A method for preparing 3-alkylquinoxalin-2-(1h)-ones by phosphine mediation

Abstract

This invention discloses a phosphine-mediated method for preparing 3-alkylquinoxaline-2(1H)-one compounds, belonging to the field of organic synthesis technology. The method includes the following steps: using quinoxaline-2(1H)-one compounds and alkyl ketones as raw materials, adding them to an organic solvent in a certain proportion, and reacting at room temperature for 12-24 hours under argon protection in the presence of tertiary phosphine compounds and a base; after the reaction is complete, 3-alkylquinoxaline-2(1H)-one compounds are obtained by column chromatography purification. The raw materials of this invention are inexpensive and readily available, the reaction conditions are mild, the operation is simple, and no metal reagents, photocatalysts, or stoichiometric strong oxidants are required, providing a new method for the green synthesis of 3-alkylquinoxaline-2(1H)-one compounds.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing phosphine-mediated 3-alkylquinoxaline-2(1H)-one compounds. Background Technology

[0002] Quinoxalo-2(1H)-ones are an important class of nitrogen-containing heterocyclic compounds, widely found in various natural products, drug molecules, and functional materials. Among them, 3-alkylquinoxalo-2(1H)-ones, as a unique and advantageous structural unit, exhibit diverse and significant biological activities in antitumor, antiviral, antibacterial, anti-asthmatic, and antidiabetic fields (J. Med. Chem. 2001, 44, 594-601.; J. Med. Chem. 2015, 58, 1254-1267.; Mini-Rev. Med. Chem. 2018, 18, 392-413.). For example, compound A, as shown in the following structural formula, is used as a multidrug resistance antagonist; compound B, as an aldose reductase inhibitor, exhibits good activity in the treatment of diabetes; and compound C is an effective anti-asthmatic drug. Furthermore, 3-alkylquinoxalo-2(1H)-ones have also found wide applications in organic synthesis and the synthesis of advanced materials. Therefore, developing novel and simple synthetic methods for constructing 3-alkylquinoxaline-2(1H)-one compounds is of great research significance and has broad application prospects.

[0003]

[0004] Traditionally, the synthesis of 3-alkylquinoxaline-2(1H)-one compounds mainly relies on condensation and radical cyclization methods (Bioorg. Med. Chem. Lett. 2003, 13, 2297-2302.; J. Org. Chem. 2008, 73, 4721-4724.). However, these methods suffer from drawbacks such as the need for pre-functionalization of the substrate, cumbersome synthetic steps, and harsh reaction conditions, which severely hinder the widespread application and further development of these compounds. In recent years, the method of directly constructing 3-alkylquinoxaline-2(1H)-one compounds based on C3-H alkylation of quinoxaline-2(1H)-one has gradually become mainstream and has been greatly developed. Most of these methods involve the addition of alkyl radicals to the C3 position of quinoxaline-2(1H)-ones, achieved through direct radical initiation, transition metal catalysis, photocatalysis, and other pathways (Org. Biomol. Chem. 2019, 17, 5863-5881.; Org. Biomol. Chem. 2025, 23, 5703-5727.). Compared to traditional methods, these methods offer advantages such as simple procedures, good functional group tolerance, high regioselectivity, and a broad substrate range. They can significantly enrich the diversity and complexity of the structures of 3-alkylquinoxaline-2(1H)-one compounds, thereby meeting the needs of high-throughput screening for related drugs. However, despite these significant advances, existing methods still have certain limitations. For example, direct radical initiation requires stoichiometric external initiators or strong oxidants and depends on high-temperature conditions (Org. Lett. 2018, 20, 5497-5501). Transition metal catalysis inevitably uses toxic and environmentally unfriendly transition metal catalysts, which can easily lead to metal residues in the products (Org. Chem. Front. 2018, 5, 3383-3390). Photocatalysis mainly relies on ruthenium or iridium complexes and organic dyes as homogeneous photocatalysts, which are difficult to recycle and are not conducive to scale-up production and long-term application (Adv. Synth. Catal. 2019, 361, 4126-4132). Therefore, developing green synthetic methods for constructing 3-alkylquinoxaline-2(1H)-one compounds by efficiently achieving C3-H alkylation of quinoxaline-2(1H)-ones under mild conditions without the participation of metal catalysts, photocatalysts, or stoichiometric oxidants remains an urgent need in this field. Summary of the Invention

