2-methylindole As An Indicative Nucleophile For Developing A Three-component Reaction Of Aldehyde With Two Different Nucleophiles

Multicomponent reactions have attracted much attention in the field of organic synthesis due to their important characteristics such as high atom economy and simple operation. Electrophilic reaction of aldehydes with two different nucleophiles is well known to be a common strategy for developing multicomponent reactions. However, this strategy is often plagued by side reactions of the aldehyde with the same nucleophile which influences the product separation and yield. Therefore, in this area, most of the research efforts are paid to rational design of substrates and catalysts to control the reaction selectivity. Unfortunately, because of the intrinsic sensitivities of these multicomponent reactions to catalyst, solvent and some other parameters, exploration of this type three-component reaction is now a labor-intensive and time-consuming task for researchers. On this account, an effective method for rapid screening of substrate, catalyst and other parameters is needed.As the result of the distinct color change of electrophilic alkylation reaction of aldehydes and indole, in this paper, we use 2-methylindole as a nucleophilic indicator to indirectly judge whether three-component reaction of aldehyde and two different nucleophiles has a good selectivity by utilizing the color change in the process of reaction to monitor whether side reactions occur extensively. When the color of the reaction system turns red quickly, indicating that only a side reaction of aldehyde with indole occurs to generate di(indolyl)methane derivatives in the system, in these cases, the reactions can be excluded directly without further analysis. In contrast, when the reaction system is no color change, indicating that all components in the system may be involved in the reaction, in these cases, further analysis is needed in order to know whether the expected three-component reaction occurs. With this strategy, three-component reactions of salicylaldehyde, acetophenone and 2-methylindole were developed to synthesize 4H-chromene derivatives by utilizing L-Proline as catalyst. The substrates scope and reaction mechanism were also be explored. At the same time, with the aid of the obtained catalytic/synthetic system, we found that 2-methylindole can be replaced by other nucleophiles, such as thiophenol and 1H-benzotriazole to get more similar multicomponent reaction in mechanism This demonstrates the feasibility of developing new multicomponent reactions with 2-methylindol as a nucleophilic indicator. In a word, we not only provided a simple and effective method for the development of new multi-component reaction, but also offered an effective and straightforward way for the synthesis of 4H-chromenes by a three-component reaction involving aldehyde.