Carbon-Nitrogen Bond Formation: Palladium-Catalyzed Synthesis Of Chiral N-heteroaryl Amino Acids Via Cross-Coupling Reaction Of Heteroaryl Halides With Amino Acids

Compounds containing C-N bond in nature and in synthesis are very cmmon.Many of them have important physiological activities, medicinal and industrial value. Their potential applications and prospects are broad. Chemical synthesis is one of practicall methods to obtain the C-N compounds. It's inevitable way holding the concept of green chemistry to develop chemisty and our society sustainablely. Pd-catalyzed cross-coupling reaction, also called Buchwald-Hartwig reaction, is an effective strategy to realize amination or arylation. At present, there is no report about palladium-catalyzed cross-coupling reaction of heteroaryl halides with amino acids. So, the study of palladium-catalyzed synthesis of chiral N-heteroaryl amino acids became our interest and some valuble achievements are arrived at as follows:1) We firstly establish the method of palladium-catalyzed C-N cross-coupling of heteroaryl halides and amino acids. There are four merits with this method:①a wider range of substrates. It is suitable for many heteroaryl halides and various of amino acis with the yield of 98.5% at most.②products with high enantiomeric purity with 100.0%ee .③low catalyst loading with 2%mmol.④short reaction time, one hour at 70℃.2) The reactivity of various heteroaryl halides and amino acids has been examined. The regularities of substrate structures to the reactivity have been summarized.Through the research, a conclusion could be made that the main factors to the sustrate reactivity are electronic effect and steric effect.For amino acids substrates, the steric properties dominate over the electronic properties, because of the strong base.For heteoaryl halides, electron deficient sustrates have better reavtivitis than electron-rich and–neutral species. 3) A series of new N-Heteroaryl Amino Acids synthesized with the method have been characterized and analyzed, with their 1H NMR, MS, IR, and chiral-HPLC.4) The mechanism of the reaction has been proposed for the first time. In this mechanism, we put forward some new hypothesis. The reaction mechanism can well explain our research results and experimental phenomena; at the same time, some of other research results reported are consistent with the mechanism. Three processes that may determine the reaction rate are listed below:①the combination of palladium precursor and ligand to generate catalytic active palladium compounds;②the addition of heteroaryl halide to palladium;③the nucleophilic substitution of amino acid to ipso-carton atom of heteroarene.