Stereocontrol of alkene synthesis via switching among electrochemistry, photocatalysis and photo-electrochemistry

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Trisubstituted alkenes are important organic synthons used to make drugs, materials, and fine chemicals. Using multicomponent reactions (MCRs) to perform one-pot alkyne difunctionalizations is a simple and powerful way to make such compounds. Nowadays, trisubstituted alkene synthesis with high stereoselectivity remains a difficult problem for organic chemists to solve.  The currently established methodologies are limited to one stereoisomer generation or require starting materials with fixed configurations. Very few instances have been able to successfully produce the corresponding alkenes in both Z and E stereoselectivities.

Figure 1: Stereocontrol of alkene synthesis via switching amoung electrochemistry, photocatalysis and photo-electrochemistry

In 2019, we developed an arylsulfonylation protocol of alkynes and obtained the trisubstituted alkenes with either cis or trans selectivity by choosing an appropriate photocatalyst with suitable triplet energy (Nature Catalysis, 2019, 2, 678-687). In this protocol, the Psyn products were generated via the late-stage energy transfer process between Panti and photocatalyst. Moreover, we did the further functionalization of the generated pure E and Z products via the cross-coupling reaction with the activated primary amine (pyridinium salt) using the method developed by the Aggarwal group, affording the corresponding arylalkylation products in good yield with good stereoselectivity (Angew. Chem. Int. Ed. 2019, 58, 5697-5701). However, in this application, we got the Z and E arylalkylation products from alkyne via two steps. Given the importance of tricarbon-substituted alkenes, we wondered whether we could develop a direct one-step method to access such compounds.

By constant trial, we finally realized the one-pot alkylarylations of alkynes via photoredox and nickel dual-catalyzed redox neutral cascade reaction (Angew. Chem. Int. Ed. 2020, 59, 5738-5746). However, we could only get syn addition trisubstituted alkenes bearing three different carbon-linked groups for this protocol, because in order to oxidize alkyl carboxylic acid to generate the alkyl radical, a photocatalyst with high triplet energy has to be used, which leads to the inevitable E to Z isomerization of the generated products via an energy transfer process. Thus, how to get the Panti alkene products via arylalkylation remained a challenge in front of us.

To address this issue and given the underlying principle in both photoredox and electrocatalytic processes is electron transfer, we supposed that electrochemical nickel catalysis would be a good choice to address this problem. However, under electrochemical conditions, the generation of alkyl radicals via an oxidation pathway is typically difficult due to anodic overoxidation that produces alkyl cations.  Therefore, we turned our attention to the reductive pathway. In this case, the radical can be generated from alkyl halides via a reduction pathway and participate in the nickel catalytic cycle without the late-stage energy transfer process that occurs in photo/Ni dual catalysis, thus allowing us to develop the nickelaelectro-catalyzed reductive cascade cross-couplings to form anti-addition products.

At the same time, we can also obtain the syn-addition products with high stereoselectivity via photo- and nickel dual catalysis due to the involvement of the late-stage energy transfer process between Panti and photocatalyst.  

During the mechanistic investigations, we found that 390 nm purple LEDs could lead to efficient isomerization of the E isomer to the Z isomer without a photocatalyst, while the Z isomer in contrast could not isomerize to the E isomer. Therefore, we wondered whether we could achieve the arylalkylation of alkynes in a syn addition manner via the combination of 390 nm LED irradiation with an electrochemically nickel catalytic cycle and without the necessity of a photocatalyst. Gratifyingly, after minor optimizations, we realized this photo-assisted electrochemical protocol for the generation of syn addition products with good to excellent stereoselectivities.

Figure 2: Photo-electro catalyzed reaction setup

This catalytic protocol features mild reaction conditions, high functional group tolerance, excellent stereocontrol, successful application of complex natural products and scale-up reaction, as well as judicious switching among electrochemistry, photocatalysis, and photo-electrochemistry. More importantly, the results undoubtedly bring us to the conclusion that the combination of metal catalysis with photoredox catalysis or electrolysis should not be seen as competitive but rather as complementary methodologies which enrich each other and even uncover novel combined photoelectrochemical processes.

https://www.nature.com/articles/s41467-022-30985-2

Chen Zhu

Research Scientist, King Abdullah University of Science and Technology