Preparation method of N-heteroaryl stilbene compounds

Abstract

The present invention belongs to the field of alkenylation of C(sp 3 )-H bonds of organic compounds by non-metal catalytic oxidation, and specifically discloses a method for preparing N-heteroaryl stilbene compounds. Under the catalysis of 2,4,6-trihydroxybenzoic acid, using DMSO as a solvent and oxygen as a green oxidant, methyl-substituted nitrogen heterocyclic compounds and benzylamine compounds as substrates, N-heteroaryl stilbene compounds can be obtained. The method uses a low catalyst loading (0.5-5 mol%), the reagents are cheap and easily available, no metal catalyst is used, the reaction conditions are mild, the operation is simple, and the yield is as high as 96%.

Description

Technical Field

[0001] The present invention belongs to the field of the alkenylation of C(sp 3 )-H bonds of organic compounds by non-metal catalyzed oxidation. More specifically, it relates to a preparation method of N-heteroaryl stilbene compounds. Specifically, 2,4,6-trihydroxybenzoic acid is used to catalyze the oxidation of methyl-substituted azacyclic compounds and benzylamine compounds for alkenylation to prepare N-heteroaryl stilbene compounds. Background Art

[0002] The alkenylation reaction of methyl-substituted azacyclic compounds has important applications in the preparation of drugs, imaging agents, pesticides, sensors, polymeric materials, etc. For example, styrylquinoline has significant biological activity, and polyarylvinyene can be used as an organic light-emitting diode in materials science. Therefore, it is considered an important chemical transformation and has attracted extensive research by chemists. The methods reported in the current literature are as follows:

[0003] (1) Achieving dehydroxylation alkenylation reaction with benzyl alcohol. Methyl-substituted azacyclic compounds can achieve the alkenylation reaction of methyl-substituted azacyclic compounds under the catalysis of Fe(NO3)3·9H2O / TEMPO (Zhang, Z.G.; Ma, Y.T.; Dai, S.W.; Zhang, Y.; Li, H. Tetrahedron Letters. 2020, 61, 151885.), NiBr2 (Das, J.; Mari Vellakkaran; Debasis Banerjee. Chemical Communications. 2019, 55, 7530 - 7533.), MnO2 (Zhang, C.Y.; Li, Z.Z.; Fang, Y.C.; Jiang, S.H.; Wang, M.R.; Zhang, G.Y. Tetrahedron. 2020, 76, 130968.) or Ru(II)-NNO (Tamilthendral, V.; Balamurugan, G.; Ramesh, R. Applied Organometalic Chemistry. 2022, 36, 6561.), etc. For example, 6-bromo-2-methylquinoline can undergo a cross-coupling reaction with benzyl alcohol at 50 °C with THF as the solvent and t-BuOK as the base, using Fe(NO3)3·9H2O / TEMPO as the catalyst, to achieve the alkenylation of the C(sp 3 )-H bond of 6-bromo-2-methylquinoline. Such reactions have relatively high yields, but require the addition of transition metals as catalysts and use an excessive amount of strong base, and the reaction process is not safe enough.

[0004]

[0005] (2) Realize the alkenylation reaction with aldehydes. Methyl-substituted azacyclic compounds can achieve the alkenylation reaction of C(sp 3 )-H bonds under the catalysis of Ca(OTf)2 (Yaragorla, S.; Singh, G.; Dada, R. Tetrahedron Letters. 2015, 56, 5924–5929.), Fe3O(BPDC)3 (Huang, T. D.; Thien, N. L.; Thanh, T.; Nam, T. S. P. Journal of Molecular Catalysis A: Chemical. 2016, 420, 237-245.), LiNTf2 (Mao, D.; Hong, G.; Wu, S. Y.; Liu, X.; Yu, J. J.; Wang, L. M.; Eur. J. Org. Chem. 2014, 14, 3009-3019.) or IN(OTf)3 (Kumar, D.; Kumar, A.; Qadri, M. M.; Ansari, M. I.; Gautam, A. RSC Adv. 2015, 5, 2920-2927.), etc. For example, 2-methylquinoline and benzaldehyde can achieve the alkenylation reaction of the C(sp 3 )-H bond of 2-methylquinoline under the catalysis of Fe3O(BPDC)3, with acetic acid as a co-catalyst and toluene as a solvent. Most of these reactions require metal catalysts, and the method using non-metal catalysts has been rarely reported.

[0006]

[0007] (3) Realize the deamination alkenylation reaction with benzylamine. Methyl-substituted azacyclic compounds can realize the deamination alkenylation reaction with benzylamine under the catalysis of La(Pfb)3 (Mao, D.; Zhu, X.Y.; Hong, G.; Wu, S.Y.; Wang, L. Synlett. 2016, 27, 2481 - 2484.), NaCl (Hazra, S.; Tiwari, V.; Verma, A.; Dolui, P.; Elias, A.J.; Org. Lett. 2020, 22, 5496 - 5501.), NBS / TBHP (Gong, L.; Xing, L.J.; Xu, T.; Zhu, X.P.; Zhou, W.; Kang, N.; Wang, B. Org. Biomol. Chem. 2014, 12, 6557 - 6560.), Bmin[BF4] (Sharma, R.; Abdullaha, M.; Bharate, S.B. J. Org. Chem. 2017, 82, 9786 - 9793.), etc. For example, 2-methylquinoline can realize the deamination alkenylation reaction of 2-methylquinoline C(sp 3 )-H with benzylamine under the catalysis of NBS, using TBHP as the oxidant in acetonitrile. In these reactions, benzylamine is used as the benzyl source. Currently, there are few research methods, and most reactions require the addition of an equivalent amount of oxidant, and the dosage of the catalyst is mostly above 5 mol%, and sometimes a corrosive strong acid needs to be added to provide an acidic environment, which may bring potential hazards of catalyst residue or unsafe operation during the drug development process.

