A preparation method of C3-position alkyl-substituted quinoxaline ketone compounds under heterogeneous photocatalysis

Abstract

The application belongs to the technical field of organic chemistry, and particularly relates to a preparation method of a heterogeneous photocatalytic C3-alkyl-substituted quinoxalinone compound. 1 H NMR, 13 C NMR, HRMS and the like, and is confirmed. The method is to use graphite phase carbon nitride as a heterogeneous photocatalyst in an organic solvent, and under the conditions of the presence of alkali and oxygen, graphite phase carbon nitride oxidizes alkyl carboxylic acid to generate alkyl radicals by decarboxylation under light, and then C-3 alkylation reaction occurs with quinoxalin-2(1H)-one to prepare the C3-alkyl-substituted quinoxalin-2(1H)-one compound I. The method is green, simple, efficient, has few side reactions, has high product purity, is convenient for separation and purification, has a wide applicable range of substrates, raw materials are simple and easy to obtain, has low cost, the heterogeneous photocatalyst is non-toxic and can be recycled and used, is suitable for industrialized preparation, and has very good application prospect.

Description

Technical Field

[0001] This invention belongs to the field of organic chemistry technology, specifically relating to a method for preparing C3-alkyl-substituted quinoxalonone compounds under heterogeneous photocatalysis. Background Technology

[0002] Nitrogen-containing heterocyclic compounds are not only widely found in natural products and drug molecules, but compounds containing this core structure are also widely used in medicine, pesticides, and industrial dyes. Among them, quinoxaline-2(1 H )-ketones are extensively studied by chemists as extremely important drug skeletons. Among them, quinoxaline-2(1) modified by C3 is particularly important. H )-Ketones can modulate the biological activity of quinoxalinones, including their role as in vitro antibacterial and antitumor agents, caroverine, antibacterial agents, and VEGFR-2 kinase inhibitors. For example, caroverine, as a class B calcium channel blocker and antiglutamate drug, has significant effects on brain function (Yoshihisa Kudo & Shoji Shibata, Br. J. Pharmac. 1984, 83 , 813-820 Kinin B1 can treat inflammation and pain caused by sepsis (JJ Chen, W. Qian, K. Biswas, VNViswanadhan, BC Askew, S. Hitchcock, RW Hungate, L. Arik and E. Johnson). Bioorg. Med. Chem. Lett. , 2008, 18 , 4477), while GW420867X is a non-nucleoside HIV-1 reverse transcriptase inhibitor (LM Cass, KHP Moore, NS Dallow, AE Jones, JR Sisson and WT Prince, J. Clin. Pharmacol. , 2001, 41 , 528).

[0003] Due to quinoxaline-2(1 H )-Ketones possess these broad biological activities and potential applications, and chemists continue to strive to develop compounds based on quinoxaline-2(1) H Novel structures of quinoxaline-2(1-ketone skeletons and synthetic methods for their derivatives. Recently, in 2021, Professor Sun Peipei's research group reported a method for synthesizing quinoxaline-2(1-ketone skeletons) directly from α-amino acids. H) ketone (Yifan Li, Changhui Dai, Shentong Xie, Ping Liu, and Peipei Sun, Org. Lett. 2021, 23 , 5906−5910). Meanwhile, Sudipta Raha Roy accomplished the decarboxylative alkylation of quinoxaline-2(1 H )-ketone using cerium trichloride via photoinduced photocatalytic cleavage (Swati Singh, Neha Dagar, and Sudipta Raha Roy, Chem. Commun. , 2022, 58, 3831-3834 ). Although the alkylation, arylation, acylation, phosphonation, amination and trifluoromethylation of quinoxaline-2(1 H )-ketone at C3 position using homogeneous photocatalysts have been reported, there are still many limitations, such as expensive transition metal catalysts, high temperature and peroxides. There is no report on the alkylation of quinoxaline-2(1 H )-ketone at C3 position mediated by green non-toxic recyclable heterogeneous photocatalysts.

