C-H 3, 3-difluoroallylation reaction method of 1, 2-dihydroquinoxaline-2-ketone derivative

Abstract

The invention discloses a C-H 3, 3-difluoroallylation reaction method of a 1, 2-dihydroquinoxaline-2-ketone derivative, which comprises the following steps: by taking the 1, 2-dihydroquinoxaline-2-ketone derivative as shown in a formula I and 3-bromo-3, 3-difluoro-1-propylene as coupling reagents, carrying out a reaction on the 1, 2-dihydroquinoxaline-2-ketone derivative and 3-bromo-3, 3-difluoro-1-propylene in an environment of inorganic alkali and organic amine under the catalysis of a photooxidation reduction catalyst, and then carrying out a reaction to obtain the C-H 3, 3-difluoroallylation reaction product of the 1, 2-dihydroquinoxaline-2-ketone derivative. And carrying out a coupling reaction under a visible light condition to obtain a compound shown in a formula II. The C-H 3, 3-difluoroallylation product of the 1, 2-dihydroquinoxaline-2-ketone derivative is synthesized under mild one-step reaction conditions for the first time, and a green synthesis path is provided for medicine molecules (such as antitumor / antiviral compounds) containing a gem-difluoroallyl structure.

Description

Technical Field

[0001] This invention relates to a method for the CH 3,3-difluoroallylation of 1,2-dihydroquinoxaloline-2-one derivatives. Background Technology

[0002] Photochemistry, as an important branch of chemistry, has demonstrated significant value in organic synthesis and medicinal chemistry in recent years. The precise construction of specific chemical bonds using photocatalysis has become one of the key research directions in this field. This technology is widely used not only in natural product synthesis, drug discovery, radioactive labeling, bioconjugation, and the development of functional materials, but also attracts considerable attention from the academic community due to its green and efficient characteristics.

[0003] Organic photoreaction technology uses light energy as a driving force. Through the absorption of photons of specific wavelengths by molecules, electrons undergo transitions, forming excited-state species, thereby initiating and propelling chemical reactions. This technology, with its advantages of mild reaction conditions, few byproducts, and high selectivity and efficiency, provides strong support for the development of green synthetic pathways. In recent years, continuous innovation in photoreaction technology has not only expanded the strategic dimensions of organic synthesis but also opened up new avenues for the construction of complex molecules. Its rapid application has become an important development trend in the field of synthetic chemistry.

[0004] Fluorine atoms, with their unique physicochemical properties and biological effects, endow fluorine-containing molecules with key functions in medicine, pesticides, and materials. Numerous fluorine-containing structural units have become indispensable frameworks for constructing functional molecules [Wang, J.; Sánchez-Roselló, M.; J,L.; del Pozo,C.; Sorochinsky,AE; Fustero,S.; Soloshonok,VA and Liu,H. Chem. Rev. 2014,114,2432; Meanwell,NA J Med. Chem. 2018,61,5822]. Among these, geminal difluoroene structures have attracted widespread attention due to their superior pharmacological activity. For example, the antiepileptic drug Seletracetam [Matagne,A.; Margineanu,D.-G.; H. Potschka,W.; W.; Michel, P.; Kenda, B. and Klitgaard, H., Eur. J. Pharmacol. 2009, 614, 30–37] Dehydrogenase I inhibitors associated with diabetes treatment [Braun, A.; Gussregen, S.; Mougeto, P.; Namane, C.; Nicolai, E.; Pacquet, F.; Philippo, C.; Venier, O.; Crespin, O.; Pascal, C. and Aletru, M. WO2008000950A2] all contain this fragment. In addition, gemini difluoroolefins are also widely used as bioisosteres of carbonyl groups to optimize drug metabolic stability and activity [Magueur, G.; Crousse, B.; Ourévitch, M.; Bonnet-Delpon, D. and Bégué, J.-PJ Fluorine Chem. 2006, 127, 637–642; Li, Y.; Nie, W.; Chang, Z.; Wang, J.-W.; Lu, X. and Fu, Y.; Nat. Catal. 2021, 4, 901–911]. In synthetic chemistry, geminofluoroolefins are also an important class of fluorine-containing building blocks that can be efficiently converted into multifunctionalized structures such as trifluoromethyl, monofluoroolefins and difluoromethylene [Zhang, X. and Cao, S.; Tetrahedron Lett. 2017, 58, 375–392; Fujita, T.; Fuchibe, K. and Ichikawa, J. Angew. Chem. Int. Ed. 2019, 58, 390–402], further expanding the structural diversity of fluorine-containing molecules.

[0005] 3-Bromo-3,3-difluoropropene (BDFP) can serve as an important initiating agent for geminal difluoroallylation reactions. Under transition metal catalysis, BDFP can undergo cross-coupling reactions with organometallic reagents to efficiently construct biologically active geminal difluoroallyl structural units. Given the wide applications of geminal difluoroallyl fragments in organic industries and bioactive molecules, developing efficient synthetic methods for them is of great significance.

[0006] Currently, the construction of difluoroolefin structural units mainly relies on a transition metal-catalyzed cross-coupling strategy [Ni, J.;Zhao, H.;Zhang, A.Org Lett.2017,19,3159.;Li, C.;Zhang, D.;Zhu, W.;Wan P and Liu H.Org.Chem.Front.,2016,3,1080.;Li, J.;Hong, C.;Niu, Y.;Wang, B.;Xiong, W.and Jiang H.Chem Asian J.2023,18,e202300579]. However, traditional metal-catalyzed methods suffer from high catalyst costs and limited resources, low tolerance to sensitive functional groups, and the need for multiple steps in the difluoroallylation process due to the coexistence of difluorine and olefins to construct the target molecular structure.

