Recently, the Eric M. Ferreira research group of the University of Georgia in the United States developed a novel Cr(III) catalyst, which successfully achieved the (3+2) cycloaddition reaction of indole and alkenyldiazo reagent under photocatalysis, and achieved the synthesis of a series of functionalized pyrroline compounds. Related results are published on Angew. Chem. Int. Ed..
(Image source: Angew. Chem. Int. Ed.)
In recent years, photoredox catalysis has become an important method for building chemical bond . This type of reaction originates from the excited state species produced under light initiation, which is subsequently generated by single electron transfer to produce highly active intermediates and then undergoes transformation. Currently, chemists have numerous metal or non-metallic photocatalysts , which show different reaction activities due to their different excitation reduction potentials. These active species can catalyze various types of reactions through electron transfer, such as atom transfer, cross-coupling and cycloaddition. Although chemists have developed many photocatalysts at present, improvements are still needed when the reaction encounters limitations. Recently, Eric M. Ferreira's research team reported the (3+2) cycloaddition reaction of olefin and alkenyl diazon species (Figure 1a). This reaction begins by the catalytic oxidation of electron-rich olefins by Cr or Ru. The authors hope that such photocatalytic cycloaddition reactions can be used to achieve the synthesis of heterocycles (such as indoles). An important challenge in achieving this transformation is that it must go through a dearizing process. This may involve a potential nucleophile addition pathway that can avoid the occurrence of aromatization of processes again. In previous pioneering reports, Nicewicz's research team implemented the re-arcanization process after the addition of N-nucleophilic or diazoacetate to aromatic radical cation (Figure 1b). Gryko's research team realized the C2- alkylation reaction of indole and α-diazoester (Figure 1c). Although photocatalysis has been reported to achieve intra- and intra-molecular dearamification cycloaddition reactions through energy transfer, it is still rare to achieve metal-photocatalytic dearamification cycloaddition process through electron transfer. Recently, the research group of Eric M. Ferreira of the University of Georgia in the United States, developed a novel Cr(III) catalyst, which successfully achieved the (3+2) cycloaddition reaction of indole and ene-diazo reagent under photocatalysis, and achieved the synthesis of a series of functionalized pyrroline compounds.
(Image source: Angew. Chem. Int. Ed.)
The author first used 5-bromoindole 3a and ethylene basediazo ethyl acetate 4a as template substrates for reaction exploration. Through conditional screening, the authors found that: 1) Benzoyl chloride can achieve the subsequent acyl transformation process of indole; 2) Although the synthesis of product 5 can be achieved with good regio-selectivity and diastereo-selectivity using Cr or Ru photocatalysts, the yield is lower than that of electron-rich olefins; 3) Other organic or inorganic photocatalysts have not achieved better reaction effects (Figure 2a). Subsequently, the authors conceived that the acylating agent could enhance catalyst activity. When the authors added the photocatalyst to BzCl and initiated it, they found that their UV-visible absorption had a significant change. This indicates that the component of the catalyst in the reaction may have changed (Figure 2b).
(Image source: Angew. Chem. Int. Ed.)
Although the activity of [Cr(Ph2phen)3](BF4)3 is lower than that of [Ru(bpz)3](PF6)2 in the cationic cycloaddition reaction of radical , the author believes that its reaction activity can be improved by modifying the catalyst. The authors found that when methoxy is introduced in the phenyl para-position, a red-shifted, higher absorbance Cr complex 1b ([Cr(PMP2phen)3](BF4)3) can be obtained (Figure 3a).When 1b is used as the photocatalyst, the yield of product 5 can be increased to 75%. Subsequently, the authors used TrocCl as the acyl reagent and 5 can be obtained in yields up to 95% by increasing the amount of acylation reagent and NaHCO3 (Figure 3b).
(Image source: Angew. Chem. Int. Ed.)
Subsequently, the author explored the scope of application of substrates for dearomerization cycloaddition reactions (Scheme 1). Experimental results show that the reaction can be compatible with various functional groups such as halogen, ester group , silane ether, cyano , nitro , etc. In addition, the indole substituted at C4-C7 positions can react smoothly (5j-l). In addition, different substituted alkenyl diazotides also have good compatibility. It is worth noting that the alkenyldiazo reagent based on acylpyrazole can also successfully achieve this (3+2) cycloaddition reaction (5x, 64% yield).
(Image source: Angew. Chem. Int. Ed.)
Next, the authors conducted a detailed evaluation of each reaction parameter of this cycloaddition reaction system. When radical capture agent TEMPO is added to the system, the reaction is effectively inhibited, indicating that this reaction contains a radical intermediate (Table 1).
(Image source: Angew. Chem. Int. Ed.)
cycloaddition process of C2 and (or) C3-substituted indole is usually challenging, and the above reaction system is not well compatible. Therefore, the author screened different acylation reagents and found that in the absence of a base, using pentanechoic anhydride 8 as the acylation reagent can obtain N-formylated cycloaddition product 7 (Scheme 2) in a yield of 86%.
(Image source: Angew. Chem. Int. Ed.)
Next, the author used 8 as an acylation reagent to explore the substrate applicability of a series of C2 and (or) C3-substituted indoles, proving that the newly developed system has good compatibility (Scheme 3).
(Image source: Angew. Chem. Int. Ed.)
In order to explore the reaction mechanism in depth, the author conducted a series of control experiments (Scheme 4) and came to the following conclusions: 1) N-H indole (Scheme 4a) must be used to achieve this cyclization process; 2) The addition of conjugated diene 10 does not affect this cyclization process, which may be due to the lack of energy transfer pathway (Scheme 4b); 3) Competitive experiments show that indoles that are more likely to be oxidized are preferred to participate in the reaction. And since the reduction potential of the alkenyl diazon species 4a is higher than that of indole, the photocatalytic oxidation process of the alkenyl diazon species is unlikely (Scheme 4c).
(Image source: Angew. Chem. Int. Ed.)
Based on the above experimental results and literature reports, the author proposed a possible reaction mechanism (Figure 4): First, the excited state Cr(III) oxidizes indoles to form radical cation 3+•; and since the C3 of 3+• has strong free radical characteristics, it can be combined with alkenyl diazotide to obtain the intermediate 11; then the cyclo-closed and reduced by Cr(II) or indole substrate can obtain indoline species 13; finally the product 5 is obtained by acylation. Compared with the (3+2) cycloaddition process similar to the rhodium catalytic intermediate reported by Davies' research group (J. Am. Chem. Soc.2010, 32, 440), this transformation has better regio-selectivity. Mainly because this reaction is completely induced by the indole radical cation intermediate 3+• to achieve selective control.
(Image source: Angew. Chem. Int. Ed.)
In addition, some experimental evidence can also prove that this transformation involves a single electron transfer mechanism. Because TEMPO inhibits reactive activity (Table 1, entry 16), it is illustrated that free radical species are involved in the reaction. Stern-Volmer quenching experiments show that there is a strong linear relationship between the concentration of indole 3a and the emission signal of the excited state of the Cr complex (Figure 5). Meanwhile, the concentration change of alkenyl diazide 4a did not affect the emission signal of the Cr complex. These photophysical experiments further verified the reaction mechanism triggered by electron transfer.
(Image source: Angew. Chem. Int. Ed.)
Finally, the authors carried out various synthetic transformations of the synthesized indoline product 5a, including the removal of trichloroethoxyacyl (Troc) (14), coupling of the aryl bromine moiety and boron reagent (15a, b), allylic oxidation (16), and reduction (17, Transformation processes such as 18) and [3+2] cycloaddition (19, 20) further prove the practicality of this reaction (Scheme 5).
(Image source: Angew. Chem. Int. Ed.)
Summary
U.S. University of Georgia Eric M. Ferreira's research group developed a novel [Cr(PMP2phen)3](BF4)3 catalyst, successfully achieved the (3+2) cycloaddition reaction of indole and ene-diazo reagent under photocatalysis, and achieved the synthesis of a series of functionalized pyrroline compounds. This reaction has good substrate suitability and functional group compatibility
