CN111606849A - Synthetic method of 2- (2-aminophenyl) quinoline compound - Google Patents
Synthetic method of 2- (2-aminophenyl) quinoline compound Download PDFInfo
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- C07D215/12—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 substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract
A method for synthesizing 2- (2-aminophenyl) quinoline compounds, belonging to the technical field of organic synthesis. The synthesis method adopts the following operations: mixing the 2-alkynyl aniline compound 1, a catalyst, an additive and hexafluoroisopropanol, and heating and reacting in an oxygen-containing gas atmosphere or an inert gas atmosphere to respectively obtain the 2- (2-aminophenyl) quinoline compound 2 or the 2- (2-aminophenyl) quinoline compound 3. The synthesis method can selectively synthesize different types of 2- (2-aminophenyl) quinoline compounds in one step by the series reaction between two molecules of 2-alkynyl aniline and changing the reaction atmosphere. The method has the advantages of simple and easily obtained raw materials, simple and convenient operation, mild conditions, wide substrate application range and the like, and has potential industrial application prospect.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthetic method of a 2- (2-aminophenyl) quinoline compound.
Background
Quinoline is an important nitrogen-containing heterocyclic ring, and a plurality of compounds containing a quinoline framework have good pharmacological activities of resisting malaria, resisting inflammation, resisting schizophrenia and the like. The quinoline derivative can also form a complex with metal, and shows good electrochemical performance. Based on the characteristics, the functional group quinoline derivatives are widely applied to the fields of medicines, fine chemicals and the like.
At present, some reliable methods have been developed for synthesizing 2- (2-aminophenyl) quinoline compounds, but the methods still have the problems of difficult obtainment of raw materials, harsh reaction conditions, complicated synthesis steps, low atom economy and the like.
Therefore, a green and efficient novel method for synthesizing the 2- (2-aminophenyl) quinoline compound by starting from simple and easily-obtained raw materials and through simple and convenient operation steps is researched and developed, and the method has very important theoretical significance and practical prospect.
Disclosure of Invention
The invention solves the technical problem of providing a synthetic method of 2- (2-aminophenyl) quinoline compounds, and the synthetic method synthesizes the 2- (2-aminophenyl) quinoline compounds in one step through the series reaction between two molecules of 2-alkynyl aniline. The method has the advantages of simple and easily obtained raw materials, simple and convenient operation, mild conditions, wide substrate application range and the like, and has potential industrial application prospect.
The invention adopts the following technical scheme for solving the technical problems, and the synthesis method of the 2- (2-aminophenyl) quinoline compound comprises the following operations: mixing the 2-alkynyl aniline compound 1, a catalyst, an additive and Hexafluoroisopropanol (HFIP), and heating and reacting in an oxygen-containing gas atmosphere or an inert gas atmosphere to respectively obtain a 2- (2-aminophenyl) quinoline compound 2 or a 2- (2-aminophenyl) quinoline compound 3, wherein the reaction equation is as follows:
wherein: r1Is hydrogen, halogen, trifluoromethyl, C1-4Alkyl or C1-4Alkoxy radical, R2Is cyclopropyl, thienyl, phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is halogen, trifluoromethyl, C1-4Alkyl or C1-4An alkoxy group.
Further, in the technical scheme, the catalyst is copper sulfate and trifluoromethanesulfonic acid ketone { Cu (OTf)2Bismuth trifluoromethanesulfonate { Bi (OTf)3Lithium trifluoromethanesulfonate (LiOTf) or bismuth acetate { Bi (OAc)3}。
Further, in the above technical scheme, the additive is trifluoroacetic acid (TFA), 2,4, 6-trimethylbenzoic acid (MesCOOH) or 1-adamantanecarboxylic acid (1-AdCOOH).
Further, in the above-mentioned embodiment, the reaction atmosphere is an oxygen-containing gas atmosphere (for example, in oxygen or air) or an inert gas atmosphere (for example, in nitrogen or argon) which is advantageous for the production of the 2- (2-aminophenyl) quinoline compound 2, and the inert gas atmosphere (for example, in oxygen or air) which is advantageous for the production of the 2- (2-aminophenyl) quinoline compound 3.
Further, in the technical scheme, the feeding molar ratio of the 2-alkynyl aniline compound 1 to the additive to the catalyst is 1:0.25-2: 0.05-0.15.
Further, in the above technical scheme, the heating reaction temperature is 60-120 ℃.
The invention has the beneficial effects that:
compared with the prior art, the invention has the following advantages: 1) the synthetic process is simple and efficient, and the 2- (2-aminophenyl) quinoline compound is obtained in one step by the series reaction between two molecules starting from the 2-alkynyl aniline compound; 2) different 2- (2-aminophenyl) quinoline compounds can be selectively synthesized by changing the reaction atmosphere; 3) the raw materials are cheap and easy to obtain, the reaction conditions are mild, the operation is simple and convenient, the application range of the substrate is wide, the atom economy is high, and the requirements of green chemistry are met. Therefore, the invention provides a novel efficient and practical method for synthesizing the 2- (2-aminophenyl) quinoline compound.
