Imidoyl Chloride Mediated One-Pot Synthesis of 3-Electron Withdrawing Group Substituted Indoles

Abstract

Indole scaffold is widely present in pharmaceutical and pesticide products, dyes and natural products. The indole skeleton substituted by the electron withdrawing group at position 3 is an important class of bioactive indole derivatives. Among them, 3-cyanoindole is a key module in the construction of privileged scaffold-based combinatory library and diversity-oriented synthesis for drug discovery. For these reasons, the design and synthesis of these scaffolds have received considerable attention in organic synthesis and have been extensively studied. However, the cyano group on the indole was introduced directly in previously reported methods. Due to the high toxicity of cyanide, the application of these reactions is limited. Imidoyl chloride, a highly reactive synthon, which was successfully used as a module for the construction of quinolones, quinazolines, benzimidazoles and other drug-like privileged scaffolds by our group. By making use of the imidoyl chloride as the active intermediate to mediate a cascade reaction to form the heterocycle, we developed a new one-pot synthesis to construct the 3-cyano or carboxylate-indole derivatives. The reaction proceeded via two sequential steps: initial formation of imidoyl chloride starting from N-substituted arylamide and thionyl chloride, followed by 2-bromo-arylnitrile carbanion nucleophilic addition, elimination and Ulmann reaction. This synthetic methodology is featured with cheap and readily available starting materials, high reaction yields, high functional group tolerance and broad substrate scope. This reaction is a direct synthesis not requiring prefunctionalization, and highly atom- and step-economic. It's worth noting that it's the first time building 3-cyanoindole scaffold commenced with the substrates bearing cyano group, which is of great importance for avoiding potential safety hazards.