A method for preparing 4-aminoquinoline derivatives by synergistic catalytic oxidative aromatization of palladium and copper

Abstract

The present invention belongs to the technical field of synthesis of small molecule compounds containing 4-aminoquinoline, and specifically relates to a method for preparing 4-aminoquinoline derivatives by coordinated catalytic oxidative aromatization of palladium and copper, which is applied to the synthesis of small molecule compounds containing 4-aminoquinoline and the synthesis of the core skeleton of antimalarial drugs. The present invention uses palladium acetate and copper acetate as catalysts, 4,4'-dimethoxybipyridine and the like as ligands, and oxygen as a green oxidant, and amination dehydrogenation aromatization occurs under the action of acid to prepare 4-aminoquinoline derivatives.

Description

Technical Field

[0001] The invention belongs to the technical field of synthesis of small molecule compounds containing 4-aminoquinoline, and specifically relates to a method for preparing 4-aminoquinoline derivatives by coordinated catalytic oxidative aromatization of palladium and copper, which is applied to the synthesis of small molecule compounds containing 4-aminoquinoline and the synthesis of the core skeleton of antimalarial drugs. Background Art

[0002] Quinoline compounds are common nitrogen-containing heterocyclic compounds with a typical bicyclic structure. Their molecular skeleton is composed of a benzene ring and a pyridine ring. They are widely present in natural products and active drug molecules. Among heterocyclic compounds, quinoline compounds have become an important research and development direction today due to their special physiological activity. In the fields of medical care, agricultural development, chemical additives, additives, materials, etc., many derivatives with quinoline ring structures have shown broad application and development prospects. Especially in the field of medical care, quinoline drugs are widely used in the prevention and treatment of many diseases because of their good physiological and pharmacological activities such as anti-inflammatory, antibacterial, antiviral, anti-tumor, anti-tuberculosis, and treatment of malaria. They are important drug intermediates.

[0003] Quinoline derivatives, especially 4-aminoquinoline derivatives, play a very important role in the physiological activities of organisms. They are important units of some drugs and other biologically active compounds. They are widely present in various natural products, biologically active compounds and drugs, and have many biological activities: including activities for the treatment of malaria, anti-tumor, nervous system analgesics, anti-inflammatory drugs, etc., which fully reflects the importance of this type of compound. The most important application of 4-aminoquinoline derivatives is their effectiveness in the treatment of malaria. Among them, chloroquine has been proven to be an effective drug for the treatment of malaria and an anti-COVID-19 drug. However, due to the increase in resistance to antimalarial drugs and the spread of drug-resistant Plasmodium falciparum species, the synthesis of new antimalarial drugs is very important. The biologically active and important 4-aminoquinoline derivatives are as follows:

[0004]

[0005] Therefore, the synthesis of this type of compound has always received extensive attention from scientists. However, there are few reports on the synthesis of 4-aminoquinoline derivatives. The most traditional synthesis method is to use 4-halogenated quinoline and amine to undergo nucleophilic substitution (Formula 1). This method requires the use of metal catalysis, excessive strong base, high temperature, multi-step synthesis of raw materials, and the use of toxic reagents such as phosphorus oxychloride, which limits the use of this method. In recent years, people are very interested in efficiently obtaining 4-aminoquinoline as the core skeleton, and some cascade reactions for these skeletons with medical value have been developed (Formulas 2-1 to 2-7).

[0006] In 2005, Elisabetta Rossi's group reported a palladium-mediated multi-component domino reaction to synthesize 2-aryl-4-aminoquinoline derivatives, using carbon monoxide, 2-aminophenylacetylene, iodobenzene and primary amines as substrates, and investigated the reaction substrate range and suitable palladium / phosphine catalytic system. At the same time, some characteristics of the action of palladium and phosphorus were reported, opening up new prospects for the application of transition metals in these and related reactions (Formula 2-1). In 2013, Gong's group developed a simple method for preparing 2-CF3-substituted 4-aminoquinoline derivatives under mild conditions of tandem reaction. The reaction mechanism includes copper-catalyzed azide-alkyne cycloaddition reaction, cyclization and isomerization. This method has a wide range of applications and good functional group compatibility (Formula 2-2). In 2013, Orru et al. first reported the use of palladium acetate to catalyze the oxygen oxidation of two CH fragments by imine acylation coupling, and synthesize 4-aminoquinoline derivatives by oxidative cyclization of N-aryl imines (Formula 2-3). In 2016, the Wezeman T group proposed the synthesis of various new, highly substituted 4-aminoquinoline derivatives from alkynesulfonamides and electrophilically activated amides. Compared with other methods, this method allows substitution at the C2 and C3 positions and C5 to C8 positions, providing further diversity of site selection (Formula 2-4). In 2017, the Park JK group developed a copper-catalyzed, regio-controlled three-component tandem reaction of nitriles, aryl iodonium salts and alkynesulfonamides to provide highly functionalized 4-aminoquinolines. Finally, this method was successfully applied to the total synthesis of the antimalarial drug CK-2-68 (Formula 2-5). In 2020, the Zhang Wei group developed a one-pot synthesis method for 2,3-disubstituted 4-aminoquinolines through a three-component reaction of 2-azidobenzaldehyde, α-fluoro-β-ketoesters and amines (including cascade-Mannich, aza-Wittig and dehydrofluorination aromatization). This method is also applicable to other functionalized quinolines. This is a one-pot synthesis of biologically significant 4-aminoquinolines related to hydroxychloroquine and chloroquine (Formula 2-6). In 2020, Zhao Yulong et al. first reported the silver-catalyzed cascade cyclization reaction of isocyanate and sulfoximide. This reaction synthesizes highly functionalized 4-aminoquinoline derivatives from simple and readily available raw materials in one step, with a wide substrate range and moderate to good yields. At the same time, it provides a new and effective method for the synthesis of 4-aminoquinoline derivatives (Formula 2-7).

[0007] Traditional synthesis of 4-aminoquinoline derivatives:

[0008] Formula 1:

[0009]

[0010] Synthesis of 4-aminoquinoline derivatives:

[0011] Formula 2-1, Palladium-mediated multi-component Domino reaction for the synthesis of 2-aryl-4-aminoquinoline derivatives

[0012]

[0013] Formula 2-2, copper-catalyzed tandem reaction to synthesize 2-CF3-substituted 4-aminoquinoline derivatives

[0014]

[0015] Formula 2-3, palladium-catalyzed CH activation / cyclization reaction to synthesize 4-aminoquinoline derivatives

[0016]

[0017] Formula 2-4, Synthesis of Highly Functionalized 4-Aminoquinoline Drugs

[0018]

[0019] Formula 2-5, copper-catalyzed three-component tandem reaction to prepare 4-aminoquinoline derivatives

[0020]

[0021] Formula 2-6, one-pot synthesis of 2,3-disubstituted 4-aminoquinoline

[0022]

[0023] Formula 2-7, Silver-catalyzed one-pot synthesis of functionalized 4-aminoquinoline derivatives

[0024]

[0025] So far, there are only a limited number of systematic synthetic methods for 4-aminoquinoline drugs, which has hindered the discovery of new drugs, and there are problems such as the difficulty in obtaining substrates, the need for specific structures of substrates, and the lack of environmentally friendly reaction conditions. Therefore, the development of a new and efficient synthetic route is promising.

[0026] It is a good strategy and idea to construct aromatic rings or heteroaromatic rings through oxidative dehydrogenation aromatization. It is reported that cyclohexanone and tetralone are used as aromatic sources for multifunctionalization reaction to prepare a wide range of functionalized aromatic products, realizing the application of dehydrogenation aromatization strategy (Formula 3). Therefore, we tried to directly synthesize 4-aminoquinoline derivatives in one step through oxidative aromatization strategy, so as to develop a more effective and direct method.

[0027] Summary of the invention

[0028] In order to solve the deficiencies of the prior art, the present invention provides a method for preparing 4-aminoquinoline derivatives by catalytic oxidative aromatization of palladium and copper. Based on substituted or unsubstituted 2,3-dihydro-1H-quinolin-4-ones and amine compounds as starting materials, the present invention discloses for the first time the synthesis of 4-aminoquinoline derivatives by oxidative dehydrogenation aromatization strategy, which provides a possibility for the development of potential new 4-aminoquinoline therapeutic drugs. More importantly, the synthesis of antimalarial drugs chloroquine and amodiaquine was successfully achieved using this strategy, which fully demonstrates the practicality of the method.

