This work is dedicated to Prof. Srinivasan Chandrasekaran on his 78th birthday
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, 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[5,1-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