[0005] To address the problems existing in the prior art, the present invention aims to provide a phosphine-mediated method for preparing 3-alkylquinoxaline-2(1H)-one compounds. This method is mild, simple, efficient, and environmentally friendly, requiring no additional metal reagents, photocatalysts, or stoichiometric oxidants. Direct C3-H alkylation of quinoxaline-2(1H)-ones by alkyl ketones can be achieved solely under the action of tertiary phosphine compounds and a base, thereby rapidly obtaining structurally diverse 3-alkylquinoxaline-2(1H)-one compounds.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows: a method for preparing phosphine-mediated 3-alkylquinoxaline-2(1H)-one compounds, characterized by comprising the following steps:

[0007] A quinoxaline-2(1H)-one compound (Structural Formula (I), an alkyl one compound (Structural Formula (II)), an organic solvent, a tertiary phosphine compound, and a base were added to a 5 mL screw-top glass bottle equipped with a magnetic stirrer in a certain proportion. The mixture was thoroughly mixed, and the reaction solution was protected with argon gas. Subsequently, the reaction was stirred at room temperature for 12–24 hours under an argon atmosphere. The reaction was monitored by thin-layer chromatography (TLC). After the reaction was complete, the organic solvent was removed by vacuum concentration to obtain the crude product. Finally, the 3-alkylquinoxaline-2(1H)-one compound (Structural Formula (III)) was purified by rapid column chromatography using a 1:9 volume ratio mixture of ethyl acetate and petroleum ether as the eluent. The general reaction formula is as follows:

[0008]

[0009] In compound I, R is a 1-12 carbon alkyl, benzyl, aryl, allyl, propargyl, or ester group; R 1 The radicals are hydrogen, alkyl, alkoxy, fluorine, chlorine, bromine, iodine, trifluoromethyl, cyano, ester, and (hetero)aryl; in compound II, the dashed line represents two groups (R 2 and R 3 Whether connected or not, the R 2 and R 3 They can be the same or different, when R 2 R 3 No connection, R 2 and R 3 It is a straight-chain or branched alkyl group with 1-12 carbon atoms, when R 2 R 3 Connection, R 2 R 3 It is a C4-C7 cycloalkyl group, including one of cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0010] The molar ratio of the compound with structural formula (I) quinoxaline-2(1H)-ketone, the compound with structural formula (II) alkyl ketone, the tertiary phosphine compound and the base is 1: 5-20: 1-4: 1-3.

[0011] The tertiary phosphine compound is one of PPh3, PPh2Me, PPh2CF3, PPh2OEt, (p-MeO-Ph)3P, (p-Me-Ph)3P, (pF-Ph)3P, PCy3, and PBu3.

[0012] The alkali is an organic or inorganic alkali, specifically one of K2CO3, DABCO, DBU, NaOAc, NaHCO3, K2HPO4, Cs2CO3, NH4OAc, KOH, NaOH, or LiOH.

[0013] The organic solvent is one of toluene, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, ethyl acetate, or methanol.

[0014] The molar volume ratio of the quinoxaline-2(1H)-one compound to the organic solvent is 0.1-0.2 mmol / mL.

[0015] The room temperature is 20~35℃.

[0016] Compared with the prior art, the present invention has the following advantages and technical effects:

[0017] (1) The raw materials used in this invention, quinoxaline-2(1H)-one and alkyl ketone compounds, are inexpensive and readily available. Under room temperature conditions, in the presence of tertiary phosphine compounds and bases, 3-alkylquinoxaline-2(1H)-one compounds can be synthesized with high selectivity in one step. It has the advantages of mild reaction conditions, short synthesis steps and simple operation.