[0029] The technical solution provided by the present invention is as follows:

[0030] A method for preparing 4-aminoquinoline derivatives by synergistic catalytic oxidative aromatization of palladium and copper, the route is as follows:

[0031]

[0032] in:

[0033] The amount of Pd(OAc)2 is 2-10 mol%; the amount of Cu(OAc)2 is 2-10 mol%;

[0034] Alternatively, the amount of Pd(OAc)2 and Cu(OAc)2 is zero.

[0035] The ligand is selected from the following substances:

[0036]

[0037] The solvent is CH3COOH or PivOH;

[0038] Temperature is 100-160℃;

[0039] R1 is hydrogen, halogen, alkyl or alkoxy;

[0040] R2 is a substituted or unsubstituted phenyl, alkyl, or alkyl with a chiral center. Preferably, the specific structure of R2 corresponds to the structure of Formula 5.

[0041] The above technical scheme uses palladium acetate and copper acetate as catalysts, 4,4'-dimethoxybipyridine and the like as ligands, and oxygen as a green oxidant, and produces amination dehydrogenation aromatization under the action of acid to prepare 4-aminoquinoline derivatives.

[0042] Preferably, the amount of Pd(OAc)2 used is 5 mol%; the amount of Cu(OAc)2 used is 5 mol%.

[0043] Based on the above technical solution, a higher yield can be ensured.

[0044] Preferably, the ligand is:

[0045]

[0046] Based on the above technical solution, a higher yield can be ensured.

[0047] Preferably, the amount of the ligand used is 10 mol%.

[0048] Based on the above technical solution, a higher yield can be ensured.

[0049] Preferably, the solvent is PivOH.

[0050] Based on the above technical solution, a higher yield can be ensured.

[0051] Preferably, the oxygen is at one atmosphere pressure.

[0052] Based on the above technical solution, a higher yield can be ensured.

[0053] Preferably, the temperature is 140°C.

[0054] Based on the above technical solution, a higher yield can be ensured.

[0055] More preferably, R1 is hydrogen and R2 is phenyl.

[0056] Based on the above technical scheme, 4-aminoquinoline derivatives are synthesized using the above two substrates. The reaction conditions are representative and can be used as substrate models to study reaction conditions.

[0057] Specifically, the synthetic route of substituted 2,3-dihydro-1H-quinoline-4-one compounds is as follows:

[0058]

[0059] R is the same as R1. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] Figure 1 It is the chloroquine synthesized by the present invention 1 H NMR spectrum.

[0061] Figure 2 It is the chloroquine synthesized by the present invention 13 C NMR spectrum.

[0062] Figure 3 Amodiaquine synthesized by the present invention 1 H NMR spectrum.

[0063] Figure 4 Amodiaquine synthesized by the present invention 13 C NMR spectrum.

[0064] Figure 5 It is the compound 3a synthesized by the present invention. 1 H NMR spectrum.

[0065] Figure 6 It is the compound 3a synthesized by the present invention. 13 C NMR spectrum.

[0066] Figure 7 The 3u synthesized by the present invention 1 H NMR spectrum.

[0067] Figure 8 The 3u synthesized by the present invention 13 C NMR spectrum.

[0068] Fig. 9 The 3ag synthesized by the present invention 1 H NMR spectrum.

[0069] Fig.10 The 3ag synthesized by the present invention 13 C NMR spectrum.

[0070] Fig.11 The 3aj synthesized by the present invention 1 H NMR spectrum.

[0071] Fig.12 The 3aj synthesized by the present invention 13 C NMR spectrum.

[0072] Fig.13 This is a possible reaction mechanism of the present invention. DETAILED DESCRIPTION

[0073] The principles and features of the present invention are described below. The examples given are only used to explain the present invention and are not used to limit the scope of the present invention.

[0074] The synthesis of the target product is achieved by oxidative aromatization using the coordinated catalysis of palladium and copper and oxygen as a green oxidant. The main reaction conditions are determined as follows:

[0075]

[0076] Table 1

[0077]

[0078]

[0079] Among them, ligands L1 to L9 are as follows:

[0080] a Reaction condition: 1(1equiv,0.2mmol),2(1.4equiv,0.28mmol),[Pd]10mol%,[Cu]10mol%,ligand 20mol%,solvent(0.16M,1.25ml),140℃,O2balloon,12h. b Isolated yield. c NR=no reaction.

[0081] d [Pd] 5mol%, [Cu] 5mol%, ligand 10mol%. Other conditions remain unchanged.

[0082] e [Pd] 2mol%, [Cu] 2mol%, ligand 5mol%. Other conditions remain unchanged.

[0083] f [Pd] 5mol%, [Cu] 5mol%, ligand 10mol%. Other conditions remain unchanged.

[0084] The study started with 2,3-dihydro-1H-quinolin-4-one and aniline as substrate models, palladium acetate and copper acetate were selected as catalysts, bipyridine was used as a ligand, and the reaction solvents were screened, including polar aprotic solvents (Table 1, entries 1-2) and protic solvents (Table 1, entry 3), but the expected target product was not generated.

[0085] However, when acetic acid was used as the reaction solvent, the aromatization product was obtained with a yield of 12%, and most of the acetic acid and aniline amidation products were also detected. It can be inferred that the commonly used reaction solvents are difficult to achieve for the first step of nucleophilic addition. Considering the formation of amidation products, the efficiency can be greatly improved by using pivalic acid with relatively large steric hindrance as the solvent, which can reach a yield of 56% (Table 1, entry 4).

[0086] Regarding the effect of ligands (bipyridine and propanedione) on oxidative aromatization (Table 1, entries 5-12), it was found that L5 as the ligand could give the target compound in 70% yield (Table 1, entry 8).

[0087] For palladium sources (Table 1, entries 13-17) and copper salts (Table 1, entries 18-21), the yield was found to be reduced. For the screening of the amount of catalyst (Table 1, entries 22-23), when the amount of catalyst was reduced to 2 mol%, the yield dropped significantly (59%). Therefore, 5 mol% was selected as the catalyst loading.

[0088] For single metal catalysis (Table 1, entries 24-25), the expected results were not achieved, with yields of 69% and 63%, respectively. However, reducing the amount of catalyst is conducive to the occurrence of the reaction. At the same time, when the reaction time is shortened, the yield of the entire reaction is not greatly affected, and the target product can be obtained with a yield of 83% (Table 1, entry 26), considering the synthesis efficiency. Choose to react for 4 hours under the same conditions. When palladium / copper synergistic catalysis is not used, only pivalic acid is used as a solvent, the aromatization product can be obtained with a yield of 67% under the same conditions (Table 1, entry 27).

[0089] Finally, the optimal conditions for the reaction were determined to be palladium acetate and copper acetate as catalysts, 4,4'-dimethoxybipyridine as a ligand, pivalic acid as a solvent, oxygen as a green oxidant, and reaction at 140°C for 4 hours.

[0090] Substrate range

[0091] Under the optimal reaction conditions, the applicable scope of substrates for amines and 2,3-dihydro-1H-quinolin-4-one was determined respectively. First, the oxidative aromatization reaction of various amines and 2,3-dihydro-1H-quinolin-4-one was studied, and the experimental results are shown in Formula 5. For para-substituted anilines, the yield of the corresponding aromatization products was 71%-91% (3b-3g). It can be seen that both electron donation and electron withdrawal can be well tolerated at the para position, indicating that the electron substitution effect at the para position has no effect. For meta-substituted anilines, the target products (3h-3k) can be obtained in moderate to good yields. For polysubstituted anilines, excellent yields of 70%-84% (3l-3p) can also be obtained. For ortho-substituted anilines (3q-3s), the results show that the yield is reduced, which may be due to the influence of steric hindrance and the electron-withdrawing group that reduces the electron cloud density on the benzene ring, thereby reducing the nucleophilicity of the reaction system. When the simple aromatic group was replaced by naphthyl, the target product (3t) was obtained with a yield of 58%. Functionalized amine benzylamine was investigated, including substitution at the ortho, meta, para and α positions (3u-3af), and aromatization products (41%-87%) were obtained with good yields. For nitrogen-containing heterocyclic and long-chain fatty amines, the corresponding target products (3ag-3an) were obtained.

