Recent advances in the synthetic developments on the 2-hydroxy-1,4-napht-hoquinone (Lawsone)

Lawsone, also known as 2-hydroxy-1,4-naphthoquinone


Introduction
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 dye. 4 Humans have utilized henna extracts containing lawsone for thousands of years as hair and skin dyes, highlighting its historical and cultural significance. 5,6 ond 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 [15] In the field of organic synthesis, 2-hydroxy-1,4-naphthoquinone has been employed in numerous reactions, playing a vital role in the construction of various molecular frameworks.[22] Recent efforts have focused on the synthesis of new derivatives of 2-hydroxy-1,4-naphthoquinone. 23[26][27] In this review article, we aim to provide an overview of the recent advances in the synthetic developments on 2-hydroxy-1,4-naphthoquinone.This review will highlight the key synthetic methodologies employed for the preparation of 2-hydroxy-1,4naphthoquinone 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 2hydroxy-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

Synthesis
Review / Short Review Template for SYNTHESIS Thieme access 2-hydroxy-1,4-naphthoquinone derivatives hold great promise for the discovery of novel compounds with enhanced biological activities and potential therapeutic applications.

Benzo[g]chromene derivatives
Benzo[g]chromene derivatives have received considerable attention in medicinal chemistry due to 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 Fengjuan and Maheshwari and their respective research groups.Fengjuan and coworkers utilized Candida sp.Lipase as an enzyme catalyst for a multi-component 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.Fengjuan and coworkers reported a novel and efficient method for synthesizing benzo[g]chromene derivatives, which 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 endeavored the reaction of 2-hydroxy-1,4-naphthoquinone 1, different aromatic aldehydes 4a-i, malononitrile 5, and using Candida sp.Lipase as an enzyme catalyst for the multicomponent reaction to synthesize benzo[g]chromene derivatives 6a-i (Route 1). 29Maheswari and co-workers, on the other hand, were able to synthesize 2-amino-4Hbenzo[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% of 2-aminopyridine(2-AP) as a reusable catalyst (Route 2). 30The reaction was performed in ethanol at reflux, and the chosen catalyst proved to be effective in facilitating the desired reaction.They 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 multi-component reactions in the synthesis of complex organic molecules (Scheme 2).

2-amino-4H-benzo[g] chromene derivatives
Gracious et al. developed a highly efficient and environmentally friendly approach for the synthesis of dihydro-4Hbenzo[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-1,4dione 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). 33heme 5 2-amino-4H-benzo[g] chromene derivatives 14a-l.

2.6.
Benzo[g] chromenes derivatives via using nanocomposite as catalyst In their study, Ghomi et al. 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 1 H NMR and Fourier transform infrared (FT-IR) spectroscopy 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). 34heme 6 Synthesis of benzo[g]chromenes using CeO2/CuO@N-GQDs@NH2 nanocomposite 17a-k.

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. 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 derivative 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, Template for SYNTHESIS Thieme 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 nano catalyst (Scheme 7). 35dditionally, the process eliminates the need for column chromatography purification steps.

Benzo[a]pyrano[2,3-c]phenazine and benzo[a]chromeno[2,3-c]phenazine derivatives
Benzophenazine is a chemical compound belonging to the class of heterocyclic aromatic compounds.It 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.Also, in materials science, benzophenazines have been investigated for their optical and electronic properties.These compounds possess conjugated pielectron 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 coworkers have discussed 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, pyranophenazines etc. 36 In continuation to this study Abadi et al. demonstrated fulvic acid as a convenient and efficient catalyst for the efficient synthesis of benzophenazines derivatives.In their study, they performed a reaction of 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, possesses good cleanliness, safety, and nontoxicity, and 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 38 This method offers several advantages, including its 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.
This article is protected by copyright.All rights reserved.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). 39heme 10 Chromene/bicyclic fused benzo[a]phenazinone derivatives 34a-k and 36a-f.

