Formation of C-N bonds has been a long-lasting interest in synthetic organic chemistry and pharmaceutical industry. Despite of numerous C-N bond formation methods developed over the past decades, novel, highly efficient C-N bond construction strategies are still urgently needed and challenging. Research in our lab focuses on development of novel C-N bond formation strategies based on the development of mild N-centered radical chemistry enabled by modulation of reactivity and selectivity of tailored novel reagents. Directions in C-N construction strategy in this lab include: 1, Amide directed ortho-, para-selective aromatic amination and benzylic C-H amination, as well as thio- and selenoamination of simple alkynes via nucleophilic amination strategy; Aqueous allylic C-H amination. 2, We have proposed the strategy of “ambient generation of metal bound N-centered radical” and developed a series of difunctionalization of unsaturated systems, such as aminocyanation, diamination, aminofluorination, aminooxygenation, oxidative amination, as well as cascade alkyne aminoarylation, et. al. Studies in our lab also include DG-free benzylic C-H amination, which revealed the superior reactivity of 1o benzylic C-H bond relative to its 2o counterparts. We also realized α-amination of carbonyl derivatives and direct C-H/N-H coupling of DG-free aromatic compounds.Synthesis of various heterocycles based on the novel methodologies developed in our lab.
Ⅱ. Asymmetric Reductive Cross-Coupling Despite the tremendous accomplishments have been disclosed by transition-metal-catalysed cross-coupling strategy in the past a few decades (as exemplified by the Nobel Prize in Chemistry in 2010), undoubtedly, it remains existing many significant opportunities. For example, the preformed organometallic reagents or metalloids were necessary as the coupling partners, nevertheless, requirement of multistep synthetic sequences, sensitivity to solvent and moisture, confining functional-group scope, impeded the options available in synthesis design, often impeded the options available in synthesis design. To address these shortcomings, we are pursuing the use of stable and readily available unsaturated alkanes as the latent carbon nucleophiles in lieu of preformed organometallic reagents under cheap metal catalysts such as copper and nickel, to enantioselectively couple with various electrophiles, namely reductive cross-coupling reactions of unsaturated alkanes. This protocol shows better atom- and step-economy, and could provide more new opportunities compared with traditional preformed organometallic reagent involved approaches.
Ⅲ. Chemistry of strained molecules.
Cyclopropene (CPE) Chemistry 1. Cyclopropane (CPA) Synthesis Cyclopropane is a ubiquitously present structural motif in bioactive and pharmaceutical molecules. Traditional cyclopropane synthesis is no trivial, and highly efficient CPA synthesis is highly desired. Starting with cyclopropene (CPE), direct functionalization with ring-retention is a direct and thermodynamically favored process. Using transition metal as a tool to manipulate cyclopropene toward diversity and target-oriented synthesis is an overarching goal of our research team. 2. Metal Carbenoid Chemistry Many transition metals readily form vinyl carbenoids with CPE. This property has received some attention with certain metals while for many others, especially base metal catalysts, its reactivates remains largely untapped. We have found that this property could be harnessed to access some important structural units of synthetic significance. 3. Strain-Promoted Novel Reactivities The enormous total strain (54 kcal/mol) and olefin strain (27 kcal/mol) confer cyclopropene with much higher reactivities than normal systems. The enthalpy trade-off allows for many facile intermolecular processes unique to cyclopropene. Uncovering the novel reactivities and extending them to non-strained systems represents a highly dynamic exploratory forefront. Ⅳ. Bioorthogonal Labelling CPE involved cycloadditions belong to a subset of click reactions, which are routinely used by chemical biologist for protein labeling and target elucidation and validation. We are actively seeking novel utility and exploring new methodologies for future applications of these molecules in chemical biology.