An expeditious and green one-pot synthesis of 12-substituted-3,3-dimethyl-3,4,5,12-tetrahydrobenzo[b]acridine-1,6,11(2H)-triones

Article abstract of DOI:10.1007/s11164-019-04014-9

In this study, several new 12-aryl/heteroaryl-3,3-dimethyl-tetrahydrobenzo[b]acridine-1,6,11(2H)-trione heterocyclic compounds that can be considered as 1,4-naphthoquinone fused with 4-substituted 7,7-dimethyl-4,6,7,8-tetrahydroquinolin-5(1H)-ones, have been synthesized through the three-component cyclocondensation of benzaldehydes/heteroaldehydes, 2-amino-1,4-naphthoquinone, and dimedone. The pot-, atom-, and step-economy reactions were implemented under reflux conditions. One of the most important aspects of this reaction is the use of ethanol as the reaction medium taking into account the principles of green chemistry. Not using a catalyst in this type of reactions is also significant from the standpoint of green chemistry. The protocol developed in this study has the benefits of the simplicity, no use of chromatographic methods for purification, structural diversity, employing non-toxic solvent, good-to-high yields, safety, and using cost-effective solvent. The structures of the newly synthesized 1,4-naphthoquinone fused with 4-substituted 7,7-dimethyl-4,6,7,8-tetrahydroquinolin-5(1H)-ones were confirmed employing spectroscopic data as well as elemental analysis.

Full text of DOI:10.1007/s11164-019-04014-9

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-019-04014-9
An expeditious and green one‑pot synthesis of
1
2‑substituted‑3,3‑dimethyl‑3,4,5,12‑tetrahydrobenzo[b]
acridine‑1,6,11(2H)‑triones
Saiedeh Kamalifar · Hamzeh Kiyani1
1
Received: 3 September 2019 / Accepted: 3 October 2019
©
Springer Nature B.V. 2019
Abstract
In this study, several new 12-aryl/heteroaryl-3,3-dimethyl-tetrahydrobenzo[b]acrid-
ine-1,6,11(2H)-trione heterocyclic compounds that can be considered as 1,4-naph-
thoquinone fused with 4-substituted 7,7-dimethyl-4,6,7,8-tetrahydroquinolin-5(1H)-
ones, have been synthesized through the three-component cyclocondensation of
benzaldehydes/heteroaldehydes, 2-amino-1,4-naphthoquinone, and dimedone. The
pot-, atom-, and step-economy reactions were implemented under reꢀux conditions.
One of the most important aspects of this reaction is the use of ethanol as the reac-
tion medium taking into account the principles of green chemistry. Not using a cata-
lyst in this type of reactions is also signiꢁcant from the standpoint of green chemis-
try. The protocol developed in this study has the beneꢁts of the simplicity, no use of
chromatographic methods for puriꢁcation, structural diversity, employing non-toxic
solvent, good-to-high yields, safety, and using cost-eꢂective solvent. The structures
of the newly synthesized 1,4-naphthoquinone fused with 4-substituted 7,7-dimethyl-
4
,6,7,8-tetrahydroquinolin-5(1H)-ones were conꢁrmed employing spectroscopic
data as well as elemental analysis.
Keywords 2-Amino-1,4-naphthoquinone · Dimedone · Green synthesis ·
1
2-Substituted-tetrahydrobenzo[b]acridine-1,6,11(2H)-trione · Three-component
cyclocondensation
Introduction
Multicomponent reactions (MCRs) are characterized by the combination of three or
more starting materials in a one-pot sequence to the production of various chemical
compounds in high chemical yields and bond-forming economy. The products which
*
Hamzeh Kiyani
hkiyani@du.ac.ir
1
School of Chemistry, Damghan University, Damghan 36716-41167, Iran
Vol.:(012
1
3456789)
3

S. Kamalifar, H. Kiyani
are synthesized via an MCR contain portions of all the reactants. These highly eꢃ-
cient reactions are powerful and atom-eꢃcient and have been successfully employed
to the synthesis of heterocycles without isolation of intermediates. Besides the char-
acteristics as mentioned earlier, these environmentally friendly processes have many
major advantages over conventional synthesis that can be seen in Fig. 1 [1–20].
