Studies On C(sp~3)-H Activation And Functionalization Of 2-Alkylazaarenes

Aromatic hydrocarbon compounds like pyridine and quinoline are important structural motifs widely existing in natural products and pharmaceuticals which exhibit pharmacological properties such as antiviral, anticancer. The pyridine and quinoline units can be modified via C-H bond activation, to synthesize the pharmaceutical moleculess substituted with azaarene at C2 position in a simply and efficiently pathway, which normally show physiological and biological properties. This approach is in accordance with the ideology and development direction of green chemistry, and is of great significance to develop new medicines.In recent years, many efforts have been devoted to the benzyl C(sp3)-H bond functionalization of 2-alkylazaarenes. To the best of our knowledge, however, extra additives likes Lewis or Brensted acids were indispensable in most of the methods to convert intrinsic imine structure of azaarenes into enamine structure. Benzyl C(sp3)-H bond functionalization of 2-alkylazaarenes has rarely been catalyzed via "substrate self-activation" or using endogenetic "designer acid" as catalysts without any extra catalysts addition, In view of this, this paper exploited the "self-catalysis" of decorated substrates and "designer acid" strategies to implement C(sp3)-H functionalization of 2-alkylazaarenes via which a serial of bioactive skeleton and fabricated newfangled heterocycle derivatives with physiological or biological activities could be furnished.This dissertation contains five sections which is summarized as follows:Section 1, Tandem Nucleophilic Addition/Decarboxylation of 2-Alkylazaarenes and Coumarin-3-carboxylic AcidWe have developed a facile catalyst-free tandem nucleophilic addition / decarboxylation reaction of 2-alkylazaarenes with coumarin-3-carboxylic acid. The study of the reaction mechanism indicates that the carboxyl group of substrate is indispensable.2-Alkylazaarenes intrinsic imine could be converted to nucleophilic enamine via "self-activation" strategy, followed by tandem nucleophilic addition/ decarboxylation of enamine with coumarin derivatives for efficient construction of 4-pyridyl (quinolyl) substituted 3,4-dihydrocoumarins. The reaction have wide substrate scope which could be extended to thiocoumarin-3-carboxylic acid and quinolinone. Therefore, the novel "self-activation" model has been successfully established for C(sp3)-H activation of 2-alkylazaarenes.Section 2, Tandem Nucleophilic Addition/Decarboxylation of 2-Alkylazaarenes with Chromone-3-carboxylic AcidSimilar to the 1st part, we applied the new "self-activation" pattern to realize tandem nucleophilic addition/decarboxylation of 2-alkylazaarenes with chromone-3-carboxylic acid via which 2-azaarene substituted 2-phenyl-chroman-4-one derivatives could be readily accessed, providing an efficient and novel protocol to construct this intriguing and significant moiety.Section 3, Three Component Reaction of 2-Alkylazaarenes, Aromatic Aldehydes and 4-HydroxycoumarinWe originally present a facile catalyst-free three-components reaction of 2-alkylazaarenes, aromatic aldehydes and 4-hydroxycoumarin for construction of azaarene-substituted 3-benzyl-4-hydroxylcoumarin in "one-pot" approach. According to the mechanism investigation, it can be confirmed that the product was generated from 4-hydroxylcoumarin and arylaldehyde which served as the endogenetic "designed acid" to promote 2-alkylazaarenes benzyl C-H functionalization. The "designed acid" was the key factor in the multi-component reactions of 2-alkylazaarenes benzyl C(sp3)-H functionalization. Besides, preliminary bioactivity of the prepared compounds has been tested and the result indicated that these compounds display the strong broad-spectrum antibacterial activities.Section 4, The Synthesis of (E)-2-Alkenylquinpline DerivativesIn this part, we developed a novel approach to synthesize (E)-2-alkenylquinoline derivatives through nucleophilic addition/dehydration of 2-methylquinoline with aromatic aldehydes via C-H activation under catalyst-free condition. Compared with the previous reports, this approach features simpler operation, catalyst-free and higher yield which meets the requirements of green chemistry.Section 5, Tandem Nucleophilic Addition/Decarboxylation of Indoles with Coumarin-3-carboxylic AcidIn this section, we developed a facile catalyst-free tandem nucleophilic addition / decarboxylation of indole derivatives with coumarin-3-carboxylic acid for the efficient construction of 4-indole substituted 3,4-dihydrocoumarins. The mechanism studies indicated that the presence of carboxylic groups is critical to the reaction. Once again, the fascinating "self-activition" strategy was exploited for construction of indole-substituted 3,4-dihydrocoumarin derivatives. Compared with the traditional methods, this substrates can be easily acquired and applied in a broad scope. The approach could also be extended to the thiocoumarin-3-carboxylic acid.