[0007] In summary, there is an urgent need in the field for a synthetic method that can achieve the 3,3-difluoroallylation reaction in a mild and efficient manner. Summary of the Invention

[0008] To address the aforementioned technical problems, the present invention aims to provide a novel method for the CH 3,3-difluoroallylation of 1,2-dihydroquinoxalin-2-one derivatives. This method not only exhibits good stability but also features one-step synthesis and simple operation, providing a novel synthetic reference for similar target compounds. Compared to traditional metal-catalyzed methods, the photo-redox catalytic strategy of this invention demonstrates significant advantages in the synthesis of gem-difluoroallyl compounds, including simple steps, mild reaction conditions, economical and readily available catalysts, and good functional group compatibility. Therefore, developing new photocatalytic methods for introducing gem-difluoroallyl groups has broad research prospects and application potential in the field of organic synthesis.

[0009] To achieve the above objectives, this invention provides a method for the CH3,3-difluoroallylation of 1,2-dihydroquinoxalin-2-one derivatives. The technical solution adopted in this invention is as follows:

[0010] A method for the CH 3,3-difluoroallylation of a 1,2-dihydroquinoxalin-2-one derivative includes the following steps:

[0011]

[0012] Using 1,2-dihydroquinoxaline-2-one derivatives and 3-bromo-3,3-difluoro-1-propene as coupling agents, a coupling reaction was carried out under visible light conditions in an environment of inorganic base and organic amine, catalyzed by a photo-redox catalyst, to obtain the compound shown in Formula II.

[0013] In the formula: X is arbitrarily selected from alkyl, phenyl, propenyl, hydroxyalkyl, haloalkyl, protected aminoalkyl, and acetate; Y1 and Y2 are both arbitrarily selected from H, halogen, and trifluoromethyl.

[0014] In some embodiments, the photo-oxidation-reduction catalyst is selected from 4CzIPN, 4DPAIPN, or 4CzTPN.

[0015] In some embodiments, the organic amine is N,N-diisopropylethylamine or triethylamine.

[0016] In some embodiments, the inorganic base is selected from potassium carbonate or cesium carbonate.

[0017] In some embodiments, the visible light is blue light with a wavelength range between 410 nm and 470 nm.

[0018] In some embodiments, the reaction steps include: mixing a 1,2-dihydroquinoxaline-2-one derivative and an inorganic base in an organic solvent; adding a catalyst, an organic amine, and 3-bromo-3,3-difluoro-1-propene to the reaction solution; carrying out a coupling reaction under blue light; and separating and purifying the coupling reaction product to obtain the CH 3,3-difluoroallylated product of the 1,2-dihydroquinoxaline-2-one derivative.

[0019] In some implementations, the method further includes the step of quenching the photocatalytic coupling reaction by opening the reaction vessel and using water.

[0020] In some implementations, the method further includes the step of: at the end of the photocatalytic coupling reaction, the reaction solution is preferentially diluted in ice water before proceeding to the next step.

[0021] In some embodiments, the method further includes the steps of separating and purifying the coupling reaction product, including extraction, washing, and column chromatography.

[0022] In some embodiments, the organic solvent is selected from any one or a combination of several of methanol, ethanol, acetonitrile, dichloromethane, 1,2-dichloroethane, ethyl acetate, N,N-dimethylacetamide, tert-butanol, and 1,4-dioxane.

[0023] In some embodiments, the molar ratio of the compound represented by Formula I to the catalyst 4CzIPN and the organic amine is 1:(0.003-0.1):(0.08-0.2); the molar ratio of the compound represented by Formula I to 3-bromo-3,3-difluoro-1-propene is 1:(1.8-3); and the molar ratio of the compound represented by Formula I to the inorganic base is 1:(1.5-3).

[0024] In some implementations, the reaction temperature is 25°C-65°C and the reaction time is 4-16 hours.

[0025] Compared with traditional technologies, the beneficial effects of this invention are:

[0026] 1) This invention proposes a novel photocatalytic method for the coupling of 3-bromo-3,3-difluoro-1-propene and 1,2-dihydroquinoxalin-2-one derivatives. Using 1,2-dihydroquinoxalin-2-one derivatives and 3-bromo-3,3-difluoro-1-propene as coupling fragments, and catalyzing the reaction with 4CzIPN as a photoredox catalyst, the C-H3,3-difluoroallylization of the 1,2-dihydroquinoxalin-2-one derivative is achieved. This coupling reaction is economical and environmentally friendly, using readily available and inexpensive raw materials, and rapidly yielding the coupling product through photocatalysis. The synthetic method is highly efficient and has significant value and potential in drug synthesis, providing an effective synthetic method for similar target compounds.

[0027] 2) This invention addresses the synthetic requirements of the 3,3-difluoroallylization reaction. Through radical capture experiments, the generation pathway of the difluoroallyl radical was verified, providing crucial mechanistic support for photoredox catalysis strategies. Compared to traditional transition metal catalysis methods, this invention offers the following significant advantages: mild reaction conditions, avoiding substrate functional group degradation; simple and efficient steps, with TEMPO capture experiments confirming the radical chain reaction mechanism, overcoming the cumbersome drawbacks of multi-step reactions; more importantly, the catalyst used in this invention is economical and readily available, with lower costs than metal catalysts; and it exhibits excellent functional group compatibility and high intermediate stability, compatible with protecting sensitive groups such as aminoalkyl and trifluoromethyl groups.