[0018] (2) The present invention effectively avoids the use of metal reagents, photocatalysts or stoichiometric oxidants, saves reaction costs, is environmentally friendly and suitable for industrial production. Attached Figure Description

[0019] Figure 1 This is a schematic diagram of the structure of the 3-alkylquinoxaline-2(1H)-ketone compounds of the present invention.

[0020] Figure 2 The product of Example 1 1 H NMR spectrum.

[0021] Figure 3 The product of Example 2 1 H NMR spectrum.

[0022] Figure 4 The product of Example 3 1 H NMR spectrum.

[0023] Figure 5 The product of Example 4 1 H NMR spectrum.

[0024] Figure 6 The product of Example 5 1 H NMR spectrum. Detailed Implementation

[0025] To more clearly illustrate the present invention, specific embodiments are described below. It should be noted that the described embodiments are only a part of the embodiments of the present invention, not all embodiments, and should not be considered as limitations on the specific implementation of the present invention. Any changes, combinations, modifications, or simplifications made by those skilled in the art based on the concept of the present invention are all within the protection scope of the present invention.

[0026] Example 1

[0027]

[0028] In a 5 mL screw-top glass bottle equipped with a magnetic stirrer, N-methylquinoxaline-2(1H)-one compound 1a (0.2 mmol, 1.0 equiv.), acetone 2a (3.0 mmol, 15.0 equiv.), KOH (0.4 mmol, 2.0 equiv.), PPh2OEt (0.4 mmol, 2.0 equiv.), and acetonitrile (CH3CN, 0.1 M) were added and mixed thoroughly. The reaction mixture was then protected with argon gas and stirred at room temperature for 24 hours under an argon atmosphere. After the reaction was complete, the organic solvent was removed by vacuum concentration to obtain a crude product. Finally, the crude product was purified by rapid column chromatography using a mixture of ethyl acetate and petroleum ether (volume ratio 1:9) as the eluent to obtain 3-alkylquinoxaline-2(1H)-one product 3a, a white solid, in a yield of 94%.

[0029] The obtained NMR spectrum data of the product are as follows: 1H NMR (400 MHz, Chloroform-d) δ 7.85 (d, J =7.9 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.34 – 7.27 (m, 2H), 3.70 (s, 3H),3.63 (dt, J = 13.6, 6.8 Hz, 1H), 1.32 (d, J = 6.8 Hz, 6H).

[0030] Example 2

[0031]

[0032] In a 5 mL screw-top glass bottle equipped with a magnetic stirrer, N-methylquinoxaline-2(1H)-one compound 1a (0.2 mmol, 1.0 equiv.), methyl ethyl ketone 2b (3.0 mmol, 15.0 equiv.), KOH (0.4 mmol, 2.0 equiv.), PPh2OEt (0.4 mmol, 2.0 equiv.), and acetonitrile (CH3CN, 0.1 M) were added and mixed thoroughly. The reaction mixture was then protected with argon gas and stirred at room temperature for 24 hours under an argon atmosphere. After the reaction was complete, the organic solvent was removed by vacuum concentration to obtain a crude product. Finally, the crude product was purified by rapid column chromatography using a mixture of ethyl acetate and petroleum ether (volume ratio 1:9) as the eluent to obtain 3-alkylquinoxaline-2(1H)-one product 3b, a white solid, in a yield of 29 mg, with a separation yield of 53%.

[0033] The obtained NMR spectrum data of the product are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.85 (d, J =7.9 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.35 – 7.28 (m, 2H), 3.70 (s, 3H),3.46 (q, J = 6.9 Hz, 1H), 1.96 – 1.89 (m, 1H), 1.64 – 1.59 (m, 1H), 1.28 (d,J = 6.9 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H).