[0092] The method proved its universality through its broad functional group tolerance. More importantly, when α-methylbenzylamine and S-(-)-α-methylbenzylamine were used under the same conditions, the target product (3ao-3ap) was obtained with 80% and 78% yields, respectively, and racemization did not occur, the configuration remained unchanged, and the ee value was as high as 98.8%.

[0093] The reaction formula is as follows:

[0094]

[0095] Determination of the scope of substituted tetrahydroquinolinone

[0096] Various substituted tetrahydroquinolinones and aniline were reacted under standard conditions, and the results are shown in Formula 4. It can be seen that no matter whether it is electron-withdrawing or electron-donating, no matter whether it is monosubstituted or disubstituted, the target products (4a-4k) can be obtained with moderate to good yields (57%-81%), which shows that the electronic effect of the aromatic ring has negligible influence on the reaction, and also shows that substituted tetrahydroquinoline has good tolerance to the reaction system. The reaction formula is as follows:

[0097]

[0098] Formula 4 and Formula 5 are as follows:

[0099]

[0100]

[0101] Application Examples

[0102] We have carried out synthetic application under standard conditions. Two biologically active molecules, chloroquine, an antimalarial drug, and amodiaquine, an antimalarial drug, have been fully synthesized, respectively, which can reflect the practical value of the preparation method provided by the present invention. The full synthetic routes of chloroquine and amodiaquine are as follows.

[0103] Total Synthesis of Chloroquine

[0104]

[0105] Total Synthesis of Amodiaquine

[0106]

[0107] Total syntheses of quinaquine and amodiaquine were obtained in 66% (5c) and 51% (7a) yields, respectively.

[0108] Reaction mechanism

[0109] like Fig.13 As shown. First, 2,3-dihydro-1H-quinolin-4-one and amine undergo nucleophilic addition to obtain hydroxylamine I, which undergoes dehydration condensation under acidic conditions to obtain imine II, which undergoes tautomerism to obtain enamine III, and then reacts to generate palladium (II) species IV. Subsequently, β-hydride elimination releases intermediate V and Pd(0) species. In the presence of Cu(II)L* complex, the latter can be oxidized to Pd(II), and the reduced Cu(I)L* complex itself is oxidized to Cu(II)L* complex under oxygen conditions and continues to participate in the redox catalytic process. In the presence of oxygen, intermediate V undergoes oxidative dehydrogenation aromatization to form the target product 3.

[0110] The present invention is based on 2,3-dihydro-1H-quinoline-4-ones and amine compounds as starting materials, and discloses for the first time the synthesis of 4-aminoquinoline derivatives by oxidative dehydrogenation aromatization strategy, which provides the possibility for the development of potential new 4-aminoquinoline therapeutic drugs. At the same time, in the entire reaction system, no additional oxidant is needed, and only oxygen is used as a green oxidant. Moreover, this method has good tolerance to the functional groups of tetrahydroquinolinone and amine compounds, and has an extremely wide range of substrates. It is not only suitable for aromatic amines, but also aliphatic amines under the same conditions, which expands the application range of tetrahydroquinolinone. More importantly, the synthesis of antimalarial drugs chloroquine and amodiaquine was successfully achieved using this strategy, which fully demonstrates the practicality of this method.

[0111] Instruments and Equipment

[0112] All separated substances 1 H NMR spectrum, 13 C NMR spectra were measured on a Bruker AVANCE NEO600 NMR spectrometer; HRMS was measured by a Waters xevo G2-XSQ-Tof time-of-flight mass spectrometer; melting points were measured by a WRX-4 micro melting point instrument; and column chromatography was performed on neutral alumina (200-300 mesh). Except for the raw materials for synthesizing substituted tetrahydroquinolinone, other chemical reagents and solvents were purchased commercially without further purification.

[0113] Implementation method:

[0114] 2,3-dihydro-1H-quinolin-4-one 1a (0.2mmol), palladium acetate (0.01mmol, 5mol%), copper acetate (0.01mmol, 5mol%), 4,4'-dimethoxybipyridine (0.02mmol, 10mol%) were added to a 10ml Schlenk tube, the reaction system was evacuated, an oxygen ball was connected, and the corresponding amine raw material (0.28mmol, 1.4eq.) was added, and finally 1.25ml of pivalic acid was added. The resulting mixture was stirred at 140°C until the reaction was complete as monitored by TLC. After cooling to room temperature, saturated potassium carbonate (10ml) was added to the Schlenk tube to quench the reaction. The resulting reaction solution was extracted with ethyl acetate (3x 10ml). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent in the filtrate was removed by reduced pressure distillation. The residue was purified by neutral alumina column chromatography with a mixture of petroleum ether and ethyl acetate to obtain the target product.

[0115] Synthesis results of chloroquine

[0116] Product 1 H NMR, 13 C NMR spectra are shown in Figure 1 , 2 shown.

[0117] Synthesis results of amodiaquine

[0118] Product 1 H NMR, 13 C NMR spectra are shown in Figure 3 , 4 shown.

[0119] Raw material synthesis method:

[0120] Synthetic route of substituted 2,3-dihydro-1H-quinolin-4-one compounds

[0121]

[0122] The substituted aniline and acrylic acid (1.5 eq.) were accurately weighed and added to a round-bottom flask containing toluene (1M), stirred and reacted at 140°C, monitored by TLC, cooled to room temperature after the reaction was completed, removed toluene by a rotary evaporator, mixed with silica gel, and finally, separated and purified by column chromatography to obtain intermediate I; polyphosphoric acid was added to intermediate I, reacted at 120°C for 6-8 hours, cooled to room temperature after the reaction was completed, added a certain amount of ice water, stirred at room temperature overnight, and then adjusted to pH = 8-10 with saturated potassium carbonate, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and separated and purified by silica gel column chromatography to obtain the target product II. Taking the above-mentioned substrate with R as hydrogen as an example, the yield was 68%.

[0123] The confirmation data of each target product are as follows:

[0124] N-phenylquinolin-4-amine(3a):83%yield.Yellow solid.Mp 184.4-185.8℃. 1 H NMR (600MHz, DMSO) δ8.99(s,1H),8.47(d,J=5.2Hz,1H),8.41(d,J=8.1Hz,1H),7.89(d,J=8.3Hz,1H),7.73–7.68(m ,1H),7.57–7.51(m,1H),7.43(t,J=7.8Hz,2H),7.39(d,J=7.5Hz,2H),7.15(t,J=7.2Hz,1H),6.95(d,J=5.2Hz,1H). 13 C NMR(150MHz,DMSO)δ151.16,149.42,148.12,141.04,129.85,129.70,129.67,125.07,124.15,122.87,122.59,120.24,101.94.HRMS(ESI)m / z:[M+H] + Calculate for C 15 H 12 N2 221.1079, found: 221.1103.

[0125] N-(p-tolyl)quinolin-4-amine(3b):86%yield.Yellow solid.Mp 164.4-165.4℃. 1HNMR(600MHz,DMSO)δ8.87(s,1H),8.41(d,J=5.2Hz,1H),8.38(d,J=7.9Hz,1H),7.86(d,J=8.3Hz,1H),7.70–7.66(m,1H),7.53–7.49(m,1H),7.25(d,J=8.5Hz,2H),7.23(d,J=8.5Hz,2H),6.81(d,J=5.2Hz,1H),2.32(s,3H). 13 C NMR(150MHz,DMSO)δ151.10,149.35,148.64,138.23,133.61,130.32,129.62,124.93,123.55,122.51,120.02,101.40,21.00.HRMS(ESI)m / z:[M+H] + calcd for C 16 H 14 N2 235.1235,found:235.1234.