Trans-1,2-dihydrobenzo[a]furo[2,3-c]phenazines derivatives
Abadi et al. have introduced a novel and efficient domino fourcomponent coupling process for the synthesis of 1,2dihydrobenzo[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, ophenylenediamine 22, aromatic aldehydes 37a-i and pyridinium ylide 38, reaction occurs in the presence of a catalytic amount of theophylline in an aqueous medium (Scheme 11).The reaction involves a sequence of condensation, Knoevenagel, Michael, and annulation steps, resulting in the formation of two C-C, two C=N, one C-O bonds, and two new rings in a single operation.This protocol offers several advantages.Firstly, it enables 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 friendliness. 40heme 11 Trans-1,2-dihydrobenzo[a]furo[2,3-c]phenazine derivatives 39a-i.

Benzo[a][1,3]oxazino[6,5-c]phenazine derivatives
Mohebat and co-workers have 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, 2hydroxy-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 [6,5c]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 Template for SYNTHESIS Thieme operational simplicity.The use of caffeine as a catalyst adds to the environmentally benign aspect of the approach. 41heme 12 Synthesis of benzo[a] [1,3]oxazino [6,5-c]phenazine derivatives 45a-j.[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 2hydroxynaphthalene-1,4-dione 1, aromatic 1,2-diamines 40a-c, hydrazine hydrate 46, phthalic anhydride 47, and aromaticaldehydes 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 catalysts 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 a suitable reaction condition.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 approach in organic synthesis (Scheme 13). 42heme 13 Benzo[a]phthalazino[2,3:1,2]pyrazolo [3,4-c]phenazine derivatives 50a-j.

Benzo[a]furo[2,3-c]phenazines derivatives
In continuation of the above-mentioned work by Abadi et al., they have also 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, gentle, and quick.By combining 2-hydroxynaphthalene-1,4-dione 1, ophenylenediamine 22, aromatic aldehydes 51a-e and substituted isocyanides 52a-b, in a solvent-free and catalystfree 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). 43heme 14 Benzo[a]furo[2,3-c]phenazines derivatives 53a-g.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). 44is article is protected by copyright.All rights reserved.[5,4:5,6]pyrido[2,3-c]phenazines 61ah.This synthesis involves condensation, Knoevenagel, Michael, and heterocyclization reactions of o-phenylenediamine 18, 2hydroxynaphthalene-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 exhibits quick reaction times, high yields of the desired products, excellent atom economy, and remarkable chemo-selectivity (Scheme 16). 45
In a separate study, Ghomi et al. have presented a simple and rapid method for the preparation of benzo[a]pyrano[2,3c]phenazine 65a-n.This method also involves a one-pot, fourcomponent reaction of 2-hydroxy-1,4-naphthoquinone 1, ophenylenediamine 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 product formation, high yields in short reaction times, and low catalyst loading. 47heme 18 Benzo[a]pyrano[2,3-c] phenazine derivatives 65a-n.

3-amino-2′-oxospiro[benzo[c]pyrano[3,2a]phenazine-1,3′-indoline]-2-carbonitrile/carboxylate derivatives
Safaei-Ghomi et al. have developed an innovative approach using an inorganic-organic hybrid catalyst for the efficient ophenylenediamine 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 This article is protected by copyright.All rights reserved.This was achieved through a sequential one-pot, two-step, pseudo-five-component tandem reaction using 2hydroxynaphthalene-1,4-dione 1, o-phenylenediamine 22, and aromatic aldehydes 68a-h.The reaction took place under solvent-free conditions at 90 °C, with the presence of 2aminopyridine 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. 49heme 20 6,6'-(Arylmethylene)bis(benzo[a]phenazin-5-ol) derivatives 69a-h.

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 = Mn 2+ , Fe 2+ , Co 2+ , Ni 2+ , Cu 2+ , and Zn 2+ ) exhibit unique structural and electronic properties, making them highly valuable in catalytic applications.In this regard, Daraie et al. successfully synthesized a Ce/PDA/CPTMS@CoFe2O4 nanocomposite, which was employed as a catalyst in 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-hydroxynaphthalene-1,4-dione 1, o-phenylenediamines 22, malononitrile 5, and various aryl aldehydes 70a-l (Scheme 22).This approach yielded a diverse set of products with remarkable yields and in short reaction times. 50heme 21 Preparation of Ce/PDA/CPTMS@CoFe2O4 nanocomposite.

