Nitrogen-centered Radical Initiated Aminative Difunctionalization Of Alkenes

Nitrogen-containing organic compounds are ubiquitous in natural products and synthetic molecules, such as dye, pesticide, medicine, synthetic resin et. al.. A vast majority of biological activitive natural products and drugs contain nitrogen atom as the indispensible interating elements with biomacromolecules in drug-receptor recognition. Therefore, the development of efficient, environmentally friendly and atom economical methods for C-N bond formation has attracted intensive attention of scientists.Nitrogen-centred radicals play an important role in many chemical and biological processes. Although many achievements in classical radical amination are developed and successfully applied in organic synthesis, the generation of nitrogen-centred radicals retails initiation under harsh conditions and the selectivity control of their reactions remains a formidable challenge. They are mostly used in the synthesis of N-containing heterocycles by intramolecular cyclization. As a result, the synthetic potential of nitrogen-centred radicals has remained largely unexplored, especially when compared with the well-established nucleophilic and electrophilic amination reactions. Recently, metal mediated radical amination with nitrogen centered radicals has proven a valuable alternative to the traditional ionic amination protocols, thus becoming an emerging amination strategy in recent years which has attracted much attention and some progress has been made.Aminative difunctionalization of alkenes is a highly efficient method for construction of C- N bonds. Metal-catalyzed aminative difunctionalization of alkenes, such as diamination, aminooxygenation, aminofluorination, aminochlorination, aminobromination, and carboamination often require employment of precious metal catalysts such as Pd, Ni, Au, et. al., which causes significant environmental and cost issues. Development of inexpensive first row transition metal catalyzed aminative difunctionalization of olefins are thus urgently needed.As a continuation of our previous work on amination reactions with N-fluorobenzeneimide(NFSI), we explored the possibility of radical amination with NFSI being the source of nitrogen centered radical species. We realized the first example of copper-catalyzed aminocyanation reaction of alkenes with NFSI and TMSCN. The interaction between trimethylsilyl cyanide and fluoride might play an important role in the efficient aminocyanation reaction. As the first example that employs NFSI as radical nitrogen source, this study paved the road for the development of general intermolecular aminative difunctionalization reaction initiated by radical amination events.Fluorinated compounds have special physical, chemical and biological properties due to fluorine’s high electronegativity and small atomic radius. They are widely used in agrochemical, pharmaceutical, material and polymer industries. Based on existing radical fluorination reaction and the radical aminating strategy we have developed above, we developed a highly regioselectivity copper-catalyzed radical aminofluorination of styrenes and 1,3-enynes, affording aminofluorination products with regioselectivities opposite to that of the palladium catalyzed and noncatalyzed processes. To our knowledge, this is the first example of employing NFSI as both radical nitrogen source and radical fluorine source, displaying perfect atom-economy. Preliminary mechanistic studies suggested that the reaction went through a radical amination and fluorination pathway which was further supported by DFT calculations.