Recent Advances in the Synthesis of 2-Hydroxy-1,4-naphthoquinone (Lawsone) Derivatives

This work is dedicated to Prof. Srinivasan Chandrasekaran on his 78^th birthday

Abstract

Lawsone, also known as 2-hydroxy-1,4-naphthoquinone, has been extensively studied and found to be a crucial precursor in the production of a diverse range of natural products such as molecular scaffolds, which are highly sought-after for biological research purposes. Due to its unique chemical composition, lawsone has been utilized for over a century as a starting material for the synthesis of numerous biologically active molecules and materials, and its intriguing properties have been showcased across a wide range of scientific and technological applications. Additionally, the various characteristics of lawsone have been widely used in organic synthesis processes. Recent advances in the synthesis of different scaffolds starting from lawsone, and their applications, are discussed in detail in the current review covering the period 2017 to 2023.

1 Introduction

2 Synthetic Developments on 2-hydroxy-1,4-naphthoquinone

3 Conclusions

Key words

multicomponent reactions - chemoenzymatic reactions - heterocyclic compounds - 2-hydroxy-1,4-naphthaquinone - magnetic nanoparticles - tandem reactions - green chemistry

Biographical Sketches

Prof. Ram Sagar received his PhD in Organic Chemistry from the Central Drug Research Institute (CDRI) Lucknow and the University of Agra in 2006 under the supervision of Dr A. K. Shaw. After his PhD, he worked as a research associate with Prof. Y. D. Vankar at IIT Kanpur during 2006–2007. He pursued his first post-doctoral research at Seoul National University South Korea with Prof Seung Bum Park during 2007–2008. He moved to the University of Oxford and worked with Prof Benjamin G. Davis as a BBSRC postdoctoral fellow until August 2012. He returned to India in August 2012 and took up a faculty position at Shiv Nadar University (SNU). He moved to the Department of Chemistry, Banaras Hindu University (BHU) as Associate Professor in February 2018 and worked there until December 2020. He subsequently became Full Professor at Jawaharlal Nehru University (JNU), New Delhi in December 2020 and is presently working there as Professor of Chemistry in the School of Physical Sciences. His current research interests include devising new ways for efficient chemical synthesis of natural-product-inspired small molecules, glycohybrids, and glycopeptides that are implicated in various diseases including tuberculosis and cancer.

Uma Shankar completed his MSc in 2017 from Kirori Mal College, University of Delhi, India. He joined the Glycochemistry laboratory of the School of Physical Sciences, Jawaharlal Nehru University, New Delhi, as a research scholar in 2022. He is currently pursuing his PhD degree under the supervision of Prof. Ram Sagar. His expertise lies in asymmetric catalysis with emphasis on C–C bond formation under mild and green conditions, organic synthesis, physical organic chemistry, synthesis of heterocyclic compounds, medicinal chemistry, and the development of new methods for the synthesis of bioactive glycohybrids.

Ashish Khanna completed his MSc at Kumaun University, Nainital, Uttarakhand, India in 2016. Since 2017, he has been part of the Department of Chemistry at the Institute of Science, Banaras Hindu University, as a research scholar in the Glycochemistry lab. He completed his PhD in March 2023 under the supervision of Prof. Ram Sagar. His expertise lies in organic synthesis, the development of carbohydrate-derived bioactive molecules and natural-product-inspired hybrid analogues. He is also focused on molecular modeling, especially in protein–ligand interactions via in-silico docking tools. He recently joined the Department of Chemistry, School of Physical Sciences, Dehradun Institute of Technology University, Dehradun as an Assistant Professor.

Kavita Singh completed her MSc at Deen Dayal Upadhyaya University, Gorakhpur, UP, India in 2019. She qualified as a CSIR-JRF then joined the Glycochemistry laboratory of the School of Physical Sciences, Jawaharlal Nehru University, New Delhi, as a junior research fellow in 2021. She is currently pursuing her PhD degree under the supervision of Prof. Ram Sagar. Her work is mainly focused on the development of new methods for the synthesis of carbohydrate-fused heterocyclic molecules as bioactive glycohybrids. She is also interested in medicinal chemistry and in the synthesis of natural-product-inspired bioactive scaffolds.

Ghanshyam Tiwari completed his MSc at Mahatma Gandhi Kashi Vidyapith, Varanasi, Uttar Pradesh, India. He joined the Glycochemistry lab of the Department of Chemistry at the Institute of Science, Banaras Hindu University, as a research scholar in 2018. He completed his PhD in April 2023 under the supervision of Prof. Ram Sagar. His expertise lies in glycoscience, microwave-assisted synthesis, organic synthesis, and the development of new methods for natural-product-inspired glycohybrids.

1

Introduction

2-Hydroxy-1,4-naphthoquinone, also known as lawsone or hennotannic acid, is a naturally occurring naphthoquinone compound that has attracted significant interest in synthetic organic chemistry.[1] [2] [3] It is one of the simplest naturally occurring naphthoquinones and is primarily known for its presence in the leaves of the henna plant (Lawsonia inermis), where it imparts a red-orange color.[4] Henna extracts containing lawsone have been used for thousands of years as hair and skin dyes, highlighting its historical and cultural significance.[5] [6]

Beyond its dyeing properties, 2-hydroxy-1,4-naphthoquinone exhibits a range of biological activities, including antibacterial, antifungal, anti-inflammatory, antiviral, and antineoplastic properties.[7] [8] It has been found to inhibit tumor cell growth and to stimulate the production of reactive oxygen species (ROS).[9–12] These attributes make it a compelling target for synthetic development, as it serves as a starting material for the synthesis of diverse biologically active compounds and materials with intriguing properties.[13–15]

In the field of organic synthesis, 2-hydroxy-1,4-naphthoquinone has been employed in numerous reactions, where it plays a vital role in the construction of various molecular frameworks. Its hydroxyquinone structure is associated with the antibacterial activity of anthracycline and antibiotics such as daunomycin and doxorubicin.[16] [17] [18] [19] The versatility of 2-hydroxy-1,4-naphthoquinone as a building block in organic synthesis has further expanded its potential for the development of novel compounds and therapeutic agents.[20–22]

Recent efforts have focused on the synthesis of new derivatives of 2-hydroxy-1,4-naphthoquinone.[23] The syntheses of such derivatives have been studied extensively, with many of the established methods involving multicomponent reactions. The versatile heterocyclic scaffolds have been used for further exploration and utilization in various synthetic transformations.[24] [25] [26] [27]

In this review article, we aim to provide an overview of the recent advances in the synthetic developments in the use of 2-hydroxy-1,4-naphthoquinone. This review will highlight the key synthetic methodologies employed for the preparation of 2-hydroxy-1,4-naphthoquinone derivatives, focusing on the advancements in reaction design, catalyst development, and the discovery of new reaction pathways. Furthermore, we will discuss the diverse applications of these synthesized compounds in medicinal chemistry, materials science, and other relevant fields.

By exploring the recent advances in synthetic strategies for 2-hydroxy-1,4-naphthoquinone, this review intends to offer valuable insights into the current state-of-the-art in this field and inspire further exploration of its synthetic potential. The development of efficient and sustainable synthetic routes to access 2-hydroxy-1,4-naphthoquinone derivatives hold great promise for the discovery of novel compounds with enhanced biological activities and potential therapeutic applications.

2

Synthetic Developments on 2-Hydroxy-1,4-naphthoquinone

2.1

2,3,4,9-Tetrahydro-9-(3-hydroxy-1,4-dioxo-1H-dihydronaphthalen-2-yl)-8-methoxy-3,3-dimethyl-1H-xanthen-1-one Derivatives

Yoshioka and co-workers[28] reported the synthesis of novel xanthene derivative 3 by the reaction of 2-hydroxy-1,4-naphthoquinone (1) and 2H-chromene derivative 2. The authors synthesized 2 by a domino three-component coupling reaction of an aryne precursor with DMF and dimedone. Nucleophilic addition of 1 (1.1 equiv) in the presence of anhydrous TBAF (3 equiv), furnished 2,3,4,9-tetrahydro-9-(3-hydroxy-1,4-dioxo-1H-dihydronaphthalen-2-yl)-8-methoxy-3,3-dimethyl-1H-xanthen-1-one (3) with a good isolated yield of 67% (Scheme [1]).[28]

Scheme 1 Synthesis of derivative 3

2.2

Benzo[g]chromene Derivatives

Benzo[g]chromene derivatives have received considerable attention in the field of medicinal chemistry because of their therapeutic potential. Additionally, they are used as intermediates in the synthesis of other organic compounds, making them significant building blocks in organic synthesis. In the field of organic synthesis, there are many different approaches that can be taken to achieve the desired product. Two examples of successful synthesis of benzo[g]chromene derivatives have been reported by Yang and Maheshwari and their respective research groups.[29] [30] Yang and co-workers utilized Candida sp. lipase as an enzyme catalyst for a multicomponent reaction, while Maheshwari and co-workers used 2-aminopyridine as a reusable catalyst in a one-pot, three-component reaction. Both methods have been found to have their own unique advantages. Yang and co-workers reported a novel and efficient method for synthesizing benzo[g]chromene derivatives that provided numerous advantages, such as high yield, simple work-up, and eco-friendliness. The utilization of Candida sp. lipase as an enzyme catalyst was found to be particularly noteworthy, as it demonstrated the expanded versatility of the enzyme. The study developed the reaction of 2-hydroxy-1,4-naphthoquinone (1), aromatic aldehydes 4a–i, and malononitrile (5), using Candida sp. lipase as an enzyme catalyst in a multicomponent reaction to synthesize benzo[g]chromene derivatives 6a–i (Route 1).[29] Maheswari and co-workers, on the other hand, were able to synthesize 2-amino-4H-benzo[g]chromene derivatives using a one-pot, three-component reaction with 2-aminopyridine as a catalyst. They employed a one-pot, three-component reaction that included malononitrile (5), aromatic aldehyde 4a–i, and 2-hydroxy-1,4-naphthoquinone (1), using 10 mol% 2-aminopyridine(2-AP) as a reusable catalyst (Route 2).[30] The reaction was performed in ethanol at reflux, and the chosen catalyst proved to be effective in facilitating the desired reaction. The authors observed that the position of the substituent group on the aromatic aldehyde could affect the yield of the reaction, with those in the para-position providing excellent yields in short reaction times. These findings highlight the importance of careful consideration of reaction conditions and catalysts in organic synthesis, as the choice of catalyst and reaction conditions can have a significant impact on the outcome of the reaction. Overall, the successful synthesis of benzo[g]chromene derivatives using different approaches demonstrates the versatility and potential of enzyme-catalyzed and one-pot, multicomponent reactions in the synthesis of complex organic molecules (Scheme [2]).

Scheme 2 Lipase-catalyzed synthesis of benzo[g]chromene derivatives 6a–i

2.3

2-(Alkylamino)-3-nitro-4-(aryl)-4H-benzo[g]chromene-5,10-dione Derivatives

Afsharnezhad et al.[31] successfully synthesized benzo[g]chromene derivatives 9a–l using a straightforward one-pot, multicomponent reaction. The reaction involved 2-hydroxy-1,4-naphthoquinone (1), N-alkyl-1-(methylthio)-2-nitroethenamine 7a–c, and aromatic aldehydes 8a–g, in acetonitrile (CH₃CN) at room temperature. Remarkably, the reaction was completed within a short timeframe of 10–25 minutes, without the need for a catalyst. The protocol offers several notable advantages in addition to not requiring a catalyst, including mild reaction conditions, a simple purification process that does not require chromatography, compatibility with various functional groups, and high product yields (Scheme [3]).[31]

Scheme 3 2-(Alkylamino)-3-nitro-4-(aryl)-4H-benzo[g]chromene-5,10-dione derivatives 9a–l

2.4

2-Amino-5,10-dioxo-4-aryl-5,10-dihydro-4H-benzo[g]chromene-3-carbonitrile Derivatives

Daloee and co-workers[32] developed a green approach to synthesize 2-amino-5,10-dioxo-4-aryl-5,10-dihydro-4H-benzo[g]chromene-3-carbonitrile derivatives 11a–j. The method involves the reaction of 2-hydroxy-1,4-naphthoquinone (1), aromatic aldehydes 10a–j, and malononitrile (5) in the presence of l-proline as an organocatalyst under reflux conditions in ethanol (Scheme [4]). The approach offers several key benefits, including mild reaction conditions, the use of an environmentally friendly catalyst, a simple reaction work-up procedure, and the potential to produce novel derivative products. Overall, this new synthetic approach represents a promising step towards the development of more sustainable and eco-friendly methods for the production of important organic compounds.

2.5

2-Amino-4H-benzo[g]chromene Derivatives

Gracious et al.[33] developed a highly efficient and environmentally friendly approach for the synthesis of dihydro-4H-benzo[g]chromene derivatives 14a–l using ultrasonic irradiation. The method involved a one-pot process that combined the Knoevenagel–Michael reaction of selected active methylene compounds 12a–c and 2-hydroxynaphthalene-1,4-dione (1) with various substituted aldehydes 13a–i in a mixture of water and ethanol at room temperature using ultrasonic irradiation. Ammonium acetate was used as a catalyst to facilitate the three-component condensation reaction. Remarkably, the reaction achieved high product yields (91–98%) within a short reaction time of 5–15 minutes. This study presents a promising strategy for the efficient synthesis of dihydro-4H-benzo[g]chromene derivatives through an environmentally benign approach utilizing ultrasonic irradiation (Scheme [5]).