Benzo[a]pyridazino[3,4-c] phenazine derivatives
The remarkable biological properties exhibited by nitrogencontaining 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 broadspectrum antibiotic, fungicidal, and antimalarial activities.To access novel functionalized benzo[a]pyridazino [3,4-c]phenazine derivatives 75a-h, Le-Nhat-Thuy et al. 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. 51emplate for SYNTHESIS Thieme .Lawsone, extracted from henna leaves (Lawsonia inermis), serves as a primary dye.In order 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, infrared, electronic, 1 H and 13 C NMR, and GC-MS spectra.Cytotoxicity experiments were performed using the MTT test on human breast adenocarcinoma (MCF-7) and colon cancer (HCT-15) cell lines to assess NIH's potential as a therapeutic agent. 53heme 25 N'-(1,4-naphtho-quinone-2-yl) isonicotinohydrazide (NIH) derivative 79.

-dione derivatives
Multi-component 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.Zhijie et al. have developed an efficient and practical method for synthesizing derivatives of 2hydroxy-3-((5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)(phenyl)methyl)naphthalene-1,4-dione 85a-h.This is achieved through a one-pot, four-component reaction involving aromatic aldehydes 84a-h, β-keto esters 83, arylhydrazine 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-This article is protected by copyright.All rights reserved.The protocol offers several notable features, including mild reaction conditions at room temperature, 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). 56heme 28 5-Aryl-2-oxo-/thioxo-2,3-dihydro-1H-benzo [6,7]

Accepted Manuscript
Scheme 29 Synthesis of 5-oxatetracene derivatives 91a-h using CMWCNTs.Maleki et al. achieved the successful synthesis of a magnetic polymeric nanocomposite, Ba0.5Sr0.5Fe12O19@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[5,1b]quinazoline-5,6-diones 94a-q from lawsone 1, tetrazoloamine aromatic aldehyde 93a-q (Scheme 30).This methodology offers several advantages, including high yields, rapid 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. 58heme 30 7-Aryl-benzo[h]tetrazolo [5,1-b] quinazoline-5,6-diones derivatives 94a-q.

CF3-Functionalized alkyl-substituted 2-amino-and 2hydroxy-1,4-naphthoquinone derivatives
The three-component di-functionalization 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. conducted a study where they utilized 2-amino-1,4-naphthoquinone derivatives 104 as radical-trapping agents in a silver-catalyzed three-component di-functionalization 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). 61heme 33 2-Amino-1,4-naphthoquinone derivatives 105a-f.In the field of biological sciences, 1,3-oxazine derivatives have gained significant attention as antibacterial and cancer screening agents.Additionally, the thio-derivatives of pyrano-1,3-benzoxazine have shown promising anti-inflammatory and anti-pyretic properties.In their study, Balouchzehi et.al. have developed a selective one-pot method for synthesizing biologically active 2-aryl-4-thioxo-4H-naphtho[2,3e][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 for their diverse pharmacological properties. 62heme 34 2-Aryl-4-Thioxo-4H-Naphtho[2,3-e][1,3]Oxazine-5,10-dione derivatives 109a-f.

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. 64These derivatives have demonstrated diverse biological activities such as antibacterial, anti-HIV, antiviral, anticoagulant, antioxidant, and anticancer properties, among others. 65til et al. have 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-1Hpyrazol-5-ol 114(1 mmol), substituted aldehyde 113a-s(1 mmol), and 2-hydroxy naphthoquinone 1 (1 mmol) in 5 mL of water, along with 10 mol% β-CD-SO3H catalyst, was stirred at room temperature (Scheme 36). 66heme 36 Synthesis of dihydro-1H-pyrazolyl Naphthalene-1,4-dione derivatives 115a-s.
Vairaperumal and co-workers have developed a synthetic route for the production of a series of potential cytotoxic agents 119ab that incorporate a pyrazolyl naphthoquinone framework.The synthesis involves the one-pot four-component reaction of 2hydroxy-1,4-naphthoquinone 1, ethylacetoacetate 116, substituted phenylhydrazines 117, and aromatic aldehydes 118a-b.Different catalysts, including metal triflates, Lewis acids, and metal oxides, were evaluated for their effectiveness in this multi-component 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). 67heme 37 Benzylpyrazolyl Naphthoquinone derivatives 119a-b.

