Bifunctional catalytic mode is widely used in organic synthesis, and bifunctional chiral catalysts with different reaction mechanisms have been developed. Classical bifunctional chiral catalysts contain multiple acid-base groups, such as chiral phosphoric acid, chiral amine-thiourea, etc., which can efficiently bind to multiple substrates through covalent or non-covalent bonding, so as to achieve chiral regulation at a smaller molecular scale with higher reaction efficiency and stereoselectivity. With the development of photochemical asymmetric catalysis, the concept of bifunctional catalysis and the field of photocatalysis have been combined to further expand the application range of bifunctional catalysts in single-electron reactions. For example, in 2017, Prof. Xiao Wenjing's research group successfully developed a class of bifunctional photocatalysts to realize the asymmetric oxidation reaction catalyzed by photonickel synergy.
Through the joint efforts of chemists at home and abroad, there have been some successful cases of electrocatalytic asymmetric synthesis, but there are still many challenges in this field, among which an important problem is the incompatibility of chiral catalytic systems and electrochemical conditions. Compared with traditional chemical reactions, many "superior" chiral catalysts are difficult to exist stably or lose their activity in electrochemical systems, and there is a great lack of chiral catalysts suitable for electrochemical synthesis. Therefore, there is an urgent need to develop new bifunctional chiral catalysts to realize asymmetric electrocatalytic reactions.
Figure 1. Design of bifunctional catalytic mode and bifunctional chiral electrocatalyst
Recently, the team of Professor Xu Hao of Central China Normal University (click to view the introduction) has successfully developed a new class of bifunctional chiral electrocatalysts and applied them to the asymmetric cross-dehydrogenation coupling reaction of 4-substituted phenol and aldehydes. The authors skillfully synthesized a new class of bifunctional chiral electrocatalysts by rational spatial assembly of electrochemical redox media and chiral secondary amines, which can realize the synchronization of organocatalysis and electrocatalytic cycles without interfering with each other, which not only significantly improves the reaction efficiency and stereoselectivity, but also greatly expands the scope of substrate application. It is verified that this kind of bifunctional chiral catalyst has obvious advantages, and it is believed that this design concept will be further promoted and applied in the field of electrochemical synthesis. The research results were published in Angew. Chem. Int. Ed., Ph.D. student Jinyu He and associate researcher Zhu Cuiju are the co-first authors.
First, the authors used 2,6-dimethyl-4-benzylphenol 1a and phenylpropionaldehyde 2a as standard substrates to try to achieve the construction of cross-coupling products 3AA under electrochemical conditions, first tried the traditional catalysts cat 1 and cat 2, and found that the OTMS substituted catalyst cat 2 could obtain the target product with excellent stereoselectivity, but the reaction yield was low. Therefore, the authors considered whether the integration of tertiary amine into the chiral catalyst could further improve the reaction efficiency and stereoselectivity, first of all, N-ethylpiperidine was added to the pyrrole ring C4 position (cat 3), and found that the yield was indeed further improved, but the diastereoselectivity was low, and continued to try to modify the catalyst, and found that when piperidine was added to the C2 position (cat 4), the reaction efficiency was further improved, and excellent stereoselectivity could be maintained. cat 5-8), and found that OTIPS had the best effect as a steric hindering group, and further screening of tertiary amine media found that different types and different chain length substituents had a greater impact on the reaction (cat 9-13), and finally cat 9 was determined to be the best bifunctional catalyst.
Figure 2. Screening of reaction conditions
Under the optimal reaction conditions, the authors investigated the universality of the substrates, first of all, the expansion of phenolic substrates, and found that when the benzene ring of phenol para-substituted benzyl group had different substituents, the target product (3AB-3AI) could be obtained with medium to excellent yield and excellent stereoselectivity, the corresponding product (3AJ-3AK) could be successfully obtained for different aromatic rings and aromatic heterocycles, and the target product (3AL) could also be obtained under low temperature conditions for unstable trimethylphenols. Next, the substituents on the phenolic ring were screened, and for the substrates substituted by electron-withdrawing groups, the reaction would go through a more active quinone intermediate, which could not be prepared by traditional methods, but the target product (3am) could be obtained smoothly under the electrochemical conditions, and a series of aromatic ring-substituted phenolic substrates could also obtain the target product (3ap-3at) with excellent stereoselectivity.
Figure 3. Phenolic substrate expansion
Subsequently, the authors expanded the aldehyde substrates to obtain the target product (3BA-3BE) with good yield and excellent stereoselectivity for different aryl-substituted aliphatic aldehydes, and was also compatible with the substrate with olefins and halogens (3bf-3bg, 3bj-3bk). Next, the authors also try to expand some drugs and bioactive molecular derivatives to further reflect the application prospects of this reaction in pharmaceutical synthesis (3BL-3BO).
Figure 4. Aldehyde substrate expansion
In order to further reflect the application value of the product, the authors then carried out gram-level experiments and transformation studies on the product 3AA, which could be successfully synthesized at gram-level and the stereoselectivity could be maintained. Next, the authors tried to achieve a condensation reaction of 3aa and different drug molecules carboxylic acids, using BF3·· Et2O can be used to prepare chiral indene derivatives 6 by Friedel-Crafts reaction, and the aldehydes in the product can also be successfully converted to alcohol 7 and olefin 8 without maintaining excellent enantioselectivity.
Figure 5. Gram-level experiments and transformation reactions
Next, the authors also compared the traditional oxidation experiments of this reaction, and found that the optimal yield and stereoselectivity can be obtained only under electrochemical conditions, so as to further reflect the advantages of this reaction. Next, the comparative experiments of the catalysts showed that when the tertiary amine and chiral catalysts were separated, the reaction yield and stereoselectivity were significantly reduced, which further demonstrated the advantages of bifunctional catalysts.
Figure 6. Oxidant comparison experiment and catalyst comparison experiment
The authors then conducted an in-depth study of the reaction mechanism, starting with the study of reaction intermediates, by electrooxidizing phenol 1a alone to obtain p-methylene benzoquinone intermediate (p-QM) 9 and HFIP substituted products 10 under standard reaction conditions (Fig. 7a), and then using 9 and aldehyde 2a to perform a direct asymmetric reaction under standard reaction conditions (Fig. 7b), the results of the obtained product are consistent with electrochemistry, which fully indicates that the reaction underwent a quinone intermediate, Next, by pre-preparing chiral enamine intermediates and reacting them with phenol under electrochemical conditions (Fig. 7c), the target product can also be obtained with high stereoselectivity, indicating that the reaction undergoes the process of enamine intermediates. The authors found that HFIP played an extremely important role in the efficiency of the reaction through comparative experiments (Fig. 7d), and it was observed that HFIP could activate the p-QM intermediate well through nuclear magnetic magnetic emission (Fig. 7e), and further showed that the rate-determining step of the reaction was not the cleavage of the benzyl C-H bond (Fig. 7f), so it was speculated that the reaction process was the first electrooxidation of the phenol ring. Next, the authors demonstrated by CV plots (Fig. 7g) that when the substrate phenol 1a is mixed with the catalyst cat 9, a new oxidation peak (Ep, oxi = 0.70 V vs. Ag/AgCl) appears, which further indicates that the designed bifunctional catalyst can promote the electrooxidation of phenols and further improve the reaction efficiency.
Figure 7. Mechanism exploration and reaction mechanism proposed
Based on the above mechanism verification experiments, the authors proposed a possible mechanism of the reaction: firstly, the bifunctional catalyst cat 9 was electrooxidized at the anode to obtain the corresponding free radical cation intermediate, and then the SET process was underwent with polysubstituted phenols to achieve phenol oxidation to quinone, and at the same time, cat 9 and aldehyde condensation formed chiral enamine intermediate IV, and under the activation of HFIP, the p-QM intermediate and IV underwent asymmetric nucleophilic addition reaction, and the final product was hydrolyzed.
summary
The authors report a novel bifunctional chiral catalyst that can be applied to electrochemical asymmetric synthesis, which can significantly improve the efficiency and stereoselectivity of the reaction, and can achieve the advantages of a wide range of substrates, good functional group compatibility, and simple reaction conditions. The advantages of this type of catalyst are further demonstrated through comparative experiments. The authors also performed a series of mechanistic verifications of the reaction, which provided a basis for the reaction mechanism through validation experiments and 1H NMR.
The research was strongly supported by the National Natural Science Foundation of China and the Engineering Research Center of the Ministry of Education for Light Energy Utilization, Pollution and Carbon Reduction.
Bifunctional Chiral Electrocatalysts Enable Enantioselective α-Alkylation of Aldehydes
Jin-Yu He,+ Cuiju Zhu,+ Wen-Xi Duan, Ling-Xuan Kong, Wei-Feng Qian, Na-Na Wang, Yan-Zhao Wang, Zhi-Yong Fan, Xin-Ying Qiao, and Hao Xu*
Angew. Chem. Int. Ed., 2024, DOI: 10.1002/anie.202401355
Instructor introduction
Xu Hao
https://www.x-mol.com/groups/Xu_Hao