Research group of Professor Wang Qingmin of Nankai University: visible light induced dehydroxylation / defluorination strategy for the synthesis of γ, γ - difluoroallylketone

Fluorine-containing compounds with high membrane permeability, anti metabolism stability, thermal stability and chemical stability are widely used in medicine, pesticides and polymer functional materials As an important class of fluorine-containing compounds, amphiphilic alkenes not only introduce the biological characteristics of fluorine atoms into the target molecules to play a unique function, but also act as the bioelectronic equivalent of carbonyl compounds (aldehydes, ketones) Amphiphilic alkenes can also simulate the chemical reaction properties of carbonyl compounds in some key molecules γ As an important kind of bifluoroalkenes, the synthesis method of γ - difluoroalkyl ketone is still very limited at present Moreover, the simple aryl carboxylic acid is used as the substrate to synthesize γ through the production of acyl radicals under mild conditions, and γ - difluoroalkyl ketone has not been reported Recently, Professor Wang Qingmin's research group of Nankai University has made important progress in this field Under the condition of photocatalysis, they obtained acyl radical by dehydrogenation of aryl carboxylic acid assisted by triphenylphosphine, which was added with α - trifluoromethylstyrene, and then synthesized γ, γ - difluoropropylketone efficiently through reducing fluorine elimination strategy Relevant research results were published in org Lett 2020, 22, 709 − 713 Brief introduction of Professor Wang Qingmin's research group The current research work of the research group includes: separation, identification, total synthesis and structural transformation of natural pesticides; molecular design, synthesis, biological activity and structure-activity relationship of new and efficient green chemical pesticides; total synthesis of natural products and efficient construction of heterocyclic molecular framework; free radical reaction under photocatalysis to build heterocyclic molecules Professor Wang Qingmin's cutting-edge scientific research achievements: visible light induced dehydroxylation / defluorination strategy for the synthesis of γ, γ - difluoroalkyl ketone in fluoroorganic compounds, and as an important fluorine-containing group, difluoroalkene widely exists in medicine and pesticide molecules (Figure 1a) It not only introduces the biological characteristics of fluorine atoms into the target molecule to play a unique function, but also acts as the bioelectronic equivalent of carbonyl compounds (aldehydes, ketones) When the carbonyl group in some drug molecules is replaced by the bifluoroethylene, the biological activity of the molecule will be significantly improved (Fig 1b) Fig 1 the representative drugs (source: org Lett.) containing dicyclopentadifluorenyl have developed many synthesis methods of dicyclopentadifluoroene Among them, it is considered to be a very efficient way to synthesize dicyclopentaduoroene by adding α - trifluoromethylstyrene and then eliminating fluorine According to the type of reagents used, this kind of method can be divided into two reaction modes: anionic nucleophilic reagent addition and free radical addition The research on the addition of anionic nucleophiles mainly focuses on Grignard reagent, organic lithium reagent, organic amine lithium reagent and enol reagent, etc due to the strong alkalinity, strong nucleophilic, the functional group tolerance is not good, and the reaction substrate is often limited In the past decade, photoreaction has been widely used as a mild and efficient synthesis method It is a highly efficient method for the synthesis of amphiphilic alkenes by the addition of free radicals generated by photoreaction to α - trifluoromethylstyrene and then reduction of fluorine to eliminate the molecules containing amphiphilic alkenes (Fig 2a) Fig 2 synthesis of amphiphilic alkenes (source: org Lett.) γ, γ - amphiphilic allylketone as an important kind of amphiphilic alkenes by fluorine elimination strategy At present, only one case of this kind of compounds is reported by Professor Zhou Lei's research group (J org Chem 2016, 81, 7908 − 7916) Their strategy is to get acyl radical by decarboxylation of α - ketoacids This radical is added to α - trifluoromethylstyrene, and then γ is synthesized by reducing fluorine, Although this method can realize the efficient synthesis of some substrates, the scope of substrates is very limited due to the non-commercial and complex synthesis of α - ketoacids and low atomic economy (Fig 2b) The corresponding aromatic carboxylic acid is a kind of cheap, easy to obtain and rich chemical raw materials Through the activation and functionalization of carboxylic acid, the library of organic small molecular compounds can be rapidly enriched After nearly ten years of development, palladium, silver and copper catalyzed deacidification and coupling strategies have made aromatic carboxylic acids become cheap aryl precursors, while carboxylic acids as acyl precursors are still rarely reported (NAT Commun 2018, 9, 3517 − 3526; angel Chem Int ed 2019, 58, 312 – 316; ACS catalyst 2018, 8, 11134-11139; green chem 2019, 21, 5368 – 5373) If a simple aryl carboxylic acid can be used as an acyl precursor to synthesize γ, γ - difluoroalkyl ketone will have very high atomic economy and step economy Based on this design, Professor Wang Qingmin's research group of Nankai University obtained acyl radical through the