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-1,4naphthoquinone 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). 70heme 40 Chiral nitroalkylated naphthoquinone derivatives 127a-q.

Quinone-based chromenopyrazole derivatives
Kandhasamy and co-workers conducted a novel approach aimed at combining naphthoquinone, chromene, and pyrazolone to create a highly active heterocyclic moiety quinone-based chromenopyrazole derivatives 130a-h with potential therapeutic applications.In this study, they 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 threecomponent coupling reaction involving 2-hydroxy-1,4naphthoquinone 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 1 H and 13 C nuclear magnetic resonance (NMR) spectroscopy, Fourier-transform infrared (FT-IR) spectroscopy, and electrospray ionization mass spectrometry (ESI-MS) (Scheme 41). 71heme 41 Quinone-based chromenopyrazole derivatives 130a-h.

2.39.
13-Aryl-5H-dibenzo[b,i]xanthenes-5,7,12,14(13H)tetraones derivatives Mousavi et al. 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-5Hdibenzo[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 noticeable 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. 72heme 42 13-aryl-5H-dibenzo[b,i]xanthenes-5,7,12,14(13H)-tetraones derive atives 132a-l.

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

Benzo[c]acridine-dione derivatives
Behbahani et al. 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, 3,4,5and 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). 79heme 51 Benzo[c]acridine-dione derivatives 160a-j.

Thio-derivatives of 2-hydroxy-1,4-naphthoquinone
In a recent study conducted by Cardenas et al., 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 to enhance the antiplatelet activity of 2-hydroxy-1,4naphthoquinone 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 thioderivatives 168a-h with improved antiplatelet properties.By exploring the structural variations and their impact on biological activity, the study provides valuable insights for further development and optimization of lawsone-based compounds 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. 81heme 53 Thio-derivatives of 2-hydroxy-1,4-naphthoquinone derivatives 169a-h.
In a recent study, Olyaei et.al. 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 2hydroxy-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-1,4dione 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). 82heme 54 Amino naphthoquinones derivatives 173a-i.
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 the similar approach, Khalafy et.al.

Naphthoquinonefuran Derivatives
Naphthofuroquinone is a well-known pharmacophoric unit with a broad range of biological activities, including cytotoxic, antiinflammatory, antitumor, trypanocidal activity, 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. has developed a transition-metal-free, tandem one-pot approach for the synthesis of naphthoquinonefuran derivatives 193a-j using 2hydroxynaphthoquinones as starting materials.The process This article is protected by copyright.All rights reserved.

Benzo[b]xanthene-triones derivatives
In the study, Rahnamafar et al. developed a one-pot three-or pseudo-five-component reaction between 2-hydroxy-1,4naphthoquinone 1, aldehyde 201a-h and dimedone or 1,3cyclohexanedione 200a-b to synthesize Benzo[b]xanthenetriones derivative 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 a significant loss of activity.The reaction used a clean methodology with mild reaction conditions, easy work-up, short reaction time, and good-to-excellent yields.Additionally, the preparation of the catalyst was simple, making it a promising approach for the synthesis of Benzo[b]xanthene-triones derivatives. 91heme 63 Benzo[b]xanthene-triones derivatives 202a-j.

4H-pyran derivatives
Kamalzare et al. have reported the synthesis of a novel, green, heterogeneous bionanocatalyst from natural, inexpensive and readily available materials.This catalyst exhibits distinctive properties such as being eco-friendly, low-cost, and 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 This article is protected by copyright.All rights reserved.

Synthesis Review / Short Review
Template for SYNTHESIS Thieme compounds (2-hydroxy-1,4-naphthaquinone 1), and malononitrile 5 with 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 bionanocatalyst is composed of natural materials, which provides a more sustainable and ecofriendly approach to the synthesis of 4H-pyran derivatives.The use of this catalyst offers advantages such as low cost, availability, and high efficiency.Furthermore, ethanol was used as the solvent of the reaction, providing an additional ecofriendly 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. 92heme 64 2-Amino-5,10-dihydro-5,10-dioxo-4H-benzo[g]chromene-3carbonitrile derivatives 204a-j.