N-Polyheterocycles are present in several natural products, various important
synthetic bioactive compounds, dyes, vitamins, agrochemicals, functional materi-
als, and drug-like candidates. Therefore, the synthesis of N-containing heterocyclic
compounds as “privileged” structures has received noteworthy consideration and
signiꢁcant interest in the ꢁelds of bioorganic, modern organic synthetic, and medici-
nal chemistry as well as drug discovery [21–30].
On the other hand, the fused 1,4-naphthoquinones (1,4-NQs) and related sub-
stances, as indispensable organic compounds, are endowed with a wide range of
remarkable physiological properties, speciꢁcally for their antioxidant [31], anti-
microbial [32], antimalarial [33], fungicidal [34], anti-inꢀammatory [35], and
indoleamine 2,3-dioxygenase 1 inhibitory [36] activities. It has been mentioned that
the 1,4-NQ structure is an important compound found in several synthetic and natu-
ral products with a wide range of pharmacological activities, including anti-inꢀam-
matory, antifungal, antiviral, anti-atherosclerosis, antileishmanial, and antitumor
eꢂects [37–41]. 1,4-NQs are also extensively employed as raw materials in the phar-
maceutical industry as well as in the preparation of pesticides in agriculture [40].
Fig. 1 Major beneꢁts of MCRs
1
3

An expeditious and green one-pot synthesis of…
Recently, 2-amino-1,4-naphthoquinones (A-1,4-NQs) have received attention
for their broad scope of bioactivities, mostly such as antimicrobial, antifungal,
antibiotic, antimalarial, antioxidant, antiplatelet, and tyrosinase inhibitory activi-
ties [42–55]. It should be underlined that the great majority of the A-1,4-NQs are
employed as attractive starting materials for the synthesis of a broad spectrum of
biologically active compounds [42–55]. Studying anticancer, antibacterial as well as
antifungal activities of these drug-like compounds is also of attention to researchers
[
56–67]. In addition to that, amino-1,4-naphthoquinones are a promising family of
drug candidates for wound healing agent in diabetic conditions [68].
Benzoacridine-based molecules containing 1,4-dihydropyridine nucleus con-
stitute well-known classes of bioactive compounds with biological eꢂects, includ-
ing antifungal, anticancer, antibacterial, and antimalarial activities [38, 69–73].
Multihydroacridineone derivatives can be used as ꢀuorescent molecular probes for
monitoring polymerization process. The framework of benzoacridineone has also
attracted much interest because it is structurally similar to the well-known 1,4-dihy-
dropyridines [74].
Keeping the importance of N-containing heterocyclic compounds and derivatives
of 1,4-naphthoquinones, we report herein the synthesis of 3,3-dimethyl-12-aryl-het-
eroaryl-hexahydrobenzo[b]acridine-1,6,11(2H)-triones through the one-pot three-
multicomponent-reaction (3-MCR) synthetic methodology (Scheme 1).
Experimental
General
All chemicals were purchased from Alfa Aesar and Aldrich and were used with-
out further puriꢁcation, except for liquid aldehydes which were distilled and puri-
ꢁ
ed before using. All solvents were distilled before use. Melting points were meas-
1
13
ured on a Buchi 510 melting point apparatus and are uncorrected. H and C NMR
Scheme 1 Three-component synthesis of 12-substituted-3,3-dimethyl-3,4,5,12-tetrahydrobenzo[b]acrid-
ine-1,6,11(2H)-triones (4a–k)
1
3

S. Kamalifar, H. Kiyani
measurements were performed by a Bruker Avance DRX-300 MHz operating at
1
13
3
00 MHz for H and 75 MHz for C using DMSO-d as the solvent. The develop-
6
ment of reactions was monitored by thin-layer chromatography (TLC) analysis on
Merck pre-coated silica gel 60 F aluminum sheets, visualized by UV light.
