Discovering novel synthetic routes for rigid nitrogen-containing polyheterocycles using sustainable, atom-economical, and efficient (= short) synthetic pathways is of high interest in organic chemistry. Here, we describe an operationally simple and short synthesis of the privileged scaffold dihydropyrrolo[1,2-a]pyrazine-dione from readily accessible starting materials. The alkaloid-type polycyclic scaffold with potential bioactivity was achieved by a multicomponent reaction (MCR)-based protocol via a Ugi four-component reaction and Pictet–Spengler sequence under different conditions, yielding a diverse library of products.

https://pubs.acs.org/doi/pdf/10.1021/acs.joc.2c00244

Highly Stereoselective Ugi/Pictet–Spengler Sequence

A high-order multicomponent reaction involving a six-component reaction to obtain the novel linked 1,5-disubstituted tetrazole-1,2,3-triazole hybrids in low to moderate yield is described. This one-pot reaction is carried out under a cascade process consisting of three sequential reactions: Ugi-azide, bimolecular nucleophilic substitution (SN2), and copper-catalyzed alkyne–azide reaction (CuAAC), with high atom and step-economy due the formation of six new bonds (one C-C, four C-N, and one N-N). Thus, the protocol developed offers operational simplicity, mild reaction conditions, and structural diversity. Finally, to evaluate the antitumoral potential of the synthetized molecules, a proliferation study was performed in the breast cancer (BC) derived cell line MCF-7. The hybrid compounds showed several degrees of cell proliferation inhibition with a remarkable effect in those compounds with cyclohexane and halogens in their structures. These compounds represent potential drug candidates for breast cancer treatment. However, additionally assays are needed to elucidate their complete effect over the cellular hallmarks of cancer.

A One-Pot Six-Component Reaction for the Synthesis of 1,5-Disubstituted Tetrazol-1,2,3-Triazole Hybrids and Their Cytotoxic Activity against the MCF-7 Cell Line.

A Diastereo and Chemo Selective Synthesis of 6-amino-4-aryl-3-oxo-2,3,3a,4-tetrahydro-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile under Environmentally Benevolent Conditions

Local anesthetics occupy a prime position in clinical medicine as they temporarily relieve the pain by blocking voltage‐gated sodium channels. However, limited structural diversity, problems with the efficiency of syntheses and increasing toxicity, mean that alternative scaffolds with improved chemical syntheses are urgently needed. Here, we demonstrate a multicomponent reaction (MCR)‐based approach both towards the synthesis of commercial local anesthetics and towards novel derivatives as potential anesthesia candidates via scaffold hopping. The reactions are efficient and scalable, and several single‐crystal structures have been obtained. In addition, our methodology has been applied to the synthesis of the antianginal drug ranolazine, via an Ugi three‐component reaction. Representative derivatives from our libraries were evaluated as neuronal activity inhibitors using local field potential recordings (LFPs) in mouse hippocampal brain slices and showed very promising results. This study highlights new opportunities in drug discovery targeting local anesthetics.

Local Anesthetics via Multicomponent Reactions

This chapter summarizes the synthesis of the main classes of heterocycles, comprising the common heteroatoms (nitrogen, oxygen, and sulfur), using multicomponent reactions (MCRs) under sustainable methods. Effectiveness was demonstrated using a minimal number of synthetic steps, targeting the synthesis of biologically active products and high-valuable synthetic building blocks. The chapter is organized according to the increasing order of the heterocyclic ring size and the increasing order of the number of heteroatoms in the ring. Only sustainable methods, with solvent-free or green solvent protocols, catalyst-free methodologies, mild reaction conditions (such as room temperature and less energetic heating sources, microwave or ultrasonic irradiation), and short reaction times, will be highlighted. The literature review was accomplished considering the last decade. 

Multicomponent Synthesis of Heterocycles

https://pubs.rsc.org/en/content/articlepdf/2021/cc/d1cc02384e

A multicomponent tetrazolo indole synthesis.

Fluorene and fluorenone are privileged structures with extensive utility in both materials science and drug discovery Here, we describe syntheses of those moieties through isocyanide-based multicomponent reactions (IMCRs) and the incorporation of the products in diverse and complex derivatives that can be further utilized We performed six different IMCRs, based on the dual functionality of 9-isocyano-9H-fluorene, and we describe 23 unprecedented adducts

Xiaofang Lei

Papers

A multicomponent tetrazolo indole synthesis.

Fluorene-Based Multicomponent Reactions