.L (0.3mmol) of 1,3, 5-trimethyl-1, 4-cyclohexadiene, 6.0. mu.L (0.04mmol) of ethyl isonicotinate and 1.0mL of trifluoromethyl benzene are taken, sealed and reacted for 18h at 120 ℃ under the protection of nitrogen. Cooling, filtering, recovering solvent under reduced pressure, and separating by column chromatography to give 46.4mg of the compound of example 14 in 51% yield.
The structure is confirmed by NMR detection;1H NMR(400MHz,CDCl3)δ7.69(t,J＝7.4Hz, 4H),7.44(d,J＝8.2Hz,2H),7.32(d,J＝7.7Hz,4H),7.26(t,J＝7.9Hz,4H), 7.15(t,J＝7.1Hz,2H),6.91(d,J＝8.4Hz,2H),4.35(t,J＝6.7Hz,1H),2.63(d,J ＝6.4Hz,2H),1.28(s,6H)；13C NMR(100MHz,CDCl3)δ194.6,160.2,145.9, 138.5,136.5,131.8,131.3,131.2,128.7,128.6,127.9,126.3,121.9,82.0,48.0, 47.5,27.6。
example 30
This example is an example of the preparation of the compound provided in example 15, the synthesis of which is:
79.1mg (0.2mmol) of NHPI 2, 2-dimethyl-5- (2, 5-dimethylphenoxy) valerate, 50.8mg (0.2mmol) of pinacol diboron, 72.5mg (0.4mmol) of 1-phenyl-1- (2-pyridyl) -ethene, 45.0. mu.L (0.3mmol) of 1,3, 5-trimethyl-1, 4-cyclohexadiene, 6.0. mu.L (0.04mmol) of ethyl isonicotinate, 1.0mL of trifluoromethylbenzene were taken, sealed under nitrogen protection, and reacted at 120 ℃ for 18 h. Cooling, filtering, decompressing and recovering the solvent, and separating by column chromatography to obtain 64.4mg of the compound of example 15 with 83 percent of yield.
The structure is confirmed by NMR detection;1H NMR(400MHz,CDCl3)δ8.54(d,J＝4.8Hz, 1H),7.52-7.44(m,1H),7.40(d,J＝7.9Hz,2H),7.24(t,J＝7.7Hz,2H),7.19(d,J ＝7.7Hz,1H),7.13(t,J＝7.3Hz,1H),7.00(t,J＝6.6Hz,2H),6.64(d,J＝7.4Hz, 1H),6.57(s,1H),4.20(t,J＝6.5Hz,1H),3.78(t,J＝6.5Hz,2H),2.56-2.45(m, 1H),2.30(s,3H),2.18(s,3H),2.07-2.00(m,1H),1.73-1.65(m,2H),1.40-1.30(m, 2H),0.81(s,6H)；13C NMR(100MHz,CDCl3)δ164.9,157.2,149.2,145.8,136.5, 130.3,128.5,128.1,128.0,126.2,123.6,123.0,121.2,120.7,112.1,68.6,50.3, 46.4,38.7,33.8,27.9,24.4,21.5,16.0。
the above description is only a preferred embodiment of the present application and is not intended to limit the present application, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present application shall be included in the protection scope of the present application.
Claims (6)
1. The application of the decarboxylation alkylation method of carboxylic acid NHPI ester is characterized in that the method is used for synthesizing diaryl derivatives, and a synthetic line of the diaryl derivatives is as follows:
wherein R is1Is independent chain-type or cyclic alkyl;
R2can independently be hydrogen,Methyl, trifluoromethyl, alkoxy, dialkylamino, cyano, alkoxyformyl, alkylaminocarbonyl or aryl;
R3can be independently hydrogen, methyl, trifluoromethyl, alkoxy, dialkylamino, cyano, alkoxyformyl, alkylaminocarboxyl or aryl;
x may be independently a hydrocarbon (CH) or a nitrogen atom;
in the synthesis line, an active pyridine-boron free radical generated by the reaction of ethyl isonicotinate and pinacol ester diboron is used for catalyzing and activating carboxylic acid NHPI ester to generate a carbon free radical;
the reaction process is shown as the following formula:
wherein R is1Is an independent chain or cyclic alkyl group.
2. The use according to claim 1, wherein the molar ratio of the substances in the synthesis line is: diboron pinacol ester: a diarylolefin: hydrogen source: isonicotinic acid ethyl ester 1: 2: 1.5: 0.2.
3. use according to claim 1, characterized in that the hydrogen source is 1,3, 5-trimethyl-1, 4-cyclohexadiene, triethylhydrosilane, diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridinedicarboxylate.
4. The use according to claim 1, wherein the reaction temperature is 110 to 130 ℃ and the reaction time is 18 to 24 hours.
5. The application of the compound of claim 1, wherein the diboron pinacol ester, the diarylolefin and the hydrogen source are dissolved in trifluoromethyl benzene, ethyl isonicotinate is added under the protection of nitrogen, the reaction is carried out at 120 ℃ for 18-24 hours, the cooling is carried out, the filtration is carried out, the solvent is recovered under reduced pressure, and the product is obtained by column chromatography separation.
6. A synthesis method of 1, 1-diaryl derivatives is characterized in that pinacol ester diboron and diaryl olefin are used as starting materials, 1,3, 5-trimethyl-1, 4-cyclohexadiene is used as a hydrogen source, and ethyl isonicotinate is used as a catalyst to react to obtain the 1, 1-diaryl derivatives;
the synthesis route is as follows:
wherein R is1Is independent chain-type or cyclic alkyl;
R2can be independently hydrogen, methyl, trifluoromethyl, alkoxy, dialkylamino, cyano, alkoxyformyl, alkylaminocarboxyl or aryl;
R3can be independently hydrogen, methyl, trifluoromethyl, alkoxy, dialkylamino, cyano, alkoxyformyl, alkylaminocarboxyl or aryl;
x may be independently a hydrocarbon (CH) or a nitrogen atom.
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