A new method for the synthesis of alpha-aryl-beta-difluoromethyl substituted ketones by visible light induction

Abstract

This invention relates to the visible light-induced synthesis of α-aryl-β-difluoromethyl-substituted ketone compounds. The method utilizes a photocatalytic strategy to construct valuable α-aryl-β-difluoromethyl-substituted ketone compounds through radical-mediated difluoromethylation and migration of 1,2-aryl groups. The method and synthetic steps include: Step 1: Using 80W blue light as a visible light source, α,α-diphenylallyl alcohol (1a), difluoromethyl ylide (2), photocatalyst fac-Ir(ppy)3, sodium acetate, and methanol are added to a 10 mL reaction tube and placed in a nitrogen atmosphere; Step 2: Under visible light irradiation, the reaction is stopped when the starting material α,α-diphenylallyl alcohol (1a) is completely consumed; Step 3: After the reaction is complete, the solvent is removed by vacuum distillation. The crude product is purified by rapid column chromatography to obtain α-aryl-β-difluoromethyl-substituted ketone compounds (3a). This reaction has the advantages of mild conditions, simple operation, broad substrate compatibility, and good functional group tolerance.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis technology, specifically relating to a method for preparing α-aryl-β-difluoromethyl substituted ketone compounds. Background Technology

[0002] Organofluorine compounds, due to their unique biological, physical, and chemical properties, play a significant role in improving metabolic stability and lipophilicity. They also play an important role in the development of various agrochemicals and pharmaceuticals. Notably, difluoromethyl (-CF₂H) has been shown to be an important donor for lipophilic hydrogen bonds, a property that allows it to function as a bioisostere for thiols and alcohols in vivo. Therefore, new synthetic methods and reagents for introducing difluoromethyl groups into organic molecules through nucleophilic, electrophilic, and free radical pathways are constantly being developed. Over the past few decades, thanks to the continuous efforts of numerous researchers, significant breakthroughs have been achieved in the difluoromethylation of aromatic and heteroaromatic hydrocarbons. The regioselective and stereoselective difluoromethylation of alkenes has also been effectively developed with researchers' attention. Meanwhile, difluoromethylating agents such as HCF2SO2Cl, Zn(SO2CF2H)2, HCF2SO2Na, and N-toluenesulfonyl-S-difluoromethyl-S-phenylsulfonylimide have also been developed and used under the above circumstances. The regioselective and stereoselective difluoromethylation of olefins has also been effectively developed with the attention of researchers.

[0003] However, most of the aforementioned difluoromethylating agents require multiple synthetic steps, and the raw materials are not readily available. Therefore, the development of new, practical, inexpensive, and easily processed difluoromethylating agents has become an important research direction. Against this backdrop, difluoromethyl ylide ([Ph3P...)... + CF2H]Br - Ph3P has been developed as a highly efficient nucleophilic difluoromethylating agent and has been successfully applied to introduce difluoromethyl groups into organic molecules. + CF2H]Br - It has advantages such as inexpensive and readily available reactants, a short synthetic route, and convenient purification. Therefore, it has good application prospects. Furthermore, in the past, thanks to the efforts of researchers, [Ph3P] has been utilized... + CF2H]Br - The introduction of difluoromethyl groups into organic molecules has also yielded some groundbreaking achievements.

[0004] For example, in the method disclosed in reference 1 (Deng Z, Lin JH, Cai J, Xiao J C.Org.Lett.2016, 18(13):3206-3209), in the presence of Cs2CO3, [Ph3P]+ CF2H]Br - A highly efficient nucleophilic difluoromethylation reaction was carried out on aldehydes and ketones to give α-difluoromethyl alcohols in moderate to excellent yields. The specific reaction procedure is shown below:

[0005]

[0006] The method disclosed in Reference 2 (Hu WQ, Xu XH, Qing F LJ Fluor. Chem. 2018, 208, 73-79.) was used to study the difluoromethylation of difluoromethyl ylides with olefinic derivatives of indole induced by visible light. The reaction yielded various difluoromethyl oxyindole in moderate to excellent yields. The specific reaction process is shown below:

[0007]

[0008] The method disclosed in Reference 3 (Zhu TH, Zhang ZY, Tao JY, Zhao K, Loh TP.; Org. Lett. 2019, 21(15): 6155-6159.) is based on photo-oxidation-reduction catalysis [Ph3P + The regioselective and stereoselective difluoromethylation of enamides by CF₂H]Br. This reaction is simple to operate and exhibits good functional group tolerance, opening a new route for the synthesis of pharmaceutically significant difluoromethylated enamides. The specific reaction process is shown below:

[0009]