[0126] N-(4-methoxyphenyl)quinolin-4-amine(3c):81%yield.Pale yellowsolid.Mp168.7-169.8℃. 1 H NMR(600MHz,DMSO)δ8.82(s,1H),8.41–8.37(m,2H),7.85(d,J=8.3Hz,1H),7.67(ddd,J=8.2,6.9,1.2Hz,1H),7.52–7.48(m,1H),7.31–7.26(m,2H),7.04–6.99(m,2H),6.63(d,J=5.3Hz,1H),3.79(s,3H). 13 C NMR(150MHz,DMSO)δ156.85,151.09,149.44,149.27,133.34,129.59,129.56,126.10,124.81,122.40,119.71,115.16,100.74,55.75.HRMS(ESI)m / z:[M+H] + calcd for C 16 H 14 N2O 251.1184,found:251.1187.

[0127] N-(4-fluorophenyl)quinolin-4-amine(3d):89%yield.Pale yellowsolid.Mp173.4-174.6℃. 1 H NMR(600MHz,DMSO)δ8.94(s,1H),8.44(d,J=5.2Hz,1H),8.37(d,J=7.9Hz,1H),7.88(d,J=8.3Hz,1H),7.72–7.66(m,1H),7.56–7.49(m,1H),7.39(dd,J=8.8,4.9Hz,2H),7.29–7.24(m,2H),6.79(d,J=5.2Hz,1H). 13 C NMR(150MHz,DMSO)δ159.99,158.40,151.13,149.30,148.63,137.23,129.71,125.48,125.07,122.46,119.98,116.49),101.42.HRMS(ESI)m / z:[M+H] + calcd for C 15 H 11 FN2 239.0985,found:239.0988.

[0128] N-(4-chlorophenyl)quinolin-4-amine(3e):74%yield.Yellow solid.Mp159.4-160.5℃. 1 H NMR(600MHz,DMSO)δ9.02(s,1H),8.49(d,J=5.1Hz,1H),8.34(t,J=12.4Hz,1H),7.88(t,J=12.2Hz,1H),7.74–7.65(m,1H),7.54(t,J=7.5Hz,1H),7.46–7.43(m,2H),7.38(d,J=8.7Hz,2H),6.97(d,J=5.2Hz,1H). 13 C NMR(150MHz,DMSO)δ151.17,149.41,147.64,140.26,129.81,129.72,127.42,125.26,123.99,122.58,120.37,102.51.HRMS(ESI)m / z:[M+H] + calcd for C 15 H 11 ClN2 255.0689,found:255.0689.

[0129] N-(4-bromophenyl)quinolin-4-amine(3f):71%yield.Yellow solid.Mp181.6-182.6℃. 1 H NMR(600MHz,DMSO)δ9.03(s,1H),8.50(d,J=4.9Hz,1H),8.36(d,J=8.4Hz,1H),7.90(d,J=8.4Hz,1H),7.71(t,J=7.6Hz,1H),7.59–7.52(m,3H),7.33(d,J=8.6Hz,2H),7.00(d,J=4.7Hz,1H). 13 C NMR(150MHz,DMSO)δ151.16,149.41,147.49,140.74,132.61,129.82,129.70,125.28,124.21,122.61,120.44,115.28,102.66.HRMS(ESI)m / z:[M+H] + calcd for C 15 H 11 BrN2 299.0184,found:299.0184.

[0130] N-(4-(methylthio)phenyl)quinolin-4-amine(3g):91%yield.Brownsolid.Mp156.9-158.0℃. 1 H NMR(600MHz,DMSO)δ8.95(s,1H),8.45(d,J=5.2Hz,1H),8.37(d,J=8.1Hz,1H),7.88(d,J=8.3Hz,1H),7.69(dd,J=11.5,4.4Hz,1H),7.53(t,J=7.2Hz,1H),7.34(s,4H),6.89(d,J=5.2Hz,1H),2.50(s,3H). 13 C NMR(150MHz,DMSO)δ151.14,149.39,148.15,138.40,132.95,129.68,128.15,125.07,123.71,122.53,120.17,101.91,16.01.HRMS(ESI)m / z:[M+H] + calcd for C 16 H 14N2S 267.0956,found:267.0958.

[0131] N-(m-tolyl)quinolin-4-amine(3h):65%yield.Yellow solid.Mp 167.4-168.3℃. 1 HNMR(600 MHz,DMSO)δ8.89(s,1H),8.45(d,J=5.2 Hz,1H),8.38(d,J=8.3 Hz,1H),7.87(d,J=8.3 Hz,1H),7.70–7.67(m,1H),7.52(t,J=7.6 Hz,1H),7.30(t,J=7.7 Hz,1H),7.19(s,1H),7.17(d,J=7.9 Hz,1H),6.96(d,J=7.5 Hz,1H),6.92(d,J=5.2 Hz,1H),2.33(s,3H). 13 C NMR(150 MHz,DMSO)δ151.14,149.39,148.22,140.94,139.19,129.65,125.02,124.95,123.49,122.56,120.22,120.04,102.00,21.55.HRMS(ESI)m / z:[M+H] + calcd forC 16 H 14 N2 235.1235,found:235.1232.

[0132] N-(3-methoxyphenyl)quinolin-4-amine(3i):75%yield.Yellowsolid.Mp142.3-143.4℃. 1 H NMR(600 MHz,DMSO)δ8.94(s,1H),8.49(d,J=5.2 Hz,1H),8.38(d,J=8.3 Hz,1H),7.88(t,J=15.8 Hz,1H),7.72–7.68(m,1H),7.54(t,J=7.6 Hz,1H),7.32(t,J=8.1 Hz,1H),7.02(d,J=5.2 Hz,1H),6.97(d,J=7.9 Hz,1H),6.93(s,1H),6.72(dd,J=8.2,2.2 Hz,1H),3.78(s,3H). 13C NMR(150 MHz,DMSO)δ160.63,151.17,149.43,147.88,142.41,130.56,129.69,129.68,125.10,122.59,120.36,114.65,109.58,108.20,102.58,55.56.HRMS(ESI)m / z:[M+H] + calcd for C 16 H 14 N2O 251.1184,found:251.1184.

[0133] N-(3-bromophenyl)quinolin-4-amine(3j):51%yield.Brown yellowsolid.Mp182.3-184.2℃. 1 H NMR(600 MHz,DMSO)δ9.07(s,1H),8.53(d,J=4.2 Hz,1H),8.34(d,J=8.3 Hz,1H),7.91(d,J=8.3 Hz,1H),7.72(t,J=7.5 Hz,1H),7.56(t,J=7.6Hz,1H),7.53(s,1H),7.40(d,J=8.0 Hz,1H),7.35(t,J=7.9 Hz,1H),7.28(d,J=7.8 Hz,1H),7.06(d,J=3.6 Hz,1H). 13 C NMR(150 MHz,DMSO)δ151.19,149.41,147.17,143.28,131.68,129.88,129.71,126.11,125.40,124.26,122.59,122.54,120.54,103.18.HRMS(ESI)m / z:[M+H] + calcd for C 15 H 11 BrN2 299.0184,found:299.0185.

[0134] N-(3-chlorophenyl)quinolin-4-amine(3k):53%yield.Yellow solid.Mp173.6-174.6℃. 1H NMR(600 MHz,DMSO)δ9.08(s,1H),8.54(d,J=5.2 Hz,1H),8.35(t,J=7.7 Hz,1H),7.92(d,J=8.3 Hz,1H),7.74–7.70(m,1H),7.59–7.54(m,1H),7.44–7.39(m,2H),7.37–7.34(m,1H),7.15(dd,J=7.9,1.1 Hz,1H),7.08(d,J=5.2 Hz,1H). 13 C NMR(150MHz,DMSO)δ151.24,149.46,147.14,143.13,134.11,131.40,129.86,129.74,125.41,123.21,122.59,121.34,120.56,120.15,103.26.HRMS(ESI)m / z:[M+H] + calcd forC 15 H 11 ClN2255.0689,found:255.0689.