Drawings
FIG. 1 is a single crystal X-ray diffraction pattern (30% ellipsoid) for Compound 2d of example 3.
Detailed Description
The present invention is described in further detail below with reference to examples, but it should not be construed that the scope of the above subject matter of the present invention is limited to the following examples, and that all the technologies realized based on the above subject matter of the present invention belong to the scope of the present invention.
Example 1
To a 15mL reaction tube were added 1a (57.9mg,0.3mmol), catalyst, additive and hexafluoroisopropanol (2mL) in that order, sealed with a stopper, placed in an oil bath, and the reaction was stirred at elevated temperature. After the reaction is finished, the reaction product is cooled to room temperature, filtered by suction, dried by spinning, and separated by a silica gel column (petroleum ether/ethyl acetate: 10/1) to obtain target products 2a and 3 a.
A series of reaction results were obtained by changing the reaction conditions such as the catalyst, the additive, the temperature, the reaction atmosphere, and the equivalent ratio of the substrate for the reaction, and are shown in Table 1.
TABLE 1 Synthesis of 2a and 3a under various conditionsa
Example 2
To a 15mL reaction tube were added 1a (57.9mg,0.3mmol), bismuth trifluoromethanesulfonate (19.7mg,0.03mmol), 2,4, 6-trimethylbenzoic acid (49.3mg,0.3mmol) and hexafluoroisopropanol (2mL) in this order, sealed with a stopper, and placed in an 80 ℃ oil bath and stirred for reaction for 20 h. After the reaction was complete, it was cooled to room temperature, filtered with suction, spin-dried, and separated on a silica gel column (petroleum ether/ethyl acetate 10/1) to give product 2a (43.2mg, 72%) as a yellow solid. Characterization data for this compound are: yellowsolid (43.2mg, 72%).1H NMR(400MHz,CDCl3):4.61(br s,2H),6.43(t,J＝7.6Hz,1H),6.74(d,J＝8.0Hz,2H),6.98-7.02(m,6H),7.26(t,J＝8.0Hz,2H),7.43(t,J＝7.6Hz,1H),7.52(t,J＝8.0Hz,1H),7.59(d,J＝7.6Hz,2H),7.66(d,J＝8.4Hz,1H),7.77(t,J＝7.6Hz,1H),8.21(d,J＝8.4Hz,1H).13C NMR(150MHz,CDCl3):116.7,117.8,123.9,124.4,125.2,127.4,127.65,127.74,127.8,128.5,129.2,129.49,129.51,130.1,131.7,131.9,133.8,136.60,136.64,145.4,146.2,146.7,158.4,197.2.HRMS calcd for C28H21N2O:401.1648[M+H]+,found:401.1647.
To a 15mL reaction tube were added 1a (57.9mg,0.3mmol), bismuth trifluoromethanesulfonate (19.7mg,0.03mmol), 2,4, 6-trimethylbenzoic acid (49.3mg,0.3mmol) and hexafluoroisopropanol (2mL) in this order, the reaction tube was sealed under a nitrogen atmosphere, and the mixture was placed in an oil bath at 80 ℃ and stirred for reaction for 20 hours. After the reaction was complete, it was cooled to room temperature, filtered with suction, spin-dried, and separated on a silica gel column (petroleum ether/ethyl acetate: 10/1) to give product 3a (37.1mg, 64%) as a pale yellow solid. Characterization data for this compound are: light yellow solid (37.1mg, 64%).1H NMR(400MHz,CDCl3):4.36(br s,2H),4.40(s,2H),6.40-6.44(m,1H),6.68(d,J＝8.0Hz,1H),6.72(dd,J1＝8.0Hz,J2＝1.6Hz,1H),6.93-6.97(m,1H),7.00(d,J＝6.8Hz,2H),7.07-7.10(m,2H),7.14-7.17(m,4H),7.20-7.23(m,2H),7.47-7.50(m,1H),7.67-7.71(m,1H),7.93(d,J＝8.4Hz,1H),8.16(d,J＝8.0Hz,1H).13C NMR(100MHz,CDCl3):35.6,116.3,117.6,125.3,126.1,126.8,126.9,127.2,127.8,128.2,128.6,128.7,129.2,129.9,130.1,131.2,136.1,138.3,140.1,144.5,144.9,147.1,158.7.HRMS calcd for C28H23N2:387.1856[M+H]+,found:387.1857.
The above reaction is simply expressed by the equation:
example 3
Various 2- (2-aminophenyl) quinolines 2 can be synthesized by varying reactant 1 according to the procedure and procedures of example 2, with the specific results shown in Table 2.
