J. Am. Chem. SOC.: copper catalyzed three component alkene amination

The development of simple methods for the construction of complex organic molecules will promote the development of organic chemistry In view of the widespread existence of C-N bonds in bioactive molecules, it is particularly important to improve the synthesis of amines In general, complex molecular structure can only be realized by multi-step synthesis, while the difunctionalization of olefins can directly obtain complex molecular skeleton in one step The carboamination of olefins is one of the difunctional reactions Through the carboamination reaction, the researchers can introduce carbon and nitrogen-containing functional groups into olefin molecules at the same time In the past, most of the methods used two-component reaction strategy to obtain ring products, but these methods are limited by the reaction module Recently, Kami L hull team from the University of Illinois at Urbana Champaign published a paper on J am Chem SOC., which reported that copper catalyzed the three-component carboamination of alkenes, amines and α - bromocarbonyl compounds, in which electrophilic alkyl free radical intermediates were generated The products have regional and chemical selectivity Figure 1 Source of three-component amination: J am Chem SOC Based on the previous research, the author first screened and optimized the reaction conditions of copper catalyzed amination The best conditions are: 5.0 mol% Cu (OTF) 2, 5.0 mol% 2,2 '- bipyridine, 1.1 equivalent K3PO4, 2.0 equivalent α - bromoisobutyrate ethyl ester, 1.0 equivalent styrene, 1.0 equivalent N-methylaniline, N 2 protection, reaction at 80 ℃ in DCE for 24 hours The separation yield of the product is 87% With the best reaction conditions, the three component substrates included in the reaction were expanded The results are shown in Fig 2, Fig 3 and Fig 4 The experimental results show that this kind of carboamination reaction can be compatible with a variety of olefins and amine substrates, and a series of styrene with different electrical properties are suitable for this reaction (Fig 2) In addition, inner olefins and aliphatic olefins can also react, and olefins containing sensitive groups such as alkyl bromide, end epoxy, ketone, acetoxy and large C-N bond can be compatible (Fig 4) Carbonyl electrophilic reagents are also widely used α - bromocarbonyl compounds containing esters, amides, amides, ketones, malonates, sulfones and other groups participate in the reaction, all of which can obtain the target product in good to excellent yield (Fig 3) Fig 2 Aryl ethylene and amine substrate development source: J am Chem SOC Fig 3 Electrophilic reagent substrate development source: J am Chem SOC Fig 4 Fatty and olefin substrate development source: J am Chem SOC In order to further expand the substrate application scope of these three-component carboamination reactions, the authors conducted preliminary mechanism research The author hypothesized that the reaction mechanism is that the intermediate of free radical addition is oxidized to produce oxygen carbon positive ions, and then relevant experiments are carried out: CYCLOPROPYLENE (3) reacts under standard conditions to obtain ring opening carboamination product (2Al) (Fig 5, Eq 1); N, n-diallyaniline (4) reacts through 5-exo-trig process to obtain product 2AP, and the enantioselectivity is 1.5:1dr (Fig 5, Eq 2) ; stereochemical reaction of endoolefins (Fig 5, Eq 3 & 4) The experimental results of mechanism study are consistent with the mechanism proposed by the author Figure 5 Experimental source of mechanism research: J am Chem SOC Summary: hull team developed copper catalyzed three-component carboamination reaction with olefins, alkyl halides and amines as raw materials The three types of substrates are widely used, and the yield of the reaction is high The team said that in the future, non enantioselective reaction conditions will be further developed Paper link: http://pubs.acs.org/doi/10.1021/jacs.7b10529 the hull group http://scs.llinois.edu/hull/klhgroup/index.html members of the hull group (Professor Kamil Hull in the front left) source: the hull group