[0028] In traditional synthetic techniques, substances containing difluoroolefin structural units cannot simultaneously contain both olefins and difluorine in the reaction steps. This is because the free radicals formed when difluorine and olefins coexist are unstable and difficult to act on the reaction substrate. However, this invention innovatively synthesizes the CH3,3-difluoroallylated product of a 1,2-dihydroquinoxalin-2-one derivative under mild one-step reaction conditions. This not only overcomes the limitations of easy decomposition and difficulty in directional reaction of free radicals when difluorine groups coexist with olefins, but also verifies the existence of a stable state of difluorine and olefin free radicals, providing a green synthetic route for drug molecules containing gem-difluoroallyl structures (such as antitumor / antiviral compounds). Detailed Implementation

[0029] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Many specific details are set forth in the following description to provide a thorough understanding of the present invention. However, the present invention may also be implemented in other ways different from those described herein. Those skilled in the art can make similar extensions without departing from the spirit of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0030] Throughout the invention, when a composition is described as having, containing, or including specific ingredients, or a method is described as having, containing, or including specific process steps, it should be understood that the compositions of the invention are also substantially composed of or consisting of the mentioned ingredients, and the methods of the invention are also substantially composed of or consisting of the mentioned process steps.

[0031] In this invention, when an element or component is referred to as being included in and / or selected from the list of mentioned elements or components, it should be understood that the element or component may be any one of the mentioned elements or components, or the element or component may be selected from the group consisting of two or more mentioned elements or components. Furthermore, it should be understood that the elements or features of the compositions, apparatus, or methods described herein, whether expressly or implicitly stated, can be combined in any manner without departing from the subject matter and scope of the invention.

[0032] It should be understood that the order of steps or the sequence of actions is not important as long as the teachings of this invention are operable. Furthermore, two or more steps or actions can be performed simultaneously.

[0033] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter described herein belongs.

[0034] All solvents used in this invention are of analytical grade. All substances used as raw materials in the examples were obtained through commercial purchase.

[0035] According to a preferred embodiment of the present invention, a method for the CH3,3-difluoroallylation of a 1,2-dihydroquinoxaloline-2-one derivative is characterized by comprising the following steps:

[0036]

[0037] Using 1,2-dihydroquinoxaline-2-one derivatives of Formula I and 3-bromo-3,3-difluoro-1-propene as coupling agents, a coupling reaction was carried out under visible light conditions in an environment of inorganic base and organic solvent, catalyzed by a photoredox catalyst; where:

[0038] X is arbitrarily selected from alkyl, phenyl, propenyl, hydroxyalkyl, haloalkyl, protected aminoalkyl, and acetate; Y1 and Y2 are both arbitrarily selected from H, halogen, or trifluoromethyl.

[0039] In some embodiments, the alkyl group of X can be a C1-C12 alkyl group, which can be a straight-chain alkyl group, a branched alkyl group, or a cyclic alkyl group, specifically such as methyl, ethyl, or phenylcyclohexane. The hydroxyalkyl group can be a C2-C12 carbon chain hydroxyl group. The benzene ring substituent is phenyl or benzyl. The protected aminoalkyl group is a carbamate attached to a C2-C12 carbon chain, which can be tert-butyl carbamate (CH2CH2NHBoc); for acetate esters, it can be tert-butyl acetate. The haloalkyl group is bromobutyl.

[0040] Based on this, the 1,2-dihydroquinoxaline-2-one derivatives are based on electron-donating or electron-withdrawing groups attached to the 1, 6, or 7 positions of 1,2-dihydroquinoxaline-2-one, or are replaced by lipid-soluble or water-soluble groups, which reflects the richness of the substrates applicable to this invention.

[0041] In some embodiments, the photo-oxidation-reduction catalyst is 4CzIPN, 4DPAIPN, 4CzTPN, or other photoinitiators with similar effects. The organic amine is N,N-diisopropylethylamine (DIEA), triethylamine, or other organic substances that can promote electron transfer from the photoinitiator. The inorganic base is selected from potassium carbonate, cesium carbonate, or other basic auxiliaries that can promote electron transfer. The organic solvent is selected from any one or a combination of methanol, ethanol, acetonitrile, dichloromethane, 1,2-dichloroethane, ethyl acetate, N,N-dimethylacetamide, tert-butanol, and 1,4-dioxane. The visible light is blue light with a wavelength range between 410 nm and 470 nm.

[0042] In specific implementation, the reaction steps include: mixing 1,2-dihydroquinoxaline-2-one derivatives and inorganic bases in an organic solvent; adding a catalyst such as 4CzIPN, an organic amine such as N,N-diisopropylethylamine, and 3-bromo-3,3-difluoro-1-propene to the reaction solution; carrying out a coupling reaction under blue light; and separating and purifying the coupling reaction product to obtain the CH 3,3-difluoroallylation reaction product of the 1,2-dihydroquinoxaline-2-one derivative.

[0043] It also includes the steps of: quenching the photocatalytic coupling reaction by opening the reaction vessel and using water; and / or, at the end of the photocatalytic coupling reaction, diluting the reaction solution in ice water before proceeding to the next step.

[0044] The separation and purification of the coupling reaction products includes extraction, washing, and column chromatography.

[0045] In some embodiments, the molar ratio of the compound represented by Formula I to the catalyst 4CzIPN and the organic amine is 1:(0.003-0.1):(0.08-0.2); the molar ratio of the compound represented by Formula I to 3-bromo-3,3-difluoro-1-propene is 1:(1.8-3); and the molar ratio of the compound represented by Formula I to the inorganic base is 1:(1.5-3).