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

3-Aryl substituted lawsone derivatives
In their study, Song et al. reported on the synthesis of a lawsonebased compound as an antimicrobial agent against methicillinresistant Staphylococcus aureus (MRSA), which has become increasingly difficult to treat due to multidrug resistance.They synthesized a series of lawsone-derivative 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 proton nuclear magnetic resonance ( 1 H NMR), mass spectrometry (MS), and single-crystal X-ray structural analysis to determine their structural properties. 95heme 67 3-Aryl substituted lawsone derivatives 216a-e.

3-Arylated 2-hydroxy-1,4-naphthoquinone derivatives
In the study, Tuyet and co-workers have efficiently synthesized novel naphthoquinone derivatives 223a-i using a microwaveassisted three-component reaction of 2-hydroxy-1,4naphthoquinone 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 2hydroxy-1,4-naphthoquinones in the development of anticancer agents. 97heme 69 3-arylated-2-hydroxy-1,4-naphthoquinone derivatives 223a-i.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 is conducted in water, a green solvent.All newly synthesized compounds are subjected to characterization using various methods, including  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. 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

Styryl linked fused dihydropyridines derivatives
Yadav et al. have 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 2hydroxy-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 onepot, and products with four different bioactive moieties. 102heme 74 Multicomponent synthesis of styryl linked fused dihydropyridines derivatives 238a-h.

Naphthoquinone chalcone hybrid derivatives
Chalcones are compounds found in nature that consist of an α,βunsaturated ketone and two aromatic rings.The α,βunsaturated 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 coworkers reported a facile and efficient method to synthesize new naphthoquinone-based chalcone hybrids 242a-i via microwave-assisted one-pot three-component reaction of Olyaei and co-workers 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-hydroxynaphthalene-1,4-dione 1, aromatic aldehydes 246a-j, and 247.This reaction involved Knoevenagel condensation, intramolecular cyclization, Michael addition, and dehydration.The reaction offers several benefits, such as operational simplicity, a clean reaction, 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). 105heme 77 6-Hydroxy-14-aryl-8H-dibenzo[a,i] xanthene-8,13(14H)-diones derivatives 248a-j.

Synthesis of biologically important 3-aryllawsones
In medicinal chemistry, 3-aryllawsones are recognized for their various applications.Krishna and co-workers conducted a study to synthesize different 3-aryllawsones 253a-i 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-aryllawsones. 106heme 78 3-aryllawsones derivatives 253a-i.

Lawsone in a Three Component Reaction with Aldehydes and Isocyanides
In medicinal chemistry and synthetic chemistry, 2-hydroxy-1,4naphthoquinone 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. have 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,

Template for SYNTHESIS Thieme
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. 107heme 79 Synthesis of naphthofuroquinones 256a-i and 257a-c .

Bis-heteroarylaminomethyl naphthoquinone derivatives
Olyaei et al. have 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 bisheteroarylaminomethylnaphthoquinone 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). 108heme 80 Bis-heteroaryl-aminomethylnaphthoquinone derivatives 260a-f.

Isoindolinones 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. have introduced a successful Mannich-type multicomponent reaction strategy to create a range of new substituted isoindolinones 263a-h derived from 2-hydroxy-1,4naphthaquinone (lawsone) 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 1 H NMR, 13  Scheme 81 Isoindolinones derivatives 263a-h.

Chromenes derivatives
Basir et al. 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-hydroxynaphthalene-1,4-dione 1, 4hydroxycoumarin 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 studies.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). 110heme 82 Chromenes derivatives 266a-i.