Scheme 4 2-Amino-5,10-dioxo-4-aryl-5,10-dihydro-4H-benzo[g]chromene-3-carbonitrile derivatives 11a–j

Scheme 5 2-Amino-4H-benzo[g]chromene derivatives 14a–l

2.6

Synthesis of Benzo[g]chromene Derivatives by using Nanocomposite Catalysts

In their study, Safaei-Ghomi et al.[34] introduced a novel catalytic system consisting of a CeO₂/CuO@N-GQDs@NH₂ nanocomposite for the efficient synthesis of benzo[g]chromene compounds 17a–k. By employing a one-pot, three-component reaction involving aromatic aldehydes 16a–h, malononitrile (15a) or ethyl cyanoacetate (15b), and 2-hydroxy-1,4-naphthoquinone (1), the nanocomposite catalyst demonstrated remarkable performance. The chemical structures of the synthesized benzo[g]chromene products were confirmed through the utilization of ¹H NMR and Fourier transform infrared (FT-IR) spectroscopic techniques. This research highlights the potential of the CeO₂/CuO@N-GQDs@NH₂ nanocomposite as an effective catalyst for the synthesis of benzo[g]chromenes (Scheme [6]).

Scheme 6 Synthesis of benzo[g]chromenes using CeO₂/CuO@N-GQDs@NH₂ nanocomposite 17a–k

2.7

Tacrine Derivatives

Tacrine, a drug known for its ability to enhance acetylcholine levels by inhibiting cholinesterase enzymes, has shown remarkable pharmacological properties and is commonly used as a reference compound in Alzheimer’s disease (AD) research. The synthesis of tacrine analogues continues to be of interest to scientists studying AD. Various methods have been explored for the synthesis of tacrine and its analogues. Mollabagher et al.[35] introduced a novel procedure for the synthesis of tacrine derivatives 21a–e, utilizing 2-hydroxynaphthalene-1,4-dione (1), malononitrile (5), aldehydes 18a–e, and cyclohexanone (20) in a one-pot reaction, eliminating the need for intermediate separation. The use of Cu-MOF as a heterogeneous catalyst facilitated the formation of pyranic intermediates, followed by the addition of aluminum chloride in the Friedländer quinoline reaction, without interfering with the two catalysts involved. The presence of active Cu sites in Cu-MOF made it a suitable candidate for the synthesis of pyrene compounds. This work presents convenient methods for synthesizing tacrine derivatives starting from readily available starting materials. Furthermore, the process offers broad substrate compatibility, high yields (up to 93%), efficient atom-economy, utilization of readily available starting materials, and the advantage of a reusable nanocatalyst (Scheme [7]).[35] Additionally, the process eliminates the need for column chromatography purification steps.

2.8

Benzo[a]pyrano[2,3-c]phenazine and Benzo[a]chromeno[2,3-c]phenazine Derivatives

Benzophenazine belongs to the heterocyclic aromatic class of compounds, and is characterized by a fused benzene and phenazine ring system. In medicinal chemistry, benzophenazines have exhibited diverse biological activities, such as anticancer, antimicrobial, and antioxidant properties. Researchers have explored their potential as therapeutic agents for various diseases and conditions. The structural versatility of benzophenazines allows for the design and synthesis of derivatives with optimized pharmacological properties and target selectivity. Furthermore, in materials science, benzophenazines have been investigated for their optical and electronic properties. These compounds possess conjugated π-electron systems, making them suitable for applications in organic electronic devices, such as organic light-emitting diodes (OLEDs) and organic photovoltaic cells (OPVs). The tunability of their electronic properties through structural modifications offers opportunities for tailoring their performance in these devices. Synthetic methodologies for the preparation of benzophenazines have been developed, involving multicomponent reactions, transition-metal catalysis, and other synthetic strategies. These methods enable the synthesis of diverse benzophenazine derivatives with varying substituents and functional groups, expanding the scope of their applications. Recently, Olyaei and co-workers[36] presented a detailed review on the synthesis and biological importance of various lawsone-derived benzo[a]phenazinols, which serves as precursors for the development of various five- and six-membered fused heterocycles such as furophenazines and pyranophenazines.[36]

Scheme 7 Synthesis of tacrine derivatives 21a–e

In a continuation of this study Yazdani-Elah-Abadi et al.[37] demonstrated the use of fulvic acid as a convenient and efficient catalyst for the efficient synthesis of benzophenazine derivatives. In their study, they performed a four-component assembly of aromatic aldehydes 4, various C–H acids (malononitrile 5 or dimedone 25), 2-hydroxy-1,4-naphthoquinone (1), and o-phenylenediamine (22) in water at a temperature of 60 °C, resulting in excellent yields of benzo[a]pyrano[2,3-c]phenazine 26a–p and benzo[a]chromeno[2,3-c]phenazine derivatives 27a–p. The catalyst, fulvic acid, offers several advantageous features; it is easily obtained, clean and easy to handle, safe and non-toxic, and it is also cost-effective (Scheme [8]). Furthermore, the catalyst can be reused multiple times without significant loss of activity. This procedure delivers high yields of the desired products while maintaining clean reaction conditions. It offers operational simplicity, making it straightforward to perform. Additionally, the method has minimal environmental impact, aligning with the principles of green chemistry.[37]

2.9

Benzo[a]pyrano[3′,4′:5,6]pyrano[2,3-c]phenazines

Scheme 8 Synthesis of benzo[a]pyrano[2,3-c]phenazine 26a–p and benzo[a]chromeno[2,3-c]phenazine derivatives 27a–p

Scheme 9 Benzo[a]pyrano[3′,4′:5,6]pyrano[2,3-c]phenazine derivatives 30a–j

Mohammadrezaei et al.[38] presented an efficient method for the domino synthesis of benzo[a]pyrano[3′,4′:5,6]pyrano[2,3-c]phenazines. This synthesis involves a one-pot, four-component condensation reaction between 2-hydroxy-1,4-naphthoquinone (1), o-phenylenediamine (22), aromatic aldehydes 28a–j, and 4-hydroxy-6-methyl-2H-pyran-2-one (29). The catalyst employed in this reaction is phosphotungstic acid (H₃PW₁₂O₄₀). The use of H₃PW₁₂O₄₀ as a solid heteropolyacid catalyst in conjunction with microwave irradiation (180 W, maximum 70 °C) in a mixture of EtOH and H₂O (1:1) proved to be highly effective, environmentally friendly, and recyclable. The catalyst exhibits remarkable catalytic activity, facilitating the synthesis of benzo[a]pyrano[3′,4′:5,6]pyrano[2,3-c]phenazines 30a–j with excellent yields (Scheme [9]).[38] This method offers several advantages, including simplicity and the ability to perform the entire synthesis in a single pot. Additionally, the use of microwave irradiation enables rapid reaction times. Furthermore, the H₃PW₁₂O₄₀ catalyst can be easily recovered and reused, contributing to the overall efficiency and sustainability of the process.

2.10

Chromene/Bicyclic Fused Benzo[a]phenazinone Derivatives

Scheme 10 Chromene/bicyclic fused benzo[a]phenazinone derivatives 34a–k and 36a–f

Bakthadoss et al.[39] developed a novel one-pot assembly method for the synthesis of highly functionalized benzo[a]phenazinone fused chromene/bicyclic scaffolds 34a–k and 36a–f. This approach involves the solid-state melt reaction of 2-hydroxynaphthalene-1,4-dione (1), o-phenylenediamine derivatives 31a–c, and o-allyl salicylaldehyde derivatives 33a–j and 35a–j, followed by a domino Knoevenagel intramolecular hetero-Diels–Alder reaction. In this single-pot reaction, three six-membered rings, three stereogenic centers, and five new bonds (two C–C bonds and three C–O bonds) are formed, resulting in the desired benzo[a]phenazinone fused chromene/bicyclic scaffolds. This synthesis strategy is particularly appealing due to its simplicity, rapidity, high yields, and the generation of only water as waste product. Furthermore, the method does not require extensive workup procedures. The innovative features of this approach make it highly attractive for the efficient synthesis of complex and functionalized benzo[a]phenazinone fused chromene/bicyclic scaffolds. The ability to achieve multiple ring formations and bond constructions in a single pot, along with the use of water as the only waste product, highlight the advantages of this method (Scheme [10]).[39]

2.11

trans-1,2-Dihydrobenzo[a]furo[2,3-c]phenazine Derivatives

Yazdani-Elah-Abadi et al.[40] introduced a novel and efficient domino four-component coupling process for the synthesis of 1,2-dihydrobenzo[a]furo[2,3-c]phenazine derivatives 39a–i. This selective and highly productive method utilizes readily available starting materials 2-hydroxy-1,4-naphthquinone (1), o-phenylenediamine (22), aromatic aldehydes 37a–i, and pyridinium ylide 38, and the reaction occurs in the presence of a catalytic amount of theophylline in aqueous medium (Scheme [11]). The reaction involves a sequence of condensation, Knoevenagel, Michael, and annulation steps, resulting in the formation of two C–C bonds, two C=N bonds, one C–O bond, and two new rings in a single operation. This protocol offers several advantages. Firstly, it enables an easy one-pot operation, simplifying the synthetic procedure. Additionally, the reaction exhibits a high atom-economy by efficiently utilizing the starting materials. The use of theophylline as a catalyst is noteworthy, as it is non-toxic, affordable, and easily accessible. Furthermore, the method eliminates the need for conventional volatile organic solvents, contributing to its environmental compatibility.[40]

Scheme 11 trans-1,2-Dihydrobenzo[a]furo[2,3-c]phenazine derivatives 39a–i

2.12

Benzo[a][1,3]oxazino[6,5-c]phenazine Derivatives

Mohebat and co-workers[41] successfully synthesized benzo[a][1,3]oxazino[6,5-c]phenazine derivatives 45a–j using a one-pot, four-component sequential condensation reaction. In this environmentally friendly approach, caffeine was employed as a natural catalyst. The reaction involved the condensation of 2-hydroxy-1,4-naphthoquinone (1), aromatic 1,2-diamines 40a–c, ammonium thiocyanate (42), and aryl-acid chlorides 43a–e, in the presence of a basic ionic liquid (1-butyl-3-methylimidazolium hydroxide). This one-pot reaction enables the formation of five bonds and two additional rings, offering a highly efficient synthetic route. The reaction proceeds in three steps. Initially, 2-hydroxy-1,4-naphthoquinone and 1,2-diamines are mixed at room temperature in [Bmim]⁺OH^– (ionic liquid), resulting in the formation of benzo[a]phenazines within a short time (<30 min). In the second step, ammonium thiocyanate and acid chlorides are combined at 70 °C under solvent-free conditions, leading to the generation of solid aroyl isothiocyanate derivatives 44a–e. Finally, the products from the first step react with the aroyl isothiocyanate derivatives in the presence of caffeine in [Bmim]⁺OH^– to yield the desired benzo[a][1,3]oxazino[6,5-c]phenazine derivatives 45a–j (Scheme [12]). This methodology offers several advantages, including its user-friendly nature, excellent yields of the desired products, avoidance of toxic or hazardous catalysts, high chemo- and regioselectivity, and operational simplicity. The use of caffeine as a catalyst adds to the environmentally benign nature of the approach.[41]

Scheme 12 Synthesis of benzo[a][1,3]oxazino[6,5-c]phenazine derivatives 45a–j

2.13

Benzo[a]phthalazino[2,3:1,2]pyrazolo[3,4-c]phenazines

Yazdani-Elah-Abadi et al.[42] successfully synthesized benzo[a]phthalazino[2,3:1,2]pyrazolo[3,4-c]phenazines 50a–j, which possess both biologically active benzophenazine and pyrazolophthalazine templates. These compounds were synthesized in a single-pot, five-component reaction using 2-hydroxynaphthalene-1,4-dione (1), aromatic 1,2-diamines 40a–c, hydrazine hydrate (46), phthalic anhydride (47), and aromatic-aldehydes 49a–f. The reaction was catalyzed by magnetic iron(III) oxide nanoparticles (Fe₃O₄ MNPs) in polyethylene glycol (PEG-400) as the reaction medium. The use of Fe₃O₄-MNPs as catalyst offered several advantages, including their ready availability, high efficiency, and recyclability. PEG-400 served as an affordable, safe, and effective medium, eliminating the need for additional organic co-solvents. Furthermore, PEG-400 is non-toxic and reusable, making it an environmentally friendly choice. The synthesis was carried out at a temperature of 70 °C, providing suitable reaction conditions. The combination of Fe₃O₄-MNPs catalyst and PEG-400 medium enabled a straightforward and efficient synthesis of the target compounds, offering a practical and sustainable synthetic approach (Scheme [13]).[42]

Scheme 13 Benzo[a]phthalazino[2,3:1,2]pyrazolo[3,4-c]phenazine derivatives 50a–j

2.14

Benzo[a]furo[2,3-c]phenazine Derivatives

In a continuation of the work by Abadi et al. discussed in Section 2.13, the same group[43] reported a one-pot, four-component synthesis of benzo[a]furo[2,3-c]phenazines 53a–g under microwave conditions. This method has proven to be effective, mild, and rapid. By combining 2-hydroxynaphthalene-1,4-dione (1), o-phenylenediamine (22), aromatic aldehydes 51a–e, and substituted isocyanides 52a–b, in a solvent-free and catalyst-free microwave environment, furan annulated heterocycles were successfully synthesized. The convenience of this methodology lies in its straightforward one-pot procedure, allowing for easy handling and manipulation. Furthermore, the work-up process is simplified, saving time and effort. The reaction times were relatively short, enabling rapid access to the desired benzo[a]furo[2,3-c]phenazines. Importantly, the products were obtained in high yields, highlighting the efficiency of this microwave-assisted synthetic approach (Scheme [14]).[43]

