Method for synthesizing C-3 substituted quinoxalinone derivative
By using the anioxopropane derivative as a radical precursor, the problem of slow progress in direct alkylation reaction of quinoxalinone was solved, and the efficient synthesis of C-3-position alkylated quinoxalinone derivatives was achieved, which broadened the selectivity of alkyl radical precursors and simplified the operation process.
Patent Information
- Application Number
- CN202510514103.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-04-23
- Publication Date
- 2025-08-01
AI Technical Summary
Research on direct alkylation reaction of quinoxalinone in the prior art has progressed slowly, and the types of alkyl radical precursors are insufficient, which limits the molecular diversity of quinoxalinone derivatives.
The C-3-position alkylation of quinoxalinone was prepared by using the nitrogen-oxalinone derivative as a radical precursor under the action of a catalyst through a single electron redox reaction to prepare the C-3-substituted quinoxalinone derivative.
The optional types of alkyl radical precursors have been broadened, with short reaction time, high yield, simple operation, wide application range, and simple, providing a simple and efficient synthesis strategy.
Smart Images
Figure CN120398774A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the field of chemical technology, and particularly relates to a method for synthesizing C-3 substituted quinoxalinone derivatives. Background Art
[0002] The quinoxalinone skeleton widely exists in natural products and drug molecules, and has pharmacological activities such as anti-cancer, antibacterial, and anti-thrombotic, and has broad application prospects in the fields of medicine and pesticides. The C-H bond functionalization reaction of quinoxalinone can efficiently introduce various functional groups, thereby preparing quinoxalinone skeleton compounds with novel structures.
[0003] Currently, in the free radical-mediated C-3 position C-H bond functionalization reaction of quinoxalinone, transition metal-catalyzed or photocatalyzed arylation, amination, acylation, phosphonylation, and polyfluoroalkylation reactions of quinoxalinone can all obtain C3-functionalized quinoxalinone products with high selectivity and high yield. In contrast, the research progress of the direct alkylation reaction of quinoxalinone is relatively slow. According to the difference in the types of alkyl radical precursors, the realized alkylation reactions can be classified into the following categories: 1) The single-electron reduction of cheap metals or photocatalyzed cyclic ketoxime esters generates cyanoalkyl radicals to achieve the cyanoalkylation reaction of quinoxalinone; 2) The oxygen radical-promoted carbon-carbon bond cleavage reaction of cyclic alcohols and cyclic alkyl peroxylsilanes generates ketoalkyl radicals, and then the ketoalkylation reaction of quinoxalinone is achieved; 3) The C-H bond adjacent to oxygen is oxidized by peroxide to obtain alkyl radicals, and then the alkylation reaction of quinoxalinone is achieved; 4) Aliphatic boronic acids, aliphatic carboxylic acids, and redox-active esters obtain alkyl radicals through a single-electron oxidation or reduction process under photocatalysis or electrocatalysis, and the C-H bond alkylation conversion of quinoxalinone is achieved. Although the above free radicals can realize the preparation of alkylated quinoxalinone compounds, the types of available alkyl radical precursors are far from sufficient, which greatly limits the molecular diversity of quinoxalinone derivatives. Therefore, it is very urgent to explore novel and green alkyl radical precursors to generate alkyl radicals containing active groups under mild conditions and attack quinoxalinone to form alkyl-substituted quinoxalinone derivatives. Summary of the Invention
[0004] To overcome the above technical defects, the purpose of the present invention is to provide a method for synthesizing C-3 substituted quinoxalinone derivatives. The synthesis method provided by the present invention, through radical-mediated C-3 alkylation, uses nitrogen-containing heterocyclopropane derivatives as radical precursors, and under the action of catalysts and the like, simply, efficiently, and inexpensively prepares C-3 substituted quinoxalinone derivatives.
[0005] To achieve the above purpose, the present invention adopts the following technical solutions:
[0006] The present invention provides a method for synthesizing C-3 substituted quinoxalinone derivatives, comprising the following steps:
[0007] Reacting a quinoxalinone derivative with a nitrogen-containing heterocyclic propane derivative under the action of a catalyst and an organic base;
[0008] The structure of the quinoxalinone derivative is shown in Formula I:
[0009]
[0010] In Formula I, R1 is selected from any one of alkyl groups having 1 to 5 carbon atoms; R2 is selected from any one of H, halogen, and alkoxy groups, and the alkoxy group has 1 to 2 carbon atoms; R3 is selected from any one of H and halogen; the halogen is F, Cl, or Br;
[0011] The structure of the nitrogen-containing heterocyclic propane derivative is shown in Formula II:
[0012]
[0013] In Formula II, is a divalent cycloalkyl group having 5 to 8 carbon atoms; R4 is selected from at least one of H and alkyl groups having 1 to 2 carbon atoms. When R4 is an alkyl group having 1 to 2 carbon atoms, the position and number of carbon atoms substituted on are not particularly limited, and it can be mono-substituted or multi-substituted. When multi-substituted, R4 can be the same or different, and can be substituted on the same carbon atom or different carbon atoms.