[0135] N-(4-fluoro-3-methylphenyl)quinolin-4-amine(3l):84%yield.Yellowsolid.Mp183.8-184.8℃. 1 H NMR(600 MHz,DMSO)δ8.88(s,1H),8.43(d,J=5.2 Hz,1H),8.37(d,J=8.3 Hz,1H),7.85(t,J=11.0 Hz,1H),7.70–7.66(m,1H),7.52(t,J=7.6 Hz,1H),7.28(d,J=7.1 Hz,1H),7.19(d,J=7.5 Hz,2H),6.77(d,J=5.2 Hz,1H),2.26(d,J=1.4 Hz,3H). 13 C NMR(150 MHz,DMSO)δ158.66,157.07,151.13),149.28,148.73,136.80,129.67,126.84,125.60,125.02,122.98,122.44,119.93,116.21,101.42,14.76.HRMS(ESI)m / z:[M+H] + calcd for C 16 H 13FN2 253.1141,found:253.1152.

[0136] N-(4-bromo-3-methylphenyl)quinolin-4-amine(3m):73%yield.Yellowsolid.Mp193.9-194.9℃. 1 H NMR(600 MHz,DMSO)δ8.96(s,1H),8.48(d,J=4.9 Hz,1H),8.35(d,J=8.4 Hz,1H),7.89(d,J=8.4 Hz,1H),7.70(t,J=7.6 Hz,1H),7.57(d,J=8.5Hz,1H),7.54(t,J=7.6 Hz,1H),7.36(s,1H),7.16–7.12(m,1H),6.98(d,J=4.9 Hz,1H),2.36(s,3H). 13 C NMR(150 MHz,DMSO)δ151.18,149.40,147.63,140.81,138.65,133.24,129.77,129.69,125.22,124.83,122.57,121.83,120.37,118.05,102.60,23.03.HRMS(ESI)m / z:[M+H] + calcd for C 16 H 13 BrN2 313.0340,found:313.0343.

[0137] N-(4-fluoro-2-methylphenyl)quinolin-4-amine(3n):70%yield.Yellowsolid.Mp160.7-162.6℃. 1 H NMR(600 MHz,DMSO)δ8.71(s,1H),8.42(d,J=7.9 Hz,1H),8.35(d,J=5.1 Hz,1H),7.87(d,J=8.4 Hz,1H),7.70–7.67(m,1H),7.52(dd,J=11.2,3.9Hz,1H),7.31(dd,J=8.4,5.7 Hz,1H),7.27(dd,J=9.6,2.8 Hz,1H),7.15(td,J=8.5,3.0Hz,1H),6.03(d,J=5.2 Hz,1H),2.17(s,3H). 13C NMR(150 MHz,DMSO)δ161.55,159.94,151.12,149.82,149.13,138.50,134.97,130.08,129.57,124.87,122.39,119.33,118.02,114.32,100.71,18.00.HRMS(ESI)m / z:[M+H] + calcd for C 16 H 13 FN2 253.1141,found:253.1145.

[0138] N-(2,4-dimethylphenyl)quinolin-4-amine(3o):76%yield.Yellowsolid.Mp123.2-124.4℃. 1 H NMR(600 MHz,DMSO)δ8.67(s,1H),8.43(d,J=7.9 Hz,1H),8.32(d,J=5.2 Hz,1H),7.85(d,J=8.3 Hz,1H),7.70–7.63(m,1H),7.52–7.47(m,1H),7.20(s,1H),7.15(d,J=7.9 Hz,1H),7.12(d,J=7.9 Hz,1H),6.04(d,J=5.2 Hz,1H),2.33(s,3H),2.13(s,3H). 13 C NMR(150 MHz,DMSO)δ151.07,149.92,149.15,136.17,136.07,135.28,132.18,129.59,129.47,128.15 127.96,124.72,122.44,119.37,100.67,21.08,17.89.HRMS(ESI)m / z:[M+H] + calcd for C 17 H 16 N2 249.1392,found:249.1391.

[0139] N-(3,5-dimethylphenyl)quinolin-4-amine(3p):72%yield.Yellowsolid.Mp196.2-197.3℃. 1H NMR(600 MHz,DMSO)δ8.83(s,1H),8.45(d,J=5.1 Hz,1H),8.38(d,J=8.3 Hz,1H),7.87(d,J=8.3 Hz,1H),7.68(t,J=7.5 Hz,1H),7.52(t,J=7.5Hz,1H),6.99(s,2H),6.92(d,J=5.2 Hz,1H),6.79(s,1H),2.29(s,6H). 13 C NMR(150 MHz,DMSO)δ151.11,149.37,148.29,140.83,138.92,129.62,125.85,124.98,122.54,120.69,120.19,102.04,21.47.HRMS(ESI)m / z:[M+H] + calcd for C 17 H 16 N2 249.1392,found:249.1399.

[0140] N-(o-tolyl)quinolin-4-amine(3q):61%yield.Orange-yellow solid.Mp159.9-162.3℃. 1 H NMR(600 MHz,DMSO)δ8.73(s,1H),8.43(d,J=8.3 Hz,1H),8.34(d,J=5.2 Hz,1H),7.86(d,J=8.4 Hz,1H),7.70–7.65(m,1H),7.51(t,J=7.5 Hz,1H),7.38(d,J=7.4 Hz,1H),7.33–7.29(m,1H),7.29–7.22(m,2H),6.08(d,J=5.2 Hz,1H),2.17(s,3H). 13 C NMR(150 MHz,DMSO)δ151.10,149.63,149.16,138.70,135.37,131.64,129.60,129.54,127.87,127.60,126.93,124.83,122.47,119.44,100.92,18.00.HRMS(ESI)m / z:[M+H] + calcd forC 16 H 14 N2 235.1235,found:235.1237.

[0141] N-(2-methoxyphenyl)quinolin-4-amine(3r):41%yield.Yellow oil. 1 H NMR(600MHz,DMSO)δ8.42(d,J=8.3 Hz,1H),8.36(d,J=5.3 Hz,1H),7.86(d,J=8.4 Hz,1H),7.68(t,J=7.6 Hz,1H),7.50(t,J=7.6 Hz,1H),7.38–7.25(m,2H),7.18(d,J=8.2 Hz,1H),7.05(t,J=7.5 Hz,1H),6.26(d,J=5.3 Hz,1H),3.77(s,3H). 13 C NMR(150 MHz,DMSO)δ154.58,150.78,149.39,148.90,129.50,129.38,128.55,127.47,127.42,124.82,122.56,121.36,119.63,112.92,101.52,55.89.HRMS(ESI)m / z:[M+H] + calcd forC 16 H 14 N2O251.1184,found:251.1185.

[0142] N-(2-chlorophenyl)quinolin-4-amine(3s):30%yield.White solid.Mp140.3-142.5℃. 1 H NMR(600 MHz,DMSO)δ8.90(s,1H),8.41(s,2H),7.89(d,J=8.3 Hz,1H),7.71(t,J=7.5 Hz,1H),7.65(d,J=8.0 Hz,1H),7.54(t,J=7.5 Hz,1H),7.48(s,2H),7.37(t,J=6.7 Hz,1H),6.19(d,J=5.1 Hz,1H). 13 C NMR(150 MHz,DMSO)δ151.02,149.13,148.82,137.65,131.01,129.65,129.35,128.96,128.12,125.13,122.55,119.62,102.11.HRMS(ESI)m / z:[M+H] + calcd for C 15 H 11ClN2 255.0689,found:255.0688.

[0143] N-(naphthalen-2-yl)quinolin-4-amine(3t):58%yield.Orange-yellowsolid.Mp206.1-207.3℃. 1 H NMR(600 MHz,DMSO)δ9.19(s,1H),8.51(d,J=5.1 Hz,1H),8.45(d,J=8.3 Hz,1H),7.96(d,J=8.7 Hz,1H),7.91(t,J=8.5 Hz,2H),7.87(d,J=8.1Hz,1H),7.84(s,1H),7.72(t,J=7.6 Hz,1H),7.60–7.54(m,2H),7.50(dd,J=11.1,3.9Hz,1H),7.44(t,J=7.5 Hz,1H),7.09(d,J=5.1 Hz,1H). 13 C NMR(150 MHz,DMSO)δ151.23,149.46,147.92,138.89,134.33,130.47,129.76,129.72,129.49,128.07,127.48,126.96),125.21,125.19,123.13,122.66,120.45,118.23,102.55.HRMS(ESI)m / z:[M+H] + calcd forC 19 H 14 N2 271.1235,found:271.1237.

