Aliphatic amines are ubiquitous in natural products, drug molecules, and other bioactive molecules, among which allyl amine is a particularly attractive synthetic target. Scientists have developed many methods for the construction of aliphatic allylamines, such as: 1) nucleophilic substitution reaction of prefunctionalized alkenes; 2) Pd-catalyzed Tsuji-Trost reaction; 3) palladium-catalyzed allyl C–H bond amination 4) Photocatalytic and electrocatalytic amination of allyl C–H bonds. However, the construction of aliphatic allylamine is seriously hindered by many factors such as selectivity, the type of nucleophile, and the steric hindrance of alkene, especially when aliphatic primary/secondary amines and pharmaceutically valuable heterocyclic rings are used as nucleophiles, and the direct realization of allyl amination reactions of different substituted alkenes remains a major challenge.
The researchers re-examined the classic Pd(II/0) catalytic process and found that the main challenges stem from Pd(II) catalysts. Recently, they exploited the strategy of photoinduced electron transfer to form multifunctional Pd(I) intermediates in the system of mild aryl bromides, developed a photocatalytic general platform for the intermolecular allyl C–H bond amination of differently substituted alkenes with primary/secondary aliphatic amines. Moreover, the enantio- and diastereoselective allyl C–H bond amination of various alkenes has been successfully achieved.
First, the researchers chose (E)-β-ethylstyrene and piperidine as model substrates to optimize the reaction conditions. Preliminary studies showed that under the conditions of (PPh3)4/Xantphos, bromobenzene and cesium carbonate and irradiating with blue LED for 15 h, allylamine was obtained in 4% yield along with biphenyl and Heck by-products. The researchers then screened aryl bromides and found that Br-9 increased the yield to 41%, and the product was obtained in 71% yield with additives. Further investigation found that Br-12 was the most potent aryl bromide. Finally, allylamine can be obtained in 90% isolated yield, and the control experiment proves that palladium catalyst and visible light are indispensable.
Under optimal conditions, the researchers explored the substrate reaction of olefins, and the results showed that olefins with different substituents on the benzene ring, heteroaryl olefin analogs, other olefin variants, and even aliphatic olefins are compatible with the reaction, and the corresponding products were obtained in good yields. Second, the researchers explored the compatibility of aliphatic amines, and the results showed that cyclic amines, morpholines, thiomorpholines, acyclic secondary amines, and even primary amines of different sizes can be effectively selectively aminated. The desired product was obtained in moderate to good yields. Similarly, various non-aliphatic nitrogen nucleophiles are effective nucleophiles. Furthermore, this method is equally effective for terminal alkenes, which are the only substrates for the amination of allyl C–H bonds under the classical Pd(II/0) catalyzed cycle.
The researchers then used the method to explore late-stage modifications of complex molecules and their natural products. A variety of drug fragments and derivatives of natural products can react smoothly and obtain corresponding aminated products. The researchers investigated a series of drugs containing piperidine and piperazine skeletons or their fragments as nucleophiles for the amination of allyl C-H bonds, and good results were obtained.
Finally, the researchers explored a chiral version of the method and successfully achieved enantio- and diastereoselective allyl C–H bond aminations of a variety of alkenes.
Related Product & Service
Reference
- Asymmetric intermolecular allylic C-H amination of alkenes with aliphatic amines
Kelvin Pak Shing Cheung, Jian Fang, Kallol Mukherjee, Andranik Mihranyan, Vladimir Gevorgyan