[0014] In the technical solution of the present invention, has 5, 6, 7, or 8 carbon atoms.
[0015] Preferably, the catalyst is a copper salt catalyst; in some specific embodiments, the copper salt catalyst can include CuI, CuSCN, CuSO4, CuCl2, CuCl, Cu(MeCN)4BF4, etc.
[0016] And / or, a ligand is further added to the reaction, and the ligand is selected from at least one of in the formula.
[0017] And / or, the organic base is 4-dimethylaminopyridine (DMAP).
[0018] Preferably, the molar ratio of the quinoxalinone derivative to the nitrogen-containing heterocyclic propane derivative is 1:(1.2 - 1.5).
[0019] And / or, the molar ratio of the quinoxalinone derivative to the catalyst is 1:(0.05 - 0.10).
[0020] And / or, the molar ratio of the quinoxalinone derivative to the ligand is 1:(0.06-0.20).
[0021] And / or, the molar ratio of the quinoxalinone derivative to the organic base is 1:(1.9-2.1).
[0022] And / or, the reaction is carried out in a solvent; the solvent is selected from methanol.
[0023] And / or, the reaction time is 12 to 18 hours.
[0024] And / or, the reaction is carried out in an inert atmosphere, such as nitrogen.
[0025] Preferably, the preparation method of the quinoxalinone derivative comprises the following steps:
[0026] Will and ethyl glyoxylate in ethanol at 85-95°C for 1-1.5h to obtain
[0027]
[0028] Will and R1I in N,N-dimethylformamide under the action of a base for 12 to 15 hours to obtain the quinoxalinone derivative.
[0029] and / or, The molar ratio of ethyl glyoxylate is 1:(1-1.2).
[0030] and / or, The molar ratio of R1I to R1I is 1:(1.4~1.8).
[0031] And / or, the base is potassium carbonate.
[0032] Preferably, the preparation method of the aziridine derivative comprises the following steps:
[0033] Will and cyclohexylamine in toluene at 115-120°C reflux for 7-12h to obtain
[0034] Will and m-chloroperbenzoic acid at -80 to -70°C for 0.5 to 2h to obtain the aziridine derivative.
[0035] and / or, The molar ratio of cyclohexylamine is 1: (1.0-1.1).
[0036] and / or, The molar ratio of benzoic acid to m-chloroperbenzoic acid is 1:(2.0-2.2).
[0037] In certain specific embodiments, the quinoxalinone derivatives may specifically include:
[0038]
[0039] In certain specific embodiments, the aziridine N-oxides may include:
[0040]
[0041] Compared with the prior art, the present invention has the following advantages:
[0042] 1. The present invention uses an aziridine N-oxide with a special structure as an alkyl radical precursor. Under the action of a catalyst, a single-electron redox reaction occurs, causing the N-O bond to break, and then through a selective cleavage reaction of the carbon-carbon bond, an alkyl radical containing an amide group is obtained, which then reacts with quinoxalinone. This broadens the optional types of alkyl radical precursors, and has a short reaction time, high yield, simple operation, simple components and easy separation, and a wide application range.
[0043] 2. The preparation method provided by the present invention realizes the synthesis of C-3 alkylated quinoxalinone derivatives by regulating the catalyst, ligand, additive, solvent, etc. The reaction has good generality and provides a simple and efficient strategy for the synthesis of natural products and drug molecules containing such structures. BRIEF DESCRIPTION OF THE DRAWINGS
[0044] Figure 1-2 are the 1H NMR and 13C NMR spectra of the synthesis product of Example 1.
[0045] Figure 3-4 are the 1H NMR and 13C NMR spectra of the product of Example 9.
[0046] Figure 5-7 are the 1H NMR, 13C NMR and 19F NMR spectra of the product of Example 10.
[0047] Figure 8-9 are the 1H NMR and 13C NMR spectra of the product of Example 11.
[0048] Figure 10-11 are the 1H NMR and 13C NMR spectra of the product of Example 12.