[0008] Summary of the Invention

[0009] The object of the present invention is to address the above deficiencies and provide a method for preparing N-heteroaryl stilbene compounds. Specifically, it is a method for catalyzing the oxidation of methyl-substituted azacyclic compounds with 2,4,6-trihydroxybenzoic acid to realize the alkenylation with benzylamine compounds. Using a low catalytic amount of 2,4,6-trihydroxybenzoic acid as the catalyst, DMSO and / or toluene as the solvent, and oxygen as the green oxidant, methyl-substituted azacyclic compounds and benzylamine compounds as the substrates, N-heteroaryl stilbene compounds can be efficiently obtained.

[0010] To achieve the above object, the present invention is realized through the following technical solutions: A method for preparing N-heteroaryl stilbene compounds, comprising the following steps:

[0011] In an oxygen atmosphere, a methyl-substituted azacyclic compound, a benzylamine compound, and 2,4,6-trihydroxybenzoic acid are mixed in a DMSO and / or toluene solvent for reaction. After the reaction is completed, purification is carried out (column chromatography purification is used in this application) to obtain an N-heteroaryldiphenylethylene compound.

[0012] Among them, the general formula of the N-heteroaryldiphenylethylene compound is:

[0013]

[0014] In the formula: is one of quinoline, quinoxaline, and benzoxazole, and R 1 is one of -hydrogen, 6-methyl, 6-methoxy, 7-chloro, or 6-nitro, and R 2 is any one of -hydrogen, 2-methyl, 4-methyl, 2-methoxy, 3-methoxy, -4-methoxy, -3,4-dimethoxy, 2-fluoro, 4-fluoro, 2-chloro, 4-chloro, 2-bromo, 4-trifluoromethyl, 4-tert-butyl, or 4-phenyl.

[0015] The general formula of the methyl-substituted azacyclic compound is:

[0016]

[0017] In the formula: is one of quinoline, quinoxaline, and benzoxazole, and R is one of -hydrogen, 6-methyl, 6-methoxy, 7-chloro, or 6-nitro.

[0018] Furthermore, this type of compound can be any one of the following compounds:

[0019]

[0020] Furthermore, the general formula of the benzylamine compound is

[0021]

[0022] In the formula: R is any one of -hydrogen, 2-methyl, 4-methyl, 2-methoxy, 3-methoxy, -4-methoxy, -3,4-dimethoxy, 2-fluoro, 4-fluoro, 2-chloro, 4-chloro, 2-bromo, 4-trifluoromethyl, 4-tert-butyl, or 4-phenyl.

[0023] This type of compound can be any one of the following compounds:

[0024]

[0025] In order to further improve the yield, the following optimizations can be carried out:

[0026] In the above preparation method, the dosage of the benzylamine compound is 1.2 to 2.0 times that of the methyl-substituted nitrogen heterocyclic compound in terms of molar ratio, and the dosage of 2,4,6-trihydroxybenzoic acid is 0.005 to 0.05 times that of the methyl-substituted nitrogen heterocyclic compound in terms of molar ratio. The concentrations of the methyl-substituted nitrogen heterocyclic compound, benzylamine compound, and 2,4,6-trihydroxybenzoic acid in the solvent are 0.6 to 3.0 mol / L.

[0027] Further, in the above preparation method, the reaction time is 18 to 48 hours, and the temperature is 110 to 140 °C.

[0028] Based on the above optimization, the yield can be as high as 96%.

[0029] Further, when column chromatography purification is adopted, the preferred column packing solvent is petroleum ether; the eluent is petroleum ether / ethyl acetate; the filler of the column used is silica gel with a mesh size of 300 - 400, and the specification is a diameter of 2 cm × height of 30 cm.

[0030] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0031] (1) For the method for catalytic oxidation of methyl-substituted nitrogen heterocyclic compounds and benzylamine compounds to carry out alkenylation to N-heteroaryl stilbene compounds according to the present invention, the catalyst loading is low (0.5 - 5 mol%), the reagents are simple and easily available, the operation is simple, no metal catalyst is used, and the atom economy is high.

