Study On The Multicomponent Reactions Of Isocyanides With Electron Deficient Alkynes/Allenes Or Arynes And Pd-catalyzed Arynes Annulation Reaction

With the aim of sustainable development, chemists have been paying close attention to the development of new synthetic methodologies which are both highly efficient and environmentally friendly. Multicomponent reactions emerge as the answer because of their high bond-forming efficiency, good substituent tolerance, and high atom economy. Isocyanides, a type of reactive small organic molecule, have become a common element in multicomponent reactions. In the well-established isocyanide chemistry, in most cases isocyanide participates multicomponent reactions due to its nucleophilicity.Based on the unique reactivity of isocyanides in organic synthesis, we have applied isocyanides to the nucleophilic addition reactions of electron deficient olefins or alkynes, and the resulting active zwitterion intermediate is then trapped by the third component to afford attractive products with or without further transformation(s). In this dissertation, we have focused on the following subjects:1. Firstly, we investigated the multicomponent reaction of acetylenic esters/ketones, isocyanides, and carboxylic acids. A novel methodology for the synthesis of (Z)-4-oxo-4-(N-acrylamido)but-2-enoates and (Z)-N-acryl-4-oxo-4-arylbut-2-en-amides with high regio- and stereoselectivity was developed. When terminal alkynes were used as the starting material, the (E)-products could be obtained in excellent yield via the Z to E isomerization. Interestingly, E-isomer could be synthesized in one pot by employing terminal alkynes under modified reaction conditions.2. Then, we extended the reaction mode of electron deficient alkynes with isocyanides and carboxylic acids to electron deficient allenes. We chose 2,3-allenoates as the starting material and realized the novel synthesis of a series of ethyl 4-(N-acrylamido)-4-oxobutanoates. Moreover, we successfully replaced allenoates and carboxylic acids with allenoic acids, providing a new approach to highly substituted 5-imino-dihydrofuran-2(3H)-ones and pyrrolidine-2,5-diones. It is notable that when asymmetric 2,3-allenoates or 2,3-allenoic acids were employed, the reaction showed good stereoselectivity, leading to (E)-isomer as the overwhelmingly major product.3. Arynes are usually considered as electron-deficient alkynes, exhibiting highly electrophilic nature. Nucleophiles such as isocyanides can easily add to arynes to produce active zwitterions, which undergo the subsequent transformation with aldehyde or imine leading to the formation of corresponding products. We envisioned that the adduct of benzyne and isocyanide (generated in-situ) may be trapped by a terminal alkyne to form a reactive alkynyl imide intermediate, which may further undergo a series of subsequent reactions. The tentative idea was then realized:the alkynyl imide underwent 1,5-hydride shift/[4+2] cycloaddition/aromatization to produce polysubstituted pyridines and isoquinolines with high chemo-and regioselectivity. Interestingly, either polysubstituted pyridines or isoquinolines could be obtained controllably by simple choosing of appropriate reaction conditions.We figured that the diversity of the products (pyridines and isoquinolines) were limited because the key intermediate alkynyl imine was formed in-situ in the reaction. Therefore, we synthesized alkynyl amines and introduced them for the [4+2]-cycloaddition with differently substituted alkynes or arynes. This strategy solved the above problem successfully, and provided an efficient approach to pyridine derivatives with different substituents.4. On the basis of our previous study on arynes, we explored the Pd-catalyzed annulation of arynes and 2-ally-3-iodocycloenones or 3-allyl-4-iodofuranones, which provided a facile and efficient method for the synthesis of hydrophenanthren-1(2H)-ones and naphtha[2,1-c]furan-3(1H)-ones. The reaction showed better regioselectivity when 3-allyl-4-iodofuranones were employed as starting material. Furthermore, when we introduced a methyl group on 2 position of allyl moiety, the reaction didn't give the expected product.