2
54
General procedure for the synthesis of 12‑substituted‑3,3‑dimethyl‑3,4,5,12‑
tetrahydrobenzo[b]acridine‑1,6,11(2H)‑trione (4a–k)
A mixture of substituted benzaldehydes (1a–k, 1 mmol), 2-amino-1,4-naphthoqui-
none (2, 0.173 g, 1 mmol), and 5,5-dimethylcyclohexane-1,3-dione, dimedone, (3,
0
.140 g, 1 mmol) was stirred in EtOH (5 mL) under reꢀux conditions for appropri-
ate times (TLC analysis). After completion of the reaction, the reaction mixture was
cooled to room temperature, and the solvent was then removed under reduced pres-
sure. The resulting solid residue was collected and recrystallized with chloroform to
give heterocyclic products (4a–k).
3,3‑Dimethyl‑12‑phenyl‑3,4,5,12‑tetrahydrobenzo[b]acridine‑1,6,11(2H)‑trione (4a)
1
Yield: 90%, reaction time: 3 h, m.p. 297–300 °C; H NMR (DMSO-d , 300 MHz) δ
6
1
1
.05 (s, 3H, CH ), 1.14 (s, 3H, CH ), 2.24 (d, J=16.4 Hz, 1H, H ), 2.31 (d, J=16.4,
3 3 4
H, H ), 2.47 (d, J=16.9 Hz, 1H, H ), 2.54 (d, J=16.8 Hz, 1H, H ), 5.43 (s, 1H,
4
2
2
CH), 7.13 (td, J=2.0, 7.4 Hz, 1H, H ), 7.24 (td, J=1.7, 7.6 Hz, 2H, H ), 7.41
4
′
3′, 5′
a
(
dd, J=1.3, 7.11 Hz, 2H, H ), 7.62–7.74 (m, 2H, H ) , 8.02–8.08 (m, 2H,
2
′, 6′
8, 9
a
13
H
) , 9.78 (s, 1H, NH); C NMR (DMSO-d , 75 MHz) δ 27.0 (CH ), 29.6 (C ),
7
, 10
6 3 3
3
1
2.6 (C ), 34.1 (CH), 50.7 (C ), 111.0 (C ), 119.5 (C ), 126.1 (C ), 126.4 (C ),
4
2
12a
11a
7
10
26.7 (C ), 128.4 (C ), 126.6 (C ), 130.8 (C ), 132.3 (C ), 133.7 (C ), 135.3
4
′
2′, 6′
3′, 5′
6a
10a
8
a
a
(
C ), 138.9 (C ), 146.1 (C ), 150.2 (C ), 180.0 (C , C═O) , 182.5 (C , C═O) ,
9
5a
1′
4a
6
11
1
95.2 (C , C═O of dimedone moiety). Anal. Calcd. For C H NO (%): C, 75.24;
1 19 13 3
H, 4.32; N, 4.62; Found: C, 75.22; H, 4.30; N, 4.62.
a
In this and other cases, the signals were assigned adapting to the literature [75,
7
6].