[0046] In other embodiments, the reaction temperature is 25°C-65°C and the reaction time is 15-20 hours.

[0047] This invention provides a preliminary exploration of the reaction mechanism of geminal difluoroallylization in the above embodiments. Through a radical scavenging experiment, we successfully detected the presence of difluoroallyl radicals. The specific experimental procedure is as follows: Under standard reaction conditions, 2 equivalents of TEMPO (2,2,6,6-tetramethylpiperidine oxide, as a radical scavenger) were added to the system. The formation of the target product was completely inhibited, and the characteristic intermediate state after the combination of TEMPO and difluoroallyl radicals was detected by LCMS (liquid chromatography-mass spectrometry). In this invention, light irradiation first generates difluoro radicals, followed by olefin double bond migration to form 3,3-difluoroallyl radicals. This result further confirms the generation pathway of difluoroallyl radicals in the reaction and verifies the existence of a steady state between difluoro and olefin radicals.

[0048]

[0049] Based on the above embodiments, the present invention selected various substrates and conducted the following specific experiments to obtain compounds represented by Formula II in different embodiments:

[0050] Example 1

[0051] Preparation of 3-(3,3-difluoroallyl)-1-ethylquinoxalin-2(1H)-one (1a):

[0052]

[0053] 1-Ethylquinoxaline-2(1H)-one (50 mg, 0.28 mmol) and cesium carbonate (187 mg, 0.57 mmol) were mixed in 3 mL of 1,2-dichloroethane. 2,4,5,6-Tetratetra(9-carbazolyl)-isophthalonitrile (11 mg, 0.014 mmol), N,N-diisopropylethylamine (3.7 mg, 0.028 mmol), and 3-bromo-3,3-difluoroprop-1-ene (90 mg, 0.57 mmol) were added to the reaction mixture. The reaction mixture was bubbled with nitrogen at 0 °C for 1 minute, and then stirred at 25 °C for 4 hours under 18 W 450 nm blue light. The reaction mixture was then diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by rapid silica gel chromatography (petroleum ether: dichloromethane 3:1) to give a yellow solid 3-(3,3-difluoroallyl)-1-ethylquinoxalin-2(1H)-one (19 mg).

[0054] MS(M+1): 251.

[0055] 1 H NMR (400MHz, CDCl3) δ7.86 (dd, J=8.4, 1.2Hz, 1H), 7.57–7.52 (m, 1H), 7.37–7.32 (m, 2H ),4.81–4.67(m,1H),4.33(q,J=7.2Hz,2H),3.68–3.64(m,2H),1.38(t,J=7.2Hz,3H).

[0056] Example 1-1

[0057] This example is essentially the same as Example 1, except that the amount of catalyst 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile is 6.6 mg (0.008 mmol), and N,N-diisopropylethylamine is 3.0 mg (0.022 mmol). The obtained yellow solid has the same mass spectrum and NMR, indicating it is 3-(3,3-difluoroallyl)-1-ethylquinoxalin-2(1H)-one, with a solid mass of 18 mg.

[0058] Examples 1-2

[0059] This example is essentially the same as Example 1, except that the amount of catalyst 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile is 0.66 mg (0.0028 mmol), and N,N-diisopropylethylamine is 3.0 mg (0.022 mmol). The obtained yellow solid has the same mass spectrum and NMR, indicating it is 3-(3,3-difluoroallyl)-1-ethylquinoxalin-2(1H)-one, with a solid mass of 15 mg.

[0060] Examples 1-3

[0061] This example is essentially the same as Example 1, except that the amount of catalyst 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile is 22 mg (0.028 mmol), and N,N-diisopropylethylamine is 7.4 mg (0.056 mmol). The obtained yellow solid has the same mass spectrum and NMR, indicating it is 3-(3,3-difluoroallyl)-1-ethylquinoxalin-2(1H)-one, with a solid mass of 22 mg.

[0062] Examples 1-4

[0063] This embodiment is basically the same as Example 1, except that the amount of cesium carbonate used is 138 mg (0.42 mmol). The mass spectrum and NMR of the obtained yellow solid are the same, indicating that it is 3-(3,3-difluoroallyl)-1-ethylquinoxaloline-2(1H)-one, and the solid mass is 18 mg.

[0064] Examples 1-5

[0065] This embodiment is basically the same as Example 1, except that the amount of cesium carbonate used is 275 mg (0.84 mmol). The mass spectrum and NMR of the obtained yellow solid are the same, indicating that it is 3-(3,3-difluoroallyl)-1-ethylquinoxaloline-2(1H)-one, and the solid mass is 20 mg.

[0066] Examples 1-6

[0067] This example is basically the same as Example 1, except that the catalyst used is 4DPAIPN. The obtained yellow solid has the same mass spectrum and NMR, and is 3-(3,3-difluoroallyl)-1-ethylquinoxalin-2(1H)-one, with a solid mass of 22 mg.

[0068] Examples 1-7

[0069] This embodiment is basically the same as Example 1, except that the catalyst used is 4CzTPN. The mass spectrum and NMR of the yellow solid obtained from the reaction are the same, indicating that it is 3-(3,3-difluoroallyl)-1-ethylquinoxaloline-2(1H)-one, and the solid mass is 20 mg.