Scheme 14 Benzo[a]furo[2,3-c]phenazine derivatives 53a–g

2.15

Spiro[benzo[a]chromeno[2,3-c]phenazine] Derivatives

Mohebat et al.[44] conducted a synthesis of spiro[benzo[a]chromeno[2,3-c]phenazine] derivatives 58a–f using a one-pot, four-component condensation reaction. The reaction involved 2-hydroxy-1,4-naphthoquinone (1), benzene-1,2-diamine 54a–c, cyclic-1,3-dicarbonyl compounds 57a–b, and isatin (56). The reaction was facilitated by p-toluenesulfonic acid, which served as an effective, non-toxic, and solid acid catalyst. The synthesis of these derivatives was achieved through a novel two-step domino protocol, employing either conventional heating or microwave irradiation. This solvent-free process resulted in the formation of five new bonds (two C–C, two C=N, and one C–O) and two new rings, leading to the generation of biologically significant heterocycles. The advantages of this reaction method include its operational simplicity, rapid reaction time, excellent yield of the desired products, elimination of time-consuming purification steps, and avoidance of potentially hazardous chemicals and solvents (Scheme [15]).[44]

Scheme 15 Spiro[benzo[a]chromeno[2,3-c]phenazine] derivatives 58a–f

2.16

Dihydrobenzo[a]pyrimido[50,40:5,6]pyrido[2,3-c]phenazine Derivatives

Dehghan et al.[45] reported the development of a rapid, efficient, and environmentally friendly procedure for synthesizing novel heteroaryl-substituted dihydrobenzo[a]pyrimido[5,4:5,6]pyrido[2,3-c]phenazines 61a–h. This synthesis involves condensation, Knoevenagel, Michael, and heterocyclization reactions of o-phenylenediamine (22), 2-hydroxynaphthalene-1,4-dione (1), aromatic aldehydes 59a–h, and 6-amino-1,3-dimethyluracil (60). The reactions take place in the presence of a recyclable heterogeneous catalyst, H₃PW₁₂O₄₀@nano-ZnO, under microwave irradiation in an aqueous medium. The current approach offers several advantages: It proceeds in short reaction times, gives high yields of the desired products, has excellent atom-economy, and exhibits remarkable chemoselectivity (Scheme [16]).[45]

Scheme 16 Dihydrobenzo[a]pyrimido[50,40:5,6]pyrido[2,3-c]phenazine derivatives 61a–h

2.17

Benzo[a]pyrano[2,3-c]phenazine Derivatives

Ghorbani-Choghamarani et al.[46] developed a catalytic system utilizing spinel ferrite FeAl₂O₄ (hercynite) magnetic nanoparticles (MNPs) for the efficient one-pot synthesis of benzo[a]pyrano[2,3-c]phenazine derivatives 63a–h through a multicomponent reaction under environmentally friendly reaction conditions. This method involves a one-pot, four-component reaction of 2-hydroxy-1,4-naphthoquinone (1), o-phenylenediamine (22), aromatic aldehydes 62a–h, and malononitrile (5) using FeAl₂O₄ MNPs as a catalyst (Scheme [17]). The structure of the synthesized nanocatalyst was thoroughly characterized using XRD, FTIR, SEM, EDS, BET, and VSM techniques. The FeAl₂O₄ MNPs exhibit Lewis acid behavior and offer numerous advantages, including high product yields, short reaction times, and easy workup procedures. Additionally, the nanocatalyst could be recycled and reused up to four times without significant loss of activity.[46]

Scheme 17 Benzo[a]pyrano[2,3-c] phenazine derivatives 63a–h

In a separate study, Safaei-Ghomi et al.[47] presented a simple and rapid method for the preparation of benzo[a]pyrano[2,3-c]phenazine 65a–n. This method also involves a one-pot, four-component reaction of 2-hydroxy-1,4-naphthoquinone (1), o-phenylenediamine (22), aromatic aldehydes 64a–n, and malononitrile (5) using nano-Fe₃O₄@chitosan as an efficient heterogeneous solid acid catalyst under reflux conditions in ethanol (Scheme [18]). The catalyst was characterized using various techniques including powder X-ray diffraction (XRD), scanning electron microscopy (SEM), magnetic susceptibility measurements, energy-dispersive X-ray spectroscopy (EDS), and Fourier transform infrared (FTIR) spectroscopy. Key features of this method include high atom-economy, excellent catalytic activity, a broad range of products, high yields in short reaction times, and low catalyst loading.[47]

Scheme 18 Benzo[a]pyrano[2,3-c]phenazine derivatives 65a–n

2.18

3-Amino-2′-oxospiro[benzo[c]pyrano[3,2-a]phenazine-1,3′-indoline]-2-carbonitrile/carboxylate Derivatives

Scheme 19 3-Amino-2′-oxospiro[benzo[c]pyrano[3,2-a]phenazine-1,3′-indoline]-2-carbonitrile/carboxylate derivatives 67a–i

Safaei-Ghomi et al.[48] developed an innovative approach using an inorganic–organic hybrid catalyst for the efficient synthesis of 3-amino-2′-oxospiro[benzo[c]pyrano[3,2-a]phenazine-1,3′-indoline]-2-carbonitrile/carboxylate derivatives 67a–i through a domino multicomponent reaction (MCR). This method also involves a one-pot, four-component reaction of 2-hydroxy-1,4-naphthoquinone (1), o-phenylenediamine 54a–b, substituted isatin derivative 66a–f, and malononitrile (15a) or ethyl cyanoacetate (15b) in EtOH (Scheme [19]). This methodology addresses the issue of employing harsh catalysts and offers significant advancements by utilizing H₃PMo₁₂O₄₀/Hyd-SBA-15 as a catalyst. The key features of this approach are the remarkably low reaction times and high yields of the products, making it both impressive and environmentally beneficial. The synthesis of the H₃PMo₁₂O₄₀/Hyd-SBA-15 catalyst is straightforward, providing a solution to the problem associated with the use of harsh catalysts. Overall, this novel inorganic–organic hybrid catalyst demonstrates excellent efficiency, while also being environmentally friendly due to its low reaction times and high product yields.[48]

2.19

Synthesis of 6,6′-(Arylmethylene)bis(benzo[a]phenazin-5-ol) Derivatives

Olyaei et al.[49] developed a straightforward and effective method for the synthesis of novel 6,6′-(arylmethylene)bis(benzo[a]phenazin-5-ol) derivatives 69a–h. This was achieved through a sequential one-pot, two-step, pseudo-five-component tandem reaction using 2-hydroxy-1,4-naphthoquinone (1), o-phenylenediamine (22), and aromatic aldehydes 68a–h. The reaction took place under solvent-free conditions at 90 °C, in the presence of 2-aminopyridine as a co-catalyst and p-TsOH as a catalyst (Scheme [20]). This green sequential method offers several advantages, including low cost, clean reactions, high yield, operational simplicity, easy handling, and the absence of any tedious work-up or purification using non-chromatographic methods.[49]

Scheme 20 6,6′-(Arylmethylene)bis(benzo[a]phenazin-5-ol) derivatives 69a–h

2.20

Benzo[a]pyrano[2,3-c]phenazine Derivatives

In the context of sustainable chemical processes, the utilization of modern nanotechnology has gained significant attention in the development of functionalized eco-friendly materials. These nanomaterials show great promise as heterogeneous catalysts in various chemical synthesis reactions. Spinel ferrites, with a general molecular formula of MFe₂O₄ (where M = Mn²⁺, Fe²⁺, Co²⁺, Ni²⁺, Cu²⁺, and Zn²⁺), exhibit unique structural and electronic properties, making them highly valuable in catalytic applications. In this regard, Daraie et al.[50] successfully synthesized a Ce/PDA/CPTMS@CoFe₂O₄ nanocomposite that was employed as a catalyst (Scheme [21]). Under green conditions, a range of biologically important benzo[a]pyrano[2,3-c]phenazine derivatives 71a–l were synthesized by condensing 2-hydroxy-1,4-naphthoquinone (1), o-phenylenediamine (22), malononitrile (5), and various aryl aldehydes 70a–l (Scheme [22]). This approach yielded a diverse set of products with remarkable yields in short reaction times.[50]

Scheme 21 Preparation of Ce/PDA/CPTMS@CoFe₂O₄ nanocomposite

Scheme 22 Benzo[a]pyrano[2,3-c]phenazine derivatives 71a–l

2.21

Benzo[a]pyridazino[3,4-c]phenazine Derivatives

The remarkable biological properties exhibited by nitrogen-containing heterocyclic molecules have positioned them as significant targets in the fields of synthetic organic and medicinal chemistry. Among these, phenazines represent a highly abundant class of synthesized and naturally occurring nitrogen-containing heterocycles, known for their broad-spectrum antibiotic, fungicidal, and antimalarial activities. To access novel functionalized benzo[a]pyridazino[3,4-c]phenazine derivatives 75a–h, Le-Nhat-Thuy et al.[51] developed a convenient one-pot, microwave-assisted, four-component synthetic approach. The reaction involved the utilization of 2-hydroxy-1,4-naphthoquinone (1), aromatic aldehydes 72a–h, methyl hydrazine (73), and o-phenylenediamine (22) as starting materials (Scheme [23]). This innovative method offers an efficient and expedient route to obtain diverse and functionalized benzo[a]pyridazino[3,4-c]phenazine derivatives, broadening the scope for their potential applications in various fields.[51]

Scheme 23 Benzo[a]pyridazino[3,4-c]phenazine derivatives 75a–h

Scheme 24 Benzopyranophenzine carbonitrile derivatives 77a–i

2.22

Benzopyranophenazine Derivatives

Theresa et al.[52] achieved an efficient synthesis of benzopyranophenazine carbonitrile 77a–i that improved the safety and cost-effectiveness, and reduced the reliance on organic solvents in the reaction. The reaction involved the effective combination of 2-hydroxy-1,4-naphthoquinone (1), o-phenylenediamine (22), malononitrile (5), and aryl aldehyde 76a–i, resulting in good to excellent yields (Scheme [24]). The synthesis of benzopyranophenazine derivatives involved a two-step process: Knoevenagel condensation reaction followed by Michael addition reaction. Initially, aldehydes and malononitrile underwent condensation via the Knoevenagel reaction. The condensation of 2-hydroxy-1,4-naphthoquinone and o-phenylenediamine led to the formation of a benzophenazine intermediate. Subsequently, the intermediate underwent Michael addition followed by cyclization, yielding benzopyranophenazine carbonitrile derivatives. To facilitate the reaction, a low-melting mixture of glycerol, urea, and NH₄Cl was utilized as both the reaction medium and catalyst, further enhancing the efficiency of the synthesis of benzopyranophenazine carbonitrile.[52]

2.23

N′-(1,4-Naphthoquinone-2-yl) Isonicotinohydrazide (NIH) Derivatives

Rani et al.[53] conducted a study in which they employed ultrasonic irradiation to react 2-hydroxy-1,4-naphthaquinone (1) with isonicotinoyl hydrazine (78) in methanol, resulting in the synthesis of N′-(1,4-naphthoquinone-2-yl)isonicotinohydrazide (NIH, 79) (Scheme [25]). Lawsone, extracted from henna leaves (Lawsonia inermis), serves as a primary dye. To enhance the compound’s activity, its structure was modified. The structural characteristics of both the parent compound and the derivative were evaluated through elemental analysis, IR, electronic, ¹H and ¹³C NMR, and GC-MS spectroscopy. Cytotoxicity experiments were performed using the MTT test on human breast adenocarcinoma (MCF-7) and colon cancer (HCT-15) cell lines to assess the potential of NIH as a therapeutic agent.[53]

Scheme 25 N′-(1,4-Naphthoquinone-2-yl)isonicotinohydrazide (NIH) derivative 79

2.24

Bis-Lawsone Derivatives

Brahmachari et al.[54] introduced a straightforward and environmentally friendly synthesis method for various functionalized bis-lawsones; specifically, 3,3′-(aryl/alkyl-methylene)bis(2-hydroxynaphthalene-1,4-dione) derivatives 81a–s. The synthesis was accomplished by using sulfamic acid as a benign organocatalyst in a one-pot, pseudo-multicomponent reaction conducted at room temperature with 2-hydroxy-1,4-naphthaquinone (1) and aryl aldehyde 80a–s (Scheme [26]). This protocol offers several noteworthy features, including mild reaction conditions, good to excellent product yields, simplicity in operation, energy efficiency, high atom-economy, environmental friendliness, easy product isolation, and the absence of column chromatographic separation.[54]

2.25

2-Hydroxy-3-((5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)(phenyl)methyl)naphthalene-1,4-dione Derivatives