[0032] (2) Using methyl-substituted nitrogen heterocyclic compounds with different structures as raw materials, in DMSO solvent, with oxygen as the green oxidant and 2,4,6-trihydroxybenzoic acid as the organic catalyst, the deamination alkenylation reaction of methyl-substituted nitrogen heterocyclic compounds and benzylamine can be realized, and a series of N-heteroaryl stilbene compounds are effectively synthesized. This method has simple and easily available reagents, mild reaction conditions, a green and clean reaction process, simple operation, no use of metal catalyst, and high atom economy. Specific Embodiments

[0033] The present invention will be further described in detail below with reference to embodiments:

[0034] The method for catalytic oxidation of methyl-substituted nitrogen heterocyclic compounds and benzylamine compounds to carry out alkenylation to N-heteroaryl stilbene compounds includes the following steps:

[0035] In an oxygen atmosphere, the methyl-substituted nitrogen heterocyclic compound, benzylamine compound, and 2,4,6-trihydroxybenzoic acid are mixed in DMSO solvent for reaction, and after the reaction is completed, N-heteroaryl stilbene compounds are obtained by column chromatography.

[0036] Among them, the general formulas of N-heteroaryl stilbene compounds, methyl-substituted azacyclic compounds and benzylamine compounds are as follows:

[0037] In the formula: is one of quinoline, quinoxaline, benzoxazole, R 1 is one of -hydrogen, 6-methyl, 6-methoxy, 7-chloro or 6-nitro, R 2 is any one of -hydrogen, 2-methyl, 4-methyl, 2-methoxy, 3-methoxy, -4-methoxy, -3,4-dimethoxy, 2-fluoro, 4-fluoro, 2-chloro, 4-chloro, 2-bromo, 4-trifluoromethyl, 4-tert-butyl or 4-phenyl.

[0038] The N-heteroaryl stilbene compound is any one of the following compounds:

[0039]

[0040]

[0041] In the above preparation method, the dosage of the benzylamine compound is 1.2 - 2.0 times that of the methyl-substituted azacyclic compound in terms of molar ratio, the dosage of 2,4,6-trihydroxybenzoic acid is 0.005 - 0.05 times that of the methyl-substituted azacyclic compound in terms of molar ratio, the concentration of the mixture of the methyl-substituted azacyclic compound, benzylamine compound, 2,4,6-trihydroxybenzoic acid and DMSO is 0.6 - 3.0 mol / L, the reaction time is 18 - 48 hours, and the temperature is 110 - 140 °C.

[0042] It was found in the experiment that the dosage of each material, reaction time and temperature mainly affect the yield of N-heteroaryl stilbene compounds, but have basically no effect on the selectivity of N-heteroaryl stilbene compounds, and the yields of N-heteroaryl stilbene compounds obtained under the above conditions are all above 70%.

[0043] The preferred embodiments of the present invention will be described in more detail below with reference to specific examples. The methods are all conventional methods unless otherwise specified. The raw materials can all be obtained from public commercial channels unless otherwise specified. In the column chromatography step of the following examples, the filler of the chromatography column used is silica gel with a mesh size of 300 - 400, and the specification is a diameter of 2 cm × a height of 30 cm.

[0044] Example 1

[0045] A cross-deamination olefination product of 2-methylquinoline and benzylamine as shown in formula III-aa, and its preparation method is as follows:

[0046]

[0047] The above reaction equation is for the synthesis of the cross-deamination olefination product of 2-methylquinoline and benzylamine:

[0048] 2-Methylquinoline (71.6 mg, 0.5 mmol), benzylamine (107.2 mg, 1.0 mmol), 2,4,6-trihydroxybenzoic acid (0.9 mg, 0.005 mmol) and DMSO (0.3 mL) were successively added to the reactor. The reaction was carried out overnight at 110 °C in an oxygen atmosphere. After the reaction was completed, 100 ml of water was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (3 × 30.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. Column chromatography was then performed to obtain 106.4 mg of 4-styrylquinoline shown as formula III-aa, with a yield of 92%.

[0049] The results of structural confirmation are as follows: 1 H NMR (400 MHz, CDCl3): δ 8.10 (t, J = 8.6 Hz, 2H), 7.78 (d, J = 8.4 Hz, 1H), 7.74 - 7.61 (m, 5H), 7.49 (t, J = 7.6 Hz, 1H), 7.45 - 7.38 (m, 3H), 7.33 (t, J = 7.4 Hz, 1H); 13 C NMR (100 MHz, CDCl3): δ 156.0, 148.3, 136.5, 136.4, 134.5, 129.8, 129.2, 129.0, 128.8, 128.7, 127.5, 127.4, 127.3, 126.2, 119.3。

[0050] The synthesized compound was identified as 4-styrylquinoline shown as the target compound III-aa by structural identification.

[0051] Under other unchanged conditions, when the solvent was replaced with toluene and the reaction temperature was 110 °C, the yield of 4-styrylquinoline was 91%; when the solvent was replaced with DMF and the reaction temperature was 110 °C, the yield of 4-styrylquinoline was 74%; when the solvent was replaced with acetonitrile and the reaction temperature was 80 °C, no reaction occurred; when the solvent was replaced with methanol and the reaction temperature was 60 °C, no reaction occurred.

[0052] Example 2

[0053] A cross-deamination olefination product of 2,6-dimethylquinoline and benzylamine as shown in formula III-ba, and its preparation method is as follows:

[0054]

[0055] The above reaction equation is for the synthesis of the cross-deamination olefination product of 2,6-dimethylquinoline and benzylamine:

[0056] 2,6-Dimethylquinoline (78.6 mg, 0.5 mmol), benzylamine (107.2 mg, 1.0 mmol), 2,4,6-trihydroxybenzoic acid (0.9 mg, 0.005 mmol) and DMSO (0.3 mL) were successively added to the reactor. The reaction was carried out overnight at 110 °C in an oxygen atmosphere. After the reaction was completed, 100 mL of water was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (3 × 30.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. Column chromatography was then performed to obtain 99.4 mg of 6-methyl-2-styrylquinoline shown as formula III-ba, with a yield of 81%.