[0049] Figure 12-13 are the 1H NMR and 13C NMR spectra of the product of Example 13.
[0050] Figure 14-15 are the 1H NMR and 13C NMR spectra of the product of Example 14.
[0051] Figure 16-171H NMR and 13C NMR spectra of the product of Example 15. Detailed Description of the Invention
[0052] The following examples are only a part of the embodiments of the present invention, rather than all embodiments. Therefore, the detailed descriptions of the embodiments of the present invention provided below are not intended to limit the scope of the claimed invention, but merely represent selected embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative efforts belong to the protection scope of the present invention.
[0053] In the present invention, unless otherwise specified, all devices and raw materials can be purchased from the market or are commonly used in this industry. The methods in the following examples are conventional methods in this field unless otherwise specified.
[0054] Example 1
[0055] N-cyclohexyl-6-[N-methyl-3-quinoxalin-2(1H)-one]hexanamide was synthesized in this example, and the reaction equation is as follows:
[0056]
[0057] The specific steps are as follows:
[0058] N-methylquinoxalinone (0.2 mmol, 32.0 mg), 2-cyclohexyl-1-oxa-2-aza[2.5]octane (0.3 mmol, 58.5 mg), CuSO4 (5 mol%, 1.6 mg), 1,10-phenanthroline (10 mol%, 3.6 mg), and DMAP (0.4 mmol, 48.8 mg) were added to a reaction flask, and the air in the flask was replaced with N2 three times; under an N2 atmosphere, 2 mL of methanol was added to completely dissolve the reagents; the reaction was stirred at room temperature for 15 hours.
[0059] After the reaction was completed, the reaction mixture was concentrated by rotary evaporation to remove methanol, and the components were separated by column chromatography (PE:EA = 1:2). The solvent was removed by rotary evaporation to obtain 59.3 mg of the product, with a yield of 84%.
[0060] The structure of the product was characterized by Figure 1 1H NMR, Figure 2 13C NMR, and was determined to be N-cyclohexyl-6-[N-methyl-3-quinoxalin-2(1H)-one]hexanamide, and the structural formula is
[0061] Figure 1 : 11H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz, 1H), 7.51–7.44 (m, 1H), 7.32–7.23 (m, 2H), 5.51–5.41 (m, 1H), 3.78–3.67 (m, 1H), 3.66 (s, 3H), 2.90 (t, J = 7.6 Hz, 2H), 2.14 (t, J = 7.6 Hz, 2H), 1.90–1.80 (m, 2H), 1.80–1.72 (m, 2H), 1.71–1.60 (m, 4H), 1.60–1.52 (m, 1H), 1.48–1.38 (m, 2H), 1.35–1.25 (m, 2H), 1.15–1.10 (m, 3H).
[0062] Figure 2 : 13 13C NMR (100 MHz, CDCl3) δ 172.0, 160.9, 154.8, 133.0, 132.6, 129.53, 129.50, 123.5, 113.5, 47.9, 36.8, 34.0, 33.2, 29.0, 28.9, 26.2, 25.6, 25.5, 24.8.
[0063] Example 2 - 15
[0064] The synthesis process in Example 2 - 15 is the same as that in Example 1, except that the types and masses of the reaction raw materials, catalysts, and ligands are changed (the amount of substance remains unchanged). The specific types and yields are shown in Table 1:
[0065] Table 1
[0066]
[0067]
[0068] In Table 1:
[0069] The quinoxalinone derivatives 1a - 1f are as follows:
[0070]
[0071] The synthesis methods of the quinoxalinone derivatives 1a - 1f are as follows:
[0072]
[0073] The specific steps are as follows: Add o-phenylenediamine derivative M1 (1.0 eq, 5 mmol), ethyl glyoxylate (1.2 eq, 6 mmol) and ethanol (20 mL) into a 100 mL three-necked flask, reflux at 90 °C for about 1 h, and monitor by TLC during this period; after the reaction stops, filter and wash the filter cake with ethanol to obtain quinoxalinone derivative M2; after drying, weigh it, and add quinoxalinone derivative M2 and iodoalkane R1I into a round-bottom flask according to a molar ratio of 1:1.6, and add K2CO3 (1.2 eq), N,N-dimethylformamide (DMF, 20 mL), and stir at room temperature for 15 h; after the reaction is completed, extract with ethyl acetate and purify by column chromatography (the volume ratio of petroleum ether to ethyl acetate is 1:1) to obtain quinoxalinone derivatives 1a-1f.
