CN111303028A - 4-cyano-2-difluoromethyl substituted quinoline compound and synthetic method thereof - Google Patents
4-cyano-2-difluoromethyl substituted quinoline compound and synthetic method thereof Download PDFInfo
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- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention provides a 4-cyano-2-difluoromethyl substituted quinoline compound and a synthesis method thereof. In the synthesis reaction, under the action of a photocatalyst, ortho-alkenyl aryl isonitrile is taken as a substrate and reacts with difluoromethyl triphenyl phosphonium bromide to synthesize the 4-cyano-2-difluoromethyl substituted quinoline compound. The synthesized 4-cyano-2-difluoromethyl substituted quinoline compound contains quinoline ring, difluoromethyl and cyano functional groups, and the quinoline ring, the difluoromethyl and the cyano functional groups have excellent activity in the aspect of biomedicine, thereby providing an effective thought for the design and synthesis of medicaments. The synthetic method provided by the invention is simple to operate, has good substrate universality and has step economy.
Description
Technical Field
The invention relates to the technical field of organic chemical synthesis, in particular to a 4-cyano-2-difluoromethyl substituted quinoline compound and a synthesis method thereof.
Background
Quinoline compounds have wide application in medicine, materials, dyes and the like. Such as 2-fluoroalkyl quinolones, are not only useful as antiprotozoal drugs, antituberculotic drugs, PDE4 inhibitors, cardiovascular drugs, VR1 receptor antagonists, and anti-infective drugs, but also as ligands for metal-catalyzed reactions. In addition, many antimalarial drugs, insecticides, anti-inflammatory drugs, and antidepressants contain quinoline skeletons, which are also important intermediates for the total synthesis of some alkaloids. Therefore, the synthesis of quinoline compounds starting from simple substrates or the direct introduction of various substituents for modification of the quinoline skeleton have attracted intense interest to chemists.
The key step of synthesizing the quinoline skeleton is the construction of a pyridine ring through the inverse synthesis analysis of the molecular structure of the quinoline. And the alkali-catalyzed domino reaction, the transition metal-catalyzed cyclization reaction or the free radical cyclization reaction can realize that the ortho-alkenyl aryl isonitrile constructs the nitrogen heterocyclic compound, so that the quinoline skeleton can be synthesized through the ortho-alkenyl aryl isonitrile free radical reaction.
Organofluorine compounds are widely used in the fields of medicine, agriculture, and life and material science due to their unique metabolic stability, lipophilicity, and biological properties, and thus, it is of great importance to develop a new synthetic method for introducing fluorine or fluoroalkyl groups into organic molecules. The introduction of difluoromethyl groups into organic molecules using mild conditions has been extensively studied over the past several decades. Among them, the addition reaction of a difluoromethyl radical with an unsaturated hydrocarbon is one of the commonly used strategies for introducing a difluoromethyl group. The visible light has the advantages of greenness, cleanness, sustainability and the like. Recently, photo-redox catalysis has become a powerful strategy for radical reactions. A key feature of this process is that visible light can be excited by a photocatalyst and then single electron transfer to initiate an organic reaction. Accordingly, chemists have endeavored to develop reactions that utilize visible light redox reactions to achieve difluoromethylation. The cyano is a substituent with stronger electron withdrawing property, and can be used as an isostere of carbonyl to change the physical properties of some small molecules, so that the interaction with a targeted protein is enhanced, and the pharmaceutical activity of the targeted protein is improved. Therefore, the synthesis of quinoline chemicals containing difluoromethyl and cyano using ortho-alkenyl aryl isonitriles as substrates is a problem to be solved by comprehensively considering the characteristics of metabolic stability and the like of organofluorine compounds and the characteristic of improving the pharmaceutical activity of cyano.
Disclosure of Invention
The invention provides a 4-cyano-2-difluoromethyl substituted quinoline compound and a synthesis method thereof, which are used for synthesizing difluoromethyl and cyano-containing quinoline chemicals by taking ortho-alkenyl aryl isonitrile as a substrate.