[0057] The results of structure confirmation are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.01 (dd, J = 22.8 Hz, 8.4 Hz, 2H), 7.69 - 7.61 (m, 4H), 7.54 (d, J = 7.2 Hz, 2H), 7.44 - 7.36 (m, 3H), 7.32 (t, J = 7.2 Hz, 1H), 2.53 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 155.2, 146.8, 136.6, 136.1, 135.7, 133.9, 132.0, 129.1, 128.9, 128.8, 128.5, 127.4, 127.2, 126.5, 119.2, 21.6.

[0058] The synthesized compound was identified as 6-methyl-2-styrylquinoline shown as the target compound III-ba.

[0059] Example 3

[0060] A cross-deamination olefination product of 6-methoxy-2-methylquinoline and benzylamine shown as formula III-ca was prepared as follows:

[0061]

[0062] The above reaction equation is for the synthesis of the cross-deamination olefination product of 6-methoxy-2-methylquinoline and benzylamine:

[0063] 6-Methoxy-2-methylquinoline (86.6 mg, 0.5 mmol), benzylamine (107.2 mg, 1.0 mmol), 2,4,6-trihydroxybenzoic acid (0.9 mg, 0.005 mmol) and DMSO (0.3 mL) were successively added to the reactor. The reaction was carried out overnight at 110 °C in an oxygen atmosphere. After the reaction was completed, 100 mL of water was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (3 × 30.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. Column chromatography was performed to obtain 117.6 mg of 6-methoxy-2-styrylquinoline shown in formula III-ca as a white solid, with a yield of 90%.

[0064] The results of structure confirmation are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.00 (dd, J = 18.8 Hz, 8.8 Hz, 2H), 7.69 - 7.57 (m, 4H), 7.43 - 7.34 (m, 4H), 7.34 - 7.29 (m, 1H), 7.06 (d, J = 2.8 Hz, 1H), 3.94 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 157.6, 153.7, 144.3, 136.7, 135.1, 133.2, 130.6, 129.1, 128.8, 128.4, 128.3, 127.1, 122.4, 119.6, 105.2, 55.6。

[0065] The synthesized compound was identified as 6-methoxy-2-styrylquinoline shown in the target compound III-ca by structure identification.

[0066] Example 4

[0067] A cross-deamination olefination product of 7-chloro-2-methylquinoline and benzylamine as shown in formula III-da was prepared as follows:

[0068]

[0069] The above reaction equation is the synthesis of the cross-deamination olefination product of 7-chloro-2-methylquinoline and benzylamine:

[0070] 7-Chloro-2-methylquinoline (88.8 mg, 0.5 mmol), benzylamine (107.2 mg, 1.0 mmol), 2,4,6-trihydroxybenzoic acid (0.9 mg, 0.005 mmol) and DMSO (0.3 mL) were successively added to the reactor. The reaction was carried out overnight at 110 °C in an oxygen atmosphere. After the reaction was completed, 100 ml of water was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (3 × 30.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography gave 111.6 mg of 7-chloro-2-styrylquinoline shown as formula III-da as a white solid, with an 84% yield.

[0071] The results of structure confirmation are as follows: 1 1H NMR (400 MHz, CDCl3) δ 8.13 - 8.06 (m, 2H), 7.75 - 7.61 (m, 5H), 7.47 - 7.31 (m, 5H); 13 13C NMR (100 MHz, CDCl3) δ 156.9, 148.7, 136.3, 136.1, 135.5, 135.2, 128.9, 128.8, 128.7, 128.5, 128.2, 127.4, 127.1, 125.7, 119.6.

[0072] The synthesized compound was identified as 7-chloro-2-styrylquinoline shown as the target compound III-da by structure determination.

[0073] Example 5

[0074] A cross-deaminative olefination product of 2-methylquinoline and 4-methoxybenzylamine as shown in formula III-ab was prepared as follows:

[0075]

[0076] The above reaction equation is the synthesis of the cross-deaminative olefination product of 2-methylquinoline and 4-methoxybenzylamine:

[0077] 2-Methylquinoline (71.6 mg, 0.5 mmol), 4-methoxybenzylamine (137.2 mg, 1.0 mmol), 2,4,6-trihydroxybenzoic acid (0.9 mg, 0.005 mmol) and DMSO (0.3 mL) were successively added to the reactor. The reaction was carried out overnight at 110 °C in an oxygen atmosphere. After the reaction was completed, 100 ml of water was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (3 × 30.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography gave 113.7 mg of 2-(4-methoxystyryl)quinoline shown as formula III-ab as a white solid, with an 87% yield.

[0078] The structural confirmation results are as follows: 1 H NMR(400MHz,CDCl3)δ8.09(dd,J=14.4Hz,8.8Hz,2H),7.77(d,J=8.4Hz,1H),7.73 - 7.56(m,5H),7.52 - 7.44(m,1H),7.29(d,J=16.0Hz,1H),6.94(d,J=8.8Hz,2H),3.85(s,3H); 13 C NMR(100MHz,CDCl3)δ160.1,156.3,148.2,136.3,134.2,129.7,129.3,129.0,128.7,127.5,127.2,126.8,126.0,119.1,114.3,55.4.

