A new approach for the synthesis of novel naphthoquinone chalcone hybrid compounds

Article abstract of DOI:10.1016/j.tetlet.2021.153337

A facile and efficient synthesis of novel naphthoquinone-based chalcone hybrids (7 and 24) via the microwave-assisted one-pot three-component reactions of 2-substituted-1,4-naphthoquinones, N,N-dimethylformamide dimethyl acetal (DMF-DMA), and acetophenone derivatives has been reported. Whereas the synthesis of hybrids 7 proceeded via a condensation, 1,4-addition, rotation, elimination, and [1,3]-H shift sequence of steps, the synthesis of hybrids 24 were formed through a three-step sequence including condensation, 1,4-addition, and elimination reactions.

Full text of DOI:10.1016/j.tetlet.2021.153337

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A new approach for the synthesis of novel naphthoquinone chalcone
hybrid compounds
a
a,b
Ha-Thanh Nguyen a,b, Tuyet Anh Dang Thi a,b, , Phuong Hoang Thi , Giang Le-Nhat-Thuy
,
⇑
Quynh Giang Nguyen Thi a,b, Anh Nguyen Tuan a, Tu Anh Le Thi a, Tuyen Van Nguyen a,b,
a Institute of Chemistry, Vietnam Academy of Science and Technology (VAST), 18 Hoang Quoc Viet, Cau Giay, Hanoi, Viet Nam
⇑
b Graduate University of Science and Technology, VAST, 18 Hoang Quoc Viet, Cau Giay, Hanoi, Viet Nam
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and efficient synthesis of novel naphthoquinone-based chalcone hybrids (7 and 24) via the micro-
wave-assisted one-pot three-component reactions of 2-substituted-1,4-naphthoquinones, N,N-dimethyl-
formamide dimethyl acetal (DMF-DMA), and acetophenone derivatives has been reported. Whereas the
synthesis of hybrids 7 proceeded via a condensation, 1,4-addition, rotation, elimination, and [1,3]-H shift
sequence of steps, the synthesis of hybrids 24 were formed through a three-step sequence including con-
densation, 1,4-addition, and elimination reactions.
Received 3 June 2021
Revised 2 August 2021
Accepted 12 August 2021
Available online xxxx
Keywords:
Ó 2021 Elsevier Ltd. All rights reserved.
Naphthoquinone-based chalcone hybrid
compounds
Microwave-assisted reaction
Three-component reaction
Introduction
Heck reaction [29], Julia ꢀ Kocienski reaction [30], and Wittig reac-
tion [31]), and a one-pot synthesis from alcohols [32].
Chalcones (1) consisting of an
aromatic rings are ubiquitous compounds in Nature (Fig 1) [1]. The
,b-unsaturated ketone functional group acts as potential
a
,b-unsaturated ketone and two
On the other hand, naphthoquinones with a wide variety of
structures based on the naphthalene skeleton possess a broad
range of biological activities, for example, atovaquone (8) [33],
NQ-1 (9) [34], vitamin K2 (MK-n) (10) [35], and lapachol (11)
(Fig. 2) [36]. Various naphthoquinone derivatives have also been
used as key intermediates for the construction of biologically
active compounds with anticancer [37–39], leishmanicidal
[40,41], anti-tumor [40,42], anti-inflammatory [43], antibacterial
[44,45], antifungal [46,47], antitrypanosomal [48], antineoplastic
[49], and apoptotic [50] activities. Although heterocycles contain-
ing chalcone and naphthoquinone moieties are of great interest,
the hybridization of these moieties into a single molecule have
rarely been studied [51]. In that respect, in continuation of our
research on the synthesis of bioactive heterocyclic naphtho-
quinone compounds [52], and multicomponent reactions [52b-d],
herein we report a facile and efficient method for the synthesis
of novel naphthoquinone-based chalcone hybrids via the micro-
wave (MW)-assisted one-pot three-component reactions of 2-sub-
stituted-1,4-naphthoquinones, N,N-dimethylformamide dimethyl
acetal (DMF-DMA), and acetophenone derivatives under metal-
free conditions.
a
a
Michael acceptor for a variety of biological nucleophiles [2–5].
Due to their small structures and Michael acceptor features, natu-
rally occurring or synthetic chalcones possess a variety of pharma-
cological properties, such as antibacterial [6,7], anticancer [8,9],
antileishmanial [10], antifungal [11], antiviral [12,13], antitubercu-
lar [14], and antimalarial activities [15]. Moreover, due to the fact
that different pharmacophores can correspond to different mecha-
nisms of action [16], the hybrid compounds of chalcones with
heterocycles, for example, anthraquinone ꢀ chalcone hybrids (2)
[17], chalcone-coumarin hybrids (3) [18], chalcone-quinoxaline
hybrids (4) [19], pyranochalcone derivatives (5) [20], chalcone-
quinoline hybrids (6) [21], b-carboline ꢀ chalcone hybrids [22],
indole ꢀ chalcone hybrids [23], and chalcone-dihydrobenzofuran
hybrids (Fig. 1) [24–26], have attracted considerable interest. A
number of literature methods for the synthesis of chalcone deriva-
tives have been developed, for example, Claisen ꢀ Schmidt con-
densation [27], various cross couplings (Suzuki reaction [28],
⇑
Corresponding author at: Institute of Chemistry, Vietnam Academy of Science
and Technology (VAST), 18 Hoang Quoc Viet, Cau Giay, Hanoi, Viet Nam.
E-mail addresses: dangtuyetanh1201@gmail.com (T.A. Dang Thi), ngvtuyen@ich.
vast.vn (T. Van Nguyen).
https://doi.org/10.1016/j.tetlet.2021.153337
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: Ha-Thanh Nguyen, Tuyet Anh Dang Thi, P. Hoang Thi et al., A new approach for the synthesis of novel naphthoquinone chalcone
hybrid compounds, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2021.153337