Multicomponent reactions (MCRs) have emerged as valuable tools for the synthesis of biologically active compounds, offering numerous advantages compared to conventional synthetic approaches. These advantages include shortened reaction times, reduced waste generation, energy conservation, and efficient utilization of starting materials. Fu et al.[55] developed an efficient and practical method for synthesizing 2-hydroxy-3-((5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)(phenyl)methyl)naphthalene-1,4-dione derivatives 85a–h. This was achieved through a one-pot, four-component reaction involving aromatic aldehydes 84a–h, β-keto esters 83, phenylhydrazine hydrate (82), and 2-hydroxy-1,4-naphthoquinone (1), catalyzed by MgCl₂ in ethylene glycol (EG) at 100 °C (Scheme [27]). The protocol offers appealing features such as a simple work-up procedure, short reaction time, high yield, and the use of an eco-friendly catalyst, making it a valuable and attractive strategy in the field of synthetic organic chemistry.[55]

Scheme 26 Bis-lawsone derivatives 81a–s

Scheme 27 2-Hydroxy-3-((5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)(phenyl)methyl)naphthalene-1,4-dione derivatives 85a–h

2.26

1H-Benzo[6,7]chromeno[2,3-d]pyrimidine Derivatives

Brahmachari et al.[56] devised a catalyst-free, energy-efficient, and practical method for the synthesis of a wide range of biologically significant 5-aryl-2-oxo-/thioxo-2,3-dihydro-1H-benzo[6,7]chromeno[2,3-d]pyrimidine-4,6,11(5H)-trione derivatives 88a–i. These derivatives were obtained through a one-pot multicomponent reaction (MCR) in aqueous ethanol at room temperature, involving barbituric/2-thiobarbituric acids 86a–d, aromatic aldehydes 87a–f, and 2-hydroxy-1,4-naphthoquinone (1). The protocol offers several notable features, including mild reaction conditions at room temperature, the absence of catalyst, operational simplicity, and clean reaction profiles. Moreover, the methodology provides excellent yields and high atom-economy. The use of commercially available and inexpensive starting materials, along with the ease of product isolation and purification without the need for time-consuming column chromatography, further adds to the advantages of this approach (Scheme [28]).[56]

Scheme 28 5-Aryl-2-oxo-/thioxo-2,3-dihydro-1H-benzo[6,7]chromeno[2,3-d]pyrimidine-4,6,11(5H)-trione derivatives 88a–i

2.27

5-Oxatetracene Derivatives

Khodabakhshi et al.[57] successfully synthesized 5-oxatetracene derivatives 91a–h, which consist of five fused rings, using carboxylated multiwall carbon nanotubes (CMWCNTs) as efficient nanocatalysts. A mixture of lawsone (1), aromatic aldehyde 89a–d, and β-naphthol (90) was heated at 110 °C to give the desired product (Scheme [29]). The CMWCNTs exhibited high efficiency and good recyclability under solvent-free conditions. The method offers several significant advantages, including short reaction times, utilization of a readily available catalyst, simple work-up procedure, high product yield, and elimination of toxic organic solvents.[57]

Scheme 29 Synthesis of 5-oxatetracene derivatives 91a–h using CMWCNTs

2.28

7-Arylbenzo[h]tetrazolo[5,1-b]quinazoline-5,6-dione Derivatives

Maleki et al.[58] achieved the successful synthesis of a magnetic polymeric nanocomposite, Ba_0.5Sr_0.5Fe₁₂O₁₉@PU-SO₃H, functionalized with Brönsted acid groups. The catalytic performance of this nanocomposite was investigated in a deep eutectic solvent (DES) based on choline chloride and urea, which is environmentally friendly and recyclable. The nanocomposite exhibited remarkable catalytic activity in the regioselective synthesis of 7-aryl-benzo[h]tetrazolo[5,1-b]quinazoline-5,6-diones 94a–q from lawsone (1), tetrazoloamine, and aromatic aldehyde 93a–q (Scheme [30]). This methodology offers several advantages, including high yields, short reaction times, the use of environmentally acceptable reaction media, straightforward product isolation, and an easy method for synthesizing nanocatalysts. Furthermore, the synthesized catalyst can undergo up to six recycling cycles with the use of an external magnetic field, all while maintaining its activity and mass without substantial degradation.[58]

Scheme 30 7-Arylbenzo[h]tetrazolo[5,1-b]quinazoline-5,6-diones derivatives 94a–q

2.29

1,4-Naphthoquinonyl-2-oxoindolinylpyrimidine Derivatives

Brahmachari et al.[59] developed a straightforward and highly efficient one-pot, three-component synthesis of diverse and functionalized 5-((1H-indol-3-yl)(aryl)methyl)-6-aminopyrimidine-2,4(1H,3H)-dione derivatives 97a–h based on a molecular hybridization approach. The target molecules were obtained through a tandem reaction involving 6-aminouracils 96, 2-hydroxy-1,4-naphthoquinone (1), and indoles 95a–h in the presence of sulfamic acid as a low-cost and environmentally friendly organocatalyst, utilizing water as the reaction medium at room temperature. The developed protocol offers high atom-economy, energy efficiency, excellent yields, metal-free synthesis, eco-friendliness, and operational simplicity (Scheme [31]).[59]

Scheme 31 1,4-Naphthoquinonyl-2-oxoindolinylpyrimidine derivatives 97a–h

2.30

Aminouracil-Tethered Trisubstituted Methane Derivatives

Kumari et al.[60] successfully achieved the synthesis of aminouracil-tethered tri-substituted methane derivatives using a mild, efficient, and environmentally friendly approach. The three-component reaction of 6-amino-1,3-dimethyluracil (98), aldehydes 99a–l, and 2-hydroxy-1,4-naphthaquinone (1), with molecular iodine as the catalyst under reflux conditions, resulted in the formation of aminouracil-tethered tri-substituted methane derivative 101a–l, respectively, in aqueous medium. Similarly, employing the same reaction conditions, the four-component reaction involving 2-hydroxy-1,4-naphthaquinone (1), o-phenylenediamine (22), aminouracil (98), and aldehyde derivatives 99a–l yielded aminouracil-tethered tri-substituted methane derivatives 100a–l (Scheme [32]).[60]

Scheme 32 Aminouracil-tethered tri-substituted methane derivatives 100a–l and 101a–l

2.31

CF₃-Functionalized Alkyl-Substituted 2-Amino- and 2-Hydroxy-1,4-naphthoquinone Derivatives

The three-component difunctionalization of alkenes through radical pathways has emerged as a highly efficient strategy for constructing polyfunctionalized molecules and has garnered significant attention in recent years. In this regard, the development of new radical trapping reagents has been an actively explored area, leading to the discovery of oxygen-based, nitrogen-based, carbon-based, and other types of radical trapping reagents. Wang et al.[61] conducted a study in which they utilized 2-amino-1,4-naphthoquinone derivative 104 as radical-trapping agent in a silver-catalyzed three-component difunctionalization of alkenes. The reaction employed various alkenes 102a–f and 2-amino-1,4-naphthoquinone 104 with diverse structures and electronic properties. This methodology offers an alternative approach for accessing CF₃-functionalized alkyl-substituted quinone derivatives 105a–f, which are commonly found in bioactive molecules (Scheme [33]).[61]

Scheme 33 2-Amino-1,4-naphthoquinone derivatives 105a–f

2.32

2-Aryl-4-thioxo-4H-naphtho[2,3-e][1,3]oxazine-5,10-dione Derivatives

In the field of biological sciences, 1,3-oxazine derivatives have gained significant attention as antibacterial agents and cancer screening agents. Additionally, the thio-derivatives of pyrano-1,3-benzoxazine have shown promising anti-inflammatory and antipyretic properties. In their study, Balouchzehi et al.[62] developed a selective one-pot method for synthesizing biologically active 2-aryl-4-thioxo-4H-naphtho[2,3-e][1,3]oxazine-5,10-diones 109a–f. This method involves the condensation of ammonium thiocyanate 107 and aromatic acyl chlorides 106a–f with 2-hydroxy-1,4-naphthoquinone (1) in the presence of catalytic amounts of N-methylimidazole 108 under solvent-free conditions at ambient temperature, resulting in excellent yields (Scheme [34]). The advantages of this new protocol include mild reaction conditions, short reaction time, utilization of an inexpensive and non-toxic catalyst, high yields of biologically active products, and the absence of hazardous solvents. The discovery of these novel oxazine compounds holds promise because of their diverse pharmacological properties.[62]

Scheme 34 2-Aryl-4-thioxo-4H-naphtho[2,3-e][1,3]oxazine-5,10-dione derivatives 109a–f

2.33

Pyrimidine-Fused Tetrahydropyridine Derivatives

Kumari and co-workers[63] conducted a study on the synthesis of regioselective pyrimidine-fused tetrahydropyridines through a one-pot, three-component reaction. The researchers employed FeCl₃·6H₂O as a catalyst under microwave irradiation to achieve the regioselective three-component reaction. By combining α,β-unsaturated aldehydes (cinnamaldehyde/crotonaldehyde) 110a–g, 2-hydroxy-1,4-naphthaquinone (1), and 6-aminouracils 111a–b, they successfully obtained pyrimidine-fused tetrahydropyridine-linked cyclic 1,3-diketones 112a–j (Scheme [35]).[63]

2.34

Benzylpyrazolyl Naphthoquinone Derivatives

In recent decades, there has been a growing interest in the synthesis of complex biologically active scaffolds using one-pot multicomponent reactions (MCRs). To enhance the synthetic efficiency of such protocols, there has been a focus on utilizing green solvents and effective heterogeneous catalysts. Benzylpyrazolyl naphthoquinone derivatives hold significant importance as they are found in numerous natural products including atovaquone, lapachol, parvaquone, and buparvaquone.[64] These derivatives have demonstrated diverse biological activities such as antibacterial, anti-HIV, antiviral, anticoagulant, antioxidant, and anticancer properties.[65]

Scheme 35 Pyrimidine-fused tetrahydropyridine derivatives 112a–j

Patil et al.[66] presented a green and cost-effective method for synthesizing benzylpyrazolyl naphthoquinone in water at room temperature, utilizing β-CD-SO₃H as a catalyst. This protocol demonstrates environmental friendliness by employing a heterogeneous and reusable catalyst in a green reaction medium. The methodology offers numerous advantages, including excellent product yield, short reaction time at room temperature, simple workup procedure, and the elimination of column chromatographic separation. The significance of pyrazolyl derivatives lies in their presence as a crucial component in many biologically active compounds. To synthesize dihydro-1H-pyrazolyl naphthalene-1,4-dione derivatives 115a–s, a mixture containing 3-methyl-1-phenyl-1H-pyrazol-5-ol 114 (1 mmol), substituted aldehyde 113a–s (1 mmol), and 2-hydroxy naphthoquinone 1 (1 mmol) in water (5 mL), along with 10 mol% β-CD-SO₃H catalyst, was stirred at room temperature (Scheme [36]).[66]

Scheme 36 Synthesis of dihydro-1H-pyrazolyl naphthalene-1,4-dione derivatives 115a–s

Vairaperumal and co-workers[67] developed a synthetic route for the production of a series of potential cytotoxic agents 119a–b that incorporate a pyrazolyl naphthoquinone framework. The synthesis involves the one-pot, four-component reaction of 2-hydroxy-1,4-naphthoquinone (1), ethyl acetoacetate (116), phenylhydrazine (117), and aromatic aldehydes 118a–b. Different catalysts, including metal triflates, Lewis acids, and metal oxides, were evaluated for their effectiveness in this multicomponent reaction. While metal triflates demonstrated good catalytic activity, their high cost, sensitivity to moisture, and non-recyclability posed challenges. Consequently, the researchers sought alternative catalysts, and V₂O₅ emerged as a suitable candidate. V₂O₅ offers advantages such as abundance, affordability, and ease of handling (Scheme [37]).[67]

Scheme 37 Benzylpyrazolyl naphthoquinone derivatives 119a–b

2.35

3,4-Dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-dione Derivatives

[GrFemBenzImi]OH was employed as a highly effective heterogeneous catalyst in the synthesis of bioactive 3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-diones 122a–h through the reaction of 2-hydroxy-1,4-naphthoquinone (1) and formaldehyde (120) with various aromatic anilines 121a–h (Scheme [38]). To synthesize a graphene oxide-supported ionic liquid phase catalyst ([GrFemBenzImi]OH), Gajare et al.[68] followed a two-step process. First, covalent grafting of 1-N-ferrocenylmethyl benzimidazole into the functionalized matrix of graphene oxide was performed, followed by an anion metathesis reaction. The resulting catalyst was characterized using various analytical techniques, including Fourier transform infrared (FT-IR), Fourier transform Raman (FT-Raman), CP-MAS ¹³C NMR spectroscopy, thermogravimetric analysis (TGA), transmission electron microscopy (TEM), X-ray diffraction (XRD), energy-dispersive X-ray (EDX) analysis, and Brunauer–Emmett–Teller (BET) surface area measurements.[68]

2.36

2-Amino-3-(2-oxothiazolmethyl)-Substituted 1,4-Naphthoquinone Derivatives

Farahani et al.[69] utilized silica-based materials to develop an environmentally friendly approach for the synthesis of potentially biologically active molecular scaffolds. They employed a one-pot, three-component reaction involving 2-hydroxy-1,4-naphthoquinone (1), 2-aminothiazole (124), and aromatic aldehydes 123a–k, facilitated by nano-SiO₂ (20% mol) as a Lewis acid and heterogeneous nanocatalyst in acetonitrile at room temperature. This reaction led to the synthesis of a series of 2-amino-3-(2-oxothiazolmethyl)-substituted 1,4-naphthoquinone compounds 125a–k with reaction times ranging from 2 to 5 hours. The structures of the synthesized molecules were determined using spectroscopic techniques (Scheme [39]).[69]

