Preparation method of C3-site alkyl substituted quinoxalinone compound under heterogeneous photocatalysis

Abstract

The invention belongs to the technical field of organic chemistry, and particularly relates to a preparation method of a heterogeneous photocatalytic C3-site alkyl substituted quinoxalinone compound. The structure of the compound is represented and confirmed by methods such as 1H NMR (nuclear magnetic resonance), 13C NMR (nuclear magnetic resonance), HRMS (high resolution mass spectrometry) and the like. According to the method, graphite phase carbon nitride is used as a heterogeneous photocatalyst in an organic solvent, in the presence of alkali and oxygen, under illumination, the graphite phase carbon nitride oxidizes alkyl carboxylic acid for decarboxylation to generate alkyl free radicals, then the alkyl free radicals and quinoxaline-2 (1H)-ketone are subjected to a C-3 alkylation reaction, and the C3 alkyl substituted quinoxaline-2 (1H)-ketone compound I is prepared. The method is green, simple and efficient in reaction, few in side reaction, high in product purity and convenient to separate and purify; conditions are mild, and the application range of a substrate is wide; the raw materials are simple and easy to obtain, the cost is low, the heterogeneous photocatalyst is non-toxic and can be recycled, and the method is suitable for industrial-scale preparation and has a very good application prospect.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemistry, and specifically relates to a method for preparing C3 alkyl-substituted quinoxalinone compounds under heterogeneous photocatalysis. Background Art

[0002] Nitrogen-containing heterocyclic compounds are not only widely present in natural products and drug molecules, but also compounds containing the parent nucleus structure are widely used in medicine, pesticides, industrial dyes and many other aspects. Among them, quinoxaline-2 (1H) -one is widely studied by chemists as an extremely important drug skeleton. Among them, quinoxaline-2 (1H) -one modified by C3 can regulate the characteristics of quinoxaline ketone biological activity, including in vitro antibacterial, antitumor agent, caroverine, antibacterial agent, VEGFR-2 kinase inhibitor. For example, caroverine, as a class B calcium channel blocker and anti-glutamate drug, has a significant effect 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, VN Viswanadhan, 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, NSDallow, AE Jones, JRSisson and W.T. Prince, J. Clin. Pharmacol., 2001, 41, 528).

[0003] Because quinoxaline-2 (1H) -one compounds have these extensive biological activities and potential applications, chemists continue to work hard to develop new structures based on quinoxaline-2 (1H) -one skeletons and synthetic methods for their derivatives. Recently, Sun Peipei's research group reported in 2021 the direct decarboxylation C3 alkylation of quinoxaline-2 (1H) -one by α-amino acids (Yifan Li, Changhui Dai, Shentong Xie, Ping Liu, and Peipei Sun, Org. Lett. 2021, 23, 5906-5910). At the same time, Sudipta Raha Roy used cerium trichloride to complete the decarboxylation alkylation of quinoxaline-2 (1H) -one by light-induced photocatalytic cleavage (Swati Singh, Neha Dagar, and Sudipta Raha Roy, Chem. Commun., 2022, 58, 3831-3834). Although there are reports on the alkylation, arylation, acylation, phosphation, amination and trifluoromethylation of quinoxaline-2(1H)-one at C3 using homogeneous photocatalysts, there are still many limitations, such as expensive transition metal catalysts, high temperatures and peroxides. However, there are no reports on the alkylation of quinoxaline-2(1H)-one compounds at C3 using green, non-toxic and recyclable heterogeneous photocatalysts.

[0004] Based on this, the present invention uses heterogeneous photocatalyst graphite phase carbon nitride to avoid the use of environmentally polluting metal catalysts, and oxidative decarboxylation of carboxylic acids under room temperature illumination as a source of free radicals, providing a new technology for the efficient, green and non-toxic synthesis of C3-alkylated quinoxaline-2(1H)-one derivative compounds. High temperature and other complicated operations are avoided, and the reaction cost and energy consumption are reduced, while the efficiency of the high reaction is improved to achieve the purpose of green chemical synthesis. Summary of the invention

[0005] The present invention aims to provide a green, simple and efficient method for preparing C3 alkyl-substituted quinoxaline-2(1H)-one derivative compounds.

[0006] The invention provides a method for preparing C3 alkyl-substituted quinoxaline-2(1H)-one derivative compounds, which utilizes heterogeneous photocatalyst graphite phase carbon nitride to photo-oxidize alkyl carboxylic acid decarboxylation as a source of alkyl free radicals to efficiently synthesize C3 alkyl-substituted quinoxaline-2(1H)-one derivative compounds.

