Switchable synthesis of natural-product-like lawsones and indenopyrazoles through regioselective ring-expansion of indantrione

Abstract

Lawsones and indenopyrazoles are the prevalent structural motifs and building blocks in pharmaceuticals and bioactive molecules, but their synthesis has always remained challenging as no comprehensive protocol has been outlined to date. Herein, a metal-free, ring-expansion reaction of indantrione with diazomethanes, generated in situ from the N-tosylhydrazones, has been developed for the synthesis of lawsone and indenopyrazole derivatives in acetonitrile and alcohol solvents, respectively. It provides these valuable lawsone and pyrazole skeletons in good yields and high levels of diastereoselectivity from simple and readily available starting materials. DFT calculations were used to explore the mechanism in different solutions. The synthetic application example also showed the prospects of this method for the preparation of valuable compounds.

Design, synthesis and identification of novel molecular hybrids based on naphthoquinone aromatic hydrazides as potential trypanocide and leishmanicidal agents

“…Consequently, hydrazide-bearing molecules and similar scaffolds such as N'-(1, 4-naphthoquinone-2-yl) isonicotinohydrazide (I), benzohydrazones (II), and quinoline-piperazine propionic acid hydrazones (III) are also reported as important compounds endowed with trypanocide, antibacterial, antiamoebic, antimalarial, anticancer, antiviral, antiinflammatory, antiatherosclerotic and antifungal activities (Bouhadir et al 2017, Caffrey et al 2002, Hu et al 2023, Kavitha et al 2015, Kumar et al 2017, Reddy et al 2013 Considering molecular hybridization strategy, we have come across only two reports in the literature in which lawsone (Figure 1) was subjected to a reaction with aromatic hydrazide to form C-2 substituted bioactive naphthoquinones (Dudley et al 1969, Hu et al 2023, Kavitha et al 2015. As part of our research interest in synthesis and biological evaluation of heterocyclic compounds (Botteselle et al 2021, dos Santos et al 2021, 2022, Franco et al 2021, Moraes et al 2023, Rafique et al 2020, Scheide et al 2020, Veloso et al 2021, Vitor et al 2021, we decided to prepare naphthoquinone aromatic hydrazide-based molecular hybrids, using a simple, inexpensive and reliable protocol.…”

Expedient and Stereoselective Access to Diverse Alkaloid-like Scaffolds via an Oxidation/Double-Mannich Reaction Sequence

“…Broader access to alkaloid-like chemical space is therefore highly desirable, 18,19 and indeed access to such analogues has seen considerable recent interest. [20][21][22][23][24] Biomimetic syntheses offer attractive approaches to such systems, 25,26 with arguably the first example of this being Robinson's synthesis of tropinone 2 (Scheme 1a), which achieved this via a one-step double-Mannich reaction. 27,28 However, such an approach has yet to be extended more broadly, despite potentially enabling a general conversion of easily accessed dialdehydes into complex natural product-like scaffolds.…”

Stereoselective Access to Diverse Alkaloid-Like Scaffolds via an Oxidation/Double-Mannich Reaction Sequence

“…The alkaloid family in particular has proven an excellent source of central nervous system (CNS)-active compounds, which is an area of medicinal chemistry that continues to offer significant challenges. − However, synthetic access to alkaloid structures is frequently limited by complex syntheses, with each route typically offering access to only a single-ring system. Broader access to alkaloid-like chemical space is therefore highly desirable, , and indeed access to such analogues has seen considerable recent interest. − Biomimetic syntheses offer attractive approaches to such systems, , with arguably the first example of this being Robinson’s synthesis of tropinone 2 (Scheme A), which achieved this via a one-step double-Mannich reaction. , However, such an approach has yet to be extended more broadly, despite potentially enabling a general conversion of easily accessed dialdehydes into complex natural product-like scaffolds. We considered that stereochemically rich 1,4-dialdehydes of type 3 , which are readily available from Diels–Alder cycloaddition and oxidative cleavage sequences, might be attractive substrates in this respect.…”

“…Broader access to alkaloid-like chemical space is therefore highly desirable, 18 , 19 and indeed access to such analogues has seen considerable recent interest. 20 − 24 Biomimetic syntheses offer attractive approaches to such systems, 25 , 26 with arguably the first example of this being Robinson’s synthesis of tropinone 2 ( Scheme 1 A), which achieved this via a one-step double-Mannich reaction. 27 , 28 However, such an approach has yet to be extended more broadly, despite potentially enabling a general conversion of easily accessed dialdehydes into complex natural product-like scaffolds.…”