Scheme 38 3,4-Dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-diones derivatives 122a–h

Scheme 39 2-Amino-3-(2-oxothiazolmethyl)-substituted 1,4-naphthoquinone derivatives 125a–k

2.37

Chiral Nitroalkylated Naphthoquinone Derivatives

Threonine-based thiourea catalysts were developed by Zheng et al. by modifying the chiral framework of l-threonine. They successfully synthesized chiral nitroalkylated naphthoquinone derivatives 127a–q through reactions involving 2-hydroxy-1,4-naphthoquinone (1), nitroalkenes 126a–q, and toluene. The reactions were carried out with a low catalyst loading, resulting in high yields (up to 93%) and excellent enantioselectivities (up to 99% ee). By modifying the chiral scaffold of l-threonine, a series of thiourea derivatives were developed and tested for their enantioselective efficiency in the catalytic asymmetric Michael addition of 2-hydroxy-1,4-naphthoquinone to nitroalkenes. This reaction yielded chiral nitroalkylated naphthoquinone derivatives with high yields (up to 93%) and enantioselectivities (up to 99% ee) using a low catalyst loading of 3 mol% (Scheme [40]).[70]

Scheme 40 Chiral nitroalkylated naphthoquinone derivatives 127a–q

2.38

Quinone-Based Chromenopyrazole Derivatives

Kandhasamy and co-workers[71] developed a novel approach aimed at combining naphthoquinone, chromene, and pyrazolone to create chromenopyrazole derivatives 130a–h based on a highly active heterocyclic moiety, with potential therapeutic applications. In this study, the authors focused on the synthesis and fabrication of a unique scaffold composed of quinone-based chromenopyrazole (QCP) loaded onto silk fibroin (SF) electrospun nanofibers for use in tissue engineering. To achieve this, the researchers employed a one-pot, three-component coupling reaction involving 2-hydroxy-1,4-naphthoquinone (1), chromene-3-carbaldehyde 128a–h, and phenyl-3-methyl-pyrazol-5-one (129). Ethanol was used as the solvent, and InCl₃ served as the catalyst. Remarkably, the reaction was completed within 3–4 hours, and the pure synthetic products were easily isolated through filtration, followed by ethanol washing and drying. The synthesized compounds were thoroughly characterized using various techniques, including ¹H and ¹³C NMR spectroscopy, Fourier-transform infrared (FT-IR) spectroscopy, and electrospray ionization mass spectrometry (ESI-MS) (Scheme [41]).[71]

Scheme 41 Quinone-based chromenopyrazole derivatives 130a–h

2.39

13-Aryl-5H-dibenzo[b,i]xanthenes-5,7,12,14(13H)-tetraone Derivatives

Mousavi et al.[72] developed a highly efficient and cost-effective approach using graphene oxide/strontium nanocatalyst for a pseudo-three-component, one-pot cyclocondensation reaction. This reaction involved the combination of aromatic aldehydes 131a–l and lawsone (1) to produce the corresponding 13-aryl-5H-dibenzo[b,i]xanthenes-5,7,12,14(13H)-tetraones 132a–l under solvent-free conditions (Scheme [42]). One of the notable features of this study was the recyclability of the nanocatalyst, which was easily separated from the reaction mixture using an external magnet and reused for up to six cycles without any notable decrease in catalytic activity. The use of this catalyst offered several advantages, including high product yields, fast reaction times, simple experimental setup, the ability to recycle the catalyst, and tolerance towards various functional groups. These aspects not only benefit the environment but also contribute to the economic feasibility of the process.[72]

Scheme 42 13-Aryl-5H-dibenzo[b,i]xanthenes-5,7,12,14(13H)-tetraone derivatives 132a–l

2.40

Benzo[g]thiazolo[3,2-a]quinolone Derivatives

Bayat et al.[73] presented an efficient one-pot synthesis method for the production of chemoselective derivatives of 4-nitro-5-phenyl-1,2-dihydro-5H-benzo[g]thiazolo[3,2-a]quinoline-6,11-dione 136a–h. This synthesis involved the reaction of 2-hydroxy-1,4-naphthoquinone (1), aromatic aldehydes 135a–h, and the condensation of the enamine analog of β-nitrothiazolidine 134 in ethanol (Scheme [43]). Ethanol was chosen as the solvent due to its environmentally benign nature and low cost, as well as its miscibility with water. The β-nitrothiazolidine used in the reaction was derived from the addition of cysteamine hydrochloride to 1,1-bis(methylthio)-2-nitroethene. To assess the cytotoxic effects of the synthesized products, an in-vitro analysis was also performed to assess their impact on lung, breast, and prostate cancer cells.[73]

Scheme 43 Benzo[g]thiazolo[3,2-a]quinolone derivatives 136a–h

2.41

Alkyne Insertion on 2-Hydroxy-1,4-naphthaquinone

Borthakur et al. introduced a novel approach involving a Pd(II)-catalyzed decarbonylative alkyne insertion reaction for six-membered ring compounds. Annulation reaction between 2-hydroxy-1,4-naphthoquinones derivative 137a–h and disubstituted alkynes 138 led to the formation of alkylidene phthalides 139a–h in good yields; these products serve as crucial intermediates in the synthesis of biologically significant compounds (Scheme [44]). This reaction encompasses multiple steps, including C–H/C–C activation, alkyne insertion, intramolecular cyclization, and decarbonylation (Scheme [45]).[74]

Scheme 44 Alkyne insertion on 2-hydroxy-1,4-naphthaquinone 139a–h

Scheme 45 Probable mechanism

Scheme 46 3′-Benzoyl-4′-hydroxy-1′-(4-methylphenyl)-2H-spiro[naphtho[2,3-b]-furan-3,2′-pyrrole]-2,4,5′,9(1′H)-tetraone derivative 142

2.42

3′-Benzoyl-4′-hydroxy-1′-(4-methylphenyl)-2H-spiro[naphtho[2,3-b]-furan-3,2′-pyrrole]-2,4,5′,9(1′H)-tetraone Derivatives

Dubovtsev et al.[75] successfully carried out a study in which methyl 3-benzoyl-1-(4-methylphenyl)-4,5-dioxo-4,5-dihydro-1H-pyrrole-2-carboxylate (140) was reacted with 2-hydroxy-1,4-naphthoquinone (1). This reaction resulted­ in the formation of 3′-benzoyl-4′-hydroxy-1′-(4-methylphenyl)-2H-spiro[naphtho[2,3-b]furan-3,2′-pyrrole]-2,4,5′,9(1′H)-tetraone (142). During this spiro heterocyclization process, an intermediate product known as the Michael adduct, specifically methyl 3-benzoyl-4-hydroxy-2-(3-hydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-1-(4-methylphenyl)-5-oxo-2,5-dihydro-1H-pyrrole-2-carboxylate (141), was isolated for the first time (Scheme [46]).[75]

2.43

2,3-Fused Pyrrole Derivatives

Borra et al.[76] successfully synthesized 2,3-fused pyrroles 144a–h through the coupling of α-azidochalcones 143a–h with 2-hydroxy-1,4-naphthoquinone (1), employing Ru(bpy)₃–(PF₆)₂ as a photocatalyst under blue LED light irradiation. This synthetic process involves the photosensitized breakdown of α-azidochalcones, leading to the formation of highly reactive 2H-azirines. These reactive intermediates are subsequently captured by 2-hydroxy-1,4-naphthoquinone, resulting in the formation of one new C–C bond and two new C–N bonds (Scheme [47]).[76]

Scheme 47 2,3-Fused pyrrole derivatives 144a–h

Scheme 48 Preparation of the starting acetal and stable 2-arylidene-1,3-diones 149a–d

2.44

Hetero-Diels–Alder Reactions of Methylidene Derivatives of Lawsone

Tsanakopoulou et al.[77] conducted a study involving the synthesis, isolation, and utilization of an acetal derivative of lawsone 147 in tandem Knoevenagel/hetero-Diels–Alder reactions catalyzed by (S)-proline (Scheme [48]). This research aimed to explore the reactivity of hydroxyquinones, providing new insights and perspectives. The in-situ formation of intermediate alkylidene-1,3-diones 149a–d, derived from lawsone (1), underwent reactions with electron-rich alkenes 150. This resulted in the predominantly high-yield formation of pyrano-1,2-naphthoquinone (β-lapachone) derivatives, as well as the isomeric pyrano-1,4-naphthoquinone (α-lapachone) derivatives 151–154(a–d) (Scheme [49]).[77]

Scheme 49 Reactions of the in situ generated alkylidene-1,3-diones 149a–d with alkyl vinyl ethers 150

2.45

Benzo[g]thiazolo[2,3-b]quinazolin-4-ium and Benzo[g]benzo[4,5]thiazolo[2,3-b]quinazolin-14-ium Hydroxide Derivatives

Nouri et al.[78] developed a novel series of benzo[g]thiazolo[2,3-b]quinazolin-4-ium and benzo[g]benzo[4,5]thiazolo[2,3-b]quinazolin-14-ium hydroxide derivatives 157a–g. These derivatives were synthesized through a one-pot, three-component reaction involving aryl glyoxal monohydrates 155a–g, 2-hydroxy-1,4-naphthoquinone (1), and 2-aminothiazole 156. The reaction took place in the presence of triethylamine and p-toluenesulfonic acid, which served as organocatalysts, in a mixture of water and acetone (2:1) at room temperature (Scheme [50]). This synthetic approach offers several advantages. Firstly, it provides mild reaction conditions, ensuring that the reaction proceeds under relatively gentle circumstances. Additionally, the method yields excellent product yields, indicating the efficiency of the reaction. The workup process is also simple and straightforward. Moreover, the starting materials and catalysts used in the reaction are readily accessible, contributing to the convenience and accessibility of the method.[78]

Scheme 50 Benzo[g]thiazolo[2,3-b]quinazolin-4-ium and benzo[g]benzo[4,5]thiazolo[2,3-b]quinazolin-14-ium hydroxide derivatives 157a–g

2.46

Benzo[c]acridine-dione Derivatives

Behbahani et al.[79] undertook the synthesis of a novel series of benzo[c]acridine-diones that incorporate pharmacophoric elements found in anti-tubulin compounds. These compounds were designed and synthesized with a central dihydropyridine bridge, aiming to develop potential anticancer agents and tubulin polymerization inhibitors. The synthesis process involved the reaction of 2-hydroxy-1,4-naphthoquinone (1), 3,4,5-trimethoxyaniline (158), and substituted benzaldehydes 159a–j in the presence of acetic acid under microwave irradiation. The reaction mixture was stirred until completion, resulting in the formation of the desired benzo[c]acridine-dione derivatives 160a–j (Scheme [51]).[79]

Scheme 51 Benzo[c]acridine-dione derivatives 160a–j

2.47

Naphtho[1,2-b]furan-4,5-diones

Li et al.[80] conducted a study involving the synthesis of two substituted naphtho[1,2-b]furan-4,5-diones (166a–e and 167a–e) derived from lawsone (1). The synthesis involved the treatment of lawsone (1) with allyl bromide (161), followed by a subsequent Claisen rearrangement to yield 2-allyl-3-hydroxynaphthene-1,4-dione (162). This intermediate was further cyclized to obtain ortho-quinone 163 using Lewis acid NbCl₅ at room temperature. The ortho-quinone 163 was then subjected to a reaction with N-bromosuccinimide (NBS) and 2,20-azobis(2-methylpropionitrile) (AIBN), resulting in its conversion into 2-(bromomethyl)naphtha[1,2-b]furan-4,5-dione 165 through a bis-radical reaction. The brominated intermediate 165 was subsequently reacted with substituted phenol or amine to yield the desired ortho-quinone derivatives 166a–e and 167a–e (Scheme [52]). The structures of these derivatives were characterized using ¹H NMR, ¹³C NMR spectroscopy, and high-resolution mass spectrometry (HRMS). The cytotoxicity activities of the synthetic derivatives were investigated against human leukemia cells K562, prostate cancer cells PC3, and melanoma cells WM9. The results of the study were used to evaluate the potential of these ortho-quinone derivatives as cytotoxic agents against these specific cancer cell lines.[80]

Scheme 52 Naphtho[1,2-b]furan-4,5-dione derivatives 167a–e

2.48

Thio-Derivatives of 2-Hydroxy-1,4-naphthoquinone

In a recent study conducted by Monroy-Cardenas et al.,[81] a novel series of thio-derivatives 169a–h of 2-hydroxy-1,4-naphthoquinone (1) was synthesized using microwave irradiation in an aqueous medium (Scheme [53]). The objective of this synthesis was to enhance the antiplatelet activity of 2-hydroxy-1,4-naphthoquinone derivatives. Furthermore, the position and nature of the substituent on the phenyl ring played a pivotal role in determining the observed biological activity. This research highlights the potential of modifying lawsone to generate thio-derivatives 168a–h with improved antiplatelet properties. By exploring the structural variations and their impact on biological activity, the study provided valuable insights for further development and optimization of lawsone-based compounds with enhanced therapeutic potential. Overall, lawsone’s versatility as a starting material opens up promising avenues for synthesizing biologically active compounds, while investigations into its structure–activity relationship pave the way for the design and development of novel agents with targeted effects against specific diseases and pathogens.[81]

Scheme 53 Thio-derivatives of 2-hydroxy-1,4-naphthoquinone derivatives 169a–h

2.49

Aminonaphthoquinone Derivatives

Aminonaphthoquinone Mannich bases, specifically 3-(aminomethyl)-2-hydroxy-1,4-naphthoquinones, constitute an intriguing class of compounds. These compounds, along with their metal complexes, have shown diverse biological properties such as antimalarial, leishmanicidal, antibacterial, anticancer, antifungal, antimolluscicidal, cholinesterase inhibitory, antiparasitic, and antiviral activities. Researchers have primarily focused on the synthesis of aminonaphthoquinone derivatives.