[0034] Example 3

[0035]

[0036] In a 5 mL screw-top glass bottle equipped with a magnetic stirrer, N-methylquinoxaline-2(1H)-one compound 1a (0.2 mmol, 1.0 equiv.), 4-phenyl-2-butanone 2c (3.0 mmol, 15.0 equiv.), KOH (0.4 mmol, 2.0 equiv.), PPh₂OEt (0.4 mmol, 2.0 equiv.), and acetonitrile (CH₃CN, 0.1 M) were added and mixed thoroughly. The reaction mixture was then protected with argon gas and stirred at room temperature for 24 hours under an argon atmosphere. After the reaction was complete, the organic solvent was removed by vacuum concentration to obtain a crude product. Finally, the crude product was purified by rapid column chromatography using a mixture of ethyl acetate and petroleum ether (volume ratio 1:9) as the eluent to obtain the 3-alkylquinoxaline-2(1H)-one product 3c, a white solid. mg, with a separation yield of 55%.

[0037] The obtained NMR spectrum data of the product are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.84 (d, J =7.9 Hz, 1H), 7.51 (t, J = 7.7 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.27 (d, J =8.3 Hz, 1H), 7.24 – 7.17 (m, 4H), 7.11 (t, J = 6.9 Hz, 1H), 3.68 (s, 3H), 3.60 (q, J = 6.8 Hz, 1H), 2.73- 2.61 (m, 2H), 2.34 – 2.25 (m, 1H), 1.95 –1.87 (m, 1H), 1.34 (d, J = 6.8 Hz, 3H).

[0038] Example 4

[0039]

[0040] In a 5 mL screw-top glass bottle equipped with a magnetic stirrer, N-methylquinoxaline-2(1H)-one compound 1a (0.2 mmol, 1.0 equiv.), cyclopentanone 2d (3.0 mmol, 15.0 equiv.), KOH (0.4 mmol, 2.0 equiv.), PPh2OEt (0.4 mmol, 2.0 equiv.), and acetonitrile (CH3CN, 0.1 M) were added and mixed thoroughly. The reaction mixture was then protected with argon gas and stirred at room temperature for 24 hours under an argon atmosphere. After the reaction was complete, the organic solvent was removed by vacuum concentration to obtain a crude product. Finally, the crude product was purified by rapid column chromatography using a mixture of ethyl acetate and petroleum ether (volume ratio 1:9) as the eluent to obtain 3-alkylquinoxaline-2(1H)-one product 3d, a white solid, in a yield of 46%.

[0041] The obtained NMR spectrum data of the product are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.82 (dd, J =7.9, 1.2 Hz, 1H), 7.52 – 7.48 (m, 1H), 7.34 – 7.27 (m, 2H), 3.77 – 3.72 (m,1H), 3.70 (s, 3H), 2.11 – 2.03 (m, 2H), 1.97 – 1.88 (m, 2H), 1.86 – 1.76 (m,2H), 1.75 – 1.68 (m, 2H).

[0042] Example 5

[0043]

[0044] In a 5 mL screw-top glass bottle equipped with a magnetic stirrer, N-methylquinoxaline-2(1H)-one compound 1a (0.2 mmol, 1.0 equiv.), cyclohexanone 2e (3.0 mmol, 15.0 equiv.), KOH (0.4 mmol, 2.0 equiv.), PPh2OEt (0.4 mmol, 2.0 equiv.), and acetonitrile (CH3CN, 0.1 M) were added and mixed thoroughly. The reaction mixture was then protected with argon gas and stirred at room temperature for 24 hours under an argon atmosphere. After the reaction was complete, the organic solvent was removed by vacuum concentration to obtain a crude product. Finally, the crude product was purified by rapid column chromatography using a mixture of ethyl acetate and petroleum ether (volume ratio 1:9) as the eluent to obtain 3-alkylquinoxaline-2(1H)-one product 3e, a white solid, in a yield of 62%.