TABLE 2 Synthesis of various 2- (2-aminophenyl) quinolines 2a,b
aReaction conditions are as follows: 1(0.3mmol), Bi (OTf)3(0.03mmol),MesCO2H(0.3mmol),HFIP(2mL),80℃,air,20h；bThe isolation yield.
Representative product characterization data are as follows:
(2-(2-Amino-5-methylphenyl)-6-methyl-3-phenylquinolin-4-yl)(pheny l)methanone(2b)
Yellow solid(39.8mg,62％).1H NMR(400MHz,CDCl3):1.92(s,3H),2.45(s,3H),4.38(br s,2H),6.56(s,1H),6.62(d,J＝8.0Hz,1H),6.80(d,J＝8.0Hz,1H),6.99-7.00(m,4H),7.23-7.27(m,3H),7.41-7.44(m,2H),7.58(d,J＝7.6Hz,3H),8.10(d,J＝8.8Hz,1H).13C NMR(150MHz,CDCl3):20.1,21.8,116.6,123.8,123.9,124.6,126.9,127.3,127.58,127.62,128.4,129.2,129.5,129.7,131.7,132.2,132.4,133.7,136.7,136.8,137.8,142.7,145.2,145.4,157.5,197.5.HRMS calcd for C30H25N2O:429.1961[M+H]+,found:429.1962.
(2-(2-Amino-5-ethylphenyl)-6-ethyl-3-phenylquinolin-4-yl)(phenyl)methanone(2c)Yellow solid(50.0mg,73％).1H NMR(400MHz,CDCl3):0.76(t,J＝7.6Hz,3H),1.23(t,J＝7.6Hz,3H),2.19(q,J＝7.6Hz,2H),2.74(q,J＝7.6Hz,2H),4.54(br s,2H),6.54(s,1H),6.66(d,J＝8.0Hz,1H),6.80(d,J＝8.0Hz,1H),6.98(br s,4H),7.23-7.27(m,3H),7.42(t,J＝7.2Hz,2H),7.59(d,J＝8.0Hz,2H),7.63(d,J＝8.8Hz,1H),8.12(d,J＝8.8Hz,1H).13C NMR(150MHz,CDCl3):15.5,15.8,27.7,29.1,116.7,122.8,123.8,124.3,127.2,127.7,128.4,128.6,129.4,129.5,131.2,131.3,131.8,133.6,133.7,136.8,137.0,143.1,144.0,145.49,145.52,157.6,197.6.HRMS calcd for C32H29N2O:457.2274[M+H]+,found:457.2279.
(2-(2-Amino-5-bromophenyl)-6-bromo-3-phenylquinolin-4-yl)(phenyl)methanone(2d)
Yellow solid(49.2mg,59％).1H NMR(400MHz,CDCl3):4.55(br s,2H),6.60(d,J＝8.4Hz,1H),6.87(s,1H),7.06-7.10(m,5H),7.26-7.30(m,3H),7.45(t,J＝7.6Hz,1H),7.56(d,J＝8.0Hz,2H),7.82(s,1H),7.85(d,J＝9.2Hz,1H),8.07(d,J＝8.8Hz,1H).13C NMR(150MHz,CDCl3):109.3,118.2,122.2,125.1,125.5,127.4,128.0,128.6,129.5,131.1,132.1,132.6,133.9,134.1,134.2,135.6,136.3,144.4,145.28,145.31,157.3,196.3.HRMS calcd for C28H19Br2N2O:556.9859[M+H]+,found:556.9852.
2-(2-Aminophenyl)-3-(4-(tert-butyl)phenyl)quinolin-4-yl)(4-(tert-butyl)phenyl)methanone(2h)
Yellow solid(41.5mg,54％).1H NMR(400MHz,CDCl3):1.11(s,9H),1.22(s,9H),4.66(br s,2H),6.42(t,J＝7.6Hz,1H),6.75(t,J＝8.4Hz,2H),6.98-7.02(m,5H),7.21(d,J＝8.4Hz,2H),7.45(d,J＝8.4Hz,2H),7.51(t,J＝8.0Hz,1H),7.70(d,J＝8.4Hz,1H),7.75(t,J＝7.6Hz,1H),8.19(d,J＝8.4Hz,1H).13C NMR(150MHz,CDCl3):30.9,31.1,34.3,35.1,116.6,117.7,124.0,124.48,124.50,125.2,125.3,127.5,129.1,129.37,129.41,129.9,130.3,131.9,132.0,133.7,134.4,145.4,146.4,146.6,150.2,157.3,158.5,197.1.HRMS calcd for C36H37N2O:513.2900[M+H]+,found:513.2890.