In a recent study, Olyaei et al.[82] employed a convenient one-pot, three-component condensation method to synthesize aminonaphthoquinone derivatives 173a–i. The reaction involved the catalyst and solvent-free condensation of 2-hydroxy-1,4-naphthoquinone (1), ninhydrin (171), and heteroaryl amines 172a–i at 75 °C. The imines, formed in situ as intermediates from the addition of 2-hydroxynaphthalene-1,4-dione to the imine, followed by the condensation reaction of ninhydrin with heteroaryl amines, yielded the desired products. This synthetic approach offers advantages such as shorter reaction times, simplicity, clean reactions, environmentally friendly conditions, simple workup procedures, high yields, and easy purification of products using non-chromatographic methods (Scheme [54]).[82]

Scheme 54 Amino naphthoquinones derivatives 173a–i

2.50

Benzo[g]pyrazolo[3,4-b]quinoline Derivatives

Pyrazoloquinoline derivatives have garnered significant attention due to their pharmaceutical and biological properties. Researchers have developed innovative nanocatalysts and durable multicomponent reactions (MCRs), which have transformed this approach into a noteworthy tool. The most notable features of nanocatalysts include high catalytic activity, stability, reusability, selectivity, and adherence to green chemistry principles. Among them, noble metal nanocatalysts, such as silver nanoparticles (AgNPs), have been extensively investigated due to their superior physicochemical, environmentally benign, biological properties, and low cost. Further, following a similar approach, Khalafy et al.[83] synthesized benzo[g]pyrazolo[3,4-b]quinolines 176a–j using AgNPs as a high-performance nanocatalyst in a one-pot, three-component reaction of aryl glyoxal monohydrates 174a–h, 5-amino-1-aryl-3-methylpyrazoles 175a–b, and 2-hydroxy-1,4-naphthoquinone (1) in H₂O/EtOH at 60 °C (Scheme [55]). The structures of benzo[g]pyrazolo[3,4-b]quinolines were confirmed using Fourier transform infrared, ¹H, and ¹³C NMR spectral data and microanalysis.[83]

Scheme 55 Benzo[g]pyrazolo[3,4-b]quinolines derivative 176a–j

2.51

β-Lapachone–Monastrol Hybrids

Wu et al.[84] synthesized a novel series of β-lapachone analogs 179a–h by incorporating the tetrahydropyrimidinethione moiety of monastrol in place of the pyran ring. The hybrid molecules were conveniently prepared via a multicomponent reaction involving the condensation of 2-hydroxy-1,4-naphthoquinone (1), thiourea (177), and 3-hydroxybenzaldehydes 178a–h. This strategy presents a promising approach for the development of new β-lapachone derivatives with potential biological activities (Scheme [56]).[84]

Scheme 56 β-Lapachone-monastrol hybrids 179a–h

2.52

3,4-Dihydro-12-aryl-1H-benzo[b]xanthene-1,6,11-(2H,12H)trione

In their study, Turhan et al.[85] synthesized 3,4-dihydro-12-aryl-1H-benzo[b]xanthene-1,6,11-(2H,12H)trione compounds 182a–h using a one-pot condensation reaction of various substituted aromatic aldehydes 180a–h, 2-hydroxy-1,4-naphthoquinone (1), and dimedone (181) in the presence of a green and reusable catalyst, Bi(OTf)₃.The novel substituted benzo[b]xanthenes were characterized using various spectroscopic methods, and their inhibitory actions against butyrylcholinesterase (BChE), acetylcholinesterase (AChE), and glutathione S-transferase (GST) were investigated. The one-pot method was utilized for the synthesis of benzoxanthene compounds to promote green chemistry, using ethanol as a solvent and recycled Bi(OTf)₃ (Scheme [57]).[85]

Scheme 57 3,4-Dihydro-12-aryl-1H-benzo[b]xanthene-1,6,11-(2H,12H)trione derivatives 182a–h

2.53

1,4-Naphthoquinones Tethered to 1,2,3-1H-Triazoles

Chipoline et al.[86] synthesized 1,4-naphthoquinones tethered to 1,2,3-1H-triazoles 188a–k using a sequence of reactions that involved C-3 alkylation by Knoevenagel condensation or [3.3]-sigmatropic rearrangement. The quinones were treated with propargyl bromide, K₂CO₃, and refluxing acetone to obtain the propargylated quinines 187a–e in yields ranging from 50 to 84%. In addition, arylazides 184a–e were prepared from commercial anilines 183a–e via treatment with sodium nitrite in hydrochloric acid at 0–5 °C followed by aromatic electrophilic substitution with sodium azide. The arylazides were obtained in quantitative yields. The reaction between the arylazides 184a–e and O-propargyl quinones 187a–e was catalyzed by Cu(I) and produced only the 1,4-disubstituted regioisomer through a Huisgen 1,3-dipolar cycloaddition CuAAC in yields ranging from 30 to 97% (Scheme [58]).[86]

Scheme 58 1,4-Naphthoquinones tethered to 1,2,3-1H-triazoles derivatives 188a–k

2.54

Trifluoromethylated Benzo[6,7]chromeno[2,3-c]pyrazoles

Duan and co-workers[87] successfully synthesized trifluoromethylpyrazolone-tethered trisubstituted methane derivatives 191a–j with high yields. The synthesis involved a one-pot, three-component reaction using 2-hydroxy-1,4-naphthoquinone (1), aromatic aldehydes 189a–j, and 1-aryl-3-trifluoromethyl-5-pyrazolone (190) in the presence of acetonitrile solvent and NH₄OAc. The authors then combined these derivatives with SOCl₂/pyridine as a dehydration agent in acetonitrile to produce appropriate annulated fused polyheterocyclic trifluoromethylated benzo[6,7]chromeno[2,3-c]pyrazole-5,10-dione derivatives 191a–j (Scheme [59]).[87]

Scheme 59 Trifluoromethylated benzo[6,7]chromeno[2,3-c]pyrazoles derivatives 191a–j

2.55

Naphthoquinonefuran Derivatives

Naphthofuroquinone is a well-known pharmacophoric unit with a broad range of biological activities, including cytotoxic, anti-inflammatory, antitumor, trypanocidal, and antileukemic activity, that is commonly found in natural products and drugs. Due to their wide spectrum of biological activities, there has been significant interest in synthesizing derivatives of naphthofuroquinone. To this end, Li et al.[88] developed a transition-metal-free, tandem one-pot approach for the synthesis of naphthoquinonefuran derivatives 193a–j using 2-hydroxynaphthoquinones as starting materials. The process involves an intermolecular alkynylation of the sp²-carbon at the 3-position of 2-hydroxy-1,4-naphthoquinone (1) with arylethynyl bromides 192a–j, followed by a base-promoted intramolecular nucleophilic annulation reaction (Scheme [60]). This method is compatible with a wide range of functional groups, and various naphtho[2,3-b]furan-4,9-diones can be produced with excellent regioselectivity and good yields.[88]

Scheme 60 Naphthoquinonefuran derivatives 193a–j

2.56

Benzodioxolo[4,5-b]xanthenedione Derivatives

Lambat et al.[89] reported the use of ZnO-β zeolite nanoparticles as a cost-effective and highly effective heterogeneous catalyst for the one-pot multicomponent synthesis of 7-benzodioxolo[4,5-b]xanthenedione derivatives 196a–j under microwave (μW) irradiation using 2-hydroxy-1,4-naphthoquinone (1), aromatic aldehyde 194a–j, and 3,4-methylenedioxyphenol (195) as starting material. The method presents numerous advantages, including fast reactions, simple work-up procedures, excellent product yields of over 90%, and the reuse of the catalyst (Scheme [61]).[89]

Scheme 61 Benzodioxolo[4,5-b]xanthenedione derivatives 196a–j

2.57

Pyrimido[4,5-b]quinoline-tetraone Derivatives

Safari and co-workers[90] successfully carried out a multicomponent reaction under reflux conditions using aromatic aldehydes 197a–g, 6-aminouracil, or 6-amino-1,3-dimethyluracil 198a–b, and 2-hydroxy-1,4-naphthoquinone (1) with the aid of a magnetic nanocomposite. Specifically, the researchers employed 12-phosphotungstic acid functionalized chitosan@NiCo₂O₄ NPs (PWA/CS/NiCo₂O₄) as the heterogeneous nanocatalyst to produce pyrimido[4,5-b]quinoline-tetraones 199a–j (Scheme [62]). The approach utilized green solvents, offered a simple procedure, gave excellent product yields, involved simple purification methods, and had short reaction times. Moreover, the reaction products were obtained with ease and in good-to-excellent yields without requiring column chromatography.[90]

Scheme 62 Pyrimido[4,5-b]quinoline-tetraone derivatives 199a–j

2.58

Benzo[b]xanthene-trione Derivatives

In the study, Rahnamafar et al.[91] developed a one-pot, three- or pseudo-five-component reaction between 2-hydroxy-1,4-naphthoquinone (1), aldehyde 201a–h and dimedone or 1,3-cyclohexanedione 200a–b to synthesize benzo[b]xanthenetrione derivatives 202a–j. The reaction was conducted under reflux conditions in ethanol by using Fe₃O₄@SiO₂/PEtOx as a nanocatalyst (Scheme [63]). This new, heterogeneous, efficient, and recyclable nanocatalyst was generated by immobilizing poly(2-ethyl-2-oxazoline) (PEtOx) on Fe₃O₄ nanoparticles. The nanocatalyst was characterized using various techniques, including scanning electron microscopy (SEM), Fourier transform infrared (FTIR), powder X-ray diffraction (XRD), vibrating-sample magnetometer (VSM), and energy-dispersive X-ray spectroscopy (EDS) analysis. One of the advantages of this catalyst was its ability to be easily separated and recycled several times without significant loss of activity. The reaction used a clean methodology with mild reaction conditions, easy work-up, short reaction time, and gave good-to-excellent yields. Additionally, the preparation of the catalyst was simple, making it a promising approach for the synthesis of benzo[b]xanthene-trione derivatives.[91]

Scheme 63 Benzo[b]xanthene-trione derivatives 202a–j

2.59

4H-Pyran Derivatives

Kamalzare et al.[92] reported the synthesis of a novel, green, heterogeneous bio-nanocatalyst from natural, inexpensive and readily available materials. This catalyst exhibits distinctive properties such as environmental compatibility and low-cost, and is highly efficient for the synthesis of 4H-pyran derivatives 204a–j. The synthesis of 4H-pyran derivatives was achieved through the mixing of aryl aldehyde 203a–j, enolizable C–H activated acidic compounds (2-hydroxy-1,4-naphthaquinone; 1), and malononitrile (5) in the presence of CuFe₂O₄@starch as a catalyst in ethanol solvent. The reaction was stirred for an appropriate amount of time at room temperature (Scheme [64]). The green heterogeneous bio-nanocatalyst is composed of natural materials, which provides a more sustainable and eco-friendly approach to the synthesis of 4H-pyran derivatives. The use of this catalyst offers advantages such as low cost, good availability, and high efficiency. Furthermore, ethanol was used as the solvent of the reaction, providing an additional eco-friendly benefit to the synthesis. The CuFe₂O₄@starch catalyst was found to exhibit excellent catalytic activity and could be reused for subsequent reactions without significant loss of activity. The synthesis conditions were mild and required no additional harmful catalysts, which is a further benefit in terms of the safety and environmental impact of the reaction.[92]

Scheme 64 2-Amino-5,10-dihydro-5,10-dioxo-4H-benzo[g]chromene-3-carbonitrile derivatives 204a–j

2.60

Pyrazolo[4′,3′:5,6]pyrano[2,3-c]phenazin-15-yl Methanone Derivatives

A novel method for synthesizing the four-component pyrazolo[4′,3′:5,6]pyrano[2,3-c]phenazin-15-yl methanone 208a–i was developed by Taheri et al.[93] The reaction involved the use of 2-hydroxy-1,4-naphthaquinone (1), benzene-1,2-diamine 205a–b, 5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one (206), and arylglyoxals 207a–e, followed by the addition of Fe₃O₄@TiO₂-SO₃H nano-composite catalyst under microwave conditions and in a solvent-free environment at 180 W (Scheme [65]). One notable advantage of using this catalyst was its ability to be reused in subsequent reaction phases without significant loss of activity. The synthesis process provided several benefits, including mild reaction conditions, a solvent-free environment, no harmful catalysts in the laboratory, low energy consumption, and economical feasibility.[93]

Scheme 65 Pyrazolo[4′,3′:5,6]pyrano[2,3-c]phenazin-15-yl methanone derivatives 208a–i