1
2‑(4‑Methoxyphenyl)‑3,3‑dimethyl‑3,4,5,12‑tetrahydrobenzo[b]acrid‑
ine‑1,6,11(2H)‑trione (4b)
1
Yield: 90%, reaction time: 3 h, m.p. 284–286 °C; H NMR (DMSO-d , 300 MHz) δ
6
0
1
.89 (s, 3H, CH ), 1.02 (s, 3H, CH ), 2.04 (d, J=16.1 Hz, 1H, H ), 2.22 (d, J=16.2,
3 3 4
H, H ), 2.54 (d, J=17.6 Hz, 1H, H ), 2.66 (d, J=17.5 Hz, 1H, H ), 3.63 (s, 3H,
4
2
2
OCH ), 5.10 (s, 1H, CH), 6.74 (d, J=8.5 Hz, 2H, H ), 7.14 (d, J=8.5 Hz, 2H,
3
′, 6′
3′, 5′
H
), 7.52–7.81 (m, 2H, H ), 7.87 (d, J=7.2 Hz, 1H, H ), 7.98 (d, J=7.7 Hz,
2
8, 9 7
1
3
1
H, H ), 9.79 (s, 1H, NH); C NMR (DMSO-d , 75 MHz) δ 26.5 (CH ), 29.1 (C ),
10 6 3 3
3
2.1 (C ), 32.6 (CH), 50.2 (C ), 54.9 (OCH ), 110.6 (C ), 113.4 (C ), 119.3
4
2
3
12a
3′, 5′
(
C
), 125.6 (C ), 125.9 (C ), 128.9 (C ), 130.2 (C ), 131.9 (C ), 133.2 (C ),
1
1a
7
10
2′, 6′
6a
10a
8
1
34.7 (C ), 138.0 (C ), 138.03 (C ), 149.5 (C ), 157.6 (C -OCH ), 179.6 (C ,
9
5a
1′
4a
Ar
3
6
1
3

An expeditious and green one-pot synthesis of…
C═O), 182.0 (C , C═O), 194.7 (C , C═O of dimedone moiety). Anal. Calcd. For
1
1
1
C H NO (%): C, 75.24; H, 4.32; N, 4.62; Found: C, 75.22; H, 4.30; N, 4.62.
1
9
13
3
1
2‑(3,4‑Dimethoxyphenyl)‑3,3‑dimethyl‑3,4,5,12,‑tetrahydrobenzo[b]acrid‑
ine‑1,6,11(2H)‑trione (4c)
1
Yield: 95%, reaction time: 2 h, m.p. 239–240 °C; H NMR (DMSO-d , 300 MHz) δ
6
0
1
.92 (s, 3H, CH ), 1.03 (s, 3H, CH ), 2.06 (d, J=16.1 Hz, 1H, H ), 2.24 (d, J=16.2,
3 3 4
H, H ), 2.55 (d, J=17.6 Hz, 1H, H ), 2.68 (d, J=17.5 Hz, 1H, H ), 3.63 (s, 3H,
4
2
2
OCH ), 3.66 (s, 3H, OCH ), 5.10 (s, 1H, CH), 6.71 (d, J=8.2 Hz, 2H, H ),
3
3
3′, 5′
7
.76 (d, J=8.3 Hz, 2H, H ), 6.83 (s, 1H, H ), 7.73–7.82 (m, 2H, H ), 7.89
2′, 6′ 2′ 8, 9
1
3
(
d, J=6.8 Hz, 1H, H ), 7.98 (d, J=6.2 Hz, 1H, H ), 9.79 (s, 1H, NH); C NMR
7 10
(
DMSO-d , 75 MHz) δ 26.4 (CH ), 29.2 (C ), 32.1 (C ), 32.9 (CH), 50.2 (C ),
6
3
3
4
2
5
5.3 (OCH ), 110.5 (C ), 111.5 (C ), 112.0 (C ), 119.2 (C ), 119.9 ( ), 125.6
3 12a 5′ 2′ 11a 6′
(
C ), 125.8 (C ), 130.3 (C ), 131.9 (C ), 133.2 (C ), 134.7 (C ), 137.9 (C ),
7
10
6a
10a
8
9
5a
1
38.3 (C ), 147.3 (C ), 148.2 (C , C -OCH ), 149.6 (C , C -OCH ), 179.5 (C ,
1 4a 4′ Ar 3 3′ Ar 3 6
′
C═O), 182.1 (C , C═O), 194.7 (C , C═O of dimedone moiety). Anal. Calcd. For
1
1
1
C H NO (%): C, 75.24; H, 4.32; N, 4.62; Found: C, 75.22; H, 4.30; N, 4.62.