[0007] Specifically, the method of the present invention uses a heterogeneous photocatalyst graphite phase carbon nitride (gC nitride) in an organic solvent (such as dimethyl sulfoxide) 3 N 4), in the presence of a base (such as cesium carbonate), the alkyl carboxylic acid is oxidized under light and decarboxylated to generate an alkyl free radical; then, the alkyl carboxylic acid undergoes a C-3 alkylation reaction with quinoxaline-2(1H)-one to efficiently obtain quinoxaline-2(1H)-one compound I, and the reaction formula is:

[0008]

[0009] in

[0010] R 2 The effect on the alkylation reaction of C3 position of quinoxalinone compounds is relatively small. The substitution position can be any position on the benzene ring, and the selection range is relatively wide, such as hydrogen, alkyl, alkoxy, nitro, ester, halogen substituent or trifluoromethyl. 2 When an alkyl group is selected, the alkyl group is C 1 ~C 8 The alkyl group may be a straight-chain alkyl group or a branched alkyl group, or a cyclic alkyl group, such as methyl, ethyl, butyl, isopropyl, cyclohexyl, etc.; R 2 When an alkoxy group is selected, the alkoxy group is C 1 ~C 8 Alkoxy groups, such as methoxy, ethoxy, isobutoxy, etc.; R 2 When a 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 C 1 ~C 8 The alkyl group may be a straight-chain alkyl group or a branched alkyl group, or a cyclic alkyl group, such as methyl, ethyl, butyl, isopropyl, cyclohexyl, etc.

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

[0013] (1) Adding quinoxaline-2(1H)-one, carbon nitride photocatalyst, base, oxygen and organic solvent to a reaction tube in sequence, and then adding the reaction substrate carboxylic acid, stirring for 12-24 hours under visible light irradiation until the reaction is complete by TLC detection;

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

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

[0016] The structure of this class of compounds 1 H NMR, 13The product was characterized and confirmed by C NMR and HRMS.

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

[0018] In the present invention, the base used in the reaction system is Cs 2 CO 3 , K 2 CO 3 , K 3 PO 4 , based on 1.0 equivalent of quinoxaline-2(1H)-one, the amount of the base used is 1.0 to 3.0 equivalents.

[0019] In the present invention, based on 1.0 equivalent of quinoxaline-2(1H)-one, the catalyst gC used in the reaction system is 3 N 4 The dosage is 10-40wt%, preferably 20wt%.

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

[0021] In the present invention, the reaction system is reacted at room temperature for 12 to 24 hours under visible light irradiation, and the visible light is preferably a blue light source.

[0022] The method of the invention has simple and efficient reaction, few side reactions, high product purity, and is easy to separate and purify; the conditions are mild, and the applicable range of the substrate is wide; the raw materials are simple and easy to obtain, the cost is low, the heterogeneous photocatalyst is non-toxic and can be recycled and reused, it is suitable for industrial-scale preparation, and has very good application prospects. DETAILED DESCRIPTION

[0023] Example 1: Catalyst preparation

[0024] A certain amount of urea was dispersed in an alumina crucible, with the volume of urea occupying 1 / 2 of the crucible volume; then, it was moved into a muffle furnace, and the parameters were set as follows: heating rate 5℃ / min, rising to 550℃, keeping warm for 3h; then naturally cooling, and a light yellow C 3 N 4 The precursor is a light yellow solid powder. The obtained light yellow solid powder is dispersed in an alumina crucible and stably placed in a muffle furnace. The parameters are set as follows: heating rate 5°C / min, rising to 550°C, keeping warm for 3 hours; then naturally cooling, to obtain a secondary calcined graphite phase carbon nitride catalyst.

[0025] Example 2

[0026]

[0027] Catalyst graphite carbon nitride (10 mg), cesium carbonate (2.0 equivalents), quinoxaline-2(1H)-one (0.2 mmol, 1.0 equivalents) and solvent dimethyl sulfoxide (4 mL) were added in sequence to a reaction tube, followed by addition of reaction substrate cyclohexylcarboxylic acid (2.0 equivalents). The mixture was irradiated with blue light at room temperature for 12 to 24 hours until the reaction was complete as detected by TLC. The reaction solution was washed with a saturated sodium bicarbonate solution, extracted with ethyl acetate, dried, concentrated and separated by column chromatography to obtain the corresponding quinoxaline-2(1H)-one derivative compound Ia.

