Research group of Professor Wang Qingmin of Nankai University: visible light induced decarboxylation coupling reaction of n-heteroaromatics and redox active esters catalyzed by copper

Source: ruthenium and iridium complexes of Professor Wang Qingmin's research group are widely used as photocatalysts for their strong visible light absorption, suitable redox potential and long-lived excited states In recent years, copper, which is abundant and cheap in the earth, has shown similar properties to the noble metal photocatalysts mentioned above under visible light Some Cu I photocatalysts play a special role in promoting electron transfer to the substrate, which is even beyond their low-cost advantages However, there are no reports of copper as a photocatalyst to promote Minisci like reactions Recently, on the basis of previous research work (chem SCI 2019, 10, 976-982; org Lett 2018, 20, 5661-5665), the research team of Professor Wang Qingmin of Nankai University has realized the visible light induced decarboxylation coupling reaction of copper catalyzed n-heteroaromatics and redox active esters Relevant research results were published in org Lett (DOI: 10.1021/acs.orglett.9b02105) Fig 1 Decarboxylation and coupling reaction of n-heteroarene and redox active ester (source: org Lett.) firstly, the author selected n - (cyclohex-3-ene-1-formyl) phthalimide 1K and isoquinoline 2A as template substrate, and determined the optimal condition as: 10mol% Cu (MeCN) 4bf4 through screening of copper catalyst, ligand, acid and solvent As copper catalyst, 15 mol% 2,9-Dimethyl-1,10-phenanthroline (DMP), 15 mol% xantphos as ligand, 10 mol% Zn (OTF) 2 as Lewis acid, 2 ml dimethylacetamide (DMA) as solvent, 1K and 2A react in argon atmosphere under 5 W blue light for 24 hours, and the corresponding product 3KA can be obtained with 87% separation yield (Table 1) Table 1 Optimization of conditions (source: org Lett.) then, under the optimal conditions, the author first investigated the application scope of alkyl NHP ester (Fig 2) The primary, secondary and tertiary aliphatic esters are suitable substrates Specifically, the first-order aliphatic acid ester can obtain the corresponding product (3AA - 3CB) in medium yield However, it is a pity that 3DA was not obtained, which may be due to the fact that methyl radicals are not as stable and nucleophilic as secondary and tertiary radicals The product 3EA - 3lb can be obtained from the ring secondary alkyl radical in medium to good yield It is gratifying that when the reaction is expanded to gram scale, 3KA can also be obtained in medium yield In addition, the chain second-order aliphatic acid ester can also obtain 3 Ma in a medium yield The alkylation strategy can also be applied to tertiary aliphatic esters The corresponding product 3Na - 3TB can be obtained from ring or non ring substrates in medium to good yields It is worth noting that the derived natural and non natural α - amino acid NHP alkyl esters show good compatibility with the reaction conditions Among them, the derivatives of phenylalanine, alanine and valine obtained the corresponding product (3ua - 3wb) in excellent yield (88-95%) Surprisingly, the isoleucine derivatives obtained the product 3XB almost in quantitative yield The yield of N-Boc proline was 46% Fig 2 application range of alkyl NHP ester (source: org Lett.) later, the author investigated the substrate range of n-heteroarene reaction (Fig 3) Because the reaction is carried out at room temperature without strong acid and oxidant, it shows good functional group tolerance Both electron donor and electron deficient substituents are well compatible in the system F CL and Br substituted Isoquinolines are good substrates (3gc - 3GG), and the different substitution positions of BR have little effect on the yield Ester, amide, methoxy or methyl substituted isoquinoline can all react with 1g to obtain the corresponding product 3gh - 3gk in medium to good yield In addition to isoquinoline, many other n-heteroarenes, such as quinoline, pyridine derivatives, pyrimidine, quinazoline, phthalazine, phenanthridine and pyridazine derivatives, are good substrates Among them, 3 go was produced in 94% yield from phthalazine with multiple reaction sites Surprisingly, the product 3gp was obtained almost quantitatively by phenanthridine In addition, in this reaction system, the author also successfully achieved the cyclohexylation of coumarin and obtained 3gr Fig 3 application scope of n-heteroaromatics (source: org Lett.) in order to further understand the reaction mechanism, the author conducted mechanism research experiments (Fig 4) When tempo or BHT were added to the reaction system, the adducts of them and alkyl radicals could be detected by high-resolution mass spectrometry, and it was found that the reaction was completely inhibited in the former reaction system When 1,1-diphenylethylene is used as the reaction substrate instead of isoquinoline, the author can successfully separate the catch product 3U of heck type These results show that the reaction is carried out through the free radical path In order to understand the role of Cu I photocatalyst, Cu (DMP) (xantphos) BF 4 photocatalyst was synthesized in advance The absorption spectrum of Cu (DMP) (xantphos) BF 4 is consistent with the emission wavelength of blue light Diamine and diphosphonic ligands improve its light absorption performance, light-emitting lifetime, redox potential and photoinitiation ability When the complex was directly used instead of the combination of Cu (MeCN) 4bf4, DMP and xantphos as photocatalyst, the yield of the product was slightly lower than that under standard conditions And in the absence of light, the reaction basically does not occur The high resolution mass spectrometry data of the reaction solution also showed that Cu (DMP) (xantphos) BF 4 was formed in the reaction system These results show that the complex is an active photocatalyst Fig 4 mechanism study experiment (source: org Lett.) finally, based on the results of mechanism study experiment and previous relevant reports, the author proposed the reaction mechanism shown in Fig 5 The photoexcited complex [Cu I l] * reduces the alkyl NHP ester to produce the free radical intermediate I Then, the N-O bond cleavage and the elimination of CO 2 occurred, and the corresponding alkyl radical II and o-phthalimide anions were obtained The complexation of Lewis acid makes n-heteroarenes more electron deficient, so they are also more vulnerable to attack by alkyl radical II, accompanied by the production of radical intermediate III Subsequently, [Cu II l] oxidizes III to produce intermediate IV and regenerates [Cu IL] Finally, the final product was obtained by dehydroaaromatization of IV It is worth noting that the whole reaction process is carried out under the redox neutral condition, and there is no need to add external oxidants Figure 5 Possible mechanism (source: org Lett.) this achievement was recently published in org Lett (DOI: 10.1021 / ACS Orglett 9b02105) The first author of this paper is Lu Xueli, a master's degree student in the Institute of elements, Nankai University, and the corresponding author is Professor Wang Qingmin, Nankai University The above research work has been supported by the national key research and development plan (2018YFD0200100) and the National Natural Science Foundation of China (21732002, 21672117) The author thanks Dr Huang Yuanqiong of Nankai University for her generous help A review of previous reports: Wang Qingmin, Professor of Nankai University Research Group: light mediated Minisci C-H alkylation of non activated haloalkanes Professor Wang Qingmin, Nankai University Research Group: silver copper synergistic catalytic intramolecular cyclization / de sulfonamide / dehydrogenation reaction for efficient synthesis of substituted carbazole