[0010] The method disclosed in Reference 4 (Fang, Y.; Liu, C.; Tang, J.; Pei, Z.; Chen, Z.; J. Org. Chem. 2023, 88, 12658-12667.) describes the visible-light photocatalytic difluoromethylation of selenium sulfonate to synthesize difluoromethyl selenide. This reaction utilizes [Ph3P... + CF2H]Br - A series of pharmaceutically active difluoromethylselenoside compounds were obtained by photocatalytic radical reactions with selenium-substituted sulfonates. The system requires no additional base or reducing agent and exhibits good tolerance to functional groups. The specific reaction process is shown below:

[0011] Summary of the Invention

[0012] The purpose of this invention is to provide a mild method for the difluoromethylation of α,α-diarylallyl alcohol into a 1,2-aryl migration tandem reaction, with the aim of constructing α-aryl-β-difluoromethyl substituted ketone compounds of significant value in organic synthesis and biomedicine.

[0013] To solve the technical problem of this invention, the proposed technical solution is: a method for visible light-induced difluoromethylation of α,α-diarylallyl alcohol into a tandem migration reaction of 1,2-aryl groups, comprising the following steps:

[0014] Step 1: Using an 80W blue light source, add α,α-diarylallyl alcohol (1a), difluoromethyl ylide (2), photocatalyst fac-Ir(ppy)3, sodium acetate and methanol to a 10mL reaction tube, and place it in a nitrogen atmosphere;

[0015] Step 2: Under blue light irradiation, the reaction stops when the raw material α,α-diarylallyl alcohol (1a) is completely consumed;

[0016] Step 3: After the reaction is complete, the solvent in the system is removed by vacuum distillation. The crude product is then purified by rapid column chromatography to obtain an α-aryl-β-difluoromethyl-substituted ketone compound (3a). The specific reaction equation is as follows:

[0017]

[0018] R1 is a substituted or unsubstituted aryl or alkyl group; R2 is a substituted or unsubstituted aryl group; R3 is hydrogen or methyl. R1 and R2 can be the same or different.

[0019] Preferably, the α,α-diarylallyl alcohol is selected from α,α-diphenylallyl alcohol and its derivatives.

[0020] Preferably, the reaction is carried out at room temperature for 24 hours.

[0021] Preferably, the solvent is methanol.

[0022] Preferably, the molar ratio of the reaction is raw material A: raw material B: photocatalyst fac-Ir(ppy)3: sodium acetate = 1:2:0.015:2.

[0023] The specific implementation scheme of the present invention is as follows:

[0024] Step 1: Using an 80W blue light source, add α,α-diphenylallyl alcohol (1a), difluoromethyl ylide (2), photocatalyst fac-Ir(ppy)3, sodium acetate and methanol to a 10mL reaction tube, and place it in a nitrogen atmosphere;

[0025]

[0026] Step 2: Under blue light irradiation, the reaction stops when the raw material α,α-diphenylallyl alcohol (1a) is completely consumed;

[0027] Step 3: After the reaction is complete, the solvent in the system is removed by vacuum distillation. The crude product is separated and purified by rapid column chromatography to obtain α-phenyl-β-difluoromethyl substituted ketone compounds (3a).

[0028]

[0029] The optimal solvent used in step one is methanol;

[0030] In step two, the reaction is monitored by a TLC plate, and the reaction time is 24 hours.

[0031] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0032] 1. The reaction system of this invention is simple, the reaction conditions are mild, and the selected substrate is stable;

[0033] 2. The method used in this invention has wide applicability. Most common α,α-diarylallyl alcohols are applicable to this method. The substrates are also widely applicable. A series of α-aryl-β-difluoromethyl substituted ketone compounds can be prepared according to this method.

[0034] 3. The main role of sodium acetate, an additive in this invention, in this reaction is as a hydrogen transfer reagent, promoting the catalytic cycle of the photocatalyst;

[0035] 4. The visible light induction method used in this invention has been screened and proven to be unique in this reaction. Attached Figure Description

[0036] Figure 1 The nuclear magnetic resonance of 4,4-difluoro-2-methyl-1,2-diphenylbut-1-one provided in Example 1 of this invention. 1 H spectrum;

[0037] Figure 2 The nuclear magnetic resonance of 4,4-difluoro-2-methyl-1,2-diphenylbut-1-one provided in Example 1 of this invention. 13 C spectrum;

[0038] Figure 3 The nuclear magnetic resonance of 4,4-difluoro-2-methyl-1,2-diphenylbut-1-one provided in Example 1 of this invention. 19 F-spectrum;

[0039] Figure 4The nuclear magnetic resonance (NMR) of 4,4-difluoro-2-methyl-1,2-di-p-tolylbut-1-one provided in Example 1 of this invention. 1 H spectrum;

