New frontiers in the transition-metal-free synthesis of heterocycles from alkynoates: an overview and current status
Heterocycles are among the well-established classes of compounds, constituting a wide range of organic molecules. These structural motifs not only have a dominant presence in a wide variety of drugs but are also equally present as ubiquitous fragments of numerous vitamins, biologically active natural products, biomolecules, and synthetic drug candidates. Their key role in medicinal chemistry in the design of safe, effective, and efficacious drug molecules gives an impetus to the scientific community to access heterocyclic entities from robust chemical reactions. In this review, we summarize a diverse range of synthetic methods employing alkynoates as key starting materials to furnish useful bioactive heterocyclic frameworks (nitrogen, oxygen, sulfur, fused- and hetero-spirocycles), thus offering new opportunities and expanding the toolbox of synthetic chemistry reactions under transition-metal-free conditions. Several reaction parameters such as the use of easily available starting materials, commercially accessible reagents, and ease of synthesis (moderate temperatures, short reaction times, high yields, limited by-products) are included in the discussion alongside the reaction scope and limitations as well as mechanistic insights. The application of these methodologies in the synthesis of natural products and pharmaceuticals has also been discussed. We hope that the diverse utilities of alkynoates in the delivery of various heterocycles will fulfil the objectives of medicinal chemists in overcoming the formidable challenges associated with drug discovery and development.