Synthesis of five-membered n-heterocycles and their biologically active derivatives

Five-membered nitrogen containing heterocycles such as pyrroles, indoles and carbazoles represent an important class of compounds and are found in an extensive number of biologically active compounds. These heterocyclic moieties are of exceptional interest in pharmaceutical applications as they make up a core part of several drugs. Examples include anti-inflammatory, antitumor, antiallergic, antiviral and antihypertensive compounds. The importance of these heterocycles provides significance and actuality for developing new methods for their syntheses. Traditional methods for the synthesis of these heterocycles typically involve the use of hazardous reagents and multi-step processes. Due to strengthening environmental regulations and safety concerns, the development of environmentally responsible synthetic methods are also highly desirable. We have developed various environmentally benign methods for the synthesis of N-heterocycles and their derivatives utilizing solid acid catalysts combined with a microwave-assisted approach. All three heterocycles described herein were synthesized by a modified Paal-Knorr type cyclization/annelation method. In all cases, the reactions were completed within 30 minutes with excellent yields and selectivities. This method has successfully demonstrated the use of montmorillonite K-10 as an effective and recyclable solid acid catalyst for various cyclialkylations. As a further advantage, reaction times have been reduced substantially from hours to minutes; also the one-pot and solvent free reaction conditions make this an environmentally benign process.;We then carried out asymmetric organocatalytic Friedel-Crafts reactions of various indoles and pyrroles with ethyl trifluoropyruvate using naturally available cinchona alkaloids to provide the related trifluoromethyl hydroxyl esters. In this process, we demonstrated that use of pseudoenantiomeric cinchona alkaloids provided both the enantiomeric products with excellent yields (up to 99%) and high enantio-selectivities (up to 95%). In the search for trifluoromethylated amino acid derivatives, we designed a new method to carry out a highly enantioselective Friedel-Crafts reaction of indoles and pyrroles with trifluoromethylated imines.;Our initial in vitro studies revealed an important application of indole trifluoro-methyl hydroxyl esters as potential inhibitors of amyloid fibrillogenesis. Application of these new compounds carries the promise of becoming potential therapeutics against Alzheimer's disease, and their use may be extended to other similar protein misfolding diseases.