(2-(2-Aminophenyl)-3-(4-methoxyphenyl)quinolin-4-yl)(4-methoxyphenyl)methanone(2i)
Yellow solid(33.1mg,48％).1H NMR(400MHz,CDCl3):3.66(s,3H),3.79(s,3H),4.61(br s,2H),6.47(t,J＝7.6Hz,1H),6.57(br s,2H),6.73-6.76(m,4H),6.99-7.03(m,3H),7.48(t,J＝7.6Hz,1H),7.59-7.64(m,3H),7.73(t,J＝7.6Hz,1H),8.18(d,J＝8.4Hz,1H).13C NMR(150MHz,CDCl3):55.0,55.5,113.3,113.8,116.7,117.9,124.1,124.8,125.3,127.4,129.0,129.07,129.10,129.42,129.45,129.8,131.4,131.66,131.74,132.0,145.3,146.4,146.5,158.7,164.1,195.7.HRMS calcd for C30H25N2O3:461.1860[M+H]+,found:461.1849.
(2-(2-Aminophenyl)-3-(4-(trifluoromethyl)phenyl)quinolin-4-yl)(4-(trifluoromethyl)phenyl)methanone(2m)
Yellow solid(57.1mg,71％).1H NMR(400MHz,CDCl3):4.59(br s,2H),6.44(t,J＝7.6Hz,1H),6.66(d,J＝7.6Hz,1H),6.75(d,J＝8.0Hz,1H),7.03(t,J＝7.6Hz,1H),7.26(br s,4H),7.54(d,J＝8.4Hz,2H),7.58(d,J＝7.2Hz,1H),7.62-7.67(m,3H),7.83(t,J＝7.6Hz,1H),8.25(d,J＝8.4Hz,1H).13C NMR(150MHz,CDCl3):116.8,118.0,123.2(q,1JC-F＝271.2Hz),123.4,123.6,123.7(q,1JC-F＝271.2Hz),124.87,124.95,125.7(q,3JC-F＝4.5Hz),128.2,129.6,129.7,129.756(q,2JC-F＝31.8Hz),129.759,130.6,130.8,130.9,131.5,135.2(q,2JC-F＝32.9Hz),139.1,140.3,145.4,145.5,147.0,158.0,195.9.19F NMR(565MHz,CDCl3):-62.9(s),-63.4(s).HRMS calcd for C30H19F6N2O:537.1396[M+H]+,found:537.1397.
(2-(2-Aminophenyl)-3-(thiophen-2-yl)quinolin-4-yl)(thiophen-2-yl)methanone(2p)
Yellow solid(23.5mg,38％).1H NMR(400MHz,CDCl3):4.51(br s,2H),6.57(t,J＝7.6Hz,1H),6.76-6.78(m,2H),6.92-6.96(m,3H),7.08-7.13(m,2H),7.18(d,J＝4.0Hz,1H),7.55(t,J＝8.0Hz,1H),7.64(d,J＝4.8Hz,1H),7.77(t,J＝8.4Hz,2H),8.19(d,J＝8.4Hz,1H).13CNMR(150MHz,CDCl3):116.7,118.0,123.6,124.3,124.8,125.3,126.7,127.9,128.3,129.5,129.6,130.5,130.6,131.1,135.7,135.8,137.2,143.7,145.4,146.6,146.9,158.6,188.6.HRMS calcd forC24H17N2OS2:413.0777[M+H]+,found:413.0771.
(2-(2-Aminophenyl)-3-cyclopropylquinolin-4-yl)(cyclopropyl)methanone(2q)
Yellow solid(12.8mg,26％).1H NMR(400MHz,CDCl3):0.39-0.43(m,2H),0.70-0.75(m,2H),1.22-1.25(m,2H),1.56-1.59(m,2H),2.09-2.16(m,1H),2.44-2.50(m,1H),4.26(br s,2H),6.82-6.86(m,2H),7.19-7.23(m,1H),7.29(dd,J1＝8.0Hz,J2＝2.0Hz,1H),7.53-7.57(m,1H),7.68-7.72(m,1H),7.75(d,J＝8.4Hz,1H),8.10(d,J＝8.4Hz,1H).13CNMR(150MHz,CDCl3):8.6,13.6,13.9,24.4,116.7,118.0,122.6,124.4,125.7,127.2,129.3,129.5,130.3,130.5,144.5,146.4,150.4,161.3,207.6.HRMS calcd for C22H21N2O:329.1648[M+H]+,found:329.1648.