[0144] N-benzylquinolin-4-amine(3u):76%yield.Yellow solid.Mp 106.1-107.2℃. 1 H NMR(600 MHz,DMSO)δ8.33–8.28(m,2H),7.92(t,J=5.9 Hz,1H),7.81–7.77(m,1H),7.64–7.59(m,1H),7.48–7.43(m,1H),7.39(d,J=7.3 Hz,2H),7.32(t,J=7.6 Hz,2H),7.23(t,J=7.3 Hz,1H),6.33(d,J=5.3 Hz,1H),4.56(d,J=6.0 Hz,2H). 13C NMR(150MHz,DMSO)δ150.99,150.23,148.74,139.38,129.53,129.24,128.90,127.32,124.47,122.09,119.40,99.45,46.02.HRMS(ESI)m / z:[M+H] + calcd for C 16 H 14 N2 235.1235,found:235.1237.

[0145] N-(4-fluorobenzyl)quinolin-4-amine(3v):83%yield.Yellow solid.Mp164.2-165.3℃. 1 H NMR(600 MHz,DMSO)δ8.31(d,J=5.3 Hz,1H),8.28(d,J=8.3 Hz,1H),7.89(t,J=6.0 Hz,1H),7.79(d,J=8.3 Hz,1H),7.64–7.60(m,1H),7.48–7.40(m,3H),7.17–7.12(m,2H),6.33(d,J=5.3 Hz,1H),4.54(d,J=6.0 Hz,2H). 13 C NMR(150 MHz,DMSO)δ160.86,151.03,150.07,148.78,135.49,129.58,129.32,124.49,122.06,119.39,115.70,115.55,99.44,45.29.HRMS(ESI)m / z:[M+H] + calcd for C 16 H 13 FN2 253.1141,found:253.1131.

[0146] N-(4-chlorobenzyl)quinolin-4-amine(3w):74%yield.Orange-yellowsolid.Mp169.2-170.2℃. 1H NMR(600 MHz,DMSO)δ8.31(d,J=5.3 Hz,1H),8.29(d,J=8.3Hz,1H),7.92(t,J=6.0 Hz,1H),7.81–7.78(m,1H),7.63(ddd,J=8.2,6.9,1.2 Hz,1H),7.48–7.44(m,1H),7.41(d,J=8.6 Hz,2H),7.40–7.37(m,2H),6.31(d,J=5.3 Hz,1H),4.55(d,J=6.0 Hz,2H). 13 C NMR(150 MHz,DMSO)δ151.01,150.04,148.74,138.46,131.82,129.56,129.28,129.22,128.85,124.54,122.05,119.37,99.47,45.33.HRMS(ESI)m / z:[M+H] + calcd for C 16 H 13 ClN2 269.0846,found:269.0852.

[0147] N-(4-methylbenzyl)quinolin-4-amine(3x):87%yield.Yellow solid.Mp109.3-110.2℃. 1 H NMR(600 MHz,DMSO)δ8.29(d,J=5.5 Hz,2H),7.88(t,J=5.8 Hz,1H),7.78(d,J=8.3 Hz,1H),7.61(t,J=7.6 Hz,1H),7.44(t,J=7.6 Hz,2H),7.27(d,J=7.9Hz,1H),7.12(d,J=7.8 Hz,2H),6.30(d,J=5.3 Hz,1H),4.50(d,J=5.9 Hz,2H),2.25(s,3H). 13 C NMR(150MHz,DMSO)δ150.95,150.21,148.72,136.34,136.24,129.51,129.46,129.21,127.28,124.43,122.08,119.41,99.48,45.80,21.12.HRMS(ESI)m / z:[M+H]+calcdfor C 17 H 16 N2249.1392,found:249.1392.

[0148] N-(4-methoxybenzyl)quinolin-4-amine(3y):83%yield.Yellowsolid.Mp116.7-117.5℃. 1 H NMR(600 MHz,DMSO)δ8.30(d,J=5.3 Hz,1H),8.28(d,J=8.1Hz,1H),7.85(t,J=5.9 Hz,1H),7.77(d,J=8.3 Hz,1H),7.64–7.58(m,1H),7.46–7.41(m,1H),7.31(d,J=8.6 Hz,2H),6.88(t,J=5.7 Hz,2H),6.34(d,J=5.4 Hz,1H),4.48(d,J=5.9Hz,2H),3.71(s,3H). 13 C NMR(150 MHz,DMSO)δ158.69,150.95,150.19,148.71,131.10,129.49,129.20,128.62,124.41,122.08,119.41,114.30,99.46,55.48,45.47.HRMS(ESI)m / z:[M+H] + calcd for C 17 H 16 N2O 265.1341,found:265.1345.

[0149] N-(3-methylbenzyl)quinolin-4-amine(3z):78%yield.Pale yellowsolid.Mp124.0-126.1℃. 1 H NMR(600 MHz,DMSO)δ8.31–8.28(m,2H),7.88(t,J=5.9 Hz,1H),7.79–7.77(m,1H),7.64–7.58(m,1H),7.47–7.42(m,1H),7.20(t,J=7.4 Hz,2H),7.17(d,J=7.7 Hz,1H),7.04(d,J=7.0 Hz,1H),6.32(d,J=5.3 Hz,1H),4.51(d,J=6.0 Hz,2H),2.26(s,3H). 13C NMR(150 MHz,DMSO)δ151.03,150.24,148.76,139.34,137.98,129.55,129.21,128.81,128.00,127.86,124.44,124.41,122.10,119.40,99.42,46.05,21.54.HRMS(ESI)m / z:[M+H] + calcd for C 17 H 16 N2 249.1392,found:249.1396.

[0150] N-(3-methoxybenzyl)quinolin-4-amine(3aa):86%yield.Yellowsolid.Mp104.1-106.2℃. 1 H NMR(600 MHz,DMSO)δ8.30(t,J=7.4 Hz,2H),7.89(t,J=6.0Hz,1H),7.80–7.77(m,1H),7.64–7.60(m,1H),7.48–7.43(m,1H),7.26–7.21(m,1H),6.96(d,J=7.3 Hz,2H),6.82–6.78(m,1H),6.33(d,J=5.4 Hz,1H),4.53(d,J=6.0 Hz,2H),3.71(s,3H). 13 C NMR(150 MHz,DMSO)δ159.90,151.01,150.23,148.74,141.10,129.99,129.55,129.23,124.48,122.06,119.44,119.39,113.19,112.49,99.49,55.41,46.00.HRMS(ESI)m / z:[M+H] + calcd for C 17 H 16 N2O 265.1341,found:265.1340.

[0151] N-(3-chlorobenzyl)quinolin-4-amine(3ab):79%yield.Yellow solid.Mp166.7-167.8℃. 1H NMR(600 MHz,DMSO)δ8.33(d,J=5.3 Hz,1H),8.30(d,J=8.2 Hz,1H),7.99(t,J=5.8 Hz,1H),7.80(d,J=8.3 Hz,1H),7.66–7.62(m,1H),7.49–7.46(m,1H),7.45(s,1H),7.38–7.34(m,2H),7.31–7.28(m,1H),6.35(d,J=5.4 Hz,1H),4.58(d,J=5.9Hz,2H). 13 C NMR(150 MHz,DMSO)δ150.83,150.20,148.43,142.14,133.63,130.81,129.46,129.31,127.35,127.17,126.06,124.67,122.10,119.29,99.44,45.44.HRMS(ESI)m / z:[M+H] + calcd for C 16 H 13 ClN2 269.0846,found:269.0850.

[0152] N-(2-methylbenzyl)quinolin-4-amine(3ac):74%yield.Yellowsolid.Mp142.8-145.5℃. 1 H NMR(600 MHz,DMSO)δ8.34(d,J=7.9 Hz,1H),8.31(d,J=5.3Hz,1H),7.80(dd,J=8.4,0.8 Hz,1H),7.76(t,J=5.6 Hz,1H),7.63(ddd,J=8.3,6.9,1.2Hz,1H),7.45(ddd,J=8.2,6.9,1.2 Hz,1H),7.20(t,J=8.0 Hz,2H),7.15(dd,J=10.5,4.2 Hz,1H),7.09(t,J=7.3 Hz,1H),6.27(d,J=5.4 Hz,1H),4.51(d,J=5.6 Hz,2H),2.38(s,3H). 13C NMR(150 MHz,DMSO)δ151.01,150.39,148.71,136.49,136.17,130.61,129.48,129.27,127.21,126.67,126.21,124.46,122.19,119.36,99.37,44.35,19.19.HRMS(ESI)m / z:[M+H] + calcd for C 17 H 16 N2 249.1392,found:249.1391.