hydroxylation of aryl carboxylic acid assisted by triphenylphosphine under the condition of photocatalysis This radical was added with α - trifluoromethylstyrene, and then γ, γ - difluoroalkyl ketone was efficiently synthesized by reducing fluorine (Fig 2C) A variety of photocatalysts and reducers were screened by using 4-methylbenzoic acid and α - trifluoromethylstyrene as reaction substrates When [IR (CF (3) PPy) 2 (dtbbpy)] pf 6 (2 mol%) was used as photocatalyst, triphenylphosphine as reducing agent, NaHCO 3 as base and 4 Å molecular sieve as additive, the target product 3A could be obtained with 90% separation yield When other bases are used instead of NaHCO 3, the yield will be reduced The author has made further control experiments, and the reaction can not occur without light, photocatalyst and reductant (Table 1) Table 1 After selecting the optimal reaction condition a (source: org Lett.), the author first investigated the substrate range of aryl carboxylic acid, and found that the reaction has a wide application range for aryl carboxylic acid, and the target product can be obtained in a medium to good yield (Table 2) The reaction is well compatible with all kinds of alkyl and halogen (3a-3g, 3L), and with the o-and m-substituents on the aromatic ring (3j, 3K) The target product (3h-3i, 3m-3n) can also be obtained in high yield for the substrate reaction with active functional groups The target product (3O – 3V) can be obtained from aromatic carboxylic acids containing fused ring, fused heterocycle and heteroaromatic ring in medium to good yield The reaction system can obtain the product (3w, 3x) by decarbonylation coupling in good yield for the phenylacetic acid type carboxylic acid, but it is not suitable for the ordinary alkyl carboxylic acid and the aryl carboxylic acid containing the electron pulling group Table 2 carboxylic acid substrate range a (source: org Lett.) next, the author investigated the substrate range of trifluoromethylstyrene (Table 3) When R is phenyl, the author found that the reaction is very suitable for the benzene ring containing halogen, o-substituent and m-substituent (4b-4e ）At the same time, the reaction can also be well applied to the substrate (4f-4l) containing alkyl, fluoroalkoxy, alkoxy and ester substituents on the benzene ring; R is fused aromatic ring and heteroaromatic ring, which can also be applied to the reaction (4m, 4N) For the conjugated 2-trifluoromethyl-1,3-enyne, the target product (4o-4p) can also be obtained in medium yield Table 3 The late functionalization of trifluoromethylstyrene substrate range a (source: org Lett.) is of great significance for chemists to find more active drugs In order to show the practicability of this method, the author used this method to study the late functionalization of some common pesticide and medicine molecules (Table 4) For example, the herbicide dicamba, adapalene for the treatment of acne and psoriasis, and indomethacin, a non steroidal anti-inflammatory drug for antipyretic and analgesic, can obtain the target product (5a-5c) in good yield Table 4 later functionalization of bioactive molecules (source: org Lett.) after exploring the scope of application of the reaction substrate and the applicability of the reaction, the author studied the mechanism of the reaction (Table 5) When the free radical inhibitor tempo was added to the reaction system, the main reaction was completely inhibited, and the addition of tempo and acyl radicals could be detected by high-resolution mass spectrometry When 1,1-diphenylethylene is added to the reaction system, the main reaction is completely inhibited and the coupling product 6 of acyl radical and 1,1-diphenylethylene can be successfully separated These results show that the reaction is carried out through the free radical path When DMF and water were used instead of the original DMF, the products of difluoride and trifluoromethane could be obtained in the ratio of 1:1, which indicated that there might be a anion intermediate in the reaction Table 5 mechanism experiment a (source: org Lett.) based on mechanism experiment and related literature reports, the author proposed the following reaction mechanism (Figure 3) Under the condition of illumination, the photocatalyst is excited The excited trivalent photocatalyst oxidizes triphenylphosphine to ph3p + •, and at the same time, the strong reducing bivalent photocatalyst is obtained PH 3P + • combines with carboxylic acid anion to obtain free radical intermediate a, which will undergo cleavage of β - C (acyl) - O to obtain acyl radical intermediate B, B and α - trifluoromethylstyrene to obtain benzyl radical intermediate C, which will be reduced by bivalent photocatalyst to obtain negative ion intermediate C D At the same time, the catalyst is regenerated and enters the next cycle The anion intermediate D is then eliminated by β - fluorine to get γ, γ - bifluorallyl ketone The whole reaction process was carried out under the condition of oxidation-reduction neutrality, and no external redox agent was needed Fig 3 possible reaction mechanism (source: org Lett.) the author of this paper is Professor Wang Qingmin from Nankai University Guo yuanqiang, a doctoral candidate of Nankai University, is the first author of the paper Liu Yuxiu, an associate researcher of Nankai University, song Hongjian, an associate researcher, and Wang ruiguo, a master's student, have also made great contributions to the smooth progress of the work The above research work was supported by the key project of NSFC (21732002).