(2-(2-Amino-5-methylphenyl)-3-(4-chlorophenyl)-6-methylquinolin-4-yl)(4-chlorophenyl)methanone(2r)
Yellow solid(44.7mg,60％).1H NMR(400MHz,CDCl3):1.96(s,3H),2.46(s,3H),4.36(br s,2H),6.52(s,1H),6.64(d,J＝8.0Hz,1H),6.83(d,J＝8.0Hz,1H),6.99(br s,3H),7.25-7.27(m,3H),7.34(s,1H),7.52(d,J＝8.4Hz,2H),7.61(d,J＝8.4Hz,1H),8.10(d,J＝8.8Hz,1H).13CNMR(150MHz,CDCl3):20.2,21.8,116.8,123.6,123.7,124.3,127.2,128.0,129.1,129.3,130.0,130.4,130.8,131.9,132.7,133.7,134.8,135.2,138.1,140.7,142.7,144.8,145.5,157.3,196.0.HRMS calcd forC30H23Cl2N2O:497.1182[M+H]+,found:497.1168.
(2-(2-Amino-5-methylphenyl)-3-(3-chlorophenyl)-6-methylquinolin-4-yl)(3-chlorophenyl)methanone(2s)
Yellow solid(43.2mg,58％).1H NMR(400MHz,CDCl3):1.96(s,3H),2.48(s,3H),4.42(br s,2H),6.55(s,1H),6.64(d,J＝8.4Hz,1H),6.83(d,J＝8.4Hz,1H),7.00-7.01(m,4H),7.21(t,J＝8.0Hz,1H),7.38(s,1H),7.40-7.43(m,2H),7.60(s,1H),7.63(d,J＝8.4Hz,1H),8.11(d,J＝8.4Hz,1H).13C NMR(150MHz,CDCl3):20.2,21.9,116.8,123.5,123.7,124.0,127.1,127.66,127.69,128.9,129.0,129.4,129.9,130.0,130.3,131.8,132.9,133.9,135.0,138.1,138.2,138.5,142.7,144.6,145.6,157.1,196.0.HRMS calcdfor C30H23Cl2N2O:497.1182[M+H]+,found:497.1173.
example 4
Various 2- (2-aminophenyl) quinolines 3 were synthesized by varying reactant 1 according to the procedure and procedure of example 2, with the specific results shown in Table 3.
TABLE 3 Synthesis of various 2- (2-aminophenyl) quinolines 3a,b
aReaction conditions are as follows: 1(0.3mmol), Bi (OTf)3(0.03mmol),MesCO2H(0.3mmol),HFIP(2mL),80℃,N2,20h；bThe isolation yield.
Representative product characterization data are as follows:
2-(4-Benzyl-6-methyl-3-phenylquinolin-2-yl)-4-methylaniline(3b)
Light yellow solid(40.4mg,65％).1H NMR(600MHz,CDCl3):1.93(s,3H),2.48(s,3H),4.37(br s,4H),6.54(s,1H),6.58(d,J＝7.8Hz,1H),6.75(dd,J1＝8.4Hz,J2＝1.8Hz,1H),7.00(d,J＝7.2Hz,2H),7.05-7.07(m,2H),7.14-7.18(m,4H),7.22(t,J＝7.8Hz,2H),7.53(dd,J1＝8.4Hz,J2＝1.8Hz,1H),7.71(s,1H),8.06(d,J＝8.4Hz,1H).13CNMR(150MHz,CDCl3):20.1,22.1,35.5,116.3,124.1,126.0,126.3,126.7,126.8,127.1,127.6,128.2,128.5,129.1,129.6,130.1,131.4,131.8,136.0,136.7,138.5,140.3,142.3,143.6,145.7,157.9.HRMS calcd for C30H27N2:415.2169[M+H]+,found:415.2169.
2-(4-Benzyl-6-chloro-3-phenylquinolin-2-yl)-4-chloroaniline(3d)
Light yellow solid(39.5mg,58％).1H NMR(400MHz,DMSO-d6):4.32(s,2H),5.14(br s,2H),6.57(d,J＝8.4Hz,1H),6.80(d,J＝2.4Hz,1H),6.88(dd,J1＝8.8Hz,J2＝2.8Hz,1H),7.06(d,J＝7.2Hz,2H),7.14(t,J＝7.6Hz,1H),7.20-7.23(m,7H),7.77(dd,J1＝8.8Hz,J2＝2.4Hz,1H),7.96(d,J＝2.0Hz,1H),8.09(d,J＝9.2Hz,1H).13C NMR(150MHz,DMSO-d6):35.0,116.7,118.6,124.7,126.6,126.8,127.6,127.9,128.2,128.4,128.5,129.0,130.0,130.1,130.2,131.8,132.3,137.1,137.9,140.0,143.9,145.5,145.9,158.2.HRMS calcd for C28H21Cl2N2:455.1076[M+H]+,found:455.1075.
