The construction of C-C bonds is the core of synthetic organic chemistry. The value of the traditional transformations, such as Grignard reaction, Diels-Alder reaction, Wittig reaction, and aldolreaction, lies in their solution to some key problem in the construction of C-C bonds. The development of modern organic synthesis increasingly relies on cross-coupling reaction with transition-metal catalysis: the electrophilic components and the nucleophilic components that cannot undertake direct reaction according to the traditional model, react in the presence of transition-metal catalysts to form C-C bonds, followingthe mechanisms that are different from traditional reactions.
After decades of developments, a series of efficient C-C bond construction methods have been established with transition-metal catalysis, such as Heck reaction,Suzuki-Miyaura coupling,Negishi coupling,Stille coupling,Sonogashiracoupling, etc. These methods play important roles in various fields,including pharmaceutical synthesis, chemical biology, and material sciences. However, many challenges and opportunities remain in this area, including how to further improve the efficiency, selectivity, step and atomic economy, as well as the expandingof the scope of the reactions. Today, transition-metal-catalyzed cross-coupling still remains as a very dynamic part of research in organic chemistry. One of the key themes of these researches is to merge the transition-metal catalysis withand other fields, such as radical chemistry, carbene chemistry, electrochemistry, as well as photochemistry, to further expand the scope of the coupling components and the reaction modes.
On the other hand, as the majortype of organic compounds, ketones and aldehydes play very important roles in organic synthesis. The rich reactivity of ketones and aldehydes is largely derived from the electrophilicity of the carbonyl carbon and the acidity ofa-hydrogen. For example, a wide range of reactions that are commonly used in organic synthesis, including nucleophilic additions, Wittig reactions, aldol condensations, andC-H bond alkylation and arylations, and so on, all related to these properties of ketones and aldehydes. If ketones or aldehydes are converted into their corresponding triflates (-OTf),they can be used as electrophilic components to participate in transition-metal-catalyzed cross-coupling. This is a well-developed method of indirect use of ketones or aldehydes as cross-coupling components. In addition, tosylhydrazones (NNHTs),which can be derived from ketones or aldehydesthrough simple condensation with tosylhydrazine (TsNHNH2), is also a very important typeof synthons that can be applied in Shapiro reaction and Bamford-Stevens reaction for olefin synthesis. In particular, the Shapiro reaction, which convert ketones or aldehydes into vinylicnucleophilesto participate in nucleophilic additions and substitutions, are frequently used in organic synthesis.For example, it was used as one of the key steps in the total synthesis of Taxol.
The further development of new conversion patterns based on ketones and aldehydes is an important topic due to the widespread occurrence of these compounds and their irreplaceable role in the transformation of organic molecules. In recent years, it has been found that the tosylhydrazones can participate transition-metal-catalyzed cross-couplingthrough diazo intermediate.The basic processes of these coupling reaction include in situ generation of diazo intermediate, the formation of metal carbene, and the migratory insertion of metal carbene. The carbene-based coupling reaction of this type makes possible the ketones and aldehydes being used as reaction partners in transition-metal-catalyzed cross-coupling reactions, thus greatly expanding the application of ketones and aldehydes in organic synthesis. The group of Jianbo Wang has been working in this field in the past ten years, developing a series of cross-coupled reactions with ketones and aldehydes through tosylhydrazone. Recently, they were invited by the editor ofJournal of the American Chemical Society to write a Perspective paper, summarizing and looking ahead to the development of the transition-metal-catalyzed carbene coupling reaction through tosylhydrazones.
Based on the types of C-C bonds formed in the cross-coupling reaction of ketones and aldehydes, these transformations are roughly divided into four categories:a) The ketones serve as alkenyl coupling partners, forming C−C single bonds to produce poly-substituted olefins; b) New C="C" double bonds are constructed on the carbonyl functionality, which can be regarded as carbonyl olefination transformations. The formation of allene, ketene and ketenimine on the carbonyl functionality also falls into this category; c) Ketones serve as alkyl coupling partners, forming C−C single bonds to produce the corresponding alkylation products; d) Ketones serve as amphiphile, in which two C−C single bonds are formed on the carbonyl carbon. After introducing the latest progress of these four kinds of reactions, the Perspective points out their problems and limitations, and the possible further developments in this field.
The related research of this project was supported by the Beijing National Laboratory of Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, the Ministry of Science and Technology and the National Natural Science Foundation of China.
Ying Xia* and Jianbo Wang,*J. Am. Chem. Soc.2020, 142, 10592-10605.
https://pubs.acs.org/doi/10.1021/jacs.0c04445