[0079] The synthesized compound was identified as the target compound III - ab, 2-(4 - methoxystyryl)quinoline.

[0080] Example 6

[0081] A cross - dehydrogenative olefination product of 2 - methylquinoline and 4 - fluorobenzylamine as shown in formula III - ac was prepared as follows:

[0082]

[0083] The above reaction equation is for the synthesis of the cross - dehydrogenative olefination product of 2 - methylquinoline and 4 - fluorobenzylamine:

[0084] 2 - methylquinoline (71.6 mg, 0.5 mmol), 4 - fluorobenzylamine (125.1 mg, 1.0 mmol), 2,4,6 - trihydroxybenzoic acid (0.9 mg, 0.005 mmol) and DMSO (0.3 mL) were successively added to a reactor. The reaction was carried out overnight at 110 °C in an oxygen atmosphere. After the reaction was completed, 100 ml of water was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (3 × 30.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. Column chromatography was then performed to obtain 110.9 mg of the white solid 2-(4 - fluorostyryl)quinoline as shown in formula III - ac, with a yield of 89%.

[0085] The structural confirmation results are as follows: 11H NMR (400 MHz, CDCl3) δ 8.11 (dd, J = 20.4 Hz, 8.4 Hz, 2H), 7.79 (d, J = 8.4 Hz, 1H), 7.74 - 7.69 (m, 1H), 7.69 - 7.58 (m, 4H), 7.54 - 7.47 (m, 1H), 7.33 (d, J = 16.4 Hz, 1H), 7.09 (t, J = 8.6 Hz, 2H); 13 13C NMR (100 MHz, CDCl3) δ 163.0 (C-F, 1 J C-F = 247.3 Hz), 155.8, 148.2, 136.5, 133.3, 132.7 (C-F, 3 J C-F = 3.3 Hz), 129.86, 129.1, 128.9, 128.8, 128.7, 127.5, 127.4, 126.3, 119.3, 115.85 (C-F, 2 J C-F = 21.6 Hz).

[0086] The synthesized compound was identified as the target compound III-ac, 2-(4-fluorostyryl)quinoline as shown.

[0087] Example 7

[0088] A cross-deaminative olefination product of 2-methylquinoline and 2-chlorobenzylamine as shown in formula III-ad was prepared as follows:

[0089]

[0090] The above reaction equation is for the synthesis of the cross-deaminative olefination product of 2-methylquinoline and 2-chlorobenzylamine:

[0091] 2-Methylquinoline (71.6 mg, 0.5 mmol), 2-chlorobenzylamine (141.6 mg, 1.0 mmol), 2,4,6-trihydroxybenzoic acid (0.9 mg, 0.005 mmol) and DMSO (0.3 mL) were successively added to the reactor. The reaction was carried out overnight at 110 °C in an oxygen atmosphere. After the reaction, 100 ml of water was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (3 × 30.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. Column chromatography was then performed to obtain 111.6 mg of the white solid 2-(2-chlorostyryl)quinoline as shown in formula III-ad, with an 84% yield.

[0092] The results of structure confirmation are as follows: 11H NMR (400 MHz, CDCl3) δ 8.13 (dd, J = 21.6 Hz, 8.8 Hz, 2H), 8.04 (d, J = 16.4 Hz, 1H), 7.85 - 7.68 (m, 4H), 7.56 - 7.47 (m, 1H), 7.46 - 7.38 (m, 2H), 7.32 - 7.23 (m, 2H); 13 13C NMR (100 MHz, CDCl3) δ 155.8, 148.2, 136.5, 134.6, 134.1, 131.7, 130.3, 130.0, 129.9, 129.5, 129.3, 127.5, 127.4, 127.1, 127.0, 126.5, 118.9.

[0093] The synthesized compound was identified by structure as the target compound III - ad, 2-(2 - chlorostyryl)quinoline.

[0094] Example 8

[0095] A cross - deaminative olefination product of 6 - methoxy - 2 - methylquinoline and 4 - methoxybenzylamine as shown in formula III - cb, and its preparation method is as follows:

[0096]

[0097] The above reaction equation is for the synthesis of the cross - deaminative olefination product of 6 - methoxy - 2 - methylquinoline and 4 - methoxybenzylamine:

[0098] 6 - Methoxy - 2 - methylquinoline (86.6 mg, 0.5 mmol), 4 - methoxybenzylamine (137.1 mg, 1.0 mmol), 2,4,6 - trihydroxybenzoic acid (0.9 mg, 0.005 mmol) and DMSO (0.3 mL) were successively added to a reactor. The reaction was carried out overnight at 110 °C in an oxygen atmosphere. After the reaction was completed, 100 mL of water was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (3 × 30.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. Column chromatography was then performed to obtain 131.1 mg of white solid 6 - methoxy - 2-(4 - methoxystyryl)quinoline shown in formula III - cb, with a yield of 90%.

