Applications of Clauson-Kaas Reaction in Organic Synthesis.

Pyrrole-embedded organic molecules received a considerable importance due to their numerous biological and material applications. Hence, several synthetic strategies have been devised for the construction of diverse pyrrole analogues over the years. Among these, the Clauson-Kaas reaction is one of the most widely used protocols for the synthesis of various N-substituted pyrroles. This review briefly describes the Clauson-Kaas reaction along with modifications and a detailed account on its applications in the various sectors of organic synthesis.

N-substituted pyrrole carboxylic acid derivatives from 3,4-dihydroxyketons.

Since the chemical industry is largely dependent on petrol-based feedstocks, new sources are required for a sustainable industry. Conversion of biomass to high-value compounds provides an environmentally friendly and sustainable approach, which might be a potential solution to reduce petrol-based starting materials. This also applies for N-heterocycles, which are a common structural motif in natural products, pharmaceuticals and functional polymers. The synthesis of pyrroles is a well-studied and established process. Nevertheless, most routes described are not in line with the principles of green and sustainable chemistry and employ harsh reaction conditions and harmful solvents. In this study, 3,4-dihydroxyketons are used as excellent platform chemicals for the production of N-substituted pyrrole-2-carboxylic- and pyrrole-2,5-dicarboxylic acids, as they can be prepared from glucose through the intermediate d-glucarate and converted into pyrrolic acid derivatives under mild conditions in water. The scope of this so far unknown reaction was examined using a variety of primary amines and aqueous ammonium chloride leading to pyrrolic acid derivatives with N-substituents like alkane-, alkene-, phenyl- and alcohol-groups with yields up to 20 %. The combination of both, enzymatic conversion and chemical reaction opens up new possibilities for further process development. Therefore, a continuous chemo-enzymatic system was set up by first employing an immobilized enzyme to catalyze the conversion of d-glucarate to the 3,4-dihydroxyketone, which is further converted to the pyrrolic acid derivatives by a chemical step in continuous flow.

Clauson-Kaas pyrrole synthesis using diverse catalysts: a transition from conventional to greener approach.

Pyrrole is an important aromatic heterocyclic scaffold found in many natural products and predominantly used in pharmaceuticals. Continuous efforts are being made to design and synthesize various pyrrole derivatives using different synthetic procedures. Among them, the Clauson-Kaas reaction is a very old and well-known method for synthesizing a large number of N-substituted pyrroles. In recent years, due to global warming and environmental concern, research laboratories and pharmaceutical industries around the world are searching for more environmentally friendly reaction conditions for synthesizing compounds. As a result, this review describes the use of various eco-friendly greener protocols to synthesize N-substituted pyrroles. This synthesis involves the reaction of various aliphatic/aromatic primary amines, and sulfonyl primary amines with 2,5-dimethoxytetrahydrofuran in the presence of numerous acid catalysts and transition metal catalysts. The goal of this review is to summarize the synthesis of various N-substituted pyrrole derivatives using a modified Clauson-Kaas reaction under diverse conventional and greener reaction conditions.

Multicomponent Reactions for the Synthesis of Active Pharmaceutical Ingredients.

Multicomponent reactions 9i.e., those that engage three or more starting materials to form a product that contains significant fragments of all of them), have been widely employed in the construction of compound libraries, especially in the context of diversity-oriented synthesis. While relatively less exploited, their use in target-oriented synthesis offers significant advantages in terms of synthetic efficiency. This review provides a critical summary of the use of multicomponent reactions for the preparation of active pharmaceutical principles.

Modular Synthesis of Polymers Containing 2,5-di(thiophenyl)-N-arylpyrrole.

A modular facile route has been developed to synthesize functionalized 2,5-di(thiophen-2-yl)-1-H-arylpyrroles from readily available starting materials. These units are compatible with various polymerization conditions and are versatile building blocks for conjugated polymers. The polymers show high thermal stability and solubility in a number of solvents. Characterization of the polymers reveals a correlation between molecular packing, controllable by polymer design, and charge carrier mobility.

Synthesis of Multi-Substituted Pyrrole Derivatives Through [3+2] Cycloaddition with Tosylmethyl Isocyanides (TosMICs) and Electron-Deficient Compounds.

Pyrrole and its polysubstituted derivatives are important five-membered heterocyclic compounds, which exist alone or as a core framework in many pharmaceutical and natural product structures, some of which have good biological activities. The Van Leusen [3+2] cycloaddition reaction based on tosylmethyl isocyanides (TosMICs) and electron-deficient compounds as a substrate, which has been continuously developed due to its advantages such as operationally simple, easily available starting materials, and broadly range of substrates, is one of the most convenient methods to synthetize pyrrole heterocycles. In this review, we discuss the different types of two carbon synthons in the Van Leusen pyrrole reaction and give a summary of the progress of these synthesis methods in the past two decades.

Efficient [Cu(NHC)]-Catalyzed Multicomponent Synthesis of Pyrroles.

Efficient [Cu(NHC)]-catalyzed syntheses of pyrroles via two and three-component coupling methods are described. Various 1,2-, 1,2,3-, 1,2,3,5- and fully substituted pyrroles were readily accessible through a suitable choice of ketone, primary amine and diol in a three-component reaction. The N-unsubstituted pyrrole formation is also feasible through a two-component reaction involving a ß-amino alcohol and a ketone.

Sustainable Pathways to Pyrroles through Iron-Catalyzed N-Heterocyclization from Unsaturated Diols and Primary Amines.

Pyrroles are prominent scaffolds in pharmaceutically active compounds and play an important role in medicinal chemistry. Therefore, the development of new, atom-economic, and sustainable catalytic strategies to obtain these moieties is highly desired. Direct catalytic pathways that utilize readily available alcohol substrates have been recently established; however, these approaches rely on the use of noble metals such as ruthenium or iridium. Here, we report on the direct synthesis of pyrroles using a catalyst based on the earth-abundant and inexpensive iron. The method uses 2-butyne-1,4-diol or 2-butene-1,4-diol that can be directly coupled with anilines, benzyl amines, and aliphatic amines to obtain a variety of N-substituted pyrroles in moderate-to-excellent isolated yields.

Synthesis of Substituted Pyrroles via Copper-Catalyzed Cyclization of Ethyl Allenoates with Activated Isocyanides.

A new method for the synthesis of di- and trisubstituted pyrroles via copper-catalyzed cyclization of ethyl allenoates with activated isocyanides has been developed. In contrast to related annulation reactions previously reported, this new process features a skeletal rearrangement in which the aryl sulfonyl moiety, which functions as the electron-withdrawing group in the α-carbon of the isocyanide, was found to migrate to the γ-carbon of the starting allenoate in the final product for the first time.

Design, synthesis and anti-mycobacterial activity of 1,2,3,5-tetrasubstituted pyrrolyl-N-acetic acid derivatives.

A novel synthesis of highly substituted pyrrole-N-acetic derivatives is described through the coupling of 1,4-diketones with amino acids following Paal-Knorr's approach. These pyrrole-N-acetic acid derivatives are found to exhibit potent anti-mycobacterial activity against Mycobacterium smegmatis and Mycobacterium tuberculosis strain H37Rv. In particular, 5n, 5q &5r are found to display excellent anti-mycobacterial activity against M. tuberculosis strain H37Rv with MIC values in the range of 2.97 µM. Conversely, these compounds showed low cytotoxicity (selectivity index: >16.83) against HEK-293T cell line.

Catalyst-dependent divergent synthesis of pyrroles from 3-alkynyl imine derivatives: a noncarbonylative and carbonylative approach.

A novel Ru(0)- and Rh(I)-catalyzed noncarbonylative and carbonylative cycloisomerization of readily available 3-alkynyl imine derivatives has been developed to provide 3,4-fused or nonfused pyrrole derivatives efficiently in moderate to excellent yields. The key steps involve the formation of a ruthenium carbenoid intermediate or a rhodacycle intermediate, respectively. In these reactions, CO can serve as a ligand or a reagent.