Swapandeep Singh Chimni

Asymmetric Addition of Indoles to Isatins Catalysed by Bifunctional Modified Cinchona Alkaloid Catalysts

The development of new and more efficient catalytic reactions is of paramount importance, particularly for the synthesis of complex molecules. Recently, organocatalytic asymmetric reactions mediated by organocatalysts have emerged as an active area of research in synthetic chemistry. Organocatalysts offer many advantages over traditional transitionmetal-mediated processes; for example, the reactions can often be carried out under wet and aerobic conditions, the catalysts are generally inexpensive and there are no associated toxicity problems. The use of organocatalysts for the formation of stereogenic quaternary carbon centres by the addition of carbon nucleophiles to ketones or ketimines has been less explored. The low reactivity of these substrates relative to aldehydes and aldimines is often a limitation. This requires the activation of both the nucleophile as well as the substrate by a bifunctional organocatalyst, which has acidic and basic sites. Cinchona alkaloids and their modified derivatives are very efficient catalysts for a variety of enantioselective organic transformations. Thus, they are attractive catalytic targets for further applications and developments. We reasoned that, while the 9-hydroxy/or 6’-hydroxy (in the case of cupreine and cupreidine) group of the cinchona alkaloid activates the carbonyl group of isatin through hydrogen bonding, the quinuclidine N group binds and orients the indole through the formation of a hydrogen bond. Therefore, we planned to explore the applicability of cinchona and modified cinchona alkaloid catalysts for the Friedel–Crafts-type addition of indole to isatin to procure enantiopure 3-hydroxyoxindole derivatives. 3-Hydroxyoxindole derivatives are important structural motifs in a variety of natural products and biologically active compounds, which have a quaternary chiral carbon. The enantioselective approaches for the synthesis of 3-hydroxyoxindoles involve nucleophilic addition to the carbonyl carbon of the isatin; these are limited to the metal-catalysed addition of arylboronic acids, addition of organozinc reagents, allylation, crotylation and reverse prenylation reactions. The organocatalytic approach for the synthesis of chiral substituted 3-hydroxyoxindole is limited to aldol-type addition reaction by enamine catalysis. However, the enantioselective organocatalytic Friedel–Crafts-type addition to the isatin for the synthesis of 3-hydroxyoxindole motifs are not known. During the preparation of this manuscript, a metal-complex-catalysed reaction of isatin with indole was reported by Franz and co-workers. Herein, we report the first asymmetric organocatalytic reaction of isatin derivatives with indole for procuring optically active 3-(indolyl)hydroxyoxindole derivatives. Initially, the catalytic ability of cinchona alkaloids CD, CN, QN and QD (Scheme 1) was studied for the Friedel–

Catalytic asymmetric synthesis of 3-hydroxyoxindole: a potentially bioactive molecule

The recent emergence of biological activities of chiral 3-substituted-3-hydroxy-2-oxindoles has inspired synthetic chemists to develop new methodologies for their synthesis. Both chiral organocatalysts and organometallic catalysts have provided an important platform for their synthesis and in recent years, great achievements have been made in their catalytic asymmetric synthesis. This review summarizes the catalytic strategies for enantioselective synthesis of targeted frameworks.

Asymmetric Organocatalytic Addition Reactions of Maleimides: A Promising Approach Towards the Synthesis of Chiral Succinimide Derivatives

Recent progress in asymmetric organocatalysis has led to the development of several asymmetric transformations that employ various substrates. Among these substrates, maleimides have emerged as excellent Michael acceptors, dienophiles, and dipolarophiles. In this Focus Review we highlight the advances in the asymmetric synthesis of succinimide derivatives through asymmetric organocatalytic addition reactions of maleimides.

Aromatic hydroxyl group—a hydrogen bonding activator in bifunctional asymmetric organocatalysis

Recent progress in asymmetric catalysis has contributed to the development of a diverse range of chiral organocatalysts that differ in their origin, structure and mode of activation. The bifunctional organocatalysts bearing aromatic hydroxyl (or phenolic) groups have emerged as a privileged class of organocatalyst. In these bifunctional organocatalysts, the aromatic hydroxyl group functions as a weak Bronsted acid or hydrogen bonding site and a nucleophilic or basic moiety such as amine and phosphine serve as a base or hydrogen bond acceptor. The bifunctional organocatalysts having these moieties have not been reviewed. In this review we are presenting the asymmetric transformations catalyzed by the bifunctional organocatalyst bearing an aromatic hydroxyl group.

Stereoselective synthesis of 3-amino-2-oxindoles from isatin imines: new scaffolds for bioactivity evaluation

3-Substituted-3-aminooxindoles have attracted the attention of organic and medicinal chemists because these motifs constitute the core structure of a number of natural products and drug candidates. The catalytic potential of chiral organocatalysts and metal catalysts has been successfully exploited for the synthesis of enantioenriched 3-amino-2-oxindoles via the addition of various nucleophiles to isatin imines. This review focuses on the catalytic asymmetric synthesis of chiral 3-amino-3-substituted-2-oxindoles.

Recent advances in asymmetric organocatalytic conjugate addition of arenes and hetero-arenes

The asymmetric organocatalytic conjugate addition reaction of various nucleophiles to the unsaturated acceptor provides an important route for the synthesis of valuable chiral entities. Recently, aromatic and hetero-aromatic compounds have been successfully used as nucleophiles in the enantioselective conjugate addition reaction. This review provides an overview on the recent developments made in organocatalytic enantioselective conjugate addition of arenes and hetero-arenes to unsaturated acceptors.

Mechanochemistry assisted asymmetric organocatalysis: A sustainable approach

Summary Ball-milling and pestle and mortar grinding have emerged as powerful methods for the development of environmentally benign chemical transformations. Recently, the use of these mechanochemical techniques in asymmetric organocatalysis has increased. This review highlights the progress in asymmetric organocatalytic reactions assisted by mechanochemical techniques.

Asymmetric syn-selective direct aldol reaction of protected hydroxyacetone catalyzed by primary amino acid derived bifunctional organocatalyst in the presence of water

A new series of water compatible primary-tertiary diamine catalysts derived from natural primary amino acids bearing a hydrophobic side chain have been synthesized. These new primary-tertiary diamine-Brønsted acid conjugates bifunctional organocatalysts efficiently catalyzes the asymmetric direct syn selective cross-aldol reaction of different protected hydroxyacetone with various aldehydes in high yield (94%) and high enantioselectivity (up to 97% ee of syn) and dr of 91 : 9 (syn/anti) under mild reaction conditions.

Novel indium-mediated ternary reactions between indole-3-carboxaldehydes-allyl bromide-enamines : Facile synthesis of bisindolyl- and indolyl-heterocyclic alkanes

Indole-3-carboxaldehydes undergo indium-mediated ternary reactions with allyl bromide and indoles to provide symmetrical and unsymmetrical bisindolyl alkanes and with other heterocyclic enamines viz. pyrrole, pyrazole, 6-aminouracil and imidazole to provide indolyl-heterocyclic alkanes in excellent yields. The reactions with substituted allyl bromides proceed with greater ease.

Organocatalytic enantioselective aza-Henry reaction of ketimines derived from isatins: access to optically active 3-amino-2-oxindoles

An organocatalytic asymmetric aza-Henry reaction of ketimines derived from isatins with nitroalkanes has been achieved using Cinchona alkaloid organocatalysts. This method works efficiently with several ketimines to produce a good (up to 82%) yield of the corresponding 3-substituted 3-amino-2-oxindoles with a good (up to 89%) enantiomeric excess.