The application provides a 4-cyano-2-difluoromethyl substituted quinoline compound, which has a structural general formula shown as I:
wherein R is1Is selected from cycloalkyl, phenyl, heteroaryl or substituted phenyl, wherein the heteroaryl is one, two or three of pyridyl, thienyl and furyl; the substituent on the phenyl is one, two or three of C1-C5 alkyl, alkoxy, trifluoromethyl, cyano, nitro, F, Cl, Br and I;
R2one, two or three selected from C1-C5 hydrogen, alkyl, alkoxy, trifluoromethyl, cyano, nitro, F, Cl, Br and I.
Based on the compound shown in the formula I, the application also provides a synthesis method of the 4-cyano-2-difluoromethyl substituted quinoline compound, which comprises the following steps:
s01: adding ortho-alkenyl aryl isonitrile, difluoromethyl triphenyl phosphonium bromide, a photocatalyst and a solvent into a reactor in sequence.
Respectively measuring the ortho-alkenyl aryl isonitrile, difluoromethyl triphenyl phosphonium bromide, the photocatalyst and the solvent according to a preset proportion. Adding ortho-alkenyl aryl isonitrile, difluoromethyl triphenyl phosphonium bromide, a photocatalyst and a solvent into a reactor in sequence. In the present application, the molar ratio of the ortho-alkenylarylisonitrile to the difluoromethyl triphenylphosphonium bromide is 1: 1.1-2. The amount of the photocatalyst is 2 mol% of the amount of the ortho-alkenyl aryl isonitrile. The amount of solvent used is 0.5-10mL per millimole of ortho-alkenyl aryl isonitrile. More preferably, the molar ratio of the ortho alkenyl aryl isonitrile to the difluoromethyl triphenyl phosphonium bromide is 1: 1.5.
In the present application, the synthesis reaction formula of the ortho-alkenyl aryl isonitrile is:
wherein R is1Is selected from cycloalkyl, phenyl, heteroaryl or substituted phenyl, wherein the heteroaryl is one, two or three of pyridyl, thienyl or furyl; the substituent on the phenyl is one, two or three of C1-C5 alkyl, alkoxy, trifluoromethyl, cyano, nitro, F, Cl, Br and I;
R2one, two or three selected from C1-C5 hydrogen, alkyl, alkoxy, trifluoromethyl, cyano, nitro, F, Cl, Br and I.
The procedure for the synthesis of the arylalkenyl isonitrile is specifically described below using (E) -2- (2-isocyanophenyl) -3-phenylacetonitrile, i.e., arylalkenyl isonitrile 1a in example 1, according to the above synthesis reaction scheme. The remaining ortho-alkenylarylisocyanides differ only from the substituents of (E) -2- (2-isocyanophenyl) -3-phenylacrylonitrile 1a, but the synthetic procedure is the same.
S1: benzaldehyde and piperidine are added into a methanol solution containing o-nitrobenzonitrile. The reaction system was heated to reflux at 70 ℃. After 4 hours of reaction, it was cooled to room temperature and a yellow precipitate was collected. And recrystallizing the precipitate with methanol to obtain a yellow solid product (E) -2- (2-nitrophenyl) -3-phenyl acrylonitrile, as shown in a formula II.
S2: (E) -2- (2-nitrophenyl) -3-phenylacetonitrile, Sn powder and ethanol were mixed and stirred at room temperature. HCl was slowly added dropwise to the mixture at 0 ℃. After the completion of the dropwise addition, the mixture was stirred at room temperature for another 2 hours. Will be provided withThe mixture was saturated NaHCO3Quench with CH2Cl2And (4) extracting. The combined organic layers were combined with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and purifying the residue by flash column chromatography using hexane and ethyl acetate as eluent to give (E) -2- (2-aminophenyl) -3-phenylacetonitrile as a pale yellow solid, as shown in formula III.
