Chen Gong’s and He Gang’s groups, from State Key Laboratory of Elemento-organic Chemistry, reported an efficient strategy to achieve the syntheses of highly strained four-membered benzazetidines. Their method represents the first practical synthetic method for benzazetidines, which was thought to be a breakthrough in the synthesis of desired C-N cyclized products selectively. The journal Nature Chemistry published Chen’s research finding on August 1st.
A heterocyclic compound is a cyclic compound that has carbon atoms and heteroatoms as members of its ring(s). The atoms that are neither carbon nor hydrogen are normally referred to in organic chemistry as heteroatoms, such as nitrogen, oxygen, sulphur, etc. N-heterocycle is an important branch of heterocyclic compound as its diversity in nature and fundamental roles in vivo. Thus, N-heterocycles are considered as important structures in organic synthesis of drugs, pesticides and functional materials. Among them, small sized N-heterocycles are of particular interest to organic chemists to both uncover new chemical reactivities and explore new chemical spaces for biomedical research. However, for the sake of their higher ring strain, efficient synthesis of them remains poorly addressed.
“Ring strain is a type of instability that exists when bonds in a molecule form angles that are abnormal,” Chen said. “It is like a bow. When a bow is in an unnatural state, it bears strain, and even breaks.”
Four-membered benzazetidines are typical above-mentioned N-heterocycles with small sizes and strained structures. However, their higher ring strain result of benzo-structures brought about great challenge to the chemical synthesis. With a lack of practical syntheses, the chemical activity and function of benzazetidine has not yet entirely clear.
“Although there were reports about the syntheses of benzazetidines, they required harsh conditions such as extreme high temperature, perfect vacuum or strong bases. What’s more, the yield and the application scope are far from practical use.” Chen said. His group hoped to find a more efficient way to synthesize benzazetidines with low cost.
Chen’s group has spent a couple of years on palladium-catalyzed C-H Bond Activation. Based on their former achievements, they developed an efficient synthesis of benzazetidines via the Pd-catalyzed intramolecular C-H amination of N-benzyl picolinamides. These reactions enable access to a range of complex benzazetidines from easily obtainable starting materials.
One of the highlights in the research is the discovery of PhI (DMM). The use of a newly designed phenyliodonium dimethylmalonate (PhI(DMM)) reagent is critical, as the oxidation of Pd(II) palladacycles with this reagent favours a kinetically controlled C-N RE pathway that provides the desired cyclized products.
“We solved a difficult problem that puzzled us many years. We anticipate that the new agent will not only improve benzazetidines’ applications, but also open new avenues for other challenging syntheses of heterocycles with high ring strain.” Chen’s group are focusing on the further research of benzazetidines’ chemical reactivities and medicinal applications.
Professor Liu Peng, from the University of Pittsburgh, coordinated with Chen on the computational studies and he is one of the corresponding authors.
To read Chen’s article, please click the link: