The J. Du Bois group of Stanford University develops the method of intermolecular SP3 C-H amination of complex molecules

Nitrogen-containing molecules are ubiquitous in nature, drugs and pesticides, so the development of C-N bond construction method is very important The general method is the selective oxidation of C-H bond to form amine derivatives One of its significant advantages is that it can modify the structure of existing molecules later and increase the diversity of molecules However, the potential of such reactions is not fully exploited, because the range of substrates and intermolecular reactions are still limited In addition, the yield of C-H amination is relatively low for complex molecules and polar substrates such as ammonium salts and nitrogen heterocycles Recently, the J Du Bois group of Stanford University reported a general and effective one-step amination method for complex molecules, which only needs 1 equivalent substrate, a small amount of reaction additives and convenient nitrogen source (Figure 1) Relevant papers were published on angelw Chem Int ed (DOI: 10.1002 / anie 201713225) under the title of "intermolecular SP 3 C – h amination of complex molecules" Figure 1 General method of amination of SP 3 C-H (source: angelw Chem Int ed.) in order to realize amination of nitrogen rich substrate and ammonium salt, the author tried to use polar solvent to promote the dissolution of substrate Using isomenthol 1A as the substrate, [RH 2 (ESP) 2] as the catalyst, and phoso 2nh 2 (psnh 2) as the nitrogen source, the author tested a series of reaction solvents (Fig 2) The results show that the yield of C-H amination is the best when the solvent is t-bucn or phcn (entry10,11) Figure 2 Rhodium catalyzed C-H amination reaction conditions optimization (source: angelw Chem Int ed.) with the best reaction conditions, the author expanded the amination substrate As shown in Fig 3, cycloheximide (2b), estrone (2C), perilla lactone (2D) and other active pharmaceutical components (2G, 2K, 2O, 2P) can be functionalized successfully with a yield of 40-75% The reaction has a special selectivity for the oxidation of benzyl and tertiary C-H bonds, and a moderate enantioselectivity for the stereocenter near the amination site Figure 3 Substrate expansion of C-H amination reaction (source: angelw Chem Int ed.) is consistent with the expected results The products obtained from the reaction of electron deficient and space blocked substrates are usually of low yield If the substrate requirement is not strict, 2-3 equivalent substrate reaction can be used to obtain the product close to the nitrogen source equivalent It is important that the sulfamate product can be heated with pyridine in an open solution of acetonitrile to convert to the corresponding primary amine (Fig 4) Aryl acetate, β - ketoacetate, lactone, methyl ester and other functional groups sensitive to hydrolysis can also tolerate such hydrolysis conditions Fig 4 Deprotection of sulfamate products (source: angelw Chem Int ed.) next, the authors conducted a series of experiments to explore the reason why terpentylnitrile enhanced intermolecular C-H amination The UV-vis spectra of [RH 2 (ESP) 2] complex show that acetonitrile, terpentylene nitrile and benzonitrile have similar σ - donor strengths, and their electron supplying ability is stronger than that of isopropyl acetate, Sulfolane and propylene carbonate According to the previous work and literature of the research group (J am Chem SOC 2009, 131, 7558 – 7559; chem EUR J 2011, 17, 5827 – 5832), intermolecular C – h amination will generate Rh (II) / Rh (III) dimer through single electron catalyst oxidation The stability and life span of the complex are very important for the realization of high conversion number (ton) It is speculated that strong coordination solvents such as terpentylene nitrile can stabilize the oxidation of the complexes, thus increasing the conversion number of the reactions But this explanation can not explain why the effect of terpentylene and benzonitrile is better than acetonitrile which is also a strong coordination solvent The authors note that the solvents in C-H amination are also oxidized to form ions (J am Chem SOC 2007, 129, 562-568) Further deuterium solvent experiments and 19 F NMR real-time monitoring of 19 f labeled H 2 (ESP) ligands showed that compared with acetonitrile and dichloromethane, more complete catalyst complexes could be retained in terpentylene nitrile (Fig 6), which confirmed that the solvent had an impact on the life and degradation pathway of [RH 2 (ESP) 2] Fig 5 UV-Vis spectrum of rhodium catalyst complex (source: angelw Chem Int ed.) Fig 6 19 FNMR detection of catalyst complex (source: angelw Chem Int ed.) Summary: Bois group developed a general method for intermolecular C-H amination reaction, and used this method to generate sulfamic acid derivatives of complex molecules such as natural products and active components of drugs It was found that t-butonitrile (t-bucn) can significantly increase the conversion number of catalyst and reach an unprecedented reaction range Corresponding author: Professor J Du Bois