S3: in a dry three-necked flask equipped with a dropping funnel, (E) -2- (2-aminophenyl) -3-phenylacetonitrile and THF were added under nitrogen and cooled to 0 ℃. Formic acid acetic anhydride prepared by reacting acetic anhydride with formic acid at 55 ℃ for 2 hours was transferred to a dropping funnel and added dropwise to a solution containing (E) -2- (2-aminophenyl) -3-phenylacetonitrile at 0 ℃. After completion of the dropwise addition, the mixture was warmed to room temperature and stirred for 2 hours. After the reaction was complete, the mixture was washed with saturated NaHCO3Quenched in solution with CH2Cl2Extraction was carried out three times. Extracting the extractive solution with Na2SO4Drying, and concentrating under reduced pressure to obtain pale white solid (E) -N- (2- (1-cyano-2-phenyl vinyl) phenyl) formamide shown in formula 1 a.
S4: THF and NEt were added to a dry three-necked flask equipped with a dropping funnel under nitrogen atmosphere3And (E) -N- (2- (1-cyano-2-phenylvinyl) phenyl) carboxamide, and cooled to 0 ℃. Then POCl was added dropwise3After completion of the dropwise addition, the mixture was stirred at 0 ℃ for 2 hours. After the reaction was completed, the mixture was saturated with Na2CO3The solution was quenched and stirred for 1 hour. Reaction mixture with CH2Cl2Extracting, combining organic layers and using anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and purifying the compound by column to obtain (E) -2- (2-isocyano phenyl) -3-phenyl acrylonitrile shown in formula V.
NMR (nuclear magnetic Resonance) analysis was performed on the prepared (E) -2- (2-isocyanophenyl) -3-phenylacrylonitrile 1a to obtain a spectrum H shown in FIG. 2, a spectrum C shown in FIG. 3, and the following data:
1HNMR(400MHz,CDCl3)δ7.93-7.91(m,2H),7.58-7.56(m,1H),7.52-7.42(m,7H)；
13C NMR(100MHz,CDCl3)δ169.8,149.0,132.9,132.2,131.5,130.0,129.9,129.5,129.1,128.4,124.5,117.1,106.6；
HRMS(ESI):calcd for C16H10N2([M+H]+)231.0917,found.231.0921.
in the present application, the photocatalyst is selected from eosin Y, eosin B, rose bengal, 4CzIPN (Chinese name: 2,4,5, 6-tetrakis (9-carbazolyl) -isophthalonitrile), fac-Ir (ppy)3(Chinese name: facial type-tri (2-phenylpyridine) iridium complex). The solvent is one or two selected from N, N-Dimethylformamide (N, N-Dimethyl formamide; DMF), N-Dimethylacetamide (DMAc), Dimethyl sulfoxide (DMSO), dichloromethane, acetonitrile, 1,4-dioxane (1, 4-dioxane), 1,2-Dichloroethane (1, 2-Dichloroethane; DCE), Tetrahydrofuran (THF), ethanol and methanol.
S02: stirring and reacting at normal temperature under the conditions of visible light irradiation and nitrogen atmosphere to obtain the product.
Stirring and reacting at normal temperature under the conditions of visible light irradiation and nitrogen atmosphere to obtain the product. Wherein the generation reaction formula of the product is as follows:
in the reaction formula, the reference numeral 1 is ortho alkenyl aryl isonitrile, the reference numeral 2 is difluoromethyl triphenyl phosphonium bromide, and the reference numeral 3 is a 4-cyano-2-difluoromethyl substituted quinoline compound with a structural formula I. In the application, an LED lamp with the power of 10W can be selected as the visible light, and the stirring time is 12 h.
S03: and (4) extracting the solvent in the product by adopting a rotary evaporator to obtain a crude product.
S04: and carrying out column chromatography on the crude product to obtain the 4-cyano-2-difluoromethyl substituted quinoline compound.
And (3) carrying out column chromatography on the crude product through a chromatographic column to obtain the 4-cyano-2-difluoromethyl substituted quinoline compound. Wherein, the eluent of the column chromatography is a mixed solvent of petroleum ether and ethyl acetate.