[0153] N-(2-fluorobenzyl)quinolin-4-amine(3ad):72%yield.Pale yellowsolid.Mp139.6-140.3℃. 1 H NMR(600 MHz,DMSO)δ8.34(d,J=5.3 Hz,1H),8.30(d,J=8.0Hz,1H),7.82(t,J=5.9 Hz,1H),7.80(dd,J=8.4,0.7 Hz,1H),7.65–7.60(m,1H),7.46(ddd,J=8.2,6.9,1.1 Hz,1H),7.35(t,J=7.7 Hz,1H),7.34–7.27(m,1H),7.23(dd,J=14.2,4.5 Hz,1H),7.15–7.11(m,1H),6.35(d,J=5.3 Hz,1H),4.60(d,J=5.9 Hz,2H). 13 CNMR(150MHz,DMSO)δ161.64,160.02,151.11,150.06,148.77,129.58,129.40,129.30,125.83,124.90,124.57,122.10,119.34,115.80,99.08,39.93.HRMS(ESI)m / z:[M+H] + calcd forC 16 H 13 FN2 253.1141,found:253.1138.

[0154] N-benzyl-N-methylquinolin-4-amine(3ae):41%yield.Yellow oil. 1H NMR(600 MHz,DMSO)δ8.61(d,J=5.0 Hz,1H),8.07(d,J=8.4 Hz,1H),7.94(d,J=8.3 Hz,1H),7.67(t,J=7.6 Hz,1H),7.48(t,J=7.6 Hz,1H),7.39–7.34(m,4H),7.29(t,J=6.8Hz,1H),6.94(d,J=5.1 Hz,1H),4.51(s,2H),2.87(s,3H). 13 C NMR(150 MHz,DMSO)δ156.59,150.86,149.70,137.99,130.01,129.40,129.06,127.94,127.74,125.42,124.23,123.04,109.21,59.65,40.94.HRMS(ESI)m / z:[M+H] + calcd for C 17 H 16 N2 249.1392,found:249.1390.

[0155] N-benzhydrylquinolin-4-amine(3af):73%yield.Pale yellow solid.Mp186.4-188.1℃. 1 H NMR(600 MHz,DMSO)δ8.51(d,J=8.4 Hz,1H),8.33(d,J=5.3 Hz,1H),7.81–7.78(m,1H),7.64–7.61(m,1H),7.59(d,J=7.4 Hz,1H),7.46(d,J=7.4 Hz,4H),7.45–7.41(m,1H),7.36(t,J=7.7 Hz,4H),7.27(t,J=7.3 Hz,2H),6.48(d,J=5.4 Hz,1H),6.03(d,J=7.3Hz,1H). 13 C NMR(150 MHz,DMSO)δ150.97,149.57,148.77,142.42,129.40,129.27,128.92,128.20,127.68,124.40,122.90,119.58),100.69,60.57.HRMS(ESI)m / z:[M+H] + calcd for C 22 H 18 N2 311.1548,found:311.1551.

[0156] 4-(pyrrolidin-1-yl)quinoline(3ag):37%yield.Colorless oil. 1 H NMR(600MHz,DMSO)δ8.38(d,J=5.5 Hz,1H),8.28(d,J=8.6 Hz,1H),7.81(d,J=8.4 Hz,1H),7.60(t,J=7.6 Hz,1H),7.37(dd,J=11.3,4.1 Hz,1H),6.52(d,J=5.5 Hz,1H),3.63(t,J=6.3 Hz,4H),1.96(dd,J=7.7,5.0 Hz,4H). 13 C NMR(150 MHz,DMSO)δ152.45,149.82,149.73,129.16,129.00,125.84,123.48,121.02,103.17,52.32,25.93.HRMS(ESI)m / z:[M+H] + calcd forC 13 H 14 N2 199.1235,found:199.1237.

[0157] 4-(quinolin-4-yl)morpholine(3ah):39%yield.Colorless oil. 1 H NMR(600MHz,DMSO)δ8.70(d,J=4.9 Hz,1H),8.05(d,J=8.3 Hz,1H),7.96(d,J=8.3 Hz,1H),7.72–7.68(m,1H),7.54(dd,J=11.2,4.0 Hz,1H),6.99(d,J=4.9 Hz,1H),3.88–3.86(m,4H),3.17–3.14(m,4H). 13 C NMR(150 MHz,DMSO)δ156.49,151.34,149.54,130.05,129.52,125.89,124.23,123.09,109.39,66.59,52.68.HRMS(ESI)m / z:[M+H] + calcd forC 13 H 14 N2O215.1184,found:215.1185.

[0158] 1-(4-(quinolin-4-yl)piperazin-1-yl)ethan-1-one(3ai):30%yield.Yellowoil. 1 H NMR(600 MHz,DMSO)δ8.70(d,J=4.9 Hz,1H),8.08(t,J=8.2 Hz,1H),7.96(d,J=8.3 Hz,1H),7.71(dd,J=9.6,5.5 Hz,1H),7.59–7.54(m,1H),6.99(dd,J=9.3,5.0 Hz,1H),3.75–3.69(m,4H),3.20–3.15(m,2H),3.13–3.09(m,2H),2.07(s,3H). 13 C NMR(150MHz,DMSO)δ169.00,156.35,151.34,149.52,130.04,129.58,126.02,124.19,123.19,109.75,52.36,46.13,21.72.HRMS(ESI)m / z:[M+H] + calcd for C 15 H 17 N3O 256.1450,found:256.1449.

[0159] N-pentylquinolin-4-amine(3aj):83%yield.Yellow solid.Mp 97.2-99.3℃. 1 H NMR(600 MHz,DMSO)δ8.37(d,J=5.3 Hz,1H),8.22(d,J=7.9 Hz,1H),7.77(dd,J=8.4,0.8Hz,1H),7.61–7.55(m,1H),7.48–7.30(m,1H),7.12(t,J=5.2 Hz,1H),6.41(d,J=5.4 Hz,1H),3.24(dd,J=12.8,7.0 Hz,2H),1.69–1.63(m,2H),1.40–1.27(m,4H),0.88(t,J=7.0Hz,3H). 13 C NMR(150 MHz,DMSO)δ151.16,150.38,148.82,129.48,129.09,124.13,122.17,119.34 98.53,42.82,29.35,28.04,22.45,14.42.HRMS(ESI)m / z:[M+H] +calcdforC 14 H 18 N2 215.1548,found:215.1548.

[0160] N-hexylquinolin-4-amine(3ak):75%yield.Yellow solid.Mp 81.2-82.4℃. 1 HNMR(600 MHz,DMSO)δ8.37(t,J=7.4 Hz,1H),8.23(t,J=10.3 Hz,1H),7.76(d,J=8.3Hz,1H),7.64–7.56(m,1H),7.40(t,J=7.6 Hz,1H),7.14(t,J=5.0 Hz,1H),6.40(dd,J=18.3,5.8 Hz,1H),3.31–3.17(m,2H),1.71–1.61(m,2H),1.38(dd,J=14.5,6.8 Hz,2H),1.30(dd,J=8.7,5.3 Hz,4H),0.90–0.81(m,3H). 13 C NMR(150 MHz,DMSO)δ151.08,150.43,148.72,129.39,129.13,124.15,122.18,119.31,98.53,42.86,31.56,28.31,26.83,22.59,14.40.HRMS(ESI)m / z:[M+H] + calcd for C 15 H 20 N2 229.1705,found:229.1707.