[0099] The results of structure confirmation are as follows: 11H NMR (400 MHz, CDCl3) δ 7.99 (dd, J = 12.0 Hz, 8.4 Hz, 2H), 7.64 - 7.53 (m, 4H), 7.35 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 7.25 (d, J = 16.4 Hz, 1H), 7.05 (d, J = 2.8 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 3.93 (s, 3H), 3.84 (s, 3H); 13 13C NMR (100 MHz, CDCl3) δ 160.0, 157.5, 154.0, 144.2, 135.1, 133.0, 130.5, 129.5, 128.5, 128.1, 126.8, 122.3, 119.4, 114.2, 105.3, 55.5, 55.4.

[0100] The synthesized compound was identified as 6 - methoxy - 2-(4 - methoxystyryl)quinoline shown in the target compound III - cb through structure determination.

[0101] Example 9

[0102] A cross - dehydrogenative olefination product of 2 - methylquinoxaline and 4 - methoxybenzylamine as shown in formula III - eb, and its preparation method is as follows:

[0103]

[0104] The above reaction equation is the synthesis of the cross - dehydrogenative olefination product of 2 - methylquinoxaline and 4 - methoxybenzylamine:

[0105] 2 - Methylquinoxaline (72.1 mg, 0.5 mmol), 4 - methoxybenzylamine (137.1 mg, 1.0 mmol), 2,4,6 - trihydroxybenzoic acid (0.9 mg, 0.005 mmol) and DMSO (0.3 mL) were successively added to the reactor. The reaction was carried out overnight at 110 °C in an oxygen atmosphere. After the reaction was completed, 100 ml of water was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (3 × 30.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. Column chromatography was then performed to obtain 80.0 mg of white solid 2-(4 - methoxystyryl)quinoline shown in formula III - eb, with a yield of 61%.

[0106] The results of structure confirmation are as follows: 11H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.12 - 8.03 (m, 2H), 7.86 (d, J = 16.4 Hz, 1H), 7.80 - 7.68 (m, 2H), 7.64 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 5.6 Hz, 1H), 6.98 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H); 13 13C NMR (100 MHz, CDCl3) δ 160.6, 151.0, 144.4, 142.4, 141.4, 136.1, 130.3, 129.1, 129.0, 129.0, 128.9, 128.8, 123.1, 114.38, 55.40.

[0107] The synthesized compound was identified as the target compound III-eb, 2-(4-methoxystyryl)quinoxaline.

[0108] Example 10

[0109] A cross-deaminative olefination product of 2-methylquinoline and 3,4-dimethoxybenzylamine as shown in formula III-ae was prepared as follows:

[0110]

[0111] The above reaction equation is for the synthesis of the cross-deaminative olefination product of 2-methylquinoline and 3,4-dimethoxybenzylamine:

[0112] 2-Methylquinoline (71.6 mg, 0.5 mmol), 3,4-dimethoxybenzylamine (167.2 mg, 1.0 mmol), 2,4,6-trihydroxybenzoic acid (0.9 mg, 0.005 mmol) and DMSO (0.3 mL) were successively added to the reactor. The reaction was carried out overnight at 110 °C in an oxygen atmosphere. After the reaction was completed, 100 ml of water was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (3 × 30.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. Column chromatography was performed to obtain 123.8 mg of white solid 2-(3,4-dimethoxystyryl)quinoline as shown in formula III-ae, with a yield of 85%.

[0113] The results of structure confirmation are as follows: 11H NMR (400 MHz, CDCl3) δ 8.10 (dd, J = 21.1 Hz, 8.4 Hz, 2H), 7.81 - 7.57 (m, 4H), 7.49 (t, J = 7.4 Hz, 1H), 7.31 (d, J = 16.4 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.17 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H); 13 13C NMR (100 MHz, CDCl3) δ 156.3, 149.9, 149.2, 148.2, 136.4, 134.4, 129.8, 129.6, 129.0, 127.5, 127.2, 127.1, 126.1, 121.4, 118.9, 111.1, 108.9, 56.0, 55.9.

[0114] The synthesized compound was identified as the target compound III-ae, 2-(3,4-dimethoxystyryl)quinoline.

[0115] Example 11

[0116] A cross-deaminative olefination product of 2-methylquinoline and 4-(trifluoromethyl)benzylamine as shown in formula III-af, and its preparation method is as follows:

[0117]

[0118] The above reaction equation is for the synthesis of the cross-deaminative olefination product of 2-methylquinoline and 4-(trifluoromethyl)benzylamine:

[0119] 2-Methylquinoline (71.6 mg, 0.5 mmol), 4-(trifluoromethyl)benzylamine (175.1 mg, 1.0 mmol), 2,4,6-trihydroxybenzoic acid (0.9 mg, 0.005 mmol) and DMSO (0.3 mL) were successively added to a reactor. The reaction was carried out overnight at 110 °C in an oxygen atmosphere. After the reaction was completed, 100 ml of water was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (3 × 30.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. Column chromatography was then performed to obtain 136.2 mg of the white solid 2-(4-(trifluoromethyl)styryl)quinoline shown in formula III-af, with a yield of 91%.