In the application, in order to analyze the influence of the photocatalyst and the solvent on the synthesis of the 4-cyano-2-difluoromethyl substituted quinoline compound, the application also takes a 4-cyano-2-difluoromethyl substituted quinoline compound as an example for condition optimization and screening, and the specific data are shown in table 1. Wherein, the structural formula and the synthesis reaction formula of the 4-cyano-2-difluoromethyl substituted quinoline compound used for optimizing and screening the conditions are respectively as follows:
structural formula (xvi):
the synthesis reaction formula is as follows:
the conditions of the synthesis reaction are as follows: the reaction is carried out for 12 hours under the condition of nitrogen, 0.2mmol of ortho-alkenyl aryl isonitrile 1a, 0.3mmol of difluoromethyl triphenyl phosphonium bromide, a photocatalyst, 1mL of solvent and 10W of blue LEDs. The synthesis conditions specifically identified in Table 2 are different from the conditions of the synthesis reaction, i.e.c)8W blue LEDs;d)no illumination is needed;e)in the air.
Table 1: data relating to comparative example based on example 1
As is clear from Table 1, in the experiment No. 4, when the photocatalyst was 2 mol% fac-Ir (ppy)3When the solvent is DMAc and 10W blue light LEDs, the synthesized 4-cyano-2-difluoromethyl substituted quineThe quinoline compound has higher yield, namely 70 percent.
The technical scheme provided by the embodiment of the invention can have the following beneficial effects:
in the 4-cyano-2-difluoromethyl substituted quinoline compound and the synthesis method thereof, under the action of a photocatalyst, ortho-alkenyl aryl isonitrile is taken as a substrate and reacts with difluoromethyl triphenyl phosphonium bromide to synthesize the 4-cyano-2-difluoromethyl substituted quinoline compound. The synthesized 4-cyano-2-difluoromethyl substituted quinoline compound contains quinoline ring, difluoromethyl and cyano functional groups, and the quinoline ring, the difluoromethyl and the cyano functional groups have excellent activity in the aspect of biomedicine, thereby providing an effective thought for the design and synthesis of medicaments. The synthetic method provided by the invention is simple to operate, has good substrate universality and has step economy.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
Drawings
In order to more clearly explain the technical solution of the present application, the drawings needed to be used in the embodiments will be briefly described below, and it is obvious to those skilled in the art that other drawings can be obtained according to the drawings without any creative effort.
FIG. 1 is a schematic flow chart of a synthetic method of a 4-cyano-2-difluoromethyl substituted quinoline compound provided by an embodiment of the invention;
FIG. 2 is a chart showing the H site of (E) -2- (2-isocyanophenyl) -3-phenylacetonitrile 1a provided in the example of the present invention;
FIG. 3 is a C spectrum of (E) -2- (2-isocyanophenyl) -3-phenylacetonitrile 1a provided in the example of the present invention;
FIG. 4 is a chart of an H spectrum of a 4-cyano-2-difluoromethyl-substituted quinoline compound 3a in example 1 according to the present invention;
FIG. 5 is a C spectrum of 4-cyano-2-difluoromethyl-substituted quinoline compound 3a in example 1 according to the present invention;
FIG. 6 is a spectrum F of 4-cyano-2-difluoromethyl-substituted quinoline compound 3a in example 1 according to the present invention;
FIG. 7 is a chart of the H spectrum of 4-cyano-2-difluoromethyl-substituted quinoline compound 3b in example 2 according to the present invention;
FIG. 8 is a C spectrum of 4-cyano-2-difluoromethyl-substituted quinoline compound 3b in example 2 according to the present invention;
FIG. 9 is a spectrum F of 4-cyano-2-difluoromethyl-substituted quinoline 3b of example 2 according to the present invention;
FIG. 10 is a chart showing the spectrum H of 4-cyano-2-difluoromethyl-substituted quinoline compound 3c of example 3 according to the present invention;
FIG. 11 is a C spectrum of 4-cyano-2-difluoromethyl-substituted quinoline compound 3C of example 3 according to the present invention;
FIG. 12 is a chart showing the F spectrum of 4-cyano-2-difluoromethyl-substituted quinolines 3c from example 3 according to the present invention;
FIG. 13 is a chart of example 4-cyano-2-difluoromethyl-substituted quinolines 3d according to the present invention as shown in FIG. 4;
FIG. 14 is a C spectrum of 4-cyano-2-difluoromethyl-substituted quinoline 3d of example 4 according to the present invention;
FIG. 15 is a chart showing the F spectrum of 4-cyano-2-difluoromethyl-substituted quinoline 3d of example 4 according to the present invention;
FIG. 16 is a chart of example 5 showing the spectrum H of 4-cyano-2-difluoromethyl-substituted quinoline 3 e;
FIG. 17 is a C spectrum of 4-cyano-2-difluoromethyl-substituted quinolines 3e from example 5 according to the present invention;
FIG. 18 is a chart showing the F spectrum of 4-cyano-2-difluoromethyl-substituted quinolines 3e from example 5.