[0004] Based on this, the present application provides a new technology for efficiently and greenly synthesizing C3-alkylated quinoxaline-2(1 H )-ketone derivatives by using heterogeneous photocatalyst graphite phase carbon nitride to avoid the use of metal catalysts polluting the environment, and using carboxylic acid oxidation decarboxylation as a radical source under room temperature illumination. This method avoids high temperature and other complex operations, reduces reaction cost and energy consumption, and achieves the purpose of green chemical synthesis. SUMMARY

[0005] The present application aims to provide a green, simple and efficient method for preparing C3-alkylated quinoxaline-2(1 H )-ketone derivatives.

[0006] The present application provides a method for preparing C3-alkylated quinoxaline-2(1 H )-ketone derivatives, which uses graphite phase carbon nitride as a heterogeneous photocatalyst to efficiently synthesize C3-alkylated quinoxaline-2(1 H )-ketone derivatives by using alkyl carboxylic acid decarboxylation photooxidation as an alkyl radical source.

[0007] Specifically, the method of the present application is to use heterogeneous photocatalyst graphite phase carbon nitride (g-C3N4) in an organic solvent (such as dimethyl sulfoxide) in the presence of a base (such as cesium carbonate), and under light irradiation, the alkyl carboxylic acid is oxidized to decarboxylate to generate alkyl radicals; then, C-3 alkylation reaction with quinoxaline-2(1 H )-ketone occurs to efficiently obtain quinoxaline-2(1 H )-ketone compounds I, and the reaction formula is as follows:

[0008]

[0009] wherein

[0010] R 2 The C3 alkylation reaction of quinoxaline ketone compounds has relatively small influence, and the substitution position can be any position on the benzene ring that can be substituted, and the selection range is wide, such as hydrogen, alkyl, alkoxy, nitro, ester, halogen substituent or trifluoromethyl, etc. 2 When the alkyl is selected, the alkyl is C1-C8 alkyl, which can be a straight-chain alkyl or a branched-chain alkyl, or a cyclic alkyl, and specific examples include methyl, ethyl, butyl, isopropyl, cyclohexyl, etc. 2 When the alkoxy is selected, the alkoxy is C1-C8 alkoxy, such as methoxy, ethoxy, isobutoxy, etc. 2 When the halogen substituent is selected, the halogen substituent is fluorine, chlorine or bromine.

[0011] R 3 is a C3-substituted group, which can be selected as C1-C8 alkyl, which can be a straight-chain alkyl or a branched-chain alkyl, or a cyclic alkyl, and specific examples include methyl, ethyl, butyl, isopropyl, cyclohexyl, etc.

[0012] The specific steps of the method of the present application are as follows:

[0013] (1) In a reaction tube, quinoxaline-2(1 H )-ketone, carbon nitride photocatalyst, base, oxygen and organic solvent are sequentially added, and then the reaction substrate carboxylic acid is added, and stirring is performed under visible light irradiation for 12-24 hours until complete reaction is detected by TLC;

[0014] (2) The reaction solution is washed with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried, concentrated and column chromatography separated to obtain the corresponding C3-alkylated quinoxaline-2(1 H )-ketone derivative compound I.

[0015] The above reaction yield is 72-90%.

[0016] The structure of the compound is verified by 1 H NMR,13 C NMR, HRMS and other methods to characterize and confirmed.

[0017] In the present application, in step (1), the organic solvent used in the reaction system is DMSO, DMF, MeCN, DCE;

[0018] In the present application, the base used in the reaction system is Cs2CO3, K2CO3, K3PO4, based on quinoline-2(1 H )-ketone is 1.0 equivalent, the amount of base is 1.0 ~ 3.0 equivalent.

[0019] In the present application, based on quinoline-2(1 H )-ketone is 1.0 equivalent, the amount of catalyst g-C3N4 used in the reaction system is 10 ~ 40 wt%, preferably 20 wt%.

[0020] In the present application, based on quinoline-2(1 H )-ketone is 1.0 equivalent, the amount of alkyl carboxylic acid used in the reaction system is 1.5-3.0 equivalent, preferably 2.0 equivalent.

[0021] In the present application, the reaction system is irradiated under visible light at room temperature for 12 ~ 24 hours, and the visible light is preferably blue light source.