Phthalide-fulvene derivatives
Wang et al. presented a novel approach involving palladiumcatalyzed 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 1,4benzoquinone (BQ) significantly enhanced the conversion of the reaction .The desired phthalide fulvene derivatives 268a-i obtained in a good yield from the ring contraction of naphthoquinone.(Scheme 83).The plausible mechanism of the ring contraction of six membered naphthoquinone through various intermediates 267a'-267f' have also been discussed (Scheme 84). 111emplate for SYNTHESIS Thieme

Naphthoquinone-Polyphenol derivatives
Filho et al. have developed an innovative, fast and simple method for the one-step synthesis of naphthoquinonepolyphenols 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 infrared (IR), nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry (Scheme 85).The antiproliferative activity of the polyphenols against four cancer cell lines (HCT116, PC3, HL60, and SNB19) was also observed.This method offers a simple and efficient way to synthesize naphthoquinone-polyphenols with potential pharmacological applications. 112heme 85 Naphthoquinone-Polyphenol derivatives 271a-f.The method involves a one-pot four-component condensation reaction of 2-hydroxynaphthalene1,4-dione 1, ophenylenediamine 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, quick 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 any 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.

Acetylated 1,2,3-triazoles-quinoidic derivatives
Costa and co-workers utilized an oxidative cycloaddition reaction, promoted by ceric ammonium nitrate (CAN) in an alkaline medium, to obtain 1,2,3-triazoles-naphthoquinodoic acetyl derivatives 278a-h and 279a-h from lawsone 1 and 4vinyl-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). 114is article is protected by copyright.All rights reserved.

Chiral Naphthoquinone-pyran derivative
In earlier reports it has been discussed that lawsone and their derivatives serves as a synthon for several asymmetric synthesis of biologically active molecules. 117Among these recently Ramachary and co-workers have developed 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 presence of hantzsch ester 288.This results into coupling product 289 which undergo lewis acid mediated annulative ring opening chiral cyclopropane furnished chiral naphthoquinone-fused 3,4-dihydro-2H-pyran 290 in good yield with ee> 99% (Scheme 90).This chiral naphthoquinone based pyran derivative have several pharmacological importance.2.85.Synthesis of chiral Tandem Michael/aldol product of naphthoquinone Ramachary and coworkers 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-aryllawsone derivatives 291a-e through Ramachary reductive coupling reaction.Further in 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 diasteroselectivities (upto 99%).The authors have reported the reaction followed 5-(enolexo)-exo-trig annulation reaction (Scheme 91). 119The plausible mechanism showed the concerted annulation of ring by the involvement of catalyst (Scheme 92).

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 be low in toxicity towards host cells, making them attractive targets for in-vivo investigation.Over the years, researchers have synthesized and investigated many different naphthoquinone compounds, which 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 describes 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, environmentally friendly approaches have been employed for the efficient synthesis.This review gives ample information on recent synthetic strategies employed to prepare 2-hydroxy naphthoquinone derivatives.We hope it will be helpful for the preparation of new hybrids analogs of these bioactive molecules with enhanced properties.

Scheme 9
Scheme 9 Benzo[a]pyrano[3',4':5,6]pyrano[2,3-c]phenazine derivatives 30a-j.2.10.Chromene/bicyclic fused benzo[a]phenazinone derivativesBakthadoss et al. have 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 respectively.This approach involves the solid-state melt reaction of 2-hydroxynaphthalene-1,4-dione 1, ophenylenediamine 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 [a]chromeno[2,3-

Scheme 23
Scheme 23 Benzo[a]pyridazino[3,4-c] phenazine derivatives 75a-h.2.22.Benzopyranophenazine derivativesTheresa et al. achieved the efficient synthesis of benzopyranophenazine carbonitrile 77a-i, which improved the safety, 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, ophenylenediamine 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 ophenylenediamine 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

118
Scheme 90 Tandem protocol for organocatalytic synthesis of chiral naphthoquinone-pyran derivative 290 100s article is protected by copyright.All rights reserved.Enaminone derivatives are widely used in the synthesis of bioactive compounds and natural products with diverse therapeutic activities such as anti-tumor, anti-inflammatory, anti-epileptic, antibacterial, and more.Olyaei et al. have 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 1 H-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-d6 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 The synthesis of the naphthoquinone-based chalcone hybrids involved a sequence of steps, including condensation, This article is protected by copyright.All rights reserved.