Mild and Efficient C-H Arylation and Amination Reactions
Direct functionalization of hydrocarbons has emerged as an important research topic in chemistry. However, mild and selective cleavage of strong carbon-hydrogen (C−H) bonds and conversion to carbon-carbon (C–C) or carbon-nitrogen (C–N) bonds is still a major challenge in the field. Hydrocarbons, while they are presented in large quantities in nature, are difficult to use as starting materials.
Recently, KAIST researchers in the Department of Chemistry and the Institute of Basic Science led by Professors Sukbok Chang and Mu-Hyun Baik have developed mild and efficient methods to introduce aryl or amino groups in hydrocarbons at targeted C–H positions. These findings were attributed to the design and use of tailored, high-valent iridium catalysts based on the detailed understanding of mechanisms by combining experimental observations and computer modeling.
In addition, these studies described that two reactions occur via non-conventional mechanistic scaffolds. These pathways are ter med ‘oxidatively induced reductive elimination’ for the arylation reaction, and ‘asynchronous concerted insertion’ for the amination reaction.
Development of iridium catalyzed mild C–H arylation via oxidatively induced reductive elimination pathways
Transition metal-catalyzed direct C–H arylation has been recognized as a straightforward and powerful way of preparing valuable chemical compounds that contain carbon-aryl bonds. However, most of the currently available C–H arylation procedures suffer from harsh reaction conditions, such as high reaction temperature and excess amounts of additives, which make this strategy not sufficiently effective to be practical alternatives to conventional cross-coupling reactions. Therefore, the development of mild C–H arylation, especially based on a clear mechanistic understanding, is highly desirable in this field.
The team led by Chang and Baik helped devise, characterize, and elucidate the workings of an iridium catalyst system to successfully develop efficient and broad C–H arylation that can be operated even at ambient temperature. To investigate the reaction mechanism in detail, the research group conducted various mechanistic experiments, such as isolation of the reaction intermediate, cyclics voltammetry (CV) studies, electron paramagnetic resonance (EPR) analysis and density functional theory (DFT) calculation, and found that the high-valent iridium(IV)-aryl intermediate is generated during the reaction. As a result, the research team clearly disclosed that the iridium-catalyzed arylation proceeds through ‘oxidatively induced reductive elimination’ pathway (oxidation of a post-transmetalation intermediate and subsequent reductive elimination), which is different from the conventional metal-catalyzed C–H arylation pathway.
Reference: Kwangmin Shin, Yoonsu Park, Mu-Hyun Baik and Sukbok Chang, Nat. Chem. 2018, 10, 218.
Including website for more information : https://www.nature.com/articles/nchem.2900
Selective formation of γ-lactams via C–H amidation enabled by tailored iridium catalysts
Catalytic amination of C–H bonds is the most desirable and direct route to convert abundant raw feedstocks to value-added nitrogen-containing molecules. Over the last 35 years, chemists have searched for ways to introduce amino groups in C–H bonds by applying transition metals with nitrene precursors, and successfully synthesized N-heterocycles such as indoles or pyrrolidines. However, the formation of lactam via same approaches cannot be conquered until recently. This long-standing challenge lies on the notorious instability of the putative carbonylnitrene intermediate, which may readily decompose via a Curtius-type rearrangement.
The KAIST Research team predicted and analyzed three plausible reaction pathways of carbonylnitrene (C–H amination, the Curtius rearrangement and catalyst degradation) using density functional theory (DFT) calculations. Based on the computational details, the team designed tailored iridium catalysts which can stabilize the reactive intermediate and allow the formation of lactam via C–H amination to proceed. Through the further mechanistic investigation such as kinetic isotope effect (KIE) study, the researchers concluded that the C–N bond formation is accompanied with C–H bond cleavage in a concerted fashion, so called ‘asynchronous concerted insertion’.
The power of this new synthetic tool was demonstrated by the synthesis of 48 lactam molecules including the derivatives of amino acids, steroids, and other bio-relevant molecules. In addition, this method is also effective in complex molecules which possessed multiple reactive C–H bonds and the variety of functional group. In this context, it is anticipated that the amination protocol will enable the development of potential drugs in a much shorter time and at a lower cost.
Reference: Seung Youn Hong, Yoonsu Park, Yeongyu Hwang, Yeong Bum Kim, Mu-Hyun Baik, and Sukbok Chang, Science 2018, 359, 1016.
Including website for more information: http://science.sciencemag.org/content/359/6379/1016
* lab webpage : http://sbchang.kaist.ac.kr/