2-(4-Benzyl-6-bromo-3-phenylquinolin-2-yl)-4-bromoaniline(3e)
Light yellow solid(51.2mg,63％).1H NMR(400MHz,CDCl3):4.34(br s,4H),6.55(d,J＝8.4Hz,1H),6.83(d,J＝1.6Hz,1H),6.96(d,J＝7.2Hz,2H),7.04-7.05(m,3H),7.18-7.24(m,6H),7.78(d,J＝7.6Hz,1H),8.01(d,J＝8.8Hz,1H),8.11(s,1H).13C NMR(150MHz,CDCl3):35.5,109.3,117.9,121.4,126.4,127.2,127.6,127.8,128.08,128.10,128.2,128.7,129.9,131.52,131.55,133.0,133.7,136.7,137.3,139.4,144.0,144.2,145.6,157.7.HRMS calcd for C28H21Br2N2:543.0066[M+H]+,found:543.0065.
2-(4-(4-Ethylbenzyl)-3-(4-ethylphenyl)quinolin-2-yl)aniline(3f)
Light yellow solid(34.5mg,52％).1H NMR(400MHz,CDCl3):1.15-1.22(m,6H),2.53-2.62(m,4H),4.37(s,4H),6.40-6.44(m,1H),6.69(d,J＝8.0Hz,1H),6.72(dd,J1＝7.6Hz,J2＝1.6Hz,1H),6.92-6.96(m,3H),6.97-7.01(m,4H),7.05(d,J＝8.0Hz,2H),7.45-7.49(m,1H),7.65-7.69(m,1H),7.93(d,J＝7.6Hz,1H),8.14(d,J＝8.0Hz,1H).13C NMR(150MHz,CDCl3):15.3,15.5,28.4,28.5,35.3,116.3,117.6,125.4,126.3,126.7,126.8,127.3,128.0,128.1,128.5,129.0,129.8,130.1,131.3,135.4,136.0,137.5,141.9,143.0,144.87,144.90,147.0,158.9.HRMS calcd for C32H31N2:443.2482[M+H]+,found:443.2477.
2-(4-(4-Fluorobenzyl)-3-(4-fluorophenyl)quinolin-2-yl)aniline(3g)
Light yellow solid(38.0mg,60％).1H NMR(400MHz,CDCl3):4.30(br s,2H),4.34(s,2H),6.43-6.47(m,1H),6.67-6.70(m,2H),6.86(t,J＝8.8Hz,2H),6.90-6.92(m,4H),6.96-7.02(m,3H),7.51-7.55(m,1H),7.71-7.75(m,1H),7.93(d,J＝8.0Hz,1H),8.17(d,J＝8.0Hz,1H).13CNMR(150MHz,CDCl3):34.7,114.9(d,2JC-F＝20.9Hz),115.4(d,2JC-F＝20.7Hz),116.4,117.8,125.0,125.8,126.6,127.1,128.8,129.5(d,3JC-F＝7.7Hz),130.0,131.0,131.6(d,3JC-F＝7.7Hz),134.1(d,4JC-F＝3.3Hz),135.0,135.4(d,4JC-F＝3.3Hz),144.6,144.8,147.2,158.8,161.4(d,1JC-F＝244.1Hz),162.0(d,1JC-F＝245.0Hz).19F NMR(376MHz,CDCl3):-114.5–-114.6(m),-116.7–-116.8(m).HRMS calcd forC28H21F2N2:423.1667[M+H]+,found:423.1667.
2-(4-(4-(Trifluoromethyl)benzyl)-3-(4-(trifluoromethyl)phenyl)quinolin-2-yl)aniline(3j)
Light yellow solid(53.2mg,68％).1H NMR(400MHz,CDCl3):4.40(br s,4H),6.43(t,J＝7.6Hz,1H),6.64-6.66(m,1H),6.69(d,J＝8.0Hz,1H),6.96-7.00(m,1H),7.08(d,J＝8.4Hz,2H),7.18(d,J＝8.0Hz,2H),7.43(d,J＝8.0Hz,2H),7.48(d,J＝8.0Hz,2H),7.55(t,J＝8.0Hz,1H),7.76(t,J＝7.2Hz,1H),7.88(d,J＝8.4Hz,1H),8.20(d,J＝8.4Hz,1H).13C NMR(150MHz,CDCl3):35.4,116.5,117.9,124.0(q,1JC-F＝270.2Hz),124.1(q,1JC-F＝270.3Hz),124.85(q,3JC-F＝6.6Hz),124.90,125.3,125.7(q,4JC-F＝3.2Hz),126.3,127.5,128.3,128.8(q,2JC-F＝31.7Hz),129.1,129.6(q,2JC-F＝31.7Hz),129.9,130.1,130.4,130.9,134.9,142.0,143.5,143.6,144.9,147.3,158.4.19F NMR(376MHz,CDCl3):-62.4(s),-62.6(s).HRMS calcd for C30H21F6N2:523.1603[M+H]+,found:523.1602.