[0120] The results of structure confirmation are as follows: 11H NMR (400 MHz, CDCl3) δ 8.14 (dd, J = 27.6 Hz, 8.4 Hz, 2H), 7.81 (d, J = 9.2 Hz, 1H), 7.76 - 7.63 (m, 7H), 7.56 - 7.51 (m, 1H), 7.48 (d, J = 16.0 Hz, 1H); 13 13C NMR (100 MHz, CDCl3) δ 155.2, 148.2, 140.0, 136.7, 132.8, 131.2, 130.3, 130.00, 129.2, 129.2, 127.6, 127.5, 127.3, 126.6, 125.7 (C-F, J = 3.8 Hz), 125.5, 119.49.

[0121] The synthesized compound was identified as the target compound III-af, 2-(4-(trifluoromethyl)styryl)quinoline as shown below.

[0122] Example 12

[0123] A cross-deaminative olefination product of 2-methylquinoline and 2-bromobenzylamine as shown in formula III-ag was prepared as follows:

[0124]

[0125] The above reaction equation is for the synthesis of the cross-deaminative olefination product of 2-methylquinoline and 2-bromobenzylamine:

[0126] 2-Methylquinoline (71.6 mg, 0.5 mmol), 2-bromobenzylamine (186.1 mg, 1.0 mmol), 2,4,6-trihydroxybenzoic acid (0.9 mg, 0.005 mmol) and DMSO (0.3 mL) were successively added to a reactor. The reaction was carried out overnight at 110 °C in an oxygen atmosphere. After the reaction was completed, 100 ml of water was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (3 × 30.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. Column chromatography was then performed to obtain 77.5 mg of the white solid 2-(2-bromostyryl)quinoline as shown in formula III-ag, with a 50% yield.

[0127] The results of structure confirmation are as follows: 1 1H NMR (400 MHz, CDCl3) δ 8.13 (dd, J = 25.6 Hz, 8.8 Hz, 2H), 7.99 (d, J = 16.4 Hz, 1H), 7.84 - 7.68 (m, 4H), 7.63 (d, J = 8.0 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.41 - 7.33 (m, 2H), 7.22 - 7.15 (m, 1H); 1313C NMR (100 MHz, CDCl3) δ 155.8, 148.2, 136.5, 136.3, 133.2, 133.0, 132.0, 129.9, 129.8, 129.3, 127.8, 127.6, 127.5, 127.2, 126.5, 124.7, 118.9.

[0128] The synthesized compound was identified as the target compound III-ag, 2-(2-bromovinyl)quinoline.

[0129] Example 13

[0130] A cross-deaminative olefination product of 2-methylquinoline and 2-fluorobenzylamine as shown in formula III-ah, and its preparation method is as follows:

[0131]

[0132] The above reaction equation is for the synthesis of the cross-deaminative olefination product of 2-methylquinoline and 2-fluorobenzylamine:

[0133] 2-Methylquinoline (71.6 mg, 0.5 mmol), 2-fluorobenzylamine (125.1 mg, 1.0 mmol), 2,4,6-trihydroxybenzoic acid (0.9 mg, 0.005 mmol) and DMSO (0.3 mL) were successively added to the reactor. The reaction was carried out overnight at 110 °C in an oxygen atmosphere. After the reaction was completed, 100 mL of water was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (3 × 30.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. Column chromatography gave 99.7 mg of the white solid 2-(2-fluorovinyl)quinoline as shown in formula III-ah, with an 80% yield.

[0134] The results of structure confirmation are as follows: 1 1H NMR (400 MHz, CDCl3) δ 8.12 (dd, J = 20.8 Hz, 8.4 Hz, 2H), 7.85 (d, J = 16.8 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.77 - 7.69 (m, 3H), 7.54 - 7.46 (m, 2H), 7.33 - 7.27 (m, 1H), 7.19 (t, J = 7.3 Hz, 1H), 7.15 - 7.07 (m, 1H); 13 13C NMR (100 MHz, CDCl3) δ 160.8 (C-F, 1 J C-F = 249.6 Hz), 155.86, 148.18, 136.49, 131.2 (C-F, 3 J C-F= 4.8 Hz), 129.9 (C-F, 3 J C-F = 8.5 Hz), 129.84, 129.26, 127.7 (C-F, 2 J C-F = 3.3 Hz), 127.53, 127.46, 126.7 (C-F, 2 J C-F = 3.9 Hz), 126.38, 124.5, 124.41, 124.37, 119.21, 116.0 (C-F, 2 J C-F = 21.9 Hz).

[0135] The compound synthesized through structure identification is the target compound III-ah, i.e., 2-(2-fluorostyryl)quinoline.

[0136] Example 14

[0137] A cross-deamination olefination product of 2-methylquinoline and 4-chlorobenzylamine as shown in Formula III-ai, and its preparation method is as follows:

[0138]

[0139] The above reaction equation is for the synthesis of the cross-deamination olefination product of 2-methylquinoline and 4-chlorobenzylamine:

[0140] 2-Methylquinoline (71.6 mg, 0.5 mmol), 4-chlorobenzylamine (141.6 mg, 1.0 mmol), 2,4,6-trihydroxybenzoic acid (0.9 mg, 0.005 mmol) and DMSO (0.3 mL) were successively added to the reactor. The reaction was carried out overnight at 110 °C in an oxygen atmosphere. After the reaction was completed, 100 ml of water was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (3 × 30.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. Column chromatography was then performed to obtain 94.3 mg of white solid 2-(4-chlorostyryl)quinoline as shown in Formula III-ai, with a yield of 71%.