[0022] The method of the present application has the advantages of simple and efficient reaction, less side reaction, high product purity, easy separation and purification, mild conditions, wide range of substrate application, simple and readily available raw materials, low cost, non-toxic heterogeneous photocatalyst and recyclable use, suitable for industrial scale preparation, and has very good application prospect. DETAILED DESCRIPTION

[0023] Example 1: Catalyst preparation

[0024] A certain amount of urea was dispersed in an alumina crucible, and the volume of urea occupied 1 / 2 of the volume of the crucible; then it was moved into a muffle furnace, and the parameter settings were as follows: heating rate 5℃ / min, rising to 550℃, holding for 3h; then natural cooling, to obtain a light yellow C3N4 precursor, which was a light yellow solid powder. The obtained light yellow solid powder was dispersed in an alumina crucible and placed stably in a muffle furnace, and the parameter settings were as follows: heating rate 5℃ / min, rising to 550℃, holding for 3h; then natural cooling, to obtain a second calcined heterogeneous carbon nitride catalyst.

[0025] Example 2

[0026]

[0027] A reaction tube was charged with catalyst carbon nitride (10 mg), cesium carbonate (2.0 equiv), quinoxaline-2(l H )-one (0.2 mmol, 1.0 equiv) and solvent dimethyl sulfoxide (4 mL), followed by the addition of the reaction substrate 2-aminobenzyl bromide (2.0 equiv) and irradiated with blue light at room temperature for 12 ~ 24 hours until complete reaction was detected by TLC. The reaction was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried, concentrated and separated by column chromatography to give the corresponding quinoxaline-2(l H )-one derivative compound Ia.

[0028] 1 H NMR (400 MHz, CDCl3): δ 7.81 (d, J = 8.5 Hz, 1H), 7.48 (t, J = 7.9Hz, 1H), 7.33 – 7.21 (m, 2H), 3.67 (s, 3H), 3.37-3.25 (m, 1H), 1.97-1.89 (m,2H), 1.88-1.79 (m, 2H), 1.78-1.68 (m, 1H), 1.61-1.36 (m, 4H), 1.35-1.21 (m,1H). 13 C NMR (100 MHz, CDCl3) δ164.4, 154.6, 133.0, 132.9, 129.8, 129.5,123.5, 113.6, 40.8, 30.6, 29.2, 26.4, 26.2.

[0029] Example 3

[0030]

[0031] A reaction tube was charged with catalyst carbon nitride (10 mg), cesium carbonate (2.0 equiv), quinoxaline-2(l H )-one (0.2 mmol, 1.0 equiv) and solvent dimethyl sulfoxide (4 mL), followed by the addition of the reaction substrate N-(2-chlorobenzyloxycarbonyl)-L-ornithine (2.0 equiv) and irradiated with blue light at room temperature for 12 ~ 24 hours until complete reaction was detected by TLC. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried, concentrated and separated by column chromatography to give the corresponding quinoxaline-2(l H )-one derivative compound Ib.

[0032] 1 H NMR (400 MHz, CDCl3): δ 7.82 (d,J = 8.2 Hz, 1H), 7.58-7.48 (m, 1H), 7.41-7.26 (m, 4H), 7.23-7.16 (m, 2H), 5.88 (d, J = 9.1 Hz, 1H), 5.28-5.05 (m, 4H), 3.66 (s, 3H), 3.27 (s, 2H), 2.00-1.91 (m, 2H), 1.74-1.64 (m,3H), 1.43 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ 158.5, 156.3, 155.7, 153.9,134.6, 133.4, 133.3, 132.2, 130.5, 130.1, 129.5, 129.5, 129.2, 126.9, 126.9,126.9, 123.9, 113.8, 79.5, 63.8, 52.1, 40.6, 31.6, 29.2, 28.5, 26.1.HRMScalcd for C 26 H 32 N4O5Cl (M + +H): 515.2061, found: 515.2078.

