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Chemical Science Back Cover Research:Highly Regioselectivity Access to Primary Anilines via Copper-mediated C–H Amination
Update time: 2018-07-13
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Primary anilines are important structural motifs present in many natural and pharmaceutical compounds. The development of efficient and practical C–H bond primary amination reaction in the rapid diversification and modification of drug molecules and drug-like molecules attracted widespread attention from the organic and pharmaceutical chemist in recent years. However, several reported transition metal catalyzed C–H bond primary amination reactions still has drawbacks such as poor substrate compatibility, poor regioselectivity, special and toxic amination reagents and narrow application etc.

Prof. DAI Huixiong’s group from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences (SIMM) has developed a new directing group Amide-Oxazoline auxiliary four years ago, and has successfully accomplished multiple C–H functionalization reactions via Copper-mediated C–H aviation, including C–H amination (J. Am. Chem. Soc. 2014, 136, 3354), trifluoromethylation (Angew. Chem. Int. Ed. 2014, 53, 10439), alkynylation (J. Am. Chem. Soc. 2014, 136, 11590), arylation (Org. Lett. 2014, 16, 5666) etc.

Oxazoline-based directing group not only capable of overriding the poisoning effect of a wide range of heterocycle substrates, but also could overcome the directing ability of heterocycle and enable amidation to occur at the position proximal to the amide functionality.

The potential use of this directing group in pharmaceutical drug discovery is illustrated by diversification of Telmisartan (an antagonist for the angiotensin II receptor) through copper-mediated C–H amination, hydroxylation, thiolation, arylation, and trifluoromethylation (Angew. Chem. Int. Ed. 2017, 56, 5317) (scheme 1).

Based on the previous development of oxazoline directing group, DAI’s group developed an efficient Cu(I)-mediated C–H amination reaction with oximes as amino donors to introduce NH2 groups directly (scheme 2). Various strongly coordinating heterocycles including quinoline, pyrimidine, pyrazine, pyrazole and triazole were tolerated well.

The oxime ester as an easily accessible and inexpensive amino donor has two obvious advantages: First, this allows an additional role of aminating reagents to serve as an internal oxidant, thus not requiring stoichiometric external oxidants in the catalytic process; Second, The imine formed by the reaction can access to primary anilines under mild hydrolysis conditions, and the resulting ketone can also be recovered in an almost equivalent amount.

The finding provides a promising new approach to the synthesis of regioselective primary anilines. Notably, this approach can rapidly access the diversification and modification of the complex drug molecules with exclusive site selectivity.

In addition, the primary anilines can be obtained with complete removal of the amide-oxazoline part under the acidic conditions. This method provides a good idea for the construction of aryl amino acids and aryl amine products.

The study was funded by the Chinese Academy of Sciences, the National Science Foundation of China, the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, the Youth Innovation Promotion Association CAS, the Institutes for Drug Discovery and Development, Chinese Academy of Sciences and the Science and Technology Commission of Shanghai Municipality.

Link to the article: http://pubs.rsc.org/en/content/articlelanding/2018/sc/c8sc01256c

Scheme 1. Selective late-stage diversification of Telmisartan. (Image by DAI’s group)

 Scheme 2. Copper-mediated C–H primary amination.(Image by DAI’s group)

The back cover report of Chemical Science
(Image courtesy of Chemical Science)


Contact person:
Prof. DAI Huixiong
Email: hxdai@simm.ac.cn

(Credit: WANG Xing)

 

 

 
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