[0070] Examples 1-8

[0071] This example is basically the same as Example 1, except that N,N-diisopropylethylamine is replaced with 3.0 mg (0.022 mmol) of triethylamine, and the reaction temperature is 65 °C. The obtained yellow solid has the same mass spectrum and NMR, and is 3-(3,3-difluoroallyl)-1-ethylquinoxaloline-2(1H)-one, with a solid mass of 21 mg.

[0072] Examples 1-9

[0073] This example is basically the same as Example 1, except that the amount of 3-bromo-3,3-difluoroprop-1-ene is 80 mg, 0.504 mmol. The obtained yellow solid has the same mass spectrum and NMR, and is 3-(3,3-difluoroallyl)-1-ethylquinoxalin-2(1H)-one, with a solid mass of 20 mg.

[0074] Comparative Example 1

[0075] This example is essentially the same as Example 1, except that the conventional metal catalyst Pd(PPh3)4 is used instead of 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile. As a result, the solid product 3-(3,3-difluoroallyl)-1-ethylquinoxalin-2(1H)-one was not isolated.

[0076] Example 2

[0077] Preparation of 3-(3,3-difluoroallyl)-1-methylquinoxaloline-2(1H)-one (1b):

[0078]

[0079] 1-Methylquinoxalin-2(1H)-one (50 mg, 0.31 mmol) and cesium carbonate (203 mg, 0.62 mmol) were mixed in 3 mL of 1,2-dichloroethane. 2,4,5,6-Tetratetra(9-carbazolyl)-isophthalonitrile (12 mg, 0.015 mmol), N,N-diisopropylethylamine (4 mg, 0.031 mmol), and 3-bromo-3,3-difluoro-1-propene (98 mg, 0.62 mmol) were added to the reaction mixture. The reaction mixture was bubbled with nitrogen at 0 °C for 1 minute, and then stirred at 25 °C for 6 hours under 18 W 450 nm blue light. The reaction mixture was then diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by rapid silica gel chromatography (petroleum ether: dichloromethane 3:1) to give a yellow solid 3-(3,3-difluoroallyl)-1-methylquinoxalin-2(1H)-one (24 mg).

[0080] MS(M+1): 237.

[0081] 1H NMR(400MHz,DMSO-d6)δ7.81(dd,J=8.0,1.2Hz,1H),7.66–7.60(m,1H),7.59–7.54(m ,1H),7.42–7.35(m,1H),4.95–4.79(m,1H),3.64(s,3H),3.55(dt,J=7.6,1.6Hz,2H).

[0082] Example 3

[0083] Preparation of 1-benzyl-3-(3,3-difluoroallyl)quinoxalin-2(1H)-one (1c):

[0084]

[0085] 1-Benzylquinoxaline-2(1H)-one (71 mg, 0.30 mmol) and potassium carbonate (83 mg, 0.60 mmol) were mixed in 3 mL of 1,2-dichloroethane. 2,4,5,6-Tetratetra(9-carbazolyl)-isophthalonitrile (12 mg, 0.015 mmol), N,N-diisopropylethylamine (3.88 mg, 0.030 mmol), and 3-bromo-3,3-difluoro-1-propene (94 mg, 0.60 mmol) were added to the reaction mixture. The reaction mixture was bubbled with nitrogen at 0 °C for 1 minute, and then stirred at 25 °C for 8 hours under 18 W 450 nm blue light. The reaction mixture was then diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by rapid silica gel chromatography (petroleum ether: dichloromethane 3:1) to give a yellow solid 1-benzyl-3-(3,3-difluoroallyl)quinoxalin-2(1H)-one (18 mg).

[0086] MS(M+1): 313.

[0087] 1 H NMR (400MHz, CDCl3) δ7.88–7.85(m,1H),7.45–7.40(m,1H),7.33–7.27(m, 4H),7.25–7.21(m,3H),5.51(s,2H),4.85–4.71(m,1H),3.74–3.71(m,2H).

[0088] Example 4

[0089] Preparation of 2-(3-(3,3-difluoroallyl)-2-oxoquinoxaloline-1(2H)-yl)tert-butyl acetate (1d):

[0090]

[0091] 2-(2-oxoquinoxalo-1(2H)-yl)tert-butyl acetate (78 mg, 0.30 mmol) and potassium carbonate (83 mg, 0.60 mmol) were mixed in 3 mL of 1,2-dichloroethane. 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (12 mg, 0.015 mmol), N,N-diisopropylethylamine (3.88 mg, 0.030 mmol), and 3-bromo-3,3-difluoro-1-propene (94 mg, 0.60 mmol) were added to the reaction mixture. The reaction mixture was bubbled with nitrogen at 0 °C for 1 minute, and then stirred at 25 °C for 10 hours under 18 W 450 nm blue light. The reaction mixture was then diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by rapid silica gel chromatography (petroleum ether: dichloromethane 3:1) to give a yellow solid tert-butyl 2-(3-(3,3-difluoroallyl)-2-oxoquinoxaloline-1(2H)-yl)acetate (18 mg).

[0092] MS(M+1): 337.

[0093] 1 H NMR (400MHz, CDCl3) δ7.87 (dd, J=8.0, 1.2Hz, 1H), 7.54–7.49 (m, 1H), 7.37–7.33 (m, 1H), 7. 22–7.15(m,1H),4.94(s,2H),4.80–4.67(m,1H),3.67(dt,J=7.2,1.6Hz,2H),1.46(s,9H).

[0094] Example 5

[0095] Preparation of 3-(3,3-difluoroallyl)-1-phenylquinoxaloline-2(1H)-one (1e):

[0096]

[0097] 1-Phenylacetin-2(1H)-one (67 mg, 0.30 mmol) and cesium carbonate (196 mg, 0.60 mmol) were mixed in 3 mL of 1,2-dichloroethane. 2,4,5,6-Tetratetra(9-carbazolyl)-isophthalonitrile (12 mg, 0.015 mmol), N,N-diisopropylethylamine (3.88 mg, 0.030 mmol), and 3-bromo-3,3-difluoro-1-propene (94 mg, 0.60 mmol) were added to the reaction mixture. The reaction mixture was bubbled with nitrogen at 0 °C for 1 minute, and then stirred at 25 °C for 12 hours under 18 W 450 nm blue light. The reaction mixture was then diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by rapid silica gel chromatography (petroleum ether: dichloromethane 3:1) to give a yellow solid 3-(3,3-difluoroallyl)-1-phenylquinoxalin-2(1H)-one (15 mg).

[0098] MS(M+1): 299.

[0099] 1 H NMR (400MHz, CDCl3) δ7.91–7.87(m,1H),7.64–7.60(m,2H),7.58–7.54(m,1H),7.35–7.31(m ,2H),7.30–7.27(m,2H),6.71–6.65(m,1H),4.85–4.71(m,1H),3.69(dt,J=7.6,1.6Hz,2H).

[0100] Example 6

[0101] Preparation of 1-allyl-3-(3,3-difluoroallyl)quinoxalin-2(1H)-one (1f):

[0102]

[0103] 1-Allylquinoxalin-2(1H)-one (56 mg, 0.30 mmol) and potassium carbonate (83 mg, 0.60 mmol) were mixed in 3 mL of 1,2-dichloroethane. 2,4,5,6-Tetratetra(9-carbazolyl)-isophthalonitrile (12 mg, 0.015 mmol), N,N-diisopropylethylamine (3.88 mg, 0.030 mmol), and 3-bromo-3,3-difluoro-1-propene (94 mg, 0.60 mmol) were added to the reaction mixture. The reaction mixture was bubbled with nitrogen at 0 °C for 1 minute, and then stirred at 25 °C for 8 hours under 18 W 450 nm blue light. The reaction mixture was then diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by rapid silica gel chromatography (petroleum ether: dichloromethane 3:1) to give a yellow solid 1-allyl-3-(3,3-difluoroallyl)quinoxaline-2(1H)-one (14 mg).

[0104] MS(M+1): 263.

[0105] 1H NMR(400MHz, CDCl3) δ7.86(d,J=8.0Hz,1H),7.55–7.48(m,1H),7.38–7.31(m,1H),7.29(d,J=8.4Hz,1H),6.00–5.87 (m,1H),5.28(d,J=10.4Hz,1H),5.17(d,J=17.2Hz,1H),4.93–4.90(m,2H),4.81–4.68(m,1H),3.67(d,J=7.6Hz,2H).

[0106] Example 7

[0107] Preparation of 1-(4-bromobutyl)-3-(3,3-difluoroallyl)quinoxalin-2(1H)-one (1g):

[0108]

[0109] 1-(4-bromobutyl)quinoxaline-2(1H)-one (84 mg, 0.30 mmol) and cesium carbonate (196 mg, 0.60 mmol) were mixed in 3 mL of 1,2-dichloroethane. 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (12 mg, 0.015 mmol), N,N-diisopropylethylamine (3.88 mg, 0.030 mmol), and 3-bromo-3,3-difluoro-1-propene (94 mg, 0.60 mmol) were added to the reaction mixture. The reaction mixture was bubbled with nitrogen at 0 °C for 1 minute, and then stirred at 25 °C for 12 hours under 18 W 450 nm blue light. The reaction mixture was then diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by rapid silica gel chromatography (petroleum ether: dichloromethane 3:1) to give a yellow solid 1-(4-bromobutyl)-3-(3,3-difluoroallyl)quinoxalin-2(1H)-one (17 mg).

[0110] MS(M+1): 357 / 359.

[0111] 1 H NMR (400MHz, CDCl3) δ7.87 (dd, J=8.0, 1.2Hz, 1H), 7.58–7.53 (m, 1H), 7.38–7.32 (m, 2H), 4.79–4. 67(m,1H),4.32–4.28(m,2H),3.65(dt,J=7.6,1.6Hz,2H),3.51–3.48(m,2H),2.02–1.95(m,4H).

[0112] Example 8

[0113] Preparation of tert-butyl (2-(3-(3,3-difluoroallyl)-2-oxoquinoxalo-1(2H)-yl)ethyl)carbamate (1h):

[0114]

[0115] (2-(2-oxoquinoxalo-1(2H)-yl)ethyl)tert-butyl carbamate (87 mg, 0.30 mmol) and potassium carbonate (83 mg, 0.60 mmol) were mixed in 3 mL of 1,2-dichloroethane. 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (12 mg, 0.015 mmol), N,N-diisopropylethylamine (3.88 mg, 0.030 mmol), and 3-bromo-3,3-difluoro-1-propene (94 mg, 0.60 mmol) were added to the reaction mixture. The reaction mixture was bubbled with nitrogen at 0 °C for 1 minute, and then stirred at 25 °C for 16 hours under 18W 450 nm blue light. The reaction mixture was then diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by rapid silica gel chromatography (petroleum ether: ethyl acetate 3:1) to give a yellow solid (2-(3-(3,3-difluoroallyl)-2-oxoquinoxaloline-1(2H)-yl)ethyl)carbamate tert-butyl ester (29 mg).

[0116] MS(M+1): 366.

