The 3,3'-pyrrolidinyl-spirooxindole unit is a privileged heterocyclic motif that forms the core of a large family of alkaloid natural products with strong bioactivity profiles and interesting structural properties. Significant recent advances in the synthesis of this fused heterocyclic system have led to intense interest in the development of related compounds as potential medicinal agents or biological probes.

Pyrrolidinyl-spirooxindole natural products as inspirations for the development of potential therapeutic agents.

Catalyst-free reactions developed during the last decade and the latest developments in this emerging field are summarized with a focus on catalyst-free reactions in-water and on-water. Various named reactions, multi-component reactions and the synthesis of heterocyclic compounds are discussed including the use of various energy input systems such as microwave- and ultrasound irradiation, among others. Organic chemists and the practitioners of this art both in academia and industry hopefully will continue to design benign methodologies for organic synthesis in aqueous media under catalyst-free conditions by using alternative energy inputs based on fundamental principles.

Benign by design: catalyst-free in-water, on-water green chemical methodologies in organic synthesis

Natürliche Pyrrolidinylspirooxindole als Vorlagen für die Entwicklung medizinischer Wirkstoffe

Spirooxindoles are important synthetic targets possessing extended biological activity and drug discovery applications. This review focuses on the various strategies for the enantioselective synthesis of spirocyclic oxindoles relying on reports over the past decade and from earlier work. The spirooxindoles in this review are separated into three structural classes, and then further categorized into the method type from which the spirocycle is generated.

Molecular diversity of spirooxindoles. Synthesis and biological activity

An efficient tandem reaction for the asymmetric synthesis of six-membered spirocyclic oxindoles has been successfully developed through a formal [2+2+2] annulation strategy. The amine-catalysed stereoselective Michael addition of aliphatic aldehydes to electron-deficient olefinic oxindole motifs gave chiral C3 components, which were further combined with diverse electrophiles (activated olefins or imines) to afford spirocyclic oxindoles with versatile molecular complexity (up to six contiguous stereogenic centres, high diastereo- and enantioselectivities).

Organocatalytic Tandem Reaction to Construct Six-Membered Spirocyclic Oxindoles with Multiple Chiral Centres through a Formal [2+2+2] Annulation

The synthesis and local anesthetic properties of five 1-dealkyloxindole-3-spiropyrrolidines and six 1-dealkyloxindole-3-spiropiperidines are described. The compounds studied include members of all five possible positional isomers of the two classes of spirooxindoles; all showed local anesthetic activity by the rat sciatic nerve block method. The coincidence of the least variability in the relative positions of basic nitrogen, amide carbonyl, and aromatic ring (compounds 1 and 6) with lowest normalized toxicity is noteworthy.

Oxindole-3-spiropyrrolidines and -piperidines. Synthesis and local anesthetic activity.

Oxindole-3-spiropyrrolidines and -piperidines. synthesis and local anesthetic activity

The methyl esters of 2-methoxy-3, 6-dichlorobenzoic acid and three phenoxyacetic acids were prepared by the admixture of an excess of both methyl iodide and anhydrous alkali-metal carbonate to a solution of the carboxylic acids in acetone. The reaction was completed within the shortest period of time when cesium carbonate was used, and the reaction mixture was injected without further work-up into a gas chromatograph fitted with a flame ionization detector. Further reduction of reaction time was achieved by heating the mixture to 50°C and by ultrasonic treatment; this technique is also suitable for esterification of microliter quantities and obviates the need for a microrefluxer. Butylesters of 2, 4-D and 2, 4, 5-T were prepared in an analogous manner. The methyl esters of 2, 4-D and 2, 4, 5-T, and the butyl ester of 2, 4-D were obtained in better than 90% yield.

Alkylation of Carboxylate Salts of Acidic Herbicides for Gas Chromatographic Analysis

Herbicidal carboxylic acids were analyzed via ECD gas chromatography of their pentafluorobenzyl esters. The derivatives were formed by direct injection of a mixture of the acids and pentafluorobenzyl bromide in acetone; yields showed marked dependence on pKa of the acids. Carboxylic acids which have pKa values greater than 4.5 yielded the corresponding derivatives in poor yield unless triethylamine is included in the mixture. The procedure is fast and particularly convenient for low-level screening, identification and analysis of highly acidic chlorobenzoic, chlorophenoxyalkanoic, and arylacetic acids in the presence of less acidic carboxylic acids and phenols.

In-Block Derivatization of Herbicidal Carboxylic Acids by Pentafluorobenzyl Bromide

Atrazine and simazine were analyzed and confirmed via their pyrrolidino derivatives by gas chromatography on SPWax-10 megabore column using a NP-detector and propazine as the internal standard. The s -chlorotriazines were reacted in dimethylformamide with an excess of pyrrolidine at 60°C for 30 minutes to afford practically quantitative substitution of the chlorine. The retention times of the derivatives were increased markedly compared to those of the parent compounds. Reproducibility as measured by response ratios relative to the propazine derivative was very good: C.V. for atrazine and simazine were 0.60% and 0.26% respectively (n = 5). Good linearity was seen at 0.4 to 2.2 ng/μL concentration: measured in duplicate at 4 dilutions, the coefficient of determination r2 was 0.9998 for atrazine derivatives and 0.9994 for simazine derivatives. Very good agreement was found when analytical results were correlated with data obtained by gas chromatography of the parent compounds.

Alan P. Thio

Papers

Oxindole-3-spiropyrrolidines and -piperidines. Synthesis and local anesthetic activity.

Oxindole-3-spiropyrrolidines and -piperidines. synthesis and local anesthetic activity

Alkylation of Carboxylate Salts of Acidic Herbicides for Gas Chromatographic Analysis

In-Block Derivatization of Herbicidal Carboxylic Acids by Pentafluorobenzyl Bromide

Confirmation and Analysis of s-Chlorotriazines by Derivatization with Pyrrolidine