Detailed Description
The invention is described in the following with specific embodimentsFurther description will be given. The photocatalyst and solvent are more optional in this application and more examples are formed, and for the convenience of describing the present disclosure and reducing the space, the following examples are only the optimum conditions determined in the present disclosure: photocatalyst fac-Ir (ppy)3Solvent DMAc, 10W blue LEDs, for example, without limiting the scope of the invention.
Referring to fig. 1, fig. 1 shows a schematic flow chart of a synthetic method of a 4-cyano-2-difluoromethyl substituted quinoline compound provided by an embodiment of the application. The following description of the embodiments is based on fig. 1.
Example 1
The embodiment of the invention provides a 4-cyano-2-difluoromethyl substituted quinoline compound 3a, wherein the 4-cyano-2-difluoromethyl substituted quinoline compound 3a has the following structural formula:
the embodiment of the invention also provides a synthesis method of the 4-cyano-2-difluoromethyl substituted quinoline compound 3a, which specifically comprises the following steps:
s101: 0.2mmol (46.1mg) of an o-alkenylaryl isonitrile 1a, 0.3mmol (117.8mg) of difluoromethyl triphenyl phosphonium bromide 2, 2 mol% (2.6mg) of fac-Ir (ppy) were charged in this order into the reactor31mL of N, N-dimethylformamide (DMAc);
s102: stirring for 12 hours at normal temperature under the conditions of blue LED irradiation with power of 10W and nitrogen atmosphere to obtain a product; wherein the generation reaction formula of the product is as follows:
s103: after the reaction is finished, extracting the solvent in the product by adopting a rotary evaporator to obtain a crude product;
s104: the crude product was subjected to column chromatography using a mixed solvent of petroleum ether and ethyl acetate as an eluent to give 39.2mg of 4-cyano-2-difluoromethyl-substituted quinolines 3a in a separation yield of 70%.
NMR (nuclear magnetic Resonance) was performed on the prepared 4-cyano-2-difluoromethyl-substituted quinoline compound 3a to obtain a spectrum H shown in FIG. 4, a spectrum C shown in FIG. 5, and a spectrum F shown in FIG. 6, and the following data:
1H NMR(400MHz,CDCl3)δ8.35(d,J＝8.4Hz,1H),8.29(dd,J＝0.8,8.4Hz,1H),7.97-7.93(m,1H),7.90-7.86(m,1H),7.59-7.57(m,3H),7.49-7.46(m,2H),6.69(t,J＝54.0Hz,1H)；
13C NMR(100MHz,CDCl3)δ149.9(t,J＝23.1Hz),146.3,137.7,132.9,131.7,131.0,130.8,129.8,129.7,128.8,126.4,125.2,120.7,114.3,112.6(t,J＝241.3Hz)；
19F NMR(377MHz,CDCl3)δ-112.6(s,2F)；
HRMS(ESI):calcd for C17H10F2N2([M+H]+)281.0885,found.281.089。
example 2
The embodiment of the invention provides a 4-cyano-2-difluoromethyl substituted quinoline compound 3b, wherein the 4-cyano-2-difluoromethyl substituted quinoline compound 3b has the following structural formula:
the embodiment of the invention also provides a synthesis method of the 4-cyano-2-difluoromethyl substituted quinoline compound 3b, which specifically comprises the following steps:
s201: 0.2mmol (31.2mg) of an o-alkenylaryl isonitrile 1b, 0.3mmol (117.8mg) of difluoromethyl triphenyl phosphonium bromide 2, 2 mol% (2.6mg) of fac-Ir (ppy) were charged in this order into the reactor31mL of N, N-dimethylformamide (DMAc);
s202: stirring for 12 hours at normal temperature under the conditions of blue LED irradiation with power of 10W and nitrogen atmosphere to obtain a product; wherein the generation reaction formula of the product is as follows:
s203: after the reaction is finished, extracting the solvent in the product by adopting a rotary evaporator to obtain a crude product;
s204: the crude product was subjected to column chromatography using a mixed solvent of petroleum ether and ethyl acetate as an eluent to give 39.2mg of 4-cyano-2-difluoromethyl-substituted quinolines 3b in 53% isolated yield.