[0117] 1 H NMR (400MHz, CDCl3) δ7.85 (d, J = 8.0Hz, 1H), 7.63–7.53 (m, 2H), 7.38–7.32 (m, 1H), 4.91 (s, 1H), 4.7 9–4.66(m,1H),4.42(t,J=6.8Hz,2H),3.65(dt,J=7.6,1.6Hz,2H),3.52–3.46(m,2H),1.43(s,9H).

[0118] Example 9

[0119] Preparation of tert-butyl(12-(3-(3,3-difluoroallyl)-2-oxoquinoxaloline-1(2H)-yl)dodecyl)carbamate (1l):

[0120]

[0121] (12-(2-oxoquinoxalo-1(2H)-yl)dodecyl)carbamate tert-butyl ester (129 mg, 0.30 mmol) and cesium carbonate (196 mg, 0.60 mmol) were mixed in 3 mL of 1,2-dichloroethane. 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (12 mg, 0.015 mmol), N,N-diisopropylethylamine (3.88 mg, 0.030 mmol), and 3-bromo-3,3-difluoro-1-propene (94 mg, 0.60 mmol) were added to the reaction mixture. The reaction mixture was bubbled with nitrogen at 0 °C for 1 minute, and then stirred at 25 °C for 18 hours under 18W 450 nm blue light. The reaction mixture was then diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by rapid silica gel chromatography (petroleum ether: ethyl acetate 2:1) to give a yellow solid tert-butyl (12-(3-(3,3-difluoroallyl)-2-oxoquinoxaloline-1(2H)-yl)dodecyl)carbamate (31 mg).

[0122] MS(M+1): 506.

[0123] 1 H NMR(400MHz, DMSO-d6)δ7.81(d,J=7.6Hz,1H),7.69–7.56(m,2H),7.41–7.32(m,1H),6.74(dd,J=7.2,4.0Hz,1H),4. 99–4.76(m,1H),4.30–4.10(m,2H),3.55(d,J=7.6Hz,2H),2.97–2.79(m,2H),1.68–1.53(m,2H),1.37–1.15(m,27H).

[0124] Example 10

[0125] Preparation of 3-(3,3-difluoroallyl)-1-(12-hydroxydodecyl)quinoxaloline-2(1H)-one (1i):

[0126]

[0127] 1-(12-hydroxydodecyl)quinoxalin-2(1H)-one (100 mg, 0.30 mmol) and cesium carbonate (196 mg, 0.60 mmol) were mixed in 3 mL of 1,2-dichloroethane. 2,4,5,6-tetrakis(9-carbazolyl)-isophthalonitrile (12 mg, 0.015 mmol), N,N-diisopropylethylamine (3.88 mg, 0.030 mmol), and 3-bromo-3,3-difluoro-1-propene (94 mg, 0.60 mmol) were added to the reaction mixture. The reaction mixture was bubbled with nitrogen at 0 °C for 1 minute, and then stirred at 25 °C for 10 hours under 18 W 450 nm blue light. The reaction mixture was then diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by rapid silica gel chromatography (petroleum ether: ethyl acetate 2:1) to give a yellow solid 3-(3,3-difluoroallyl)-1-(12-hydroxydodecyl)quinoxaline-2(1H)-one (29 mg).

[0128] MS(M+1): 407.

[0129] 1 H NMR(400MHz, CDCl3)δ7.86(dd,J=8.0,1.2Hz,1H),7.56–7.51(m,1H),7.36–7.29(m,2H),4.81–4.65(m,1H),4.2 6–4.21(m,2H),3.66–3.62(m,4H),1.77–1.71(m,2H),1.57–1.55(m,2H),1.47–1.42(m,2H),1.35–1.26(m,14H).

[0130] Example 11

[0131] Preparation of 7-bromo-3-(3,3-difluoroallyl)-1-methylquinoxalin-2(1H)-one (1j):

[0132]

[0133] 7-Bromo-1-methylquinoxalin-2(1H)-one (72 mg, 0.30 mmol) and potassium carbonate (83 mg, 0.60 mmol) were mixed in 3 mL of 1,2-dichloroethane. 2,4,5,6-Tetratetra(9-carbazolyl)-isophthalonitrile (12 mg, 0.015 mmol), N,N-diisopropylethylamine (3.88 mg, 0.030 mmol), and 3-bromo-3,3-difluoro-1-propene (94 mg, 0.60 mmol) were added to the reaction mixture. The reaction mixture was bubbled with nitrogen at 0 °C for 1 minute, and then stirred at 25 °C for 6 hours under 18 W 450 nm blue light. The reaction mixture was then diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by rapid silica gel chromatography (petroleum ether: ethyl acetate 3:1) to give a yellow solid 7-bromo-3-(3,3-difluoroallyl)-1-methylquinoxalin-2(1H)-one (6 mg).

[0134] MS(M+1): 315 / 317.

[0135] 1 H NMR (400MHz, CDCl3) δ7.71–6.69(m,1H),7.47–7.44m,2H),4.77–4.63(m,1H),3.67(s,3H),3.63(dt,J=7.6,1.6Hz,2H).

