Synthesis Of Oxindoles Via Cu-mediated ATRA Between N-phenylacrylamides And Ethyl 2-bromo-2-methylpropionate

Oxindoles are important heterocyclic scaffolds found in a wide range of bioactive natural products and pharmaceutical molecules. As such, the synthesis of oxindoles has always attracted considerable attention from synthetic chemists and extensive research effort has been devoted to the development of new methods for a convenient access to oxindoles. Even though the reported synthetic strategies do provide convenient access to various oxindoles starting from a relative simple starting material, however, the use of an expensive noble metal has severely limited the practicality of these methods. Meanwile, recently Cu-catalyzed or mediated atom-transfer radical addition (ATRA) have emerged as a powerful method for the addition of alkyl C-X bonds across C-C double bonds and triple bonds. Inspired by these results, we wonder whether Cu-catalyzed or mediated ATRA strategy can be applied to the synthesis of oxindoles. In summary, for the synthesis of alkylated oxindoles we find a new approach and the main content is divided into four parts as follows:Firstly, we report that oxindoles can indeed be efficiently synthesized from 2-bromo-2-methylpropionate and N-arylacrylamides with the assistance of CuBr.Secondly, we examine kinds of reaction conditions including ligand, solvent, and so on, and found the standard conditions for synthesis of oxindoles: N-arylacrylamides with 3 equiv of 2-bromo-2-methylpropionate in the presence of 1 equiv of CuBr and 0.5 equiv of diamin ligand in DMSO at 130? for 18 h.Thirdly, we examine the scope of this reaction. Under the standard conditions, a variety of diversely substituted oxindoles were efficiently synthesized from the corresponding N-phenylacrylamides in 43-76% yield. We are delighted to see substrates bearing halogen substituents including F, Cl, Br, and I work satisfactorily to afford the desired products in yields ranging from 43-68%. Furthermore, it was found that ortho-substituted substrates could participate in the transformation as well, but the yields are slightly lower compared to para-substituted substrates.In the end, In order to gain some information on the reaction mechanism, several control reactions are performed. When the reaction of N-arylacrylamides with 2-bromo-2-methylpropionate was carry out in presence of a stoichiometric amount of radical scavenger TEMPO, no reaction take place. Based on literature precedents and the results, a tentative reaction is proposed and depicted by the author.