NMR (nuclear magnetic Resonance) was performed on the prepared 4-cyano-2-difluoromethyl-substituted quinolines 3b to obtain a spectrum H shown in FIG. 7, a spectrum C shown in FIG. 8, and a spectrum F shown in FIG. 9, and the following data:
1H NMR(400MHz,CDCl3)δ8.35(d,J＝8.4Hz,1H),8.28(dd,J＝0.8,8.4Hz,1H),7.97-7.92(m,1H),7.89-7.85(m,1H),7.48-7.44(m,1H),7.39-7.37(m,1H),7.27-7.25(m,2H),6.68(t,J＝54.0Hz,1H),2.47(s,3H)；
13C NMR(100MHz,CDCl3)δ149.9(t,J＝23.0Hz),146.3,138.7,137.8,132.8,131.7,131.0,130.8,130.6,130.2,128.7,126.8,126.4,125.2,120.5,114.4,112.2(t,J＝241.0Hz),21.5；
19F NMR(377MHz,CDCl3)δ-113.0(s,2F)；
HRMS(ESI):calcd for C18H12F2N2([M+H]+)295.1041,found.295.1044。
example 3
The embodiment of the invention provides a 4-cyano-2-difluoromethyl substituted quinoline compound 3c, wherein the 4-cyano-2-difluoromethyl substituted quinoline compound 3c has the following structural formula:
the embodiment of the invention also provides a synthesis method of the 4-cyano-2-difluoromethyl substituted quinoline compound 3c, which specifically comprises the following steps:
s301: 0.2mmol (47.2mg) of an o-alkenylaryl isonitrile 1c, 0.3mmol (117.8mg) of difluoromethyl triphenyl phosphonium bromide 2, 2 mol% (2.6mg) of fac-Ir (ppy) were charged in this order into the reactor31mL of N, N-dimethylformamide (DMAc);
s302: stirring for 12 hours at normal temperature under the conditions of blue LED irradiation with power of 10W and nitrogen atmosphere to obtain a product; wherein the generation reaction formula of the product is as follows:
s303: after the reaction is finished, extracting the solvent in the product by adopting a rotary evaporator to obtain a crude product;
s304: the crude product was subjected to column chromatography using a mixed solvent of petroleum ether and ethyl acetate as an eluent to give 13.2mg of 4-cyano-2-difluoromethyl-substituted quinolines 3c in 23% isolated yield.
