Synthesis And Applications Of Cyclopropyl Trifluoromethyl Ketone With Indoles

The position of the element fluorine in the periodic table indicates its special properties. Introduction of fluorine-containing groups or fluorine atoms to organic molecules can significantly change their physical and chemical properties and biological activitity. Nowadays organofluorine compounds are widely used in pharmaceutical, pesticide, space industry, material atomic energy industry and many other fields. Organofluorine compounds are rarely found in nature, so synthesis of those useful compounds has attracted more and more attentions. At present, there are two ways to introducing fluorine atoms into organic molecules:direct fluorination and fluorine-containing building blocks. Owing to the mild reaction conditions, operational convenience, multiple reactivities and higher chemoselectivity, the approach of using fluorine-containing building blocks has become one of the most important methods for synthesis of organofluorine compounds,Introduction of trifluoromethyl group into organic compounds has been a hot area of research for a long time. Therefore, it is very important to synthesize and study the transformation of trifluoromethyl building blocks. On the other hand, cyclopropane and methylenecyclopropane compounds have been widely applied in organic synthesis. With the transition metal and Lewis acid catalyzation, various reactions can occurr. Introduction of trifluoromethyl group into cyclopropane can be used as a novel fluorine-containing building block for preparing various organofluorine compounds.1. Synthesis of Cyclopropyl Trifluoromethyl KetoneWith1mol%cesium fluoride as catalyst, benzyl cyclopropanecarboxylate reacted with Ruppert-Prakash reagent (TMSCF3), and then hydrolyzed with2mol%TBAF·3H2O to give the cyclopropyl trifluoromethyl ketone in good yield. This reaction is with operational simplicity, and the conditions are mild. The purification of product is easy to implement due to solvent-free. Hence, we have developed a good method for large scale preparation of cyclopropyl trifluoromethyl ketone. 2. Bronsted Acid-Catalyzed Solvent-Free Bisindolylation of Trifluoromethyl KetonesBisindolylalkanes and their derivatives exhibit a wide range of bioactivities. The most straightforward ways for synthesizing bisindolylalkane compounds are Lewis or Br(?)nsted acid-catalyzed addition reactions of indoles with carbonyl compounds. We have developed a trifluoromethanesulfonic acid-catalyzed bisindolylation reaction of indoles with alkyl and aryl trifluoromethyl ketones. The solvent-free condition and convenient operation make this protocol an eco-friendly and practical method. The trifluoromethyl-substituted bisindolylalkane derivatives were synthesized in moderate to excellent yields.3. Inorganic Base-Catalyzed Nucleophilic Addition Reaction of Indoles with Trifluoromethyl KetonesDue to its unique features, trifluoromethyl-substituted tertiary alcohols have attracted a lot of attentions in pharmaceutical, agrochemical and material sciences. Inorganic base-catalyzed addition reactions of indoles with alkyl trifluoromethyl ketones have not been reported. In this part, we have documented an efficient and practical cesium carbonate-catalyzed addition reaction of indoles with cyclopropyl trifluoromethyl ketone. This method offers several advantages, including operational simplicity, mildness of the reaction conditions, wide substrate scope, low catalyst loading, and high yields. Trifluoromethyl-indolyl-cyclopropylethanols are compounds with potential physiological activities, and valuable chiral building blocks.4. Two-Step Method of Bisindolylation of Trifluoromethyl KetonesWe have developed a trifluoromethanesulfonic acid-catalyzed bisindolylation reaction of indoles with cyclopropyl trifluoromethyl ketones in part2. However, this method requires harsh reaction conditions, and the substrate scope is poor. Besides, this method can only introduce the same indolyl substituents, which limits the variety of the substrates. In part3, we have documented a cesium carbonate-catalyzed addition reaction of indoles with cyclopropyl trifluoromethyl ketone at room temperature. Combining the part2with part3, we have developed a "Two-Step Method" bisindolylation of trifluoromethyl ketones with different indoles under mild conditions. In the first step, with the cesium carbonate catalyzed, the nucleophilic addition of indoles to cyclopropyl trifluoromethyl ketone to afford the intermediate products trifluoromethyl-indolyl-cyclopropyl-ethanols. Then it reacted with other indoles under catalyzed by Lewis or Br(?)nsted acid to afford trifluoromethyl-substituted bisindolylalkane derivatives. Using this method, series of unsymmetric bisindolylalkanes with different substituent groups were obtained in excellent yields.