[0045] The obtained NMR spectrum data of the product are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.84 (d, J =8.0 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.34 – 7.27 (m, 2H), 3.70 (s, 3H),3.38 – 3.31 (m, 1H), 1.95 (d, J = 12.2 Hz, 2H), 1.89 – 1.85 (m, 2H), 1.77 (d, J = 12.7 Hz, 1H), 1.60 – 1.41 (m, 4H), 1.37 – 1.29 (m, 1H).

Claims

1. A method for preparing 3-alkylquinoxaline-2(lH)-one compounds mediated by phosphine, characterized in that, The following steps are taken: using quinoxaline-2(1H)-one compounds and alkyl ketone compounds shown in structural formula (I) as raw materials, they are added to a reaction vessel in a certain proportion, dissolved in an organic solvent and mixed evenly, and then a certain amount of tertiary phosphine compound and base are added; subsequently, the reaction is carried out at room temperature for 12 to 24 hours under an argon atmosphere. After the reaction was monitored by TLC, the product was concentrated and purified by column chromatography to obtain a 3-alkylquinoxaline-2(1H)-one compound with structural formula (III); the general reaction formula is as follows:

2. The method according to claim 1, wherein the phosphine-mediated preparation of 3-alkylquinoxalin-2(lH)-one compounds is characterized by, In structural formula (I), R is a 1-12 carbon alkyl, benzyl, aryl, allyl, propargyl, or ester group; R 1 The radicals are hydrogen, alkyl, alkoxy, fluorine, chlorine, bromine, iodine, trifluoromethyl, cyano, ester, and (hetero)aryl; in structural formula (II), the dashed line represents two groups (R 2 and R 3 Whether connected or not, the R 2 and R 3 They can be the same or different, when R 2 R 3 No connection, R 2 and R 3 It is a straight-chain or branched alkyl group with 1-12 carbon atoms, when R 2 R 3 Connection, R 2 R 3 It is a C4-C7 cycloalkyl group, including one of cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

3. The method according to claim 1, wherein the phosphine-mediated preparation of 3-alkylquinoxalin-2(lH)-one compounds is characterized by, The molar ratio of the compound with structural formula (I) quinoxaline-2(1H)-ketone, the compound with structural formula (II) alkyl ketone, the tertiary phosphine compound and the base is 1: 5-20: 1-4: 1-3.

4. The method according to claim 1, wherein the method for preparing 3-alkylquinoxalin-2(lH)-one compounds is characterized by, The tertiary phosphine compound is one of PPh3, PPh2Me, PPh2CF3, PPh2OEt, (p-MeO-Ph)3P, (p-Me-Ph)3P, (pF-Ph)3P, PCy3, and PBu3.

5. The method for preparing a phosphine-mediated 3-alkylquinoxaline-2(1H)-one compound according to claim 1, characterized in that, The alkali mentioned is an organic or inorganic alkali, specifically K2CO3, DABCO, DBU, NaOAc, NaHCO3, K2HPO4, Cs2CO3, NH4OAc, KOH, NaOH, or LiOH.

6. The method for preparing a phosphine-mediated 3-alkylquinoxaline-2(1H)-one compound according to claim 1, characterized in that, The organic solvent is toluene, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, ethyl acetate, or methanol.

7. The method according to claim 1, wherein the phosphine-mediated preparation of 3-alkylquinoxalin-2(lH)-one compounds is characterized by The molar volume ratio of quinoxaline-2(1H)-ketone compounds to organic solvents is 0.1-0.2 mmol / mL.

8. The method for preparing a phosphine-mediated 3-alkylquinoxaline-2(1H)-one compound according to claim 1, characterized in that, The room temperature is 20~35℃.

9. The method for preparing a phosphine-mediated 3-alkylquinoxaline-2(1H)-one compound according to claim 1, characterized in that, After the reaction was completed, the reaction solution was concentrated under vacuum to obtain a crude product. The crude product was then purified by column chromatography using a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 1:9 as the eluent. The target 3-alkylquinoxaline-2(1H)-ketone compound was obtained by rapid column chromatography.

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