NMR (nuclear magnetic Resonance) was performed on the prepared 4-cyano-2-difluoromethyl-substituted quinolines 3C to obtain a spectrum H shown in FIG. 10, a spectrum C shown in FIG. 11, and a spectrum F shown in FIG. 12, and the following data:
1H NMR(400MHz,CDCl3)δ8.35(d,J＝8.4Hz,1H),8.28(dd,J＝0.8,8.0Hz,1H),7.99-7.95(m,1H),7.91-7.87(m,1H),7.66(dd,J＝1.2,5.2Hz,1H),7.35-7.33(m,1H),7.27-7.25(m,1H),6.79(t,J＝54.0Hz,1H)；
13C NMR(100MHz,CDCl3)δ150.3(t,J＝22.8Hz),146.5,132.2,131.8,131.2,131.1,130.8,130.6,129.3,127.8,126.4,125.3,122.1,114.1,112.2(t,J＝241.5Hz)；
19F NMR(377MHz,CDCl3)δ-113.1(s,2F)；
HRMS(ESI):calcd for C15H8F2N2S([M+H]+)287.0449,found.287.0453。
example 4
The embodiment of the invention provides a 4-cyano-2-difluoromethyl substituted quinoline compound 3d, wherein the 4-cyano-2-difluoromethyl substituted quinoline compound 3d has the following structural formula:
the embodiment of the invention also provides a synthesis method of the 4-cyano-2-difluoromethyl substituted quinoline compound 3d, which specifically comprises the following steps:
s401: 0.2mmol (47.2mg) of an o-alkenylaryl isonitrile 1d, 0.3mmol (117.8mg) of difluoromethyl triphenyl phosphonium bromide 2, 2 mol% (2.6mg) of fac-Ir (ppy) were sequentially charged in the reactor31mL of N, N-dimethylformamide (DMAc);
s402: stirring for 12 hours at normal temperature under the conditions of blue LED irradiation with power of 10W and nitrogen atmosphere to obtain a product; wherein the generation reaction formula of the product is as follows:
s403: after the reaction is finished, extracting the solvent in the product by adopting a rotary evaporator to obtain a crude product;
s404: using a mixed solvent of petroleum ether and ethyl acetate as an eluent, and carrying out column chromatography on the crude product to obtain 22.5mg of 4-cyano-2-difluoromethyl substituted quinoline compound 3d, wherein the separation yield is 39%.
NMR (nuclear magnetic Resonance) was performed on the prepared 4-cyano-2-difluoromethyl-substituted quinolines 3d to obtain a spectrum H shown in FIG. 13, a spectrum C shown in FIG. 14, a spectrum F shown in FIG. 15, and the following data:
1H NMR(400MHz,CDCl3)δ8.29-8.26(m,1H),8.18-8.16(m,1H),7.86-7.82(m,2H),6.91(t,J＝54.4Hz,1H),3.55-3.47(m,1H),2.38-2.32(m,2H),1.99-1.93(m,2H),1.91-1.85(m,2H),1.84-1.81(m,1H),1.55-1.44(m,3H)；
13C NMR(100MHz,CDCl3)δ150.8(t,J＝25.4Hz),144.5(t,J＝1.8Hz),143.3,130.8,130.5,130.3,127.6,124.6,118.4,117.9(t,J＝238.4Hz),115.6,38.7,30.8,26.9,25.4；
19F NMR(377MHz,CDCl3)δ-110.5(s,2F)；
HRMS(ESI):calcd for C17H16F2N2([M+H]+)287.1354,found.287.1359。
example 5
The embodiment of the invention provides a 4-cyano-2-difluoromethyl substituted quinoline compound 3e, wherein the 4-cyano-2-difluoromethyl substituted quinoline compound 3e has the following structural formula:
the embodiment of the invention also provides a synthesis method of the 4-cyano-2-difluoromethyl substituted quinoline compound 3e, which specifically comprises the following steps:
s501: 0.2mmol (49.6mg) of orthoalkenylarylisonitrile 1e, 0.3mmol (117.8mg) of difluoromethylbiphenylphosphonium bromide 2, 2 mol% (2.6mg) of fac-Ir (ppy)31mL of N, N-dimethylformamide (DMAc);
s502: stirring for 12 hours at normal temperature under the conditions of blue LED irradiation with power of 10W and nitrogen atmosphere to obtain a product; wherein the generation reaction formula of the product is as follows:
s503: after the reaction is finished, extracting the solvent in the product by adopting a rotary evaporator to obtain a crude product;
s504: the crude product was subjected to column chromatography using a mixed solvent of petroleum ether and ethyl acetate as an eluent to give 25.1mg of 4-cyano-2-difluoromethyl-substituted quinolines 3e in 42% isolated yield.