Ha-Thanh Nguyen, Tuyet Anh Dang Thi, P. Hoang Thi et al.
Tetrahedron Letters xxx (xxxx) xxx
Fig. 1. Hybrid compounds of chalcones with heterocycles.
Fig. 2. Selected bioactive naphthoquinones.
was chosen as an effective catalyst for the reaction between enam-
inone 14b and 2-hydroxy-1,4-naphthoquinone 15. Besides that,
CH3CN was chosen as the solvent for the one-pot two-step synthe-
sis of compound 7b starting from DMF-DMA, 1-(4-chlorophenyl)
ethan-1-one 13b and 2-hydroxy-1,4-naphthoquinone 15.
Results and discussion
In order to obtain the optimal reaction conditions, the one-pot
two-step synthesis of (E)-2-(3-(4-chlorophenyl)-3-oxoprop-1-en-
1-yl)-3-hydroxynaphthalene-1,4-dione 7b was studied as a model
reaction. In the first step, the reaction between DMF-DMA 12
(1 mmol) and 1-(4-chlorophenyl)ethan-1-one 13b (1 mmol) was
carried out in different organic solvents (t-BuOH, i-PrOH, toluene,
and CH3CN) under MW irradiation at reflux without a catalyst. In
all cases, the reaction proceeded smoothly and compound 13b
was completely converted into the enaminone intermediate 14b
in 60 min.
In the next step, the reaction of 2-hydroxy-1,4-naphthoquinone
15 (1 mmol) with enaminone 14b was investigated under several
different conditions (Table 1). The reactions carried out for
30 min in t-BuOH, i-PrOH, toluene or CH3CN under catalyst-free
conditions afforded trace amounts of the desired compound 7b
(Entries 1–4). In the cases using 10 mol% of glacial acetic acid, com-
pound 7b was obtained in 12–23% yield (Entries 5–8). Further
increasing the catalyst loading to 20 mol% led to improved yields
(Entries 9–12). Notably, when the reaction was performed in CH3-
CN at reflux in the presence of 20 mol% of glacial AcOH, the yield
increased dramatically to 83% (Entry 12). At the same time, the
yield was not improved further when an increased amount of cat-
alyst (30 mol%) was used (Entry 13). Thus, 20 mol% of glacial AcOH
Using the optimal conditions, the scope of the microwave-
assisted three-component reaction was explored using various
acetophenone derivatives 13a–m containing electron-donating
groups or electron-withdrawing groups at different positions
(Scheme 1). Novel 3-alkylated-2-hydroxy-1,4-naphthoquinone
derivatives 7a–m were obtained in good yields (76–89%) under
the optimized conditions. It worth noting that the electronic effect
of the substituents in different positions on the aryl group did not
affect the reaction outcome. The structures of all synthesized com-
pounds 7a–m were fully characterized by 1D and 2D NMR, and
mass spectra. Taking a close look at the 1H NMR spectrum of com-
pound 7c, two doublets at 8.50 and 8.39 ppm corresponding to H-
20 and H-10, shared coupling constants of 15.6 Hz, confirming the
double bond is in the trans configuration (see ESI).
A plausible mechanism is outlined in Scheme 2. In the first step,
the condensation between acetophenone derivatives 13 and DMF-
DMA affords enaminone intermediates 14. The 1,4-addition reac-
tion of 1,4-naphthoquinone 15 with enaminones 14 gives interme-
diates 19, which then rotates about the carbon–carbon single
(sigma) bond. Intermediates 19 undergo elimination of the amine,
2