[0141] The results of structure confirmation are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.11 (dd, J = 22.8 Hz, 8.4 Hz, 2H), 7.79 (d, J = 8.0 Hz, 1H), 7.75 - 7.69 (m, 1H), 7.65 (dd, J = 13.2 Hz, 4.8 Hz, 2H), 7.59 - 7.48 (m, 3H), 7.42 - 7.33 (m, 3H); 1313C NMR (100 MHz, CDCl3) δ 155.6, 148.2, 136.5, 135.0, 134.3, 133.1, 129.9, 129.4, 129.2, 129.0, 128.4, 127.5, 127.4, 126.4, 119.4.

[0142] The synthesized compound was identified by its structure as the target compound 2-(4-chlorostyryl)quinoline shown in III-ai.

[0143] Example 15

[0144] A cross-deamination olefination product of 6-methoxy-2-methylquinoline and 4-fluorobenzylamine as shown in formula III-cc, and its preparation method is as follows:

[0145]

[0146] The above reaction equation is for the synthesis of the cross-deamination olefination product of 6-methoxy-2-methylquinoline and 4-fluorobenzylamine:

[0147] 6-Methoxy-2-methylquinoline (86.6 mg, 0.5 mmol), 4-fluorobenzylamine (125.1 mg, 1.0 mmol), 2,4,6-trihydroxybenzoic acid (0.9 mg, 0.005 mmol) and DMSO (0.3 mL) were successively added to a reactor. The reaction was carried out overnight at 110 °C in an oxygen atmosphere. After the reaction was completed, 100 ml of water was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (3 × 30.0 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. Column chromatography was then performed to obtain 76.8 mg of the white solid 2-(4-fluorostyryl)-6-methoxyquinoline shown in formula III-cc, with a yield of 55%.

[0148] The results of structure confirmation are as follows: 1 1H NMR (400 MHz, CDCl3) δ 8.00 (dd, J = 17.6 Hz, 8.8 Hz, 2H), 7.65 - 7.55 (m, 4H), 7.37 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 7.29 (d, J = 16.4 Hz, 1H), 7.13 - 7.03 (m, 3H), 3.94 (s, 3H); 13 13C NMR (100 MHz, CDCl3) δ 162.8 (C-F, 1 J C-F = 246.8 Hz), 157.7, 153.5, 144.2, 135.22, 132.9 (C-F, 3 J C-F= 3.3 Hz), 132.0, 130.6, 128.8, 128.7, 128.3, 122.4, 119.6, 115.8 (C-F, 2 J C-F = 21.5 Hz), 105.25, 55.58。

[0149] The compound synthesized through structure identification is the target compound 2-(4-fluorostyryl)-6-methoxyquinoline shown in III-cc.

[0150] The embodiments of the present invention have been described above. The above description is exemplary and not exhaustive, and is not limited to the disclosed embodiments. Many modifications and changes are obvious to those of ordinary skill in the art without departing from the scope and technical principles of the described embodiments, and these modifications and changes should also be regarded as within the protection scope of the present invention.

Claims

1. A method for preparing N-heteroaryl stilbene compounds, characterized in that: It includes the following steps: In an oxygen atmosphere, a methyl-substituted nitrogen heterocyclic compound, a benzylamine compound, and 2,4,6-trihydroxybenzoic acid are dissolved in a DMSO and / or toluene solvent and mixed for reaction. After the reaction is completed, purification is carried out to obtain an N-heteroaryl stilbene compound; Among them, the general formulas of N-heteroaryl stilbene compounds, methyl-substituted azacyclic compounds, and benzylamine compounds are as follows: , , ; in the methyl-substituted azacyclic compound, the methyl is located at the ortho position of N in the azacyclic ring; One of the carbons of the vinyl group of the N-heteroaryl stilbene compound is connected to the carbon adjacent to N in the nitrogen heterocycle; In the formula: is one of quinoline and quinoxaline, R 1 is one of hydrogen, 6-methyl, 6-methoxy, 7-chloro or 6-nitro, R 2 is any one of hydrogen, 2-methyl, 4-methyl, 2-methoxy, 3-methoxy, 4-methoxy, 3,4-dimethoxy, 2-fluoro, 4-fluoro, 2-chloro, 4-chloro, 2-bromo, 4-trifluoromethyl, 4-tert-butyl or 4-phenyl; The reaction temperature is 110~140 °C, and the reaction time is 18~48 hours; The dosage of the benzylamine compound is 1.2~2.0 times that of the methyl-substituted nitrogen heterocyclic compound in terms of molar ratio, and the dosage of 2,4,6-trihydroxybenzoic acid is 0.005~0.01 times that of the methyl-substituted nitrogen heterocyclic compound in terms of molar ratio; The concentrations of the methyl-substituted nitrogen heterocyclic compound, the benzylamine compound, and 2,4,6-trihydroxybenzoic acid in the solvent are 0.6~3.0 mol / L respectively.

2. The preparation method of the N-heteroaryl stilbene compound according to claim 1, characterized in that: The methyl-substituted azacyclic compound is any one of the following compounds: , , , , , .

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