2-(4-(3-Chlorobenzyl)-3-(3-chlorophenyl)quinolin-2-yl)aniline(3k)
Yellow solid(40.9mg,60％).1H NMR(400MHz,CDCl3):4.29-4.39(m,4H),6.46(td,J1＝7.6Hz,J2＝1.2Hz,1H),6.68-6.72(m,2H),6.81(d,J＝6.4Hz,1H),6.92(d,J＝7.6Hz,1H),6.96-7.00(m,2H),7.05-7.06(m,1H),7.09(t,J＝8.0Hz,1H),7.13-7.18(m,3H),7.52-7.57(m,1H),7.72-7.76(m,1H),7.93(d,J＝8.0Hz,1H),8.18(d,J＝8.0Hz,1H).13C NMR(100MHz,CDCl3):35.2,116.4,117.8,124.9,125.5,126.3,126.5,126.6,127.4,127.6,128.2,128.3,129.0,129.2,129.7,129.9,130.1,130.9,133.8,134.5,134.8,139.9,141.7,143.9,144.9,147.3,158.4.HRMS calcd for C28H21Cl2N2:455.1076[M+H]+,found:455.1072.
2-(4-(2-Chlorobenzyl)-3-(2-chlorophenyl)quinolin-2-yl)aniline(3l)
Light yellow solid(38.8mg,57％).1H NMR(400MHz,CDCl3):4.19(d,J＝16.8Hz,1H),4.43(br s,2H),4.60(d,J＝17.2Hz,1H),6.43(t,J＝7.6Hz,1H),6.65(d,J＝7.6Hz,1H),6.69(d,J＝8.0Hz,1H),6.85(d,J＝7.6Hz,1H),6.94-6.99(m,2H),7.02-7.10(m,3H),7.12-7.16(m,1H),7.31(t,J＝8.4Hz,2H),7.49(t,J＝8.0Hz,1H),7.72(t,J＝8.0Hz,1H),7.79(d,J＝8.4Hz,1H),8.18(d,J＝8.4Hz,1H).13C NMR(100MHz,CDCl3):32.8,116.5,117.4,125.0,125.2,126.3,126.4,126.8,127.1,127.5,129.0,129.1,129.2,129.4,129.65,129.67,130.0,130.3,131.9,133.5,133.8,134.3,136.9,137.0,145.0,145.1,147.3,158.4.HRMS calcd for C28H21Cl2N2:455.1076[M+H]+,found:455.1076.
example 5
The product 2- (2-aminophenyl) quinoline compound 2 synthesized by the invention can be subjected to a series of reactions, so as to synthesize further derivatives. For example:
to a round bottom flask was added 2a (60) sequentially at 0 deg.C (ice water bath)0mg, 0.15mmol) and aqueous HCl (2M, 1.5mL) were stirred at 0 ℃ for 15min, then sodium nitrite (11.4mg, 0.165mmol) was added to the mixture and stirring continued for 1 h. The mixture was then placed in a 60 ℃ oil bath and stirred for 3 h. After the reaction was complete, the reaction mixture was cooled to room temperature and saturated NaHCO was used3Aqueous work-up, followed by extraction with DCM (10mL × 3), the combined organic phases were washed with brine and dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give a residue which was isolated on a silica gel column (petroleum ether/ethyl acetate 20/1) to give 4(36.8mg, 64%) as a white solid.1H NMR(400MHz,CDCl3):7.29-7.35(m,3H),7.50-7.57(m,3H),7.76-7.83(m,6H),8.34(d,J＝8.4Hz,1H),8.39(d,J＝8.8Hz,1H),8.51-8.53(m,1H),8.55(d,J＝8.0Hz,1H),9.59-9.61(m,1H).13C NMR(150MHz,CDCl3):120.7,122.6,123.7,124.2,125.2,126.7,127.1,127.2,128.1,128.2,128.4,128.9,129.1,129.7,130.0,130.1,131.1,131.3,132.1,134.4,136.8,141.9,146.9,147.8,200.1.HRMScalcd for C28H18NO:384.1383[M+H]+,found:384.1383.
A round-bottomed flask was charged with 4(57.5mg, 0.15mmol), LiAlH in that order4(0.3mL, 0.3mmol, 1M in THF) and anhydrous THF (1mL), stirring at room temperature after completion of the reaction monitored by TLC, water was added to quench the reaction, followed by extraction with DCM (10mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give a residue, the residue was isolated by silica gel column (petroleum ether/ethyl acetate 10/1) to give white solid 5(30.1mg, 72%). the characterization data for this compound is as follows:1H NMR(400MHz,CDCl3):7.59(t,J＝7.6Hz,1H),7.63-7.68(m,2H),7.71-7.77(m,2H),7.79-7.82(m,1H),8.04(d,J＝8.4Hz,1H),8.32(d,J＝8.4Hz,1H),8.53-8.55(m,1H),8.57-8.59(m,1H),8.65-8.67(m,1H),9.26(s,1H),9.52-9.54(m,1H).13C NMR(150MHz,CDCl3):122.7,123.4,123.57,123.62,126.2,126.3,127.1,127.6,127.7,128.0,128.2,129.2,129.5,129.6,129.8,129.9,130.2,131.2,132.1,147.61,147.64.HRMS calcd forC21H14N:280.1121[M+H]+,found:280.1111.