[0161] N 1 ,N 1 -diethyl-N 4 -(quinolin-4-yl)pentane-1,4-diamine(3al):60%yield.Yellow oil. 1HNMR(600 MHz,DMSO)δ8.35(d,J=5.3 Hz,1H),8.29(d,J=8.4 Hz,1H),7.75(d,J=8.3Hz,1H),7.58(t,J=7.6 Hz,1H),7.38(t,J=7.6 Hz,1H),6.72(d,J=8.1 Hz,1H),6.47(d,J=5.4 Hz,1H),3.71(td,J=13.2,6.5 Hz,1H),2.40(q,J=7.1 Hz,4H),2.35(t,J=6.9 Hz,2H),1.74–1.66(m,1H),1.56–1.41(m,3H),1.23(d,J=6.4 Hz,3H),0.90(t,J=7.1 Hz,6H). 13 CNMR(150 MHz,DMSO)δ151.12,149.81,148.97,129.43,129.06,123.96,122.38,119.37,98.78,52.59,47.95,46.64,33.92,23.94,20.38,12.12.HRMS(ESI)m / z:[M+H] + calcd forC 18 H 27 N3 286.2283,found:286.2287.

[0162] N-cyclohexylquinolin-4-amine(3am):61%yield.Yellow solid.Mp 147.4-150.2℃. 1 HNMR(600 MHz,DMSO)δ8.36(d,J=5.3 Hz,1H),8.28(d,J=8.1 Hz,1H),7.75(d,J=7.8Hz,1H),7.60–7.56(m,1H),7.40–7.35(m,1H),6.73(d,J=7.7 Hz,1H),6.47(d,J=5.4 Hz,1H),3.36(s,1H),2.01(t,J=10.3 Hz,2H),1.84–1.71(m,2H),1.65(d,J=12.7Hz,1H),1.46–1.31(m,4H),1.25–1.11(m,1H). 13C NMR(150 MHz,DMSO)δ151.13,149.38,149.02,129.43,129.08,123.96,122.43,119.35,98.91,51.39,32.39,25.92,25.30.HRMS(ESI)m / z:[M+H] + calcd for C 15 H 18 N2 227.1548,found:227.1550.

[0163] N 1 ,N 6 -di(quinolin-4-yl)hexane-1,6-diamine(3an):63%yield.Orange-yellowsolid.Mp206.4-207.2℃. 1 H NMR(400 MHz,DMSO)δ8.36(d,J=5.2 Hz,1H),8.21(d,J=8.2Hz,1H),7.76(d,J=8.3 Hz,1H),7.59(t,J=7.3 Hz,1H),7.39(t,J=7.4 Hz,1H),7.13(t,J=4.2Hz,1H),6.42(d,J=5.2 Hz,1H),3.30–3.22(m,2H),1.76–1.63(m,2H),1.52–1.40(m,2H). 13 C NMR(100 MHz,DMSO)δ151.16,150.38,148.79,129.46,129.12,124.16,122.15,119.31,98.55,42.80,28.34,26.98.HRMS(ESI)m / z:[M+H] + calcd for C 24 H 26 N4 371.2236,found:371.2237.

[0164] N-(1-phenylethyl)quinolin-4-amine(3ao):80%yield.Yellow solid.Mp124.2-125.4℃. 1H NMR(600 MHz,DMSO)δ8.50(d,J=8.4 Hz,1H),8.25(d,J=5.3 Hz,1H),7.77(d,J=8.3 Hz,1H),7.62(t,J=7.6 Hz,1H),7.47(d,J=8.0 Hz,1H),7.44(d,J=7.4Hz,2H),7.41(d,J=6.8 Hz,1H),7.30(t,J=7.6 Hz,2H),7.20(t,J=7.3 Hz,1H),6.23(d,J=5.4 Hz,1H),4.78(p,J=6.8 Hz,1H),1.61(d,J=6.8 Hz,3H). 13 C NMR(150 MHz,DMSO)δ150.85,149.47,148.70,145.19,129.42,129.20,128.94,127.23,126.29,124.30,122.56,119.36,100.34,52.48,24.53.HRMS(ESI)m / z:[M+H] + calcd for C 17 H 16 N2 249.1392,found:249.1392.

[0165] N 4 -(7-chloroquinolin-4-yl)-N 1 ,N 1 -diethylpentane-1,4-diamine(5c):66%yield.Paleyellow solid.Mp 77.1-78.5℃. 1 H NMR(600 MHz,DMSO)δ8.37(d,J=2.6 Hz,1H),8.35(s,1H),7.76(d,J=2.2 Hz,1H),7.41(dd,J=9.0,2.1 Hz,1H),6.90(d,J=8.0Hz,1H),6.48(d,J=5.5Hz,1H),3.74–3.66(m,1H),2.38(q,J=7.1Hz,4H),2.33(t,J=7.0Hz,2H),1.72–1.63(m,1H),1.54–1.39(m,3H),1.22(d,J=6.4Hz,3H),0.88(t,J=7.1Hz,6H). 13CNMR(150MHz,DMSO)δ152.34,149.98,149.80,133.77,127.92,124.82,124.20,117 .99,99.27,52.56,48.05,46.63,33.84,23.91,20.30,12.11.HRMS(ESI)m / z:[M+H] + Calculate for C 18 H 26 ClN3 320.1894, found:320.1894.

[0166] 4-((7-chloroquinolin-4-yl)amino)-2-((diethylamino)methyl)phenol(7a):51%yield.Brown yellow solid.Mp 191.0-192.0℃. 1 H NMR (600MHz, DMSO) δ8.88(s,1H),8.41(d,J=9.1Hz,1H),8.36(d,J=5.4Hz,1H),7.84(d,J=2.2Hz,1H),7.51(dd,J=9.0,2.2Hz,1H),7.08 (s,1H),7.06(d,J=2.6Hz,1H),6.78(d,J=8.2Hz,1H),6.56(d,J=5.4Hz,1H),3.74(s,2H),2.57(q,J=7.1Hz,4H),1.04(t,J=7.1Hz,6H). 13 C NMR (150MHz, DMSO) δ155.55,152.33,149.97,149.96,134.17,130.87,128.06,125.84,125.14 ,125.00,124.70,124.45,118.17,116.53,100.94,55.27,46.37,11.63.HRMS(ESI)m / z:[M+H] + Calculate for C 20 H 22 ClN3O 354.1373,found:354.1374.

[0167] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing 4-aminoquinoline derivatives by coordinated catalytic oxidative aromatization of palladium and copper, characterized in that: The route is as follows: in: The amount of Pd(OAc)2 is 2-10 mol%; the amount of Cu(OAc)2 is 2-10 mol%; Alternatively, the amounts of Pd(OAc)2 and Cu(OAc)2 are both zero; The amount of the ligand used is 9-11 mol%, selected from the following substances: The solvent was PivOH; Temperature is 100-160℃; R1 is hydrogen, halogen, alkyl or alkoxy; R2 is a substituted or unsubstituted phenyl group or an alkyl group.

2. The method for preparing 4-aminoquinoline derivatives by coordinated catalytic oxidative aromatization of palladium and copper according to claim 1, characterized in that: The amount of Pd(OAc)2 used was 5 mol%; the amount of Cu(OAc)2 used was 5 mol%.

3. The method for preparing 4-aminoquinoline derivatives by coordinated catalytic oxidative aromatization of palladium and copper according to claim 1, characterized in that: The ligand is: The amount of the ligand used was 10 mol%.

4. The method for preparing 4-aminoquinoline derivatives by coordinated catalytic oxidative aromatization of palladium and copper according to claim 1, characterized in that: Oxygen at one atmosphere pressure.

5. The method for preparing 4-aminoquinoline derivatives by coordinated catalytic oxidative aromatization of palladium and copper according to claim 1, characterized in that: The temperature is 140°C.

6. The method for preparing 4-aminoquinoline derivatives by coordinated catalytic oxidative aromatization of palladium and copper according to claim 1, characterized in that: The synthetic route of substituted 2,3-dihydro-1H-quinoline-4-one compounds is as follows: R is the same as R1.

7. The method for preparing 4-aminoquinoline derivatives by coordinated catalytic oxidative aromatization of palladium and copper according to any one of claims 1 to 6, characterized in that: R1 is hydrogen; R2 is selected from the following structures:

8. The method for preparing 4-aminoquinoline derivatives by coordinated catalytic oxidative aromatization of palladium and copper according to claim 7, characterized in that: R1 is hydrogen, and R2 is phenyl.

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