1
9
13
3
(
(
3,4,5‑Trimethoxyphenyl)‑3,4,5,12‑tetrahydrobenzo[b]acridine‑1,6,11(2H)‑trione
4d)
1
Yield: 95%, reaction time: 1.5 h, m.p. 224–226 °C; H NMR (DMSO-d , 300 MHz)
6
δ 0.97 (s, 3H, CH ), 1.04 (s, 3H, CH ), 2.08 (d, J=16.2 Hz, 1H, H ), 2.24 (d,
3
3
4
J=16.2, 1H, H ), 2.56 (d, J=17.5 Hz, 1H, H ), 2.72 (d, J=17.5 Hz, 1H, H ), 3.55
4
3
2
2
(
s, 3H, p-OCH ), 3.67 (s, 6H, 2×m-OCH ), 5.11 (s, 1H, CH), 6.50 (s, 2H, H ),
3
2′, 6′
7
.73–7.83 (m, 2H, H ), 7.95 (d, J=7.4 Hz, 1H, H ), 7.99 (dd, J=1.4, 7.5 Hz, 1H,
8, 9 7
1
3
H ), 9.81 (s, 1H, NH); C NMR (DMSO-d , 75 MHz) δ 26.4 (CH ), 29.3 (C ), 32.1
1
4
0
6
3
2′, 6′
3
(
C ), 33.6 (CH), 50.2 (C ), 55.7 (OCH ), 59.8 (OCH ), 105.3 (C ), 110.1 (C ),
2
3
3
12a
1
18.8 (C ), 125.7 (C ), 125.9 (C ), 130.3 (C ), 131.9 (C ), 133.2 (C ), 134.7
11a 7 10 6a 10a 8
(
C ), 136.7 (C , C -p-OCH ), 138.1 (C ), 141.2 (C ), 149.9 (C ), 152.5 (C , ,
9
Ar
4′
Ar
3
1′
5a
4a
3′ 5′
C -m-OCH ), 179.5 (C , C═O), 182.2 (C , C═O), 194.8 (C , C═O of dimedone
3
6
11
1
moiety). Anal. Calcd. For C H NO (%): C, 75.24; H, 4.32; N, 4.62; Found: C,
1
9
13
3
7
5.22; H, 4.30; N, 4.62.
1
2‑(4‑Hydroxyphenyl)‑3,3‑dimethyl‑3,4,5,12‑tetrahydrobenzo[b]acrid‑
ine‑1,6,11(2H)‑trione (4e)
1
Yield: 95%, reaction time: 2 h, m.p. 288–290 °C; H NMR (DMSO-d , 300 MHz) δ
6
0
1
.90 (s, 3H, CH ), 1.02 (s, 3H, CH ), 2.05 (d, J=16.1 Hz, 1H, H ), 2.22 (d, J=16.2,
3 3 4
H, H ), 2.53 (d, J=18.5 Hz, 1H, H ), 2.66 (d, J=17.4 Hz, 1H, H ), 5.06 (s, 1H,
4
2
2
CH), 6.57 (d, J=8.4 Hz, 2H, H ), 7.02 (d, J=8.4 Hz, 2H, H ), 7.70–7.79 (m,
3
′, 5′
2′, 6′
2
1
3
1
H, H ), 7.87 (d, J=7.1 Hz, 1H, H ), 7.97 (dd, J=1.4, 7.4 Hz, 1H, H ), 9.12 (s,
8, 9 7 10
1
3
H, OH), 9.71 (s, 1H, NH); C NMR (DMSO-d , 75 MHz) δ 26.5 (CH ), 29.1 (C ),
6
3
3
2.1 (C ), 32.4 (CH), 50.3 (C ), 110.8 (C ), 114.8 (C ), 119.5 (C ), 125.5 (C ),
4
2
12a
3′, 5′
11a
7
25.8 (C ), 128.8 (C ), 130.2 (C ), 131.9 (C ), 133.1 (C ), 134.7 (C ), 136.4
1
0
2′, 6′
6a
10a
8
9
1
3

S. Kamalifar, H. Kiyani
(
C ), 137.9 (C ), 149.3 (C ), 155.7 (C -OH), 179.6 (C , C═O), 182.0 (C , C═O),
1
′
5a
4a
Ar
6
11
1
94.7 (C , C═O of dimedone moiety). Anal. Calcd. For C H NO (%): C, 75.24;
1 19 13 3
H, 4.32; N, 4.62; Found: C, 75.22; H, 4.30; N, 4.62.