a round-bottom flask was charged with 2a (80.0mg, 0.2mmol) and dilute sulfuric acid (1M, 2.5mL), and the resulting mixture was stirred at room temperature for 3h, then cooled to 0 deg.C (ice-water bath). An aqueous solution (1mL) of sodium nitrite (82.8mg, 1.2mmol) was then added dropwise and stirred for 1 h. To the mixture was added an aqueous solution (1mL) of sodium azide (78.1mg, 1.2mmol) over 15min and stirred at 0 ℃ for 1 h. The precipitate was filtered off and washed with water to give a grey-green solid. The solid was added to 1,2, 4-trichlorobenzene (5mL) and heated at 214 ℃ (liquid metal bath) for 3 h. The solvent was removed under reduced pressure, and the residue was separated by column on silica gel (petroleum ether/ethyl acetate 10/1) to give 6(54.9mg, 69%) as a yellow solid. The characterization data for this compound are as follows:1H NMR(600MHz,CDCl3):6.84(d,J＝8.4Hz,1H),6.97(t,J＝8.4Hz,1H),7.32(t,J＝8.4Hz,2H),7.37-7.41(m,5H),7.47-7.50(m,2H),7.55(t,J＝7.8Hz,1H),7.72-7.74(m,3H),7.83(t,J＝8.4Hz,1H),7.99(d,J＝8.4Hz,1H).9.11(d,J＝8.4Hz,1H).13C NMR(150MHz,CDCl3):116.9,117.6,117.8,121.3,121.5,122.9,126.6,126.8,128.0,128.6,128.7,128.9,129.6,129.8,130.0,130.6,131.6,133.2,133.8,134.4,137.8,149.7,197.0.HRMS calcdfor C28H19N2O:399.1492[M+H]+,found:399.1483.
the foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and the invention is intended to be covered by the appended claims.
Claims (8)
1. A synthetic method of a 2- (2-aminophenyl) quinoline compound is characterized by comprising the following operations: mixing the 2-alkynyl aniline compound 1, a catalyst, an additive and hexafluoroisopropanol, and heating and reacting in an oxygen-containing gas atmosphere or an inert gas atmosphere to respectively obtain a 2- (2-aminophenyl) quinoline compound 2 or a 2- (2-aminophenyl) quinoline compound 3, wherein the reaction equation is as follows:
wherein: r1Is hydrogen, halogen, trifluoromethyl, C1-4Alkyl or C1-4Alkoxy radical, R2Is cyclopropyl, thienyl, phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is halogen, trifluoromethyl, C1-4Alkyl or C1-4An alkoxy group.
2. The method for synthesizing 2- (2-aminophenyl) quinolines according to claim 1, wherein: the catalyst is copper sulfate, trifluoromethanesulfonic acid ketone, bismuth trifluoromethanesulfonate, lithium trifluoromethanesulfonate or bismuth acetate.
3. The method for synthesizing 2- (2-aminophenyl) quinolines according to claim 1, wherein: the additive is trifluoroacetic acid, 2,4, 6-trimethyl benzoic acid or 1-adamantane carboxylic acid.
4. The method for synthesizing 2- (2-aminophenyl) quinolines according to claim 1, wherein: the catalyst is selected from bismuth trifluoromethanesulfonate or ketone trifluoromethanesulfonate, and the additive is selected from 2,4, 6-trimethyl benzoic acid or 1-adamantanecarboxylic acid.
5. The method for synthesizing 2- (2-aminophenyl) quinolines according to claim 1, wherein: the oxygen-containing gas atmosphere is selected from oxygen or air, and the inert gas atmosphere is nitrogen or argon.
6. The method for synthesizing 2- (2-aminophenyl) quinolines as claimed in claim 5, wherein: the oxygen-containing gas atmosphere is favorable for the generation of the 2- (2-aminophenyl) quinoline compounds 2, and the inert gas atmosphere is favorable for the generation of the 2- (2-aminophenyl) quinoline compounds 3.
7. The method for synthesizing 2- (2-aminophenyl) quinolines according to claim 1, wherein: the feeding molar ratio of the 2-alkynyl aniline compound 1 to the additive to the catalyst is 1:0.25-2: 0.05-0.15.
8. The method for synthesizing 2- (2-aminophenyl) quinolines according to any one of claims 1 to 7, characterized in that: the heating reaction temperature is 60-120 ℃.
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