2.61

Aminonaphthoquinone Derivatives

A clean and facile one-pot, three-component protocol was developed by Nariya et al.[94] for the synthesis of a diverse library of derivatives of aminonaphthoquinones 211a–i using different amines 209a–c, aromatic aldehydes 210a–d, and lawsone (1), for potential anticancer applications (Scheme [66]). The synthesized compounds were characterized using various spectroscopic techniques, and their structures were confirmed by ¹H NMR, ¹³C NMR, FT-IR spectroscopy, mass spectrometry, and elemental analysis. The compounds exhibited moderate-to-good anticancer activity, and their hemocompatibility was established.[94]

Scheme 66 Aminonaphthoquinone derivatives 211a–i

2.62

3-Aryl-Substituted Lawsone Derivatives

Scheme 67 3-Aryl-substituted lawsone derivatives 216a–e

In their study, Song et al.[95] reported on the synthesis of a lawsone-based compound as an antimicrobial agent against methicillin-resistant Staphylococcus aureus (MRSA), which has become increasingly difficult to treat due to multidrug resistance. The authors synthesized a series of lawsone-derived compounds 216a–e with varying lipophilicity and screened them for minimum inhibitory concentrations against MRSA to identify a potent candidate. The identified compound showed significantly improved drug resistance profiles compared to conventional antibiotics and was validated for therapeutic efficacy using murine models of wound infection and non-lethal systemic infection induced by MRSA. In addition, the synthesis of lawsone derivatives 216a–e was achieved by incorporating aromatic rings with different lengths of carbon chains into the C3 position of lawsone (1) via an organocatalytic three-component reductive alkylation (TCRA) reaction (Scheme [67]). The entire series of lawsone derivatives was characterized using ¹H NMR spectroscopy, mass spectrometry (MS), and single-crystal X-ray structural analysis to determine their structural properties.[95]

2.63

2-Aryl-4-selenoxo-4H-naphtho[2,3-e][1,3]oxazine-5,10-dione Derivatives

A facile and efficient one-pot method for the synthesis of 2-aryl-4-selenoxo-4H-naphtho[2,3-e][1,3]oxazine-5,10-diones 220a–e was reported by Keykha et al.[96] This method involves the condensation reaction of 2-hydroxy-1,4-naphthoquinone (1) and aroyl chlorides 217a–e with potassium selenocyanate (218) in the presence of catalytic amounts of N-methylimidazole (219) under solvent-free conditions (Scheme [68]). The proposed method offers several benefits such as mild reaction conditions, short reaction time, straightforward experimental setup, and high yields of bioactive compounds.[96]

Scheme 68 2-Aryl-4-selenoxo-4H-naphtho[2,3-e][1,3]oxazine-5,10-dione derivatives 220a–e

Scheme 69 3-Arylated-2-hydroxy-1,4-naphthoquinone derivatives 223a–i

2.64

3-Arylated 2-Hydroxy-1,4-naphthoquinone Derivatives

In their study, Thi and co-workers[97] efficiently synthesized novel naphthoquinone derivatives 223a–i using a microwave-assisted three-component reaction of 2-hydroxy-1,4-naphthoquinone (1), tetronic acid (221), and various aromatic aldehydes 222a–i in AcOH. The multicomponent domino reaction proceeds through Knoevenagel condensation, Michael addition, deprotonation, and 1,3-H shift steps (Scheme [69]). The researchers also evaluated the influence of electron-donating and electron-withdrawing substituents on the phenyl moieties on the reaction outcome. The synthesized compounds were tested for their cytotoxic activity against KB and HepG2 cancer cell lines, revealing the potential importance of 3-alkylated 2-hydroxy-1,4-naphthoquinones for the development of anticancer agents.[97]

2.65

Benzo[d]naphtho[2,3-g][1,3]oxazocine-8,13(6H,14H)-diones

Scheme 70 Benzo[d]naphtho[2,3-g][1,3]oxazocine-8,13(6H,14H)-dione derivatives 225a–m

Privileged N,O-acetal heterobicyclic compounds featuring medium-sized rings have garnered considerable interest in both organic chemistry and biology. These frameworks have been widely observed among diverse natural products that exhibit antiproliferative, antimicrobial, antiallergic, anti-inflammatory, and cytotoxic activity. Oxazocine, in particular, represents one of the most significant N,O-acetal heterobicyclic compounds. The synthesis of functionalized polycyclic naphthooxazocines 225a–m was achieved by Madani Qamsari and co-workers via a tandem reaction between 2-hydroxy-1,4-naphthoquinone (1) and quinolinium salts 224a–m in the presence of DABCO (1,4-diazabicyclo[2.2.2]octane) in an aqueous medium (Scheme [70]). This method for preparing oxazocine boasts good-to-excellent yields of products, along with an operationally simple procedure. Furthermore, the products are obtained without the need for column chromatography. To minimize the hazards of chemicals and solvents, the reaction was conducted in water, a green solvent. All newly synthesized compounds were subjected to characterization using various methods, including IR, ¹H NMR, and ¹³C NMR spectroscopy.[98]

2.66

Styryl-Linked Benzo[h]pyrazolo[3,4-b]quinoline-5,6(10H)-dione Derivatives

Pyrazoles represent a widely researched class of aromatic N-heterocycles with a significant presence in synthetic bioactive scaffolds and natural products, offering an extensive range of bioactivities. Pyrazole-based moieties have been successfully combined with other bioactive molecules such as pyridine and naphthoquinone, resulting in applications with multiple uses. For instance, combining pyrazoles with quinoline may yield compounds with potential antibacterial, antitumor, antifungal, antimicrobial, anticancer, and antiangiogenic activities. Recently, Yadav et al.[99] reported an interesting multicomponent reaction involving unsaturated aldehydes 226a–f, 2-hydroxy-1,4-naphthoquinone (1), and 5-aminopyrazoles 227a–g. The reaction proceeded by liquid-assisted grinding of the three components for a period of 20–30 minutes in the presence of water, leading to the formation of styryl-linked benzo[h]pyrazolo[3,4-b]quinoline-5,6(10H)-diones 228a–j (Scheme [71]). The resulting three-component product contains four bioactive moieties, namely 1,2-naphthoquinone, pyridine, pyrazole, and styryl. This methodology has several notable features, including short reaction time, green reaction conditions, good yields, and a simplified purification process.[99]

Scheme 71 Styryl-linked benzo[h]pyrazolo[3,4-b]quinoline-5,6(10H)-dione derivatives 228a–j

2.67

Lawsone Enaminones Derivatives

Enaminone derivatives are widely used in the synthesis of bioactive compounds and natural products with diverse therapeutic activities such as antitumor, anti-inflammatory, antiepileptic, and antibacterial properties. Olyaei et al.[100] developed a new method to synthesize enaminone derivatives 231a–h and 232a–h using lawsone (1), triethyl orthoformate (229), and aromatic amines 230a–h in the presence of guanidinium chloride under solvent-free conditions. The ¹H NMR spectra of the resulting lawsone enaminones indicate that they exist in the keto–enamine tautomeric form and undergo Z/E-isomerization with respect to the C=C bond in DMSO-d ₆ at room temperature. This method offers high-to-excellent yields, short reaction times, easy purification of products without chromatographic methods, and a simple work-up procedure (Scheme [72]).[100]

Scheme 72 Lawsone enaminone derivatives 232a–h

2.68

Dihydrobenzo[g]furo[3,4-b]quinoline-1,5,10(3H)-trione Derivatives

Multicomponent reactions (MCRs) conducted in a single synthetic step are highly efficient and offer a convenient way to access a diverse range of complex compounds while maintaining excellent selectivity and atom economy. Microwave-assisted chemistry is a cutting-edge method that is frequently employed in green chemistry since it can reduce reaction times and boost yields. Thi et al.[101] utilized this approach to synthesize dihydrobenzo[g]furo[3,4-b]quinoline-1,5,10(3H)-triones (podophyllotoxin naphthoquinone) 235a–j with good yields via a four-component reaction of 2-hydroxy-1,4-naphthoquinone (1), aromatic benzaldehydes 233a–j, tetronic acid (221), and ammonium acetate (234) (Scheme [73]).[101]

2.69

Styryl-Linked Fused Dihydropyridine Derivatives

Yadav et al.[102] described a simple and rapid method for the synthesis of styryl-linked dihydropyridines fused with naphthoquinone and pyrazole moieties using a catalyst-free three-component reaction. The reaction was carried out in ethanol under reflux conditions and involved the use of 2-hydroxy-1,4-naphthoquinone (1), cinnamaldehydes 236a–e, and 3-aminopyrazoles 237a–e. A wide range of cinnamaldehyde derivatives and 3-aminopyrazoles were found to be suitable for this reaction, and the products were fully characterized using spectroscopic tools (Scheme [74]). Single-crystal XRD was used to characterize one of the products. The methodology has notable features such as catalyst-free reaction conditions, short reaction time, good yields of the products, easy purification process, formation of three new bonds (two C–C and one C–N) in one-pot, and products with four different bioactive moieties.[102]

Scheme 73 Dihydrobenzo[g]furo[3,4-b]quinoline-1,5,10(3H)-trione derivatives 235a–j

Scheme 74 Multicomponent synthesis of styryl-linked fused dihydropyridines derivatives 238a–h

2.70

Naphthoquinone Chalcone Hybrid Derivatives

Chalcones are compounds found in nature that consist of an α,β-unsaturated ketone and two aromatic rings. The α,β-unsaturated ketone group in chalcones acts as a Michael acceptor for a variety of biological nucleophiles. Chalcones, whether naturally occurring or synthetic, possess a variety of pharmacological properties due to their small structures and Michael acceptor features. These properties include antibacterial, anticancer, antileishmanial, antifungal, antiviral, antitubercular, and antimalarial activities. Nguyen and co-workers[103] reported a facile and efficient method to synthesize new naphthoquinone-based chalcone hybrids 242a–i via microwave-assisted one-pot, three-component reaction of 2-hydroxy-1,4-naphthoquinones (1), N,N-dimethylformamide dimethyl acetal (DMF-DMA; 239), and acetophenone derivatives 240a–i. The synthesis of the naphthoquinone-based chalcone hybrids involved a sequence of steps, including condensation, 1,4-addition, rotation, elimination, and [1,3]-H shift (Scheme [75]).[103]

Scheme 75 Naphthoquinone-based chalcone hybrids 242a–i

2.71

Naphtho[2,3-b][1,6]naphthyridine Derivatives Promoted by Acetic Acid

Naphthyridine derivatives have a wide range of applications in various fields such as pharmaceuticals, animal husbandry, industrial lubricants, and analytical chemistry. These compounds have been found in natural alkaloids as bipyridine scaffold molecules with significant chemical and biological importance. 1,6-Naphthyridines are particularly important due to their unique therapeutic and pharmacological properties in organic and biological chemistry. Shen and co-workers[104] synthesized naphtho[2,3-b][1,6]naphthyridine derivatives 245a–j. A three-component domino reaction was employed, which demonstrated excellent substrate scope, including 2-hydroxy-1,4-naphthoquinone (1), various enaminones 243a–h, and aldehydes 244a–e, and yielded a series of multi-functionalized naphtho[2,3-b][1,6]naphthyridine derivatives 245a–j with 70–86% yields (Scheme [76]). The advantages of this strategy are its bond-forming efficiency, the sole byproduct being water, and the accessibility of starting materials, which provide a valuable means of accessing biological 1,6-naphthyridines.[104]

Scheme 76 Naphtho[2,3-b][1,6]naphthyridines derivatives 245a–j

2.72

6-Hydroxy-14-aryl-8H-dibenzo[a,i]xanthene-8,13(14H)-diones

Olyaei and co-workers[105] investigated the synthesis of xanthenes and their derivatives, specifically benzo-fused xanthenes, which have been extensively studied for their diverse range of biological and pharmacological properties, including antibacterial, antiviral, anti-inflammatory, phototoxicity, antitumor, and anti-HIV properties. They utilized a one-pot, three-component condensation reaction in glacial acetic acid under reflux conditions to synthesize novel 6-hydroxy-14-aryl-8H-dibenzo[a,i]xanthene-8,13(14H)-dione derivatives 248a–j by combining 2-hydroxy-1,4-naphthoquinone (1), aromatic aldehydes 246a–j, and 2,3-naphthalenediol (247). This reaction involved Knoevenagel condensation, intramolecular cyclization, Michael addition, and dehydration. The reaction offers several benefits, such as operational simplicity, a clean process, easy handling, a simple purification process, high yields of the products, and direct precipitation of the products from the reaction medium, thereby avoiding a tedious workup procedure (Scheme [77]).[105]

Scheme 77 6-Hydroxy-14-aryl-8H-dibenzo[a,i] xanthene-8,13(14H)-dione derivatives 248a–j

2.73

Synthesis of Biologically Important 3-Aryl-lawsones

In medicinal chemistry, 3-aryl-lawsones are recognized for their various applications. Krishna and co-workers[106] conducted a study to synthesize different 3-aryl-lawsones 253a–i with high regioselectivity using simple lawsone (1) and aldehydes 249a–i in a seven-step, double-cascade, one-pot reaction (Scheme [78]). This was achieved by combining organocatalytic Ramachary reductive coupling and Hooker oxidation reactions. The work’s main attractions include the commercial availability of starting materials, a diverse substrate scope, the possibility of a one- or two-pot approach, regioselectivity of alkyl transfer, and the numerous medicinal applications of 3-aryl-lawsones.[106]

