Developing sustainable synthesis strategies to directly transform raw chemicals into fine products with high added value is at the heart of current organic chemistry. β,γ-unsaturated ketones are important structural motifs and building blocks in synthesis components. Many of the reported methods are based on disconnection of the bond between the α and β carbons which means α-alkenylation of an enolate or enolate equivalent;1-5 whereas disconnection of the bond between the carbonyl group and the α carbon—that is, allylation of an acyl donor—has not been thoroughly explored (Fig. 1). Traditional synthetic approaches to construct it often face several challenges, including the requirement for additional steps through prefunctionalisation of starting materials, the facile isomerization to the thermodynamically favored α,β-unsaturated ketones and limited to relatively simple targets. As a consequence, the development of new methods to promote the synthesis of β,γ-unsaturated ketones via direct allylic acylation of alkenes could be arouse enough attention due to its overall synthetic efficiency.
Fig. 1. Bioactive compounds with β,γ-unsaturated ketone motifs and approaches for their synthesis. (a) Examples of pharmaceutically active agents possessing β,γ-unsaturated ketone motifs. (b) and (c) Classic catalytic approaches for β,γ-unsaturated ketone synthesis.
To address this issue, we supposed that N-heterocyclic carbene (NHC) catalysis might be useful for β,γ-unsaturated ketone synthesis. NHC catalyst is a unique Lewis basic catalyst that uses polarity reversal to mediate various organic transformations. The combination of visible light catalysis with NHC catalysis can realize NHC-mediated radical reactions under mild conditions, and in 2022, we use this strategy to access α-amino ketones by direct acylation of α-C(sp3)–H bonds of amines with acyl imidazoles.6 But the construction of complex natural products in biological systems is often carried out by multicatalytic methods, so multiple catalysis based on the combination of three or more different catalysts is very attractive for the development of new reactions. However, triple catalysis containing the NHC catalytic cycle is still in its budding stage.7 Its challenge lies in compatibility issues between catalysts and intermediates, so we aim to use the unique characteristics of NHC catalysis with combination of photocatalysis and hydrogen atom transfer catalysis to further bridge the existing gaps in this field (Fig. 2).
Fig. 2. This work.
Based on the mechanism experiments in this article, literature reports and our own research experience, a plausible mechanism is depicted in Fig. 3. Blue light irradiation converts the IrIII photocatalyst into a long-lived triplet excited state IrIII* complex, which is reduced to an IrII species by thiolate I generated in situ. The resulting electrophilic thiyl radical (II) can be used as a powerful HAT catalyst to abstract allylic hydrogen from cyclohexene to generate transient radical III. At the same time, the carboxylic acid is activated in situ by reaction with CDI, and then NHC catalyst is added to the activated acid (1a) to generate azolium intermediate IV, which can be reduced by IrII species to provide azolium radical V and regenerate the ground state IrIII photocatalyst. Subsequently the coupling of V with radical III ultimately yields the target β, γ-unsaturated ketone 3 and releases the NHC catalyst.
Fig. 3. Proposed mechanism.
The broad substrate scope, excellent functional-group tolerance, and the mild reaction conditions which were suitable for the late-stage modification of natural products with various biological activities demonstrated the potential application of this methodology in the pharmaceutical industry.
For more details, especially on the reaction development, substrate scope, and mechanistic studies for this radical reaction, please have a look at our article.Article Link: https://doi.org/10.1038/s41467-023-38743-8
- Grigalunas, M., Ankner, T., Norrby, P., Wiest, O., & Helquist, P. Ni-Catalyzed Alkenylation of Ketone Enolates under Mild Conditions: Catalyst Identification and Optimization. Am. Chem. Soc. 137, 7019–7022 (2015).
- Lou, S., & Fu, G. C. Enantioselective Alkenylation via Nickel-Catalyzed Cross-Coupling with Organozirconium Reagents. Am. Chem. Soc. 132, 5010–5011 (2010).
- Stevens, J. M., & MacMillan, D. W. C. Enantioselective α-Alkenylation of Aldehydes with Boronic Acids via the Synergistic Combination of Copper(II) and Amine Catalysis. Am. Chem. Soc. 135, 11756–11759 (2013).
- Skucas, E., & MacMillan, D. W. C. Enantioselective α-Vinylation of Aldehydes via the Synergistic Combination of Copper and Amine Catalysis. Am. Chem. Soc. 134, 9090–9093 (2012).
- Kim, H., & MacMillan, D. W. C. Enantioselective Organo-SOMO Catalysis: The α-Vinylation of Aldehydes. Am. Chem. Soc. 130, 398–399 (2008).
- Wang, X., Zhu, B., Liu, Y., & Wang, Q. Combined Photoredox and Carbene Catalysis for the Synthesis of α-Amino Ketones from Carboxylic Acids. ACS Catal. 12, 2522–2531 (2022).
- Liu, K., & Studer, A., Direct α-Acylation of Alkenes via N-Heterocyclic Carbene, Sulfinate, and Photoredox Cooperative Triple Catalysis. Am. Chem. Soc. 143, 4903–4909 (2021).
Please sign in or register for FREE
If you are a registered user on Nature Portfolio Chemistry Community, please sign in