Nat. Catalyst.: a series of α - branched amines have been synthesized by C-H bond, amination reagent and 1,1-addition of terminal alkenes by Ellman group of Yale University

α - branched amines are widely used in many drugs and clinical candidates (Fig 1a) It is an important strategy to synthesize α - branched amines by forming C-C bond at the carbon branch site of SP 3, because it can realize the aggregation preparation through smaller synthesis precursor and introduce the stereocenter at the same time In fact, one of the most effective methods for the preparation of these compounds is the addition of nucleophiles (such as organometallic reagents) to imines, and researchers are developing new methods to catalyze this process (Fig 1b) Recently, the strategy of C-C bond formation at the α position of amines has been used in the synthesis of α - branched amines At the same time, the strategy can also introduce the stereocenter (Fig 1c) at the branched point Recently, Jonathan A Ellman of Yale University reported the method of C-H bond, amination reagent and 1,1-addition of terminal ene catalyzed by Cp * Rh (III) to synthesize α - branched amine In addition, the asymmetric synthesis of α - branched amines was also realized by using chiral catalysts Relevant research results were published in NAT Catalyst (DOI: 10.1038/s41929-019-0330-7) (source: Nat Catalyst.) the author first optimized the reaction conditions At first, the author devoted to the preparation of α - branched amine 1 protected by tert butoxycarbonyl (BOC) After extensive research on various conditions such as catalyst, additive and solvent, the author determined that the best reaction conditions were as follows: [Cp * RhCl 2] 2 as the pre catalyst, agsbf 6 as the halide extractant, DCE as the solvent, and the substrate with C-H bond reacted at the concentration of 0.2m at 30 ℃ For oxime type substrates, the reaction effect is the best when 1 equivalent NaHCO 3 is added However, for amides and triazoles, pivoh is a more effective additive Next, the author explores the scope and limitations of the response This transformation can also be widely used in the direct one-step preparation of other common α - branched amines containing protective groups (Fig 2) Styrene is a suitable olefin substrate, and amines 5 - 8 can be obtained in good yield In order to obtain a variety of α - branched amide derivatives directly in one step, a series of α - branched amide 9 - 17 were synthesized with 1,4,2-dioxazole-5-one as aminating agent In addition, the common nitrogen heterocycles such as pyridine and all kinds of amides are effective guiding groups The corresponding α - branched amines 18-33 are obtained by the reaction, and the yield is 51-86% (source: Nat Catalyst.) a variety of cheap and easy to get end alkenes, including allylbenzene, large position olefins and ethylene (Fig.3 and 4a) are also suitable for this system, and a variety of functionalized α - branched amines (34-58) are successfully obtained The reaction shows a wide range of functional group compatibility, and can be compatible with primary alcohols, aldehydes, ketones and other functional groups (source: Nat Catalyst.) in order to further prove the practicability of the reaction, the author prepared α - methylbranched amine 54 (Fig 4C) in a yield of 64% at a scale of 5g In addition, the asymmetric synthesis of α - methylbranched amine was also realized by using Rh complex 59 developed by Cramer project, and the product 60 - 63 was obtained with good yield and excellent enantioselectivity (Fig 4D) (source: Nat Catalyst.) based on the above experimental results and mechanism experiments, the author proposed a possible catalytic cycle (Fig 5) At the beginning of the reaction, a was formed by the reversible activation of o-c-h bond through the coordinated metallization and deprotonation The alkenes are coordinated and then transferred into rhodium ring B, which undergoes CIS β - H elimination to produce rh-h intermediate C combined with alkenes C is then inserted by CIS hydrogen outside the ring to produce a six membered rhodium ring D The coordination of amidation reagents and the formation of C-N bond are accompanied by the retention of configuration and the release of carbon dioxide Then, α - branched amine 27 was produced by proton demetallization, and the catalytic cycle continued (source: Nat Catalyst.) in a word, the author developed a multi-component aggregation method for the synthesis of α - branched amine derivatives The method is mild, the three starting materials are simple and easy to obtain, and the functional group compatibility is high In addition, the method is extended to the asymmetric synthesis of α - branched amines.