Scheme 78 3-Aryl-lawsone derivatives 253a–i

2.74

Lawsone in a Three-Component Reaction with Aldehydes and Isocyanides

In medicinal chemistry and synthetic chemistry, 2-hydroxy-1,4-naphthoquinone (1) is a highly sought-after structure due to the presence of the quinone fragment in numerous natural products with vital biological functions in plants, animals, and humans. Thus, Koumpoura et al.[107] synthesized a range of non-natural molecules containing the quinone scaffold and evaluated their biological activities, including anticancer, antifungal, and antimalarial properties. The first efficient synthetic method for the production of naphthofuroquinones 256a–i was achieved through a microwave-assisted reaction between lawsone (1), various aldehydes 254a–e, and three isocyanides 255a–c, yielding derivatives in moderate-to-good yields. Additionally, two naphtho-enaminodione quinines 257a–c were obtained for the first time by condensing lawsone (1) and isocyanides 255a–c for less-reactive aldehydes (Scheme [79]). All synthesized compounds were evaluated for their anti-infectious activities.[107]

Scheme 79 Synthesis of naphthofuroquinones 256a–i and 257a–c

Scheme 80 Bis-heteroarylaminomethylnaphthoquinone derivatives 260a–f

2.75

Bis-heteroarylaminomethylnaphthoquinone Derivatives

Olyaei et al.[108] developed a facile and effective one-pot, pseudo-five-component reaction utilizing p-TSA as a catalyst in CH₃CN under reflux conditions, to produce a series of bis-heteroarylaminomethylnaphthoquinones 260a–f Mannich bases. Lawsone (1), various heteroaryl amines 259a–f, and terephthalaldehyde (258) were employed as readily available starting materials. This synthetic approach offers several advantages, such as high product yields, easy operation, high atom-economy, simple workup procedure, and the ability to isolate/purify target products without chromatography (Scheme [80]).[108]

2.76

Isoindolinone Derivatives

The isoindolinone framework can be found in numerous natural and synthetic compounds, possessing diverse biological activities such as antihypertensive, anti-inflammatory, anesthetic, antiviral, and anticancer properties. Nariya et al.[109] introduced a successful Mannich-type multicomponent reaction strategy to create a range of new substituted isoindolinones 263a–h derived from 2-hydroxy-1,4-naphthaquinone (1), 2-formyl benzoic acid (262), and primary amines 261a–h of various kinds. This metal-free approach directly forms C–N and C–C bonds at room temperature, employing an environmentally friendly solvent. Synthetic isoindolinones were characterized using ¹H NMR, ¹³C NMR, FT-IR, and ESI-MS techniques (Scheme [81]).[109]

Scheme 81 Isoindolinones derivatives 263a–h

Scheme 82 Chromene derivatives 266a–i

2.77

Chromene Derivatives

Basir et al.[110] developed a magnetically recoverable heterogeneous catalyst, GO/Fe₃O₄/UiO-66-NH₂, which was used to synthesize chromene derivatives 266a–i via a one-pot, three-component condensation reaction of 2-hydroxy-1,4-naphthaquinone (1), 4-hydroxycoumarin (265), and aromatic aldehydes 264a–i. The reaction was carried out at 110 °C in a solvent-free environment, and the new process offered several advantages, such as reduced catalyst loading, excellent yields (88–98%), short reaction times (5–10 min), a simple work-up procedure, and straightforward recovery using a standard magnet. The catalyst was characterized using SEM, XRD, EDX, BET, TGA, and FT-IR analyses. Overall, the GO/Fe₃O₄/UiO-66-NH₂ catalyst showed promise for use in other catalytic reactions due to its excellent catalytic activity and magnetic recoverability (Scheme [82]).[110]

2.78

Phthalide–fulvene Derivatives

Wang et al.[111] presented a novel approach involving palladium-catalyzed ring-contraction reactions of naphthoquinones with alkynes. This methodology enabled the efficient synthesis of a diverse range of phthalides with excellent yields and regioselectivity. The resulting phthalides serve as valuable intermediates for the synthesis of various other important building blocks. The initial investigation focused on optimizing the reaction conditions using 2-hydroxy-1,4-naphthoquinone (1) and diphenylacetylene 267a–i as model substrates, along with benzoquinone as an oxidant. Pd(OAc)₂ was identified as the catalyst of choice, and the addition of 2.0 equivalents of 1,4-benzoquinone (BQ) significantly enhanced the conversion of the reaction. The desired phthalide fulvene derivatives 268a–i were obtained in good yield from the ring contraction of naphthoquinone (Scheme [83]). A plausible mechanism for the ring contraction of six-membered naphthoquinone through various intermediates 267a′–f′ have also been discussed (Scheme [84]).[111]

Scheme 83 Phthalide–fulvene derivatives 268a–i

2.79

Naphthoquinone-Polyphenol Derivatives

Filho et al.[112] developed an innovative, fast, and simple method for the one-step synthesis of naphthoquinone-polyphenols 271a–f using a multicomponent domino Mannich–Michael reaction with lawsone (1). The reaction involved the use of aromatic aldehyde 269a–f and pyrrolidine (270), and yielded good to excellent results (48 to 96% yield). The resulting polyphenols were analyzed by IR and NMR spectroscopy, and mass spectrometry (Scheme [85]). Antiproliferative activities of the polyphenols against four cancer cell lines (HCT116, PC3, HL60, and SNB19) were also observed. This method offers a simple and efficient way to synthesize naphthoquinone-polyphenols with potential pharmacological applications.[112]

2.80

2-(Phenylsulfonyl)-1H-benzo[a]pyrano[2,3-c]phenazin-3-amine Derivatives

Shirzaei and co-workers[113] developed an efficient and eco-friendly method for synthesizing 2-(phenylsulfonyl)-1H-benzo[a]pyrano[2,3-c]phenazin-3-amine derivatives 274a–f. The method involves a one-pot, four-component condensation reaction of 2-hydroxy-1,4-naphthoquinone (1), o-phenylenediamine (22), aromatic aldehydes 272a–f, and (phenylsulfonyl)acetonitrile (273) in the presence of a novel basic ionic liquid catalyst, [(EtO)₃Si(CH₂)₃NH₃ ⁺][CH₃COO⁻], under solvent-free conditions (Scheme [86]). The protocol offers several advantages, including simplicity, high yields, short reaction times, and ecological friendliness. Additionally, the catalyst used in the reaction, [(EtO)₃Si(CH₂)₃NH₃ ⁺][CH₃COO⁻],can be recovered and reused multiple times without loss of activity. Overall, this method provides a promising route for the synthesis of these important organic compounds while also promoting sustainability and efficiency in the chemical industry.[113]

Scheme 84 Plausible mechanism

Scheme 85 Naphthoquinone-polyphenol derivatives 271a–f

2.81

Acetylated 1,2,3-Triazole-quinoidic Derivatives

Scheme 86 2-(Phenylsulfonyl)-1H-benzo[a]pyrano[2,3-c]phenazin-3-amine derivatives 274a–f

Scheme 87 Acetylated 1,2,3-triazoles-quinoidic derivatives 278a–h and 279a–h

Costa and co-workers[114] utilized an oxidative cycloaddition reaction, promoted by ceric ammonium nitrate (CAN) in an alkaline medium, to obtain 1,2,3-triazole-naphthoquinodoic acetyl derivatives 278a–h and 279a–h from lawsone (1) and 4-vinyl-1H-1,2,3-triazoles 275a–h. The resulting compounds were then subjected to reductive acetylation of the quinones using excess metallic zinc and acetic anhydride, with yields exceeding 98%. Interestingly, it has been observed that acetylated naphthoquinone derivatives have the potential to act as a prodrug against tumors, making these compounds an attractive target for further investigation in the development of new therapeutic agents (Scheme [87]).[114]

2.82

Benzochromenopyrimidine Derivatives

Using a straightforward and cost-effective method, Choura et al.[115] produced 3-benzyl-5-aryl-3,5-dihydro-4H-benzo[6,7]chromeno[2,3-d]pyrimidin-4,6,11-triones 283a–j through a one-pot, three-component reaction. The reaction involved readily available 2-hydroxy-1,4-naphthoquinone (1) heated at reflux with aryl 2-cyano-3-arylacrylates 280a–j in the presence of a catalytic amount of triethylamine to form intermediate 2-amino-4-aryl-5,10-dioxo-5,10-dihydro-4H-benzo[g]chromene-3-carboxylates 281a–j. The intermediate further reacts with benzylamine (282), and triethyl orthoformate under solvent- and catalyst-free conditions to obtain benzochromenopyrimidine derivatives (Scheme [88]). The researchers tested the antiproliferative activity of all synthesized compounds against two colorectal-cancer-cell lines: human LoVo and HCT-116.[115]

Scheme 88 Benzo[g]chromeno pyrimidine derivatives 283a–j

2.83

1,3-Oxazine Derivatives

Chaudhary and co-workers[116] established a straightforward, efficient, and environmentally friendly technique for producing 1,3-oxazine derivatives (3-aryl-3,4-dihydro-2H-naphtho[2,3-e][1,3]oxazine-5,10-diones) 286a–f. The method involved a one-pot multicomponent condensation reaction of 2-hydroxy-1,4-naphthoquinone (1) with various amines 284a–f and formaldehyde (285), catalyzed by a choline chloride–oxalic acid deep eutectic solvent (Scheme [89]). The benefits of this method include mild reaction conditions, a simple operating protocol, a catalyst that is both reusable and biodegradable, high yields, and rapid reaction times.[116]

Scheme 89 1,3-Oxazine derivative 286a–f

2.84

Chiral Naphthoquinone-pyran Derivative

In earlier reports it has been discussed that lawsone and its derivatives serve as synthons for several asymmetric synthesis of biologically active molecules.[117] Among these, recently, Ramachary and co-workers[118] developed a protocol for the synthesis of chiral naphthoquinone-fused pyran derivative 290. The synthesis involves the stereoselective Knoevenagel condensation or Ramachary reductive coupling between the starting material lawsone (1) and chiral formylcyclopropane (287) in the presence of Hantzsch ester (288). This results in coupling product (289), which undergoes Lewis acid mediated annulative ring-opening of the chiral cyclopropane to furnish chiral naphthoquinone-fused 3,4-dihydro-2H-pyran 290 in good yield with ee >99% (Scheme [90]). This chiral naphthoquinone based pyran derivative has several pharmacologically important activities.[118]

Scheme 90 Tandem protocol for organocatalytic synthesis of chiral naphthoquinone-pyran derivative 290

2.85

Synthesis of Chiral Tandem Michael/Aldol Product of Naphthoquinone

Ramachary and co-workers[119] reported [3+2] annulation of naphthoquinone derivatives 291a–e and aryl vinyl ketones 292a–b to furnish chirally enriched Michael/aldol product methanobenzo[7]annulenes 294a–j as a biologically and pharmaceutically active product. This reaction proceeds with the formation of 3-aryl-lawsone derivatives 291a–e through Ramachary reductive coupling reaction. Further, in the presence of quinine thiourea 293 as a catalyst, stereoselective annulation with aryl vinyl ketones 292a–b furnished the desired product 294a–j in excellent yields with enantio- and diastereoselectivities up to 99%. The authors reported the reaction followed 5-(enolexo)-exo-trig annulation reaction (Scheme [91]).[119] A plausible mechanism involved concerted annulation of the ring, promoted by the catalyst (Scheme [92]).

Scheme 91 Tandem Michael/aldol for chiral methanobenzo[7]annulenes 294a–j

Scheme 92 Ramachary tandem Michael/aldol: plausible mechanism for catalytic asymmetric synthesis of methanobenzo[7]annulenes

3

Conclusions

Naphthoquinone is a highly important heterocyclic compound in the fields of medicinal, material, and synthetic chemistry, with a wide range of pharmacological activities. Despite this, some naphthoquinone compounds are found to have low toxicity towards host cells, making them attractive targets for in-vivo investigation. Over the years, researchers have synthesized and investigated many different naphthoquinone compounds that have displayed promising biological activity. As a result, the study of naphthoquinone derivatives continues to attract significant attention in both academic and industrial settings, with a particular focus on the development of new drugs and therapeutic agents. This review has described the recent strategies used to synthesize diverse 2-hydroxy-1,4-naphthoquinone derivatives. The review highlighted the elegant strategies developed by various research groups in academia and in the pharma industry around the globe to construct diverse derivatives of lawsone. Tandem reactions, chemoenzymatic, metal catalysis, one-pot multicomponent reactions, and environmentally friendly approaches have been employed for the efficient synthesis. This review has provided a broad overview on recent synthetic strategies employed to prepare 2-hydroxy-1,4-naphthoquinone derivatives. We hope it will be helpful for the preparation of new hybrid analogs of these bioactive molecules with enhanced properties.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

The authors are thankful to the Jawaharlal Nehru University (JNU) and Banaras Hindu University (BHU) for providing facilities to compile the literature and write this review. R.S. is grateful to Ultra International and Sanganeria Foundation for supporting lab furniture to the Glycochemistry laboratory at JNU.

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Publication History

Received: 03 August 2023

Accepted after revision: 05 October 2023

Accepted Manuscript online:
06 October 2023

Article published online:
16 November 2023