Synthesis of New Xanthenes Based on Lawsone and Coumarin via a Tandem Three‑Component Reaction

Abstract

The synthesis of several new xanthenes based on the 1,3-dicarbonyl scaffolds lawsone and coumarin was developed using tandem three-component reactions involving the reagents ortho-hydroxybenzaldehyde, as bifunctional reagent, and an appropriate thiol. These reactions generated two series of para-and ortho-naphthoxanthenes that are structurally related to α-and β-pyranaphthoquinones and one series of coumarin-xanthene derivatives.Keywords: 2-hydroxy-1,4-naphthoquinone, coumarin, multi-component reactions, organocatalysis, ortho-quinone methide IntroductionXanthenes are a class of heterocyclic compounds that are extensively found in natural products and have many biological applications and several applications in materials science. [1][2][3] Xanthenes are prepared by several synthetic methods and structurally possess carbocyclic or heterocyclic substituents fused to a central pyran ring. In general, the most commonly used methods for their preparation involve a cycloaddition reaction of a 1,3-dicarbonyl compound with aldehydes to form an adduct, a reactive α,β-unsaturated intermediate, which reacts with an appropriate nucleophile in the second step. [4][5][6] Lawsone (1) and 4-hydroxycoumarin (6) are two 1,3-dicarbonyl compounds that have been extensively used by synthetic organic chemists because of their peculiar chemical structures and their relationships with biologically important natural products. 7 Indeed, these natural products have a large variety of biological activity that has been studied in recent decades and stimulated the synthesis of a large number of synthetic analogues. [8][9][10][11] Naphthoquinones play vital roles in several biological processes and are considered to be of great importance in medicinal chemistry. Naphthoquinones are often associated with various biological activities, including anticancer, antibacterial, antimalarial, trypanocidal, tuberculostatic and fungicidal activities. 12 Some natural coumarins are found as secondary metabolites from plants, bacteria and fungi. 13 This family of compounds presents a wide variety of biological activities, including anti-inflammatory, antibacterial, antifungal, antiviral and anticancer. 14,15 In Figure 1, we highlight the following important natural and synthetic naphthoquinones that match this profile: lawsone (1), β-lapachone (2), α-lapachone (3), urdamycinone B (4), estreptonigrin (5), 4-hydroxycoumarin (6), calanolide A (7) and osthole (8). [16][17][18][19] Because of the importance of these naphthoquinones and coumarins, the search for new, simple and efficient methods of preparation of structurally related compounds remains of great interest.Tandem multi-component reactions (MCR) are convergent syntheses that begin with three or more reactants and, preferably, end with only one formed product that contains all of the starting atoms. 20 Usually, these types of reactions have a high atom economy and a high possibility of diversifying the structures of the final products. MCRs are important in industrial applications 21 and the devel...

Lawsone Unleashed: A Comprehensive Review on Chemistry, Biosynthesis, and Therapeutic Potentials

“…The presence of additional functional groups at C-3 of the quinone ring rarely improved toxicity. 83 Additionally, related compounds of lawsone like α–lapachone ( 36 ) and β-lapachone ( 37 ) were also synthesised by multicomponent reactions 84 ( Figure 7 ).

Figure 7 Structurally relevant molecules of lawsone (16-37).

…”

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

“…Hence, examining molecular frameworks to design novel antiparasitic agents preferably endowed with multitarget features, the 1,4-naphthoquinone skeletons emerged as promising starting material candidates for developing new bioactive hybrid agents (Navarro-Tovar et al 2023). The reason for this is that the literature describes, for example, lawsone, α-lapachone, β-lapachone (Figure 1) and their congeners as having diverse biological properties, including trypanocide and leishmanicidal activities (Cardoso et al 2017, Dantas et al 2017, Guimarães et al 2013, Rani et al 2022, Naujorks et al 2015.…”

Hetero-Diels–Alder Reactions of Quinone Methides: The Origin of the α-Regioselectivity of 3-Methylene-1,2,4-naphthotriones

“…The quinone methide intermediate 1a (X = O, Figure ) has been widely explored in the last decades as a versatile synthon in organic synthesis, and more recently, inspirational applications were shown in asymmetric − and natural product synthesis, , in the preparation of bioactive derivatives, − synthesis of heterocycles, free-metal catalysis, photochemical reactions, and biomedicine. − This class of intermediate is usually obtained in situ , and it can also be found as dimethane- ( 1b , X = C, Figure ), aza- ( 1c , X = N, Figure ), and thio- ( 1d , X = S, Figure ) congeners, as well as ortho ( 1 , Figure ) and para isomers ( 2 , Figure ).…”

“…Among the available methodologies for the in situ preparation of quinone methide intermediates, one of the simplest and most efficient is the Knoevenagel condensation (Figure b). This methodology has been extensively explored by our group, yielding the intermediate 3-methylene-1,2,4-naphthotriones 4 R and allowing the preparation of a large set of bioactive pyran naphthoquinone derivatives by hetero-Diels–Alder reactions. − The intermediate 4 R presents increased complexity when compared to the parent quinone methide 1 , as now two almost-symmetrical reaction sites are present: the α- and β-moieties (Figure a). Such a feature is very convenient for the synthesis of natural products and bioactive compounds since two regioisomers (α- and β-lapachones) can be formed, depending on the reaction conditions employed.…”