Ha-Thanh Nguyen, Tuyet Anh Dang Thi, P. Hoang Thi et al.
Tetrahedron Letters xxx (xxxx) xxx
Table 1
Optimization of the reaction condition for the second step of the synthesis of compound 7b.*
Entry
Solvent
Catalyst
Isolated yield 7b (%)
1
2
3
4
5
6
7
8
t-BuOH
i-PrOH
Toluene
CH3CN
t-BuOH
i-PrOH
Toluene
CH3CN
t-BuOH
i-PrOH
Toluene
CH3CN
CH3CN
–
–
–
–
trace
trace
trace
trace
14
18
12
23
45
52
13
83
83
gl. AcOH (10 mol%)
gl. AcOH (10 mol%)
gl. AcOH (10 mol%)
gl. AcOH (10 mol%)
gl. AcOH (20 mol%)
gl. AcOH (20 mol%)
gl. AcOH (20 mol%)
gl. AcOH (20 mol%)
gl. AcOH (30 mol%)
9
10
11
12
13
*All reactions were carried out on a 1 mmol scale in 3 mL solvent at reflux for 30 min under MW irradiation using an equimolar ratio of reactants.
Scheme 1. Synthesis of (E)-3-alkylated-2-hydroxy-naphthalene-1,4-diones 7a–m.
3

Ha-Thanh Nguyen, Tuyet Anh Dang Thi, P. Hoang Thi et al.
Tetrahedron Letters xxx (xxxx) xxx
Scheme 2. Plausible mechanism for the synthesis of 1,4-naphthoquinone based chalcone hybrids 7a-m.
Scheme 3. One-pot two-step reactions of acetophenone derivatives, DMF-DMA and 2-amino-1,4-hydroxy-naphthoquinone.
followed by a [1,3]-hydrogen shift to afford the desired products
(E)-3-alkylated-2-hydroxy-naphthlene-1,4-diones 7.
NMR, DEBPT and mass spectra. In the 1H NMR spectra, the olefinic
protons H-10 and H-20 showed a doublet of doublets (J = 8.4,
12.0 Hz) and a doublet (J = 8.4 Hz), respectively, confirming the
cis-configuration of enaminones 24. Furthermore, the NAH proton
appeared as a doublet (J = 12.0 Hz) at 12.13–12.17 ppm indicating
the presence of strong intramolecular hydrogen bonding in the Z-
isomer of enaminones 24 (see ESI) [53].
Amines are good nucleophiles, readily attacking the carbon b to
the carbonyl; therefore enaminones 14 undergo a 1,4-addition of
2-amino-1,4-naphthoquinone 21, followed by elimination of
dimethylamine to afford compounds 24 (Scheme 4) [54].
In order to broaden the reaction scope, the one-pot two-step
reactions of acetophenone derivatives, DMF-DMA 12, and 2-
amino-1,4-naphthoquinone 21 were carried out under the previ-
ously optimized conditions, however, no conversion was observed.
Interestingly, replacing glacial acetic acid with trifluoroacetic acid
(TFA) furnished (Z)-2-((3-oxo-3-(aryl)prop-1-en-1-yl)amino)naph-
thalene-1,4-dione derivatives 24 instead of compounds 23
(Scheme 3). Compounds 24 were synthesized in excellent yields
(90–92%) and their structures were characterized by IR, 1H, 13C
Scheme 4. Plausible mechanism for the formation of compound 24.
4

Ha-Thanh Nguyen, Tuyet Anh Dang Thi, P. Hoang Thi et al.
Tetrahedron Letters xxx (xxxx) xxx
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We have developed a facile and efficient method to synthesize
naphthoquinone-based chalcone hybrids 7a-m via the reaction of
2-hydroxy-1,4-naphthoquinone,
N,N-dimethylformamide
dimethyl acetal, and acetophenone derivatives in CH3CN at reflux
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Declaration of Competing Interest
The authors declare that they have no known competing finan-
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