NMR (nuclear magnetic Resonance) was performed on the prepared 4-cyano-2-difluoromethyl-substituted quinolines 3e to obtain a spectrum H shown in FIG. 16, a spectrum C shown in FIG. 17, a spectrum F shown in FIG. 18, and the following data:
1H NMR(400MHz,CDCl3)δ8.31(dd,J＝5.6,9.2Hz,1H),7.98(dd,J＝2.8,9.2Hz,1H),7.70-7.65(m,1H),7.59-7.57(m,3H),7.47-7.45(m,2H),6.67(t,J＝54.0Hz,1H)；
13C NMR(100MHz,CDCl3)δ164.1(d,J＝254.0Hz),151.1(t,J＝23.3Hz),147.4(d,J＝13.0Hz),137.0,132.6,130.0,129.7,128.9,127.6(d,J＝9.8Hz),123.5,121.7(d,J＝25.8Hz),120.7(d,J＝1.4Hz),114.6(d,J＝20.9Hz),114.1,112.4(t,J＝241.6Hz)；
19F NMR(377MHz,CDCl3)δ-104.7(s,1F),-112.9(s,2F)；
HRMS(ESI):calcd for C17H9F3N2([M+H]+)299.0791,found.299.0794。
other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the disclosure herein. This application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.
It is to be understood that relational terms such as "first" and "second," and the like, may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. The invention is not limited to the precise arrangements described above and shown in the drawings, and various modifications and changes may be made without departing from the scope thereof. The scope of the invention is limited only by the appended claims.
Claims (10)
1. A4-cyano-2-difluoromethyl substituted quinoline compound is characterized by having a structural general formula shown as I:
wherein R is1Is selected from cycloalkyl, phenyl, heteroaryl or substituted phenyl, wherein the heteroaryl is one, two or three of pyridyl, thienyl and furyl; the substituent on the phenyl is one, two or three of C1-C5 alkyl, alkoxy, trifluoromethyl, cyano, nitro, F, Cl, Br and I;
R2one, two or three selected from C1-C5 hydrogen, alkyl, alkoxy, trifluoromethyl, cyano, nitro, F, Cl, Br and I.
2. A method for synthesizing 4-cyano-2-difluoromethyl substituted quinolines, which is characterized by comprising the following steps:
sequentially adding ortho-alkenyl aryl isonitrile, difluoromethyl triphenyl phosphonium bromide, a photocatalyst and a solvent into a reactor;
stirring and reacting at normal temperature under the conditions of visible light irradiation and nitrogen atmosphere to obtain a product;
extracting the solvent in the product by adopting a rotary evaporator to obtain a crude product;
and carrying out column chromatography on the crude product to obtain the 4-cyano-2-difluoromethyl substituted quinoline compound.
3. The method of synthesis according to claim 2, wherein the product is formed according to the reaction formula:
4. the synthesis method according to claim 2, wherein the molar ratio of the ortho-alkenyl aryl isonitrile to the difluoromethyl triphenyl phosphonium bromide is 1: 1.1-2.
5. The method of claim 2The method of (3), wherein the photocatalyst is selected from eosin Y, eosin B, rose bengal, 4CzIPN, fac-Ir (ppy)3One or more of (a).
6. The method of claim 2, wherein the amount of the photocatalyst is 2 mol% of the amount of the arylalkylisonitrile.
7. The synthesis method according to claim 2, wherein the solvent is one or two selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, dichloromethane, acetonitrile, 1,4-dioxane, 1,2-dichloroethane, tetrahydrofuran, ethanol, and methanol.
8. The method of claim 2, wherein the solvent is used in an amount of 0.5 to 10mL per millimole of the orthoalkenylarylisonitrile.
9. The method of claim 2, wherein the reaction formula for the synthesis of the orthoalkenylarylisonitrile is:
wherein R is1Is selected from cycloalkyl, phenyl, heteroaryl or substituted phenyl, wherein the heteroaryl is one, two or three of pyridyl, thienyl or furyl; the substituent on the phenyl is one, two or three of C1-C5 alkyl, alkoxy, trifluoromethyl, cyano, nitro, F, Cl, Br and I;
R2one, two or three selected from C1-C5 hydrogen, alkyl, alkoxy, trifluoromethyl, cyano, nitro, F, Cl, Br and I.
10. The synthetic method according to claim 2, characterized in that the eluent of the column chromatography is a mixed solvent of petroleum ether and ethyl acetate.
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