[0033] Example 4

[0034]

[0035] In a reaction tube, catalyst melon (10 mg), cesium carbonate (2.0 eq), quinoxaline-2(l H )-one (0.2 mmol, 1.0 eq) and solvent dimethyl sulfoxide (4 mL) were added in sequence, followed by the addition of the reaction substrate cyclohexyl formic acid (2.0 eq), and irradiated with blue light at room temperature for 12 ~ 24 hours until complete reaction was detected by TLC. The reaction solution was washed with water, extracted with ethyl acetate, dried, concentrated and separated by column chromatography to obtain the corresponding quinoxaline-2(l H )-one derivative compound Ic

[0036] 1H NMR (400 MHz, CDC13): δ 7.62 (dd, J = 10.5, 8.2 Hz, 1H), 7.05 (dd, J = 11.4, 7.0 Hz, 1H), 3.62 (s, 3H), 3.33-3.22 (m, 1H), 1.95 - 1.85 (m, 2H), 1.87-1.79 (m, 2H), 1.77-1.67 (m, 1H), 1.55-1.35 (m, 4H), 1.33-1.20 (m, 1H). 19 F NMR (376 MHz, CDC13): δ -132.14, -132.16, -132.20, -132.23, -132.26, -142.55, -142.56, -142.60, -142.63, -142.65. 13 C NMR (100 MHz, CDC13) δ 164.9, 154.2, 152.3, 152.1, 149.7, 149.6, 147.9, 147.7, 145.4, 145.3, 130.1, 130.0, 129.2, 117.5, 117.4, 102.3, 102.0, 40.8, 30.5, 29.7, 26.3, 26.2.

Claims

1. A method for preparing C3-alkyl-substituted quinoxalinone compounds under heterogeneous photocatalysis, characterized in that... In an organic solvent, a g-C3N4 photocatalyst is used. Under alkaline conditions and light irradiation, alkyl carboxylic acids undergo oxidative decarboxylation to generate alkyl radicals; subsequently, they react with quinoxaline-2(1 H The )-ketone undergoes a C-3 alkylation reaction to yield C3 alkyl-substituted quinoxaline-2(1) H )-Ketone derivative compound I, its reaction formula is: ， in, R 1 It can be hydrogen, alkyl, or aryl; R 2 The substituents can be hydrogen, alkyl, alkoxy, nitro, ester, halogen, or trifluoromethyl. R 2 When selecting an alkyl group, the alkyl group must be a C1 to C8 alkyl group; R 2 When choosing an alkoxy group, the alkoxy group is a C1 to C8 alkoxy group; R 2 When choosing a halogen substituent, the halogen substituent can be fluorine, chlorine, or bromine; R 2 When choosing an ester group, the ester group is a methyl ester group; R 3 It is a C1 to C8 alkyl group, wherein the alkyl group is a straight-chain alkyl group, a branched alkyl group, or a cyclic alkyl group.

2. The preparation method according to claim 1, characterized in that... The specific steps are as follows: (1) Add quinoxaline-2(1) to the reaction tube sequentially. H The reaction mixture consisted of ketone, g-C3N4 photocatalyst, base, oxygen, and organic solvent, followed by the addition of the alkyl carboxylic acid substrate. The mixture was stirred under visible light for 12-24 hours until the reaction was complete as detected by TLC. (2) The reaction solution was washed with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, dried, concentrated and separated by column chromatography to obtain the corresponding quinoxaline-2(1H)-ketone derivatives.

3. The preparation method according to claim 2, characterized in that... The g-C3N4 reaction should be carried out in at least one of the following media: DMSO, DMF, MeCN, and DCE; with quinoxaline-2(1 H The amount of ketone compounds is 1.0 equivalent, the amount of base is 1.0 to 3.0 equivalent, the amount of the heterogeneous photocatalyst g-C3N4 is 10 to 40 wt%, and the amount of alkyl carboxylic acid is 1.5 to 3.0 equivalent; the base is Cs2CO3, K2CO3 or K3PO4.

4. A quinoxaline-2(1) according to claim 3 H A method for preparing ketone compounds, characterized in that: The photocatalytic reaction is carried out under light irradiation at room temperature for 12 to 24 hours. The photocatalytic reaction uses a white LED light source with a power of 3W to 24W and a blue LED light source with a power of 3W to 24W.

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