Chromeno[2,3-b] Indole Synthesis Via The Cascade Reaction Of Salicylaldehyde And Indole Derivatives

Chromeno[2,3-b]indoles are privileged motifs of both natural products and drug molecules.Moreover,chromeno[2,3-b]indole derivatives can also have biological activity,as shown by antimalarial and anticancer agents.Despite the great importance of chromeno[2,3-b]indole compounds,their synthesis lacked simple,mild and direct approaches.So far,the traditional route for the synthesis of chromeno[2,3-b]indoles was based on multistep processes.This process could be achieved by using stoichiometric reagents under harsh conditions.These features restricted the development of chromeno[2,3-b]indole derivatives bearing various substituent groups.The construction of chromeno[2,3-b]indoles remains relatively unexploited through cascade reactions from available starting materials.In this paper,we described a cascade reaction of salicylaldehyde and 2-bromoindole for a direct preparation of chromeno[2,3-b]indoles.Next,a brief introduction of elemental sulfur-promoted the cascade reaction of salicylaldehyde and indole derivatives under transition-metal-free conditions is descibed.Finally,the mechanism of reactions has been investigated in detail,which provides a new insight for the synthesis of chromeno[2,3-b]indoles.This paper includes two major research works: 1: Practical synthesis of chromeno[2,3-b]indole skeleton via an aldehyde group insertion/aromatization strategyThe synthesis of chromeno[2,3-b]indole from simple starting materials remains a demanding process.Herein,we designed a simple and efficient route to synthesize chromeno[2,3-b]indoles from 2-bromoindole and salicylaldehyde via a cascade reaction.The Pd-catalyzed regioselectively intramolecular reaction of 2-bromoindole derivatives with salicylaldehydes.2-bromoindole undergoes nucleophilic attack from salicylaldehyde,followed by intramolecular insertion of an aldehyde group and aromatization to generate the desired chromeno[2,3-b]indoles.Moreover,various functional groups were tolerated and a gram-scale synthesis of the product could be achieved under the optimized condition.This approach could open the pathway for other bromoindoles and salicylaldehydes in the synthesis of heterocyclic compounds.2: Sulfur-promoted the preparation of chromeno[2,3-b]indoles from indole and salicylaldehyde under transition-metal-free conditionsThe oxidative annulation of salicylaldehyde and indole derivatives was achieved by cascade reaction under transition-metal-free conditions.Various functional groups on salicylaldehyde derivatives were tolerated.And different indole derivatives could also be suitable substrates.In above process,indole underwent the attack of salicylaldehyde with the aid of base,followed by the intramolecular reaction and the aromatization to generate the desired product.Moreover,the preparation of chromeno[2,3-b]indoles could be realized on a gram scale.More importantly,this work represented a valuable route relative to existing procedures for the synthesis of chromeno[2,3-b]indoles.