Vicinal diamine is an important structural unit of a variety of bioactive molecules, natural products and drug molecules, and these diamine skeletons are often used as organic catalysts and ligands for transition metal catalysis. From the perspective of synthesis, asymmetric diamination is an attractive but more challenging task due to the lack of suitable amination reagents and the potential problems of regioselectivity and enantioselectivity.
In order to achieve a more challenging asymmetric diamination, the researchers envisioned whether a bifunctional reagent could be designed. In principle, the reagent could produce two nitrogen center radicals at the same rate at the same time, but their reactivity was different. Then the asymmetric o-diamine could be directly obtained by regioselective stepwise addition with the carbon-carbon double bond. Recently, they have developed a class of bifunctional nitrogen radical precursors based on oxime esters, which can generate amphiphilic imine radicals and electrophilic amide radicals simultaneously through energy transfer (EnT), thus successfully realizing the asymmetric diamination reaction of electron-rich aromatics and olefins with bifunctional diamine reagents, and preparing a series of previously unavailable o-diamines with excellent regioselectivity and non-enantioselectivity.
First of all, the researchers synthesized various nitrogen radical precursors based on oxime ester and selected 1H-indole-1-carboxylic acid tert-butyl ester as the nitrogen center radical acceptor to explore their reactivity. The results showed that under the condition of cheap and commercially available thioxanthone as photosensitizer (5.0 mol%) and acetone as solvent, after 12 hours of blue light irradiation, o-diamine could be obtained with 72% separation yield and excellent regioselectivity and enantioselectivity (>95:5 d.r.). The control experiment showed that the reaction could not be carried out without thiotonone or blue light, and the product could be obtained with 48% yield after reducing thiotonone to 1.0 mol%.
In order to further explore the reaction mechanism, the researchers carried out a series of experiments and proposed a possible reaction mechanism: first, the reactant and the excited state thioxanthone produced the excited state reactant through the photo-induced EnT process, and formed transient amide radical and persistent imine radical through the N-O bond breaking, and released CO2 and acetone. Based on the continuous free radical effect, the electrophilic amido radical is captured and added at the C2 position to produce a transient carbon center radical, and then the radical coupling with the amphiphilic imino radical from the other side to produce the required trans-diamine.
Under the optimal conditions, the researchers investigated the substrate range of aromatic hydrocarbons, and the results showed that indole protected by different groups on the N-side, N-Boc-indole with different electron donor/acceptor groups on the benzene ring or C3 position, and even complex biological active molecules could be compatible with the reaction, and the required asymmetric o-diamine was obtained with medium to good yields and excellent regioselectivity and enantioselectivity. Secondly, the researchers also investigated the applicability of this method to olefin substrates. The results showed that a series of styrene, cyclic olefins, alkynes, electron-deficient/rich olefins, acyclic 1,2-disubstituted olefins, inactive olefins and even natural products and complex active molecules can achieve this conversion, and the corresponding asymmetric diamines can be obtained with medium to good yields and excellent regioselectivity.
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Reference
- Energy transfer-enabled unsymmetrical diamination using bifunctional nitrogen-radical precursors
Guangying Tan, Mowpriya Das, Roman Kleinmans, Felix Katzenburg, Constantin Daniliuc, Frank Glorius