[0040] Figure 5 The nuclear magnetic resonance (NMR) of 4,4-difluoro-2-methyl-1,2-di-p-tolylbut-1-one provided in Example 1 of this invention. 13 C spectrum;

[0041] Figure 6 The nuclear magnetic resonance (NMR) of 4,4-difluoro-2-methyl-1,2-di-p-tolylbut-1-one provided in Example 1 of this invention. 19 F-spectrum;

[0042] Figure 7 The nuclear magnetic resonance (NMR) of 1,2-di(4-bromophenyl)-4,4-difluoro-2-methylbut-1-one provided in Example 1 of this invention. 1 H spectrum;

[0043] Figure 8 The nuclear magnetic resonance (NMR) of 1,2-di(4-bromophenyl)-4,4-difluoro-2-methylbut-1-one provided in Example 1 of this invention. 13 C spectrum;

[0044] Figure 9 The nuclear magnetic resonance (NMR) of 1,2-di(4-bromophenyl)-4,4-difluoro-2-methylbut-1-one provided in Example 1 of this invention. 19 F-spectrum. Detailed Implementation

[0045] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0046] The method of this invention can synthesize acetamide compounds with different structures through the same mechanism, depending on the different structures of the reaction substrates.

[0047] Using difluoromethyl ylide as a template substrate, the practicality of the method was discussed using different α,α-diarylallyl alcohols. The specific reaction equations are as follows:

[0048]

[0049] R1 is a substituted or unsubstituted aryl or alkyl group, R2 is a substituted or unsubstituted aryl group, and R3 is hydrogen or methyl. R1 and R2 can be the same or different. Its structural formula is as follows:

[0050]

[0052] Example 1

[0053] This embodiment demonstrates the preparation of 4,4-difluoro-2-methyl-1,2-diphenylbut-1-one, with the specific steps as follows:

[0054]

[0055] Under a nitrogen atmosphere, α,α-diphenylallyl alcohol (0.2 mmol), difluoromethyl ylide (0.4 mmol), sodium acetate (0.4 mmol), and photocatalyst fac-Ir(ppy)3 (0.003 mmol) were sequentially added to methanol (2.0 ml) to obtain a mixed solution. The mixed solution was stirred under 80 W blue light at room temperature until the reaction was complete. The reaction solution was extracted and separated by silica gel column chromatography to obtain fluoroalkylated ketone compound 4,4-difluoro-2-methyl-1,2-diphenylbut-1-one. The product was a colorless oil with a yield of 82%.

[0056] The 1H NMR data for 4,4-difluoro-2-methyl-1,2-diphenylbut-1-one are as follows: 1 H NMR (400MHz, CDCl3) δppm 7.43-7.36 (m, 5H), 7.35-7.31 (m, 3H), 7.25-7.20 (m, 2H), 5.62 (tdd, J=56.4, 5.4, 4.0Hz, 1H), 2.64-2.44 (m, 2H), 1.76 (s, 3H).

[0057] The carbon NMR data of 4,4-difluoro-2-methyl-1,2-diphenylbut-1-one are as follows: 13 C NMR (100MHz, CDCl3) δppm 202.2, 141.8, 135.8, 132.2, 129.8, 129.6, 128.2, 127.8, 126.2, 116.8 (t, J C-F =238.4Hz), 52.2(t, J) C-F =5.0Hz), 45.0(t, J) C-F =21.4Hz), 22.9.

[0058] The nuclear magnetic resonance fluorine spectrum data of 4,4-difluoro-2-methyl-1,2-diphenylbut-1-one are as follows: 19 F NMR (376MHz, CDCl3) δppm-109.98--111.96(m).

[0059] Example 2

[0060] This embodiment demonstrates the preparation of 4,4-difluoro-2-methyl-1,2-di-p-tolylbut-1-one, with the specific procedures as follows:

[0061]

[0062] Under a nitrogen atmosphere, 2-methyl-1,1-di-p-tolylprop-2-en-1-ol (0.2 mmol), fluoromethyl ylide (0.4 mmol), sodium acetate (0.4 mmol), and photocatalyst fac-Ir(ppy)3 (0.003 mmol) were sequentially added to methanol (2.0 ml) to obtain a mixed solution. The mixed solution was stirred under 80 W blue light at room temperature until the reaction was complete. After extraction and separation by silica gel column chromatography, the fluoroalkylated ketone compound 4,4-difluoro-2-methyl-1,2-di-p-tolylbut-1-one was obtained. The product was a colorless oil with a yield of 89%.

[0063] The 1H NMR data for 4,4-difluoro-2-methyl-1,2-di-p-tolylbut-1-one are as follows: 1 H NMR (400MHz, CDCl3) δppm 7.48-7.36 (m, 2H), 7.18 (s, 4H), 7.04-7.02 (m, 2H), 5.61 (tdd, J=56.5, 5. 4, 4.0Hz, 1H), 2.57-2.44(m, 2H), 2.35(s, 3H), 2.29(s, 3H), 1.73(s, 3H).

[0064] The carbon NMR data for 4,4-difluoro-2-methyl-1,2-di-p-tolylbut-1-one are as follows: 13 C NMR (100MHz, CDCl3) δppm 201.8, 142.9, 139.1, 137.4, 133.1, 130.2, 130.1, 128.9, 126.1, 117.0 (t, J C-F =238.3Hz), 51.8(t, J) C-F =4.9Hz), 45.2(t, J) C-F =21.3Hz).,23.1,21.6,21.2.

[0065] The nuclear magnetic resonance fluorine spectrum data of 4,4-difluoro-2-methyl-1,2-di-p-tolylbut-1-one are as follows: 19 F NMR (376MHz, CDCl3) δppm-109.90--111.88(m).

[0066] Example 3

[0067] This embodiment describes the preparation of 1,2-bis(4-bromophenyl)-4,4-difluoro-2-methylbut-1-one, and the specific procedures are as follows:

[0068]

[0069] Under a nitrogen atmosphere, 1,1-di(4-bromophenyl)-2-methylprop-2-en-1-ol (0.2 mmol), difluoromethyl ylide (0.4 mmol), sodium acetate (0.4 mmol), and photocatalyst fac-Ir(ppy)3 (0.003 mmol) were sequentially added to methanol (2.0 ml) to obtain a mixed solution. The mixed solution was stirred under 80 W blue light at room temperature until the reaction was complete. The reaction solution was extracted and separated by silica gel column chromatography to obtain the fluoroalkylated ketone compound 1,2-di(4-bromophenyl)-4,4-difluoro-2-methylbut-1-one. The product was a colorless oil with a yield of 91%.

[0070] The 1H NMR data for 1,2-bis(4-bromophenyl)-4,4-difluoro-2-methylbut-1-one are as follows: 1 H NMR (400MHz, CDCl3) δppm 7.55-7.52 (m, 2H), 7.41-7.38 (m, 2H), 7.32-7.29 (m, 2H), 7.19-7.15 (m, 2H), 5.64 (tdd, J=56.2, 5.2, 4.1Hz), 2.61-2.38 (m, 2H), 1.73 (s, 3H).

[0071] The carbon NMR data of 1,2-bis(4-bromophenyl)-4,4-difluoro-2-methylbut-1-one are as follows: 13 C NMR (100MHz, CDCl3) δppm200.4, 140.8, 134.0, 132.8, 131.7, 131.3, 127.9, 127.6, 122.2, 116.3 (t, J C-F =238.8Hz), 51.9 (dd, J C-F =5.6, 4.2Hz), 44.8 (t, J) C-F =21.7Hz), 22.9(t, J) C-F =1.4Hz).

[0072] The nuclear magnetic resonance fluorine spectrum data of 1,2-bis(4-bromophenyl)-4,4-difluoro-2-methylbut-1-one are as follows: 19 F NMR (376MHz, CDCl3) δppm-110.10--112.03(m).

[0073] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A novel method for the synthesis of α-aryl-β-difluoromethyl substituted ketone compounds by visible light induction, characterized by: Includes the following steps: Step 1: Using an 80W blue light source, add α,α-diphenylallyl alcohol (1a), difluoromethyl ylide (2), photocatalyst fac-Ir(ppy)3, sodium acetate and methanol to a 10mL reaction tube, and place it in a nitrogen atmosphere; Step 2: Under blue light irradiation, the reaction stops when the raw material α,α-diphenylallyl alcohol (1a) is completely consumed; Step 3: After the reaction is complete, the solvent in the system is removed by vacuum distillation. The crude product is separated and purified by rapid column chromatography to obtain α-aryl-β-difluoromethyl substituted ketone compounds (3a). The specific reaction equation is as follows: R1 is a substituted or unsubstituted aryl or alkyl group; R2 is a substituted or unsubstituted aryl group; R3 is hydrogen or methyl. R1 and R2 can be the same or different.

2. The method for preparing a synthesis of an α-aryl-β-difluoromethyl substituted ketone compound by visible light induction according to claim 1, characterized by: The reaction was carried out at room temperature for 24 hours.

3. The method for preparing α-aryl-β-difluoromethyl-substituted ketone compounds by blue light induction according to claim 1, characterized in that: The molar ratio of the reaction is α,α-diphenylallyl alcohol (1a): difluoromethyl ylide (2): photocatalyst fac-Ir(ppy)3: sodium acetate = 1:2:0.015:2.

Images