1
2‑(3‑Ethoxy‑4‑hydroxyphenyl)‑3,3‑dimethyl‑3,4,5,12‑tetrahydrobenzo[b]
acridine‑1,6,11(2H)‑trione (4f)
1
Yield: 90%, reaction time: 4 h, m.p. 262–264 °C; H NMR (DMSO-d , 300 MHz)
6
δ 0.91 (s, 3H, CH ), 1.02 (s, 3H, CH ), 1.27 (t, 3H, J=6.9 Hz, OCH CH ), 2.06 (d,
3
3
2
3
J=16.1 Hz, 1H, H ), 2.2 (d, J=16.2, 1H, H ), 2.53 (d, J=18.2 Hz, 1H, H ), 2.67
4
4
2
(
d, J=17.4 Hz, 1H, H ), 3.86–3.95 (m, 2H, OCH ), 5.05 (s, 1H, CH), 6.58 (s, 2H,
2
2
H
), 6.77 (s, 1H, H ), 7.71–7.81 (m, 2H, H ), 7.90 (dd, J=1.4, 8.6 Hz, 1H, H ),
2
′, 6′
5′ 8, 9 7
1
3
7
.98 (dd, J=1.4, 7.1 Hz, 1H, H ), 8.65 (s, 1H, OH), 9.74 (s, 1H, NH); C NMR
1
2
0
(
DMSO-d , 75 MHz) δ 14.7 (CH CH ), 26.4 (CH ), 29.2 (C ), 32.1 (C ), 32.7 (CH),
6
3
3
3
4
5
0.3 (C ), 63.8 (OCH ), 110.7 (C ), 113.9 (C ), 115.2 (C ), 119.4 (C ), 120.2
2 2 12a 2′ 5′ 11a
(
C ), 125.6 (C ), 125.8 (C ), 130.3 (C ), 131.9 (C ), 133.2 (C ), 134.7 (C ),
6
′
7
10
6a
10a
8
9
1
36.8 (C ), 137.9 (C ), 145.4 (C -OH), 146.1 (C -OEt), 149.4 (C ), 179.6 (C ,
1 5a Ar Ar 4a 6
′
C═O), 182.1 (C , C═O), 194.7 (C , C═O of dimedone moiety). Anal. Calcd. For
1
1
1
C H NO (%): C, 75.24; H, 4.32; N, 4.62; Found: C, 75.22; H, 4.30; N, 4.62.
1
9
13
3
3
,3‑Dimethyl‑12‑(4‑nitrophenyl)‑3,4,5,12‑tetrahydrobenzo[b]
acridine‑1,6,11(2H)‑trione (4g)
1
Yield: 95%, reaction time: 2 h, m.p. 293–295 °C; H NMR (DMSO-d , 300 MHz) δ
6
0
1
.86 (s, 3H, CH ), 1.02 (s, 3H, CH ), 2.05 (d, J=16.1 Hz, 1H, H ), 2.24 (d, J=16.2,
3
3
4
H, H ), 2.57 (d, J=17.5 Hz, 1H, H ), 2.68 (d, J=17.6 Hz, 1H, H ), 5.28 (s, 1H,
4
2
2
CH), 7.54 (d, J=8.7 Hz, 2H, H ), 7.75–7.88 (m, 3H, H ,
), 7.98–8.04 (m,
2
′, 6′
7
8, 9
1
3
1
7
1
H, H ), 8.07 (d, J=8.6 Hz, 2H, H ), 9.98 (s, 1H, NH); C NMR (DMSO-d ,
1
0
3′, 5′
6
5 MHz) δ 26.5 (CH ), 28.9 (C ), 32.1 (C ), 34.4 (CH), 50.1 (C ), 109.6 (C ),
3
3′, 5′
3
4
2
12a
17.6 (C ), 123.3 (C ), 125.6 (C ), 126.0 (C ), 129.3 (C ), 130.4 (C ), 131.7
1
1a
7
10
2′, 6′
6a
(
C
), 133.3 (C ), 134.8 (C ), 138.9 (C ), 146.0 (C , C -NO ), 150.3 (C ), 152.8
10a 8 9 5a 4′ Ar 2 4a
(
C ), 179.3 (C , C═O), 181.9 (C , C═O), 194.6 (C , C═O of dimedone moiety).