[0136] Example 12

[0137] Preparation of 6-bromo-3-(3,3-difluoroallyl)-1-methylquinoxalin-2(1H)-one (1k):

[0138]

[0139] 6-Bromo-1-methylquinoxalin-2(1H)-one (72 mg, 0.30 mmol) and potassium carbonate (83 mg, 0.60 mmol) were mixed in 3 mL of 1,2-dichloroethane. 2,4,5,6-Tetratetra(9-carbazolyl)-isophthalonitrile (12 mg, 0.015 mmol), N,N-diisopropylethylamine (3.88 mg, 0.030 mmol), and 3-bromo-3,3-difluoro-1-propene (94 mg, 0.60 mmol) were added to the reaction mixture. The reaction mixture was bubbled with nitrogen at 0 °C for 1 minute, and then stirred at 25 °C for 4 hours under 18 W 450 nm blue light. The reaction mixture was then diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by rapid silica gel chromatography (petroleum ether: ethyl acetate 3:1) to give a yellow solid 6-bromo-3-(3,3-difluoroallyl)-1-methylquinoxalin-2(1H)-one (9 mg).

[0140] MS(M+1): 315 / 317.

[0141] 1 H NMR (400MHz, CDCl3) δ8.02 (d, J=2.4Hz, 1H), 7.64 (dd, J=8.8, 2.4Hz, 1H), 7.19 (d,J=8.8Hz,1H),4.77–4.62(m,1H),3.69(s,3H),3.65(dt,J=7.6,1.6Hz,2H).

[0142] Example 13

[0143] Preparation of 3-(3,3-difluoroallyl)-1-methyl-6-(trifluoromethyl)quinoxalin-2(1H)-one (1m):

[0144]

[0145] 1-Methyl-6-(trifluoromethyl)quinoxalin-2(1H)-one (69 mg, 0.30 mmol) and cesium carbonate (196 mg, 0.60 mmol) were mixed in 3 mL of 1,2-dichloroethane. 2,4,5,6-Tetratetra(9-carbazolyl)-isophthalonitrile (12 mg, 0.015 mmol), N,N-diisopropylethylamine (3.88 mg, 0.030 mmol), and 3-bromo-3,3-difluoro-1-propene (94 mg, 0.60 mmol) were added to the reaction mixture. The reaction mixture was bubbled with nitrogen at 0 °C for 1 minute, and then stirred at 25 °C for 18 hours under 18 W 450 nm blue light. The reaction mixture was then diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by rapid silica gel chromatography (petroleum ether: ethyl acetate 2:1) to give a yellow solid 3-(3,3-difluoroallyl)-1-methyl-6-(trifluoromethyl)quinoxalin-2(1H)-one (25 mg).

[0146] MS(M+1): 305.

[0147] 1 H NMR (400MHz, DMSO-d6) δ8.11(s,1H),7.94(dd,J=8.8,1.6Hz,1H),7.76(d,J=8.8Hz,1H),4.96–4.81(m,1H),3.66(s,3H),3.58(d,J=7.6Hz,2H).

[0148] Based on the above-described preferred embodiments of the present invention, those skilled in the art can make various changes and modifications without departing from the inventive concept, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for the CH3,3-difluoroallylation reaction of a 1,2-dihydroquinoxalin-2-one derivative, characterized in that, Includes the following steps: Using 1,2-dihydroquinoxaline-2-one derivatives and 3-bromo-3,3-difluoro-1-propene as coupling agents, a coupling reaction was carried out under visible light conditions in an environment of inorganic base and organic amine, catalyzed by a photo-redox catalyst, to obtain the compound shown in Formula II. In the formula: X is arbitrarily selected from alkyl, phenyl, propenyl, hydroxyalkyl, haloalkyl, protected aminoalkyl, and acetate; Y1 and Y2 are both arbitrarily selected from H, halogen, and trifluoromethyl.

2. The reaction method according to claim 1, characterized in that: The photo-oxidation-reduction catalyst is selected from 4CzIPN, 4DPAIPN or 4CzTPN.

3. The reaction method according to claim 1, characterized in that: The organic amine is N,N-diisopropylethylamine or triethylamine.

4. The reaction method according to claim 1, characterized in that: The inorganic base is selected from potassium carbonate or cesium carbonate.

5. The reaction method according to claim 1, characterized in that: The visible light is blue light, with a wavelength range between 410nm and 470nm.

6. The reaction method according to claim 4, characterized in that, The reaction steps include: mixing 1,2-dihydroquinoxaline-2-one derivatives and inorganic bases in an organic solvent; adding a catalyst, an organic amine, and 3-bromo-3,3-difluoro-1-propene to the reaction solution; carrying out a coupling reaction under blue light; and separating and purifying the coupling reaction product to obtain the CH 3,3-difluoroallylation product of the 1,2-dihydroquinoxaline-2-one derivative.

7. The reaction method according to claim 6, characterized in that, Water quenching is used to quench photocatalytic coupling reactions; And / or, at the end of the photocatalytic coupling reaction, the reaction solution is preferentially diluted in ice water before proceeding to the next step; And / or, the separation and purification of the coupling reaction products includes extraction, washing, and column chromatography.

8. The reaction method according to claim 6, characterized in that, The organic solvent is selected from any one or a combination of several of methanol, ethanol, acetonitrile, dichloromethane, 1,2-dichloroethane, ethyl acetate, N,N-dimethylacetamide, tert-butanol, and 1,4-dioxane.

9. The reaction method according to claim 1, characterized in that, The molar ratio of the compound shown in Formula I to the catalyst and the organic amine is 1:(0.003~0.1):(0.08~0.2); the molar ratio of the compound shown in Formula I to 3-bromo-3,3-difluoro-1-propene is 1:(1.8~3); and the molar ratio of the compound shown in Formula I to the inorganic base is 1:(1.5~3).

10. The reaction method according to claim 1, characterized in that, The reaction temperature is 25℃-65℃, and the reaction time is 4-16h.

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