In the work undertaken here, NMR has been used to ascertain the structure of some 1,2,4-triazoles. The investigation provides information concerning the structure of potentially tautomeric triazoles such as hydroxy- and aminotriazole. Connected with this aspect of triazole chemistry is the larger problem of mesohydric tautomerism. The present study also yields information for a comparison of substituent effects in triazoles, N-heteroaromatic substances and benzene.

Malaria is considered as one of the most prevalent and debilitating diseases affecting humans. Plasmodium falciparum is the most virulent form of the parasite which developed resistance to several antimalarial drugs. Chloroquine is one of the most successful antimalarials developed that is safe, effective, and cheap. However, its use has been limited due to the emergence of drug resistance. Click chemistry, particularly, the copper(I)-catalyzed reaction between azides and alkynes has shown to have a cutting-edge advantage in medicinal chemistry by its reliability, selectivity and biocompatibility. Triazole-based antimalarials were synthesized via copper(I)-catalyzed alkyne-azide cycloaddition reaction by modifying the aliphatic chains terminal of chloroquine. The compounds synthesized contain triazole ring directly connected to an aromatic ring or via a piperazine linker. When tested for their in vitro antimalarial activity against D6, Dd2 and 7G8 strains of P. falciparum, 12 out of 28 compounds showed better activity against chloroquine resistant strains. Particularly, PL403 and PL448 exhibited potent activity than chloroquine against CQ-resistant strains Dd2 and 7G8, with IC50 values of 12.8 & 14.5 nM, and 15.2 & 11 nM respectively. The efficiency of synthesizing several triazole-based antimalarials have proven click chemistry to be fast and efficient reaction. Generally, para-substitutions and di-substitutions with electron-withdrawing groups were found to be beneficial for having better antimalarial activity for these group of click compounds. Moreover, the incorporation of piperazine linker has brought an enhanced antimalarial activity.

Aza-heterocycles such as pyridines, imidazoles, piperidines, etc. are ubiquitous structural motifs found in various natural products and pharmacologically active compounds. Thus, they are of unparalleled importance to synthetic, medicinal, and materials chemists. Despite their structural significance, organic transformations available for the functionalization of these heterocycles remain underdeveloped. The development of several synthetic methods to construct aza-heterocyclic building blocks is described in this thesis, which, in turn, should facilitate the assembly of more elaborate frameworks present in bioactive molecules. An intramolecular palladium catalyzed Mizoroki-Heck cyclization of 4-alkylidene dihydropyridines with tethered aryl iodide electrophiles is demonstrated. This provides access to substituted isoindolinones and oxindoles in high yields. An asymmetric variant of this reaction using chiral phosphine ligands delivers enantioenriched oxindoles and isoindolinones. Additionally, an intramolecular Mizoroki-Heck reaction for the synthesis of 2-substituted pyridine derivatives is also developed. An array of fused isoindolinones is constructed as a mixture of diastereomers and further manipulated using chemical transformations to yield the corresponding pyridine and piperdine derivatives. Moreover, a formal [3+2] cyclocondensation of alkylidene dihydropyridines and aryl diazonium salts has been discovered for the synthesis of triazole derivatives. Tertiary amides deliver substituted 1,2,4-triazolium salts, whereas, secondary amides provide substituted, neutral 1,2,4-triazoles in excellent yields, under mild reaction conditions. Furthermore, an intramolecular direct arylation of 2- and 4-substituted alkylpyridines is developed for the synthesis of 2,3- and 3,4-cyclized pyridines. It is shown that 4-alkylpyridines tethered to aryl halides participate in a palladium catalyzed direct arylation to give fused 7-membered lactams in excellent yields. Lastly, an intramolecular cyclization of 1,2-alkylimidazoles is reported. Alkylidene imidazolines tethered to electrophilic keto-amide sidechains participate in an aldol-like reaction to yield γ-lactam products in good yields as mixtures of diastereomers.

Increasing attention has recently been directed toward 1,2,3-triazole-containing compounds. With their unique properties and excellent stability, 1,4-disubstituted triazoles are readily accessible via the copper catalyzed azide alkyne cycloaddition (CuAAC). As compounds containing fused triazoles become common in pharmaceutical targets and biologically active substances, new strategies to synthesize this class of molecules are highly desirable. An efficient and highly modular approach toward the synthesis of three different heterocyclic motifs containing fused 1,2,3-triazoles is reported. The synthesis involved a Pd-catalyzed annulation of 5-iodo-1,2,3-triazoles, which were prepared by a Cu(I)-catalyzed cycloaddition of iodoalkynes and azides. This work demonstrates the versatility of iodotriazoles in Heck reactions and in direct arylations.

Increasing attention has recently been directed toward 1,2,3-triazole-containing compounds. With their unique properties and excellent stability, 1,4-disubstituted triazoles are readily accessible via the copper catalyzed azide alkyne cycloaddition (CuAAC). As compounds containing fused triazoles become common in pharmaceutical targets and biologically active substances, new strategies to synthesize this class of molecules are highly desirable. An efficient and highly modular approach toward the synthesis of three different heterocyclic motifs containing fused 1,2,3-triazoles is reported. The synthesis involved a Pd-catalyzed annulation of 5-iodo-1,2,3-triazoles, which were prepared by a Cu(I)-catalyzed cycloaddition of iodoalkynes and azides. This work demonstrates the versatility of iodotriazoles in Heck reactions and in direct arylations.

Diversity-oriented synthesis (DOS) involves the synthesis of several synthetic targets by transforming a collection of structurally simple and similar starting materials into a collection of structurally more complex and diverse products. This thesis describes the elaboration of a 6,6-spiroacetal scaffold to incorporate biologically useful moieties, in particular nucleobases, triazoles and amino acids, thus generating a collection of novel hybrid structures. The research reported, herein, focused on the synthesis of spiroacetal-nucleosides, triazoles and amino acids bearing a C8′-hydroxymethyl substituent.

Diversity-oriented synthesis (DOS) involves the synthesis of several synthetic targets by transforming a collection of structurally simple and similar starting materials into a collection of structurally more complex and diverse products. This thesis describes the elaboration of a 6,6-spiroacetal scaffold to incorporate biologically useful moieties, in particular nucleobases, triazoles and amino acids, thus generating a collection of novel hybrid structures. The research reported, herein, focused on the synthesis of spiroacetal-nucleosides, triazoles and amino acids bearing a C8′-hydroxymethyl substituent.

Diversity-oriented synthesis (DOS) involves the synthesis of several synthetic targets by transforming a collection of structurally simple and similar starting materials into a collection of structurally more complex and diverse products. This thesis describes the elaboration of a 6,6-spiroacetal scaffold to incorporate biologically useful moieties, in particular nucleobases, triazoles and amino acids, thus generating a collection of novel hybrid structures. The research reported, herein, focused on the synthesis of spiroacetal-nucleosides, triazoles and amino acids bearing a C8′-hydroxymethyl substituent.

Diversity-oriented synthesis (DOS) involves the synthesis of several synthetic targets by transforming a collection of structurally simple and similar starting materials into a collection of structurally more complex and diverse products. This thesis describes the elaboration of a 6,6-spiroacetal scaffold to incorporate biologically useful moieties, in particular nucleobases, triazoles and amino acids, thus generating a collection of novel hybrid structures. The research reported, herein, focused on the synthesis of spiroacetal-nucleosides, triazoles and amino acids bearing a C8′-hydroxymethyl substituent.

Thesis (M.Eng.)--University of Wollongong, 2005. / Typescript. Includes bibliographical references: leaf 113-121.