1
′
6
11
1
Anal. Calcd. For C H NO (%): C, 75.24; H, 4.32; N, 4.62; Found: C, 75.22; H,
1
9
13
3
4
.30; N, 4.62.
1
2‑(4‑Chlorophenyl)‑3,3‑dimethyl‑3,4,5,12‑tetrahydrobenzo[b]
acridine‑1,6,11(2H)‑trione (4h)
1
Yield: 90%, reaction time: 3 h, m.p. 287–288 °C; H NMR (DMSO-d , 300 MHz) δ
6
0
1
.87 (s, 3H, CH ), 1.02 (s, 3H, CH ), 2.05 (d, J=16.1 Hz, 1H, H ), 2.23 (d, J=16.2,
3 3 4
H, H ), 2.55 (d, J=17.5 Hz, 1H, H ), 2.67 (d, J=17.5 Hz, 1H, H ), 5.15 (s, 1H,
4
2
2
CH), 7.25 (m, 4H, H
), 7.76–7.82 (m, 2H, H ), 7.87 (d, J=6.7 Hz, 1H, H ),
2
′, 3′, 5′
8, 9 7
1
3
8
2
1
.00 (d, J=6.8 Hz, 1H, H ), 9.85 (s, 1H, NH); C NMR (DMSO-d , 75 MHz) δ
1
0
6
6.5 (CH ), 29.0 (C ), 32.0 (C ), 33.3 (CH), 50.1 (C ), 110.2 (C ), 118.4 (C ),
3
3
4
2
12a
11a
25.5 (C ), 125.8 (C ), 127.9 (C ), 129.8 (C ), 130.3 (C ), 130.7 (C ), 131.8
7
10
3′, 5′
2′, 6′
6a
4′
(
C
), 133.2 (C ), 134.7 (C ), 138.5 (C ), 144.5 (C ), 149.8 (C ), 179.4 (C ,
10a 8 9 5a 1′ 4a 6
1
3

An expeditious and green one-pot synthesis of…
C═O), 181.9 (C , C═O), 194.6 (C , C═O of dimedone moiety). Anal. Calcd. For
1
1
1
C H NO (%): C, 75.24; H, 4.32; N, 4.62; Found: C, 75.22; H, 4.30; N, 4.62.
1
9
13
3
1
2‑(4‑Fluorophenyl)‑3,3‑dimethyl‑3,4,5,12‑tetrahydrobenzo[b]
acridine‑1,6,11(2H)‑trione (4i)
1
Yield: 90%, reaction time: 3 h, m.p. 294–296 °C; H NMR (DMSO-d , 300 MHz) δ
6
0
1
.87 (s, 3H, CH ), 1.02 (s, 3H, CH ), 2.05 (d, J=16.1 Hz, 1H, H ), 2.23 (d, J=16.2,
3 3 4
H, H ), 2.56 (d, J=17.5 Hz, 1H, H ), 2.66 (d, J=17.5 Hz, 1H, H ), 5.16 (s, 1H,
4
2
2
CH), 7.00 (t, J=8.7 Hz, 2H, H ), 7.24–7.29 (m, 2H, H , ), 7.69–7.81 (m, 2H,
3
′, 5′
2′ 6′
H
), 7.86 (d, J=7.0 Hz, 1H, H ), 7.99 (d, J=6.9 Hz, 1H, H ), 9.86 (s, 1H, NH);
8
, 9
7 10
1
3
C NMR (DMSO-d , 75 MHz) δ 26.5 (CH ), 29.0 (C ), 32.1 (C ), 33.0 (CH), 50.2
6
3
3
4
2
(
(
(
C ), 110.4 (C ), 114.7 (d, J =84.0 Hz, C ), 118.7 (C ), 125.6 (C ), 125.9
2
1
9
′
12a
C-F
3′, 5′
11a
10a
7
3
C ), 129.7 (d, J =32.1 Hz, C ), 130.3 (C ), 131.8 (C ), 133.3 (C ), 134.7
0
C-F
2′, 6′
6a
8
4
1
C ), 138.4 (C ), 141.9 ( J =12.0 Hz, C ), 149.7 (C ), 130.7 ( J =962.7 Hz,
5a
C-F
1′
4a
C-F
C , C -F), 179.5 (C , C═O), 182.0 (C , C═O), 194.7 (C , C═O of dimedone moi-
4
Ar
6
11
1
ety). Anal. Calcd. For C H NO (%): C, 75.24; H, 4.32; N, 4.62; Found: C, 75.22;
1
9
13
3
H, 4.30; N, 4.62.