[0074] The aziridine N-oxides 2a, 2g, 2h are as follows:
[0075]
[0076] The synthesis method of aziridine N-oxides 2a, 2g-2i, taking 2a as an example, is as follows:
[0077]
[0078] Specifically, it includes the following steps: Under a nitrogen atmosphere, add toluene (20 mL), cyclohexanone (20 mmol, 2.1 mL), cyclohexylamine (22 mmol, 2.6 mL) into a 100 mL three-necked flask, reflux at 120 °C for 7 h; after the reaction is completed, cool down and distill off toluene, and add meta-chloroperoxybenzoic acid (mCPBA, 2.2 eq, 7.6 g) dissolved in dichloromethane (DCM) in batches at -78 °C, and react for 2 h; after the reaction is completed, quench with sodium thiosulfate solution, filter, and purify the filtrate by distilling off DCM and then column chromatography (the volume ratio of petroleum ether to ethyl acetate is 100:1).
[0079] The ligands L1-L3 are as follows:
[0080]
[0081] The NMR spectra of the products 3a-3h are shown in Figure 3-17 , and the specific structures are as follows:
[0082]
[0083] It can be seen from the above examples that the present invention uses aziridine N-oxides with special structures as radical precursors to synthesize C-3 alkylated quinoxalinone derivatives containing amide bonds through radical-mediated reactions, which have the characteristics of simplicity, high efficiency, and good applicability.
[0084] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.
Claims
1. A method for synthesizing C-3 substituted quinoxalinone derivatives, characterized in that, It includes the following steps: React a quinoxalinone derivative and an aziridine N-oxide derivative under the action of a catalyst and an organic base; The structure of the quinoxalinone derivative is shown in Formula I: In Formula I, R1 is selected from any one of alkyl groups having 1 to 5 carbon atoms; R2 is selected from any one of H, halogen, and alkoxy groups, and the alkoxy group has 1 to 2 carbon atoms; R3 is selected from any one of H and halogen; the halogen is F, Cl, or Br; The structure of the aziridine N-oxide derivative is shown in Formula II: In formula II, is a divalent cycloalkyl group having 5 to 8 carbon atoms; R4 is selected from at least one of H and an alkyl group having 1 to 2 carbon atoms.
2. The method according to claim 1, characterized in that The catalyst is a copper salt catalyst; And / or, a ligand is further added to the reaction, and the ligand is selected from at least one of them; And / or, the organic base is 4-dimethylaminopyridine.
3. The method according to claim 2, wherein The molar ratio of the quinoxalinone derivative to the aziridine N-oxide derivative is 1:(1.2 - 1.5); And / or, the molar ratio of the quinoxalinone derivative to the catalyst is 1:(0.05 - 0.10); And / or, the molar ratio of the quinoxalinone derivative to the ligand is 1:(0.06 - 0.20); And / or, the molar ratio of the quinoxalinone derivative to the organic base is 1:(1.9 - 2.1).
4. The method according to claim 1, characterized in that The reaction is carried out in a solvent; the solvent is selected from methanol; And / or, the reaction time is 12 - 18 hours; And / or, the reaction is carried out in an inert atmosphere.
5. The method according to claim 1, wherein The preparation method of the quinoxalinone derivative includes the following steps: React with ethyl glyoxylate in ethanol under reflux at 85 - 95 °C for 1 - 1.5 h to obtain React with R1I in N,N-dimethylformamide in the presence of a base for 12 to 15 h to obtain the quinoxalinone derivative.
6. The method according to claim 5, characterized in that, The molar ratio with ethyl glyoxylate is 1:(1 to 1.2); and / or, The molar ratio of R1I to R1I is 1:(1.4-1.8); And / or, the base is potassium carbonate.
7. The method according to claim 1, wherein The preparation method of the aziridine N-oxide derivative includes the following steps: Mix with cyclohexylamine in toluene and reflux at 115 - 120 °C for 7 - 12 h to obtain React with m-chloroperoxybenzoic acid at -80 to -70 °C for 0.5 to 2 h to obtain the aziridine N-oxide derivative.
8. The method according to claim 7, wherein The said and cyclohexylamine has a molar ratio of 1:(1.0 to 1.1); and / or, said The molar ratio of and meta-chloroperbenzoic acid is 1:(2.0-2.2).
9. The method according to claim 1, wherein The quinoxalinone derivative is selected from any one of the following:
10. The method according to claim 1, characterized in that The aziridine N-oxide derivative is selected from any one of the following: