Since Arthur Michael reported the classic Michael addition reaction in 1887, α, β-unsaturated carbonyl compounds have been widely used to construct β-position carbon-carbon bonds or carbon-heteroatom bonds as π acceptors for Michael addition (Figure 1A). In stark contrast, the α-selective Michael addition response is rarely reported. The main reason for this is that the α position selection is difficult due to the high electrophilicity of the β bit. There are two main types of strategies for the reported α-site selection of Michael addition reactions: (1) taking advantage of substrate limitations, such as intramolecular cyclization; (2) Introduce strong electron-withdrawing groups, such as nitro groups, at the β position (Fig. 1B). However, such strategies have great limitations and are difficult to be widely used in the synthesis of more complex molecules. On the other hand, although the α α of β-unsaturated carbonyl compounds has been developed and reported in recent years using transition metal catalytic , there are still limitations such as β selection side reactions and single aryl species. Therefore, the development of more generalized intermolecular α position-selective Michael's addition reactions is of high value.
Prof. Takanori Matsuda's research group from Tokyo University of Science, Japan, and Prof. Hirotsugu Suzuki, Asst. Assistant Professor Suzuki of the University of Fukui, Japan, envisaged the use of transition metal coordination of carbon-carbon double bonds to alter the electron distribution of α β-unsaturated carbonyl compounds. Thus, the β-site selectivity of the Michael addition reaction was reversed, and the α-site selected Michael addition reaction was realized. The authors successfully achieved an intermolecular α-selective Michael-addition arylation reaction by designing an α of 8-quinolinamide β-unsaturated carbonyl compounds to form a relatively stable intermediate with Pd metal, thereby activating the carbon-carbon double bond to reverse selectivity (Fig. 1C). The findings were recently published in the Journal of the American Chemical Society.
Figure 1. Selective Michael addition reaction. Image courtesy of J. Am. Chem. Soc.
The authors first used N-methylindole(2a) and compound 1a as reactants and Pd(TFA)2 as catalyst to react in acetonitrile solvent at 120 °C, resulting in a α-selected target product 3a, while the β-selected by-product 3a' was not observed (Fig. 2, entry 1). By conditional screening, it was finally possible to obtain 3A with a separation yield of 90% (Figure 2, entry 5). Subsequently, the reaction was completely stopped by replacing the 8-quinoline structure in compound 1a with a 1-naphthalene structure (1a', Fig. 2, entry 8) or by replacing the H on the amide structure nitrogen with a methyl group (1a", Fig. 2, entry 9). The above results are good evidence that the 8-quinoline amide moiety in 1a acts as the coordination of the dinitrogen ligand to Pd, which is the key to achieve this reaction.
Figure 2. Reaction condition screening and comparative experiments. Image courtesy of J. Am. Chem. Soc.
Subsequently, the authors expanded the substrates. As shown in Figure 3, this reaction can be applied to a wide range of indole derivatives, all of which can obtain a α-selected target product (3a–s) in high yields. At the same time, substrates substituted by the double bond end position are also suitable (3T–Ag). In addition, in addition to indole derivatives, a number of other electron-rich aromatic (heterocyclic) rings can also be used as nucleophiles to enable α-selected Michael addition arylation (Figure 4).
Figure 3. Substrate expansion (a). Image courtesy of J. Am. Chem. Soc.
Figure 4. Substrate expansion (II). Image courtesy of J. Am. Chem. Soc.
Finally, in order to explore the reaction mechanism, the authors conducted a series of deuterium atom labeling experiments. When the reaction is performed using 3-deuterindole2a-d1 as the feedstock, the deuterium atoms are almost entirely on the methyl group (Figure 5A). When using the α-deuterated α, β-unsaturated carbonyl compound 1b-d1 as the reactant, the deuterium atoms in product 3t-d1 are almost all in situ, while the benzyl site is completely devoid of deuterium atoms (Figure 5B). These results indicate that no β-hydrogen elimination step occurred in this reaction. Finally, when β-deuterated α was used, β-unsaturated carbonyl compounds 1c-d1 were used as reactants, the deuterium atoms in product 3t-d1 were also largely retained in situ despite a slight reduction in the deuteration ratio (Figure 5C), indicating that the main step in the reaction was not hydrocarbon activation.
Figure 5. Mechanism studies and deuterium labeling experiments. Image courtesy of J. Am. Chem. Soc.
Based on the above results, the authors proposed the mechanism of this reaction (Figure 6). First, Pd(TFA)2 is guided by the dinitrogen structure in 1a to activate the α,β-unsaturated structure with π-Lewis acid to form Pd complex B. Subsequently, 2a performs α-bit nucleophilic addition to B to form a relatively stable five-membered ring structure C containing Pd, which can be used to explain the origin of α-bit selectivity. Finally, trifluoroacetic acid protonates C to obtain the target product 3a, and regenerates Pd(TFA)2 into the next catalytic cycle.
Figure 6. Mechanism of reaction. Image courtesy of J. Am. Chem. Soc.
brief summary
In collaboration with Prof. Takanori Matsuda's research group and Prof. Hirotsugu Suzuki, the π-Lewis acid activation of carbon-carbon double bonds by Pd was used to change the electronic distribution of α and β-unsaturated carbonyl compounds, inhibiting the β selectivity of Michael's addition reaction, and successfully realized the α-selected Michael's addition arylation reaction. The research results were recently published in J. J. Murphy. Am. Chem. Soc.
Palladium-Catalyzed anti-Michael-Type (Hetero)arylation of Acrylamides
Hirotsugu Suzuki, Ryota Moro, Takanori Matsuda
J. Am. Chem. Soc. 2024, 146, 13697–13702. DOI: 10.1021/jacs.4c00841
Introduction of the research group and supervisors
Tokyo University of Science, Japan, Faculty of Science, Department of Applied Chemistry Matsuda-Kim Laboratory (https://www.rs.tus.ac.jp/mtd/) has been engaged in research related to organic synthesis, organometallic chemistry, and the development of transition metal catalytic reactions. Supervisor: Prof. Dr. Takanori Matsuda, Ph.D., received his Ph.D. from Kyoto University in 2002, and has been working at Tokyo University of Science since 2008. Am. Chem. Soc.、 Angew. He has published more than 100 papers in academic journals such as Chem. Int. Ed. Supervisor Dr. Yushu Jin, assistant professor, received his Ph.D. from Kyushu University in 2018, then engaged in postdoctoral research at Tokyo Institute of Technology and RIKEN respectively, and has been an assistant professor at Tokyo University of Science since 2024, and has published more than 10 papers in academic journals such as Science, Nat. Commun., and ChemSusChem.
Matsuda-Kim Research Laboratory, affiliated to the Kagurazaka Campus of Tokyo University of Science, is located in the bustling urban area of Iidabashi Station in the Tokyo metropolitan area, with convenient living and transportation, and a strong international atmosphere. Due to the business development needs of the laboratory, we are recruiting master's and doctoral students (long-term valid).