[0028] 1 H NMR (400 MHz, CDCl 3 ): δ7.81(d,J=8.5Hz,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, CDCl 3 )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] Catalyst graphite carbon nitride (10 mg), cesium carbonate (2.0 equivalents), quinoxaline-2(1H)-one (0.2 mmol, 1.0 equivalents) and solvent dimethyl sulfoxide (4 mL) were added in sequence to a reaction tube, followed by addition of reaction substrate N-(2-chlorobenzyloxycarbonyl)-L-ornithine (2.0 equivalents). The mixture was irradiated with blue light at room temperature for 12 to 24 hours until the reaction was complete as 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(1H)-one derivative compound Ib.

[0032] 1 H NMR (400 MHz, CDCl 3): δ7.82(d,J=8.2Hz,1H),7.58-7.48(m,1H),7.41-7.26(m,4H),7.23-7.16(m,2H),5.88(d,J=9.1Hz, 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, CDCl 3 )δ158.5,156.3,155.7,153.9,134.6,133.4,133.3,132.2,130.5,130.1,129.5,129.5,129.2 ,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 N 4 O 5 Cl(M + +H):515.2061,found:515.2078.

[0033] Example 4

[0034]

[0035] Catalyst graphite carbon nitride (10 mg), cesium carbonate (2.0 equivalents), quinoxaline-2(1H)-one (0.2 mmol, 1.0 equivalents) and solvent dimethyl sulfoxide (4 mL) were added to the reaction tube in sequence, and then the reaction substrate cyclohexylcarboxylic acid (2.0 equivalents) was added. The mixture was irradiated with blue light at room temperature for 12 to 24 hours until the reaction was complete as 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(1H)-one derivative compound Ic

[0036] 1 H NMR (400 MHz, CDCl 3 ): δ7.62(dd,J=10.5,8.2Hz,1H),7.05(dd,J=11.4,7.0Hz,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). 19F NMR(376MHz,CDCl 3 ):δ-132.14,-132.16,-132.20,-132.23,-132.26,-142.55,-142.56,-142.60,-142.63,-142.65. 13 C NMR(100MHz,CDCl 3 )δ164.9,154.2,152.3,152.1,149.7,149.6,147.9,147.7,145.4,145.3,130.1,130.0,129.2,117.5,117.4,102.3,102.0,40.8,30.5,29.7,26.3,26.2。

Claims

1. A method for preparing C3 alkyl-substituted quinoxalinone compounds under heterogeneous photocatalysis. Features The method uses a heterogeneous carbon nitride photocatalyst in an organic solvent. In the presence of a base, an alkyl carboxylic acid undergoes oxidative decarboxylation under light to generate an alkyl free radical; then a C-3 alkylation reaction occurs with quinoxaline-2(1H)-one to obtain a C3 alkyl-substituted quinoxaline-2(1H)-one derivative compound I. The reaction formula is: in, R 1 is hydrogen, alkyl or aryl; R 2 independently selected from hydrogen, alkyl, alkoxy, nitro, ester, halogen substituent or trifluoromethyl; R 2 When an alkyl group is selected, the alkyl group is C 1 ~C 8 Alkyl; R 2 When an alkoxy group is selected, the alkoxy group is C 1 ~C 8 Alkoxy; R 2 When a halogen substituent is selected, the halogen substituent is fluorine, chlorine, or bromine; R 2 When an ester group is selected, the ester group is a methyl ester group; R 3 An alkyl group.

2. The preparation method according to claim 1, Features The specific steps are as follows: (1) Adding quinoxaline-2(1H)-one, carbon nitride photocatalyst, base, oxygen and organic solvent to a reaction tube in sequence, and then adding the reaction substrate carboxylic acid, stirring for 12-24 hours under visible light irradiation until the reaction is complete by TLC detection; (2) The reaction solution was washed with a saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, dried, concentrated and separated by column chromatography to obtain the corresponding quinoxaline-2(1H)-one derivative compound.

3. The preparation method according to claim 2, Features The photocatalytic reaction is carried out in at least one reaction medium of DMSO, DMF, MeCN and DCE; based on 1.0 equivalent of the quinoxaline-2(1H)-one compound, the amount of the base is 1.0 to 3.0 equivalents, the heterogeneous photocatalyst is 10 to 40 wt% of graphite phase carbon nitride, and the amount of the carboxylic acid is 1.5 to 3.0 equivalents; the base is Cs 2 CO 3 , K 2 CO 3 or K 3 PO 4 .

4. A method for preparing a quinoxaline-2(1H)-one compound according to claim 3, Features: The conditions of the visible light catalytic reaction are: reacting at room temperature for 12 to 24 hours under visible light irradiation. The visible light catalytic reaction uses an LED white light source with a power of 3W to 24W and a blue light source with a power of 3W to 24W.

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