3
,3‑Dimethyl‑12‑(4‑(triꢀuoromethyl)phenyl)‑3,4,5,12‑tetrahydrobenzo[b]
acridine‑1,6,11(2H)‑trione (4j)
1
Yield: 95%, reaction time: 2 h, m.p. 283–284 °C; H NMR (DMSO-d , 300 MHz) δ
6
0
1
.87 (s, 3H, CH ), 1.02 (s, 3H, CH ), 2.06 (d, J=16.1 Hz, 1H, H ), 2.24 (d, J=16.2,
3 3 4
H, H ), 2.56 (d, J=17.5 Hz, 1H, H ), 2.68 (d, J=17.6 Hz, 1H, H ), 5.24 (s, 1H,
4
2
2
CH), 7.48 (d, J=8.1 Hz, 2H, H ), 7.56 (d, J=8.3 Hz, 2H, H , ), 7.38–7.81 (m,
2
7
′, 6′
3′ 5′
1
3
2
H, H ), 7.86–7.89 (m, 1H, H ), 78.00–8.03 (m, 1H, H ), 9.94 (s, 1H, NH);
C
8
, 9
10
NMR (DMSO-d , 75 MHz) δ 26.6 (CH ), 28.9 (C ), 32.1 (C ), 34.1 (CH), 50.1 (C ),
6
3
3
4
2
1
09.9 (C ), 118.1 (C ), 124.9 (CF ), 125.0 (C ), 125.6 (C ), 125.9 (C ), 126.6
12a 11a 3 3′, 5′ 7 10
(
C ), 128.8 (C ), 130.4 (C ), 131.8 (C ), 133.3 (C ), 134.8 (C ), 138.8 (C ),
4
′
2′, 6′
6a
10a
8
9
5a
1
50.0 (C ), 150.2 (C ), 179.4 (C , C═O), 181.9 (C , C═O), 194.7 (C , C═O of
1 4a 6 11 1
′
dimedone moiety). Anal. Calcd. For C H NO (%): C, 75.24; H, 4.32; N, 4.62;
1
9
13
3
Found: C, 75.22; H, 4.30; N, 4.62.
3
,3‑Dimethyl‑12‑(pyridin‑3‑yl)‑3,4,5,12‑tetrahydrobenzo[b]
acridine‑1,6,11(2H)‑trione (4k)
1
Yield: 80%, reaction time: 5 h, m.p. 275–278 °C; H NMR (DMSO-d , 300 MHz) δ
6
0
1
.86 (s, 3H, CH ), 1.02 (s, 3H, CH ), 2.05 (d, J=16.1 Hz, 1H, H ), 2.23 (d, J=16.2,
3 3 4
H, H ), 2.55 (d, J=17.4 Hz, 1H, H ), 2.68 (d, J=17.5 Hz, 1H, H ), 5.16 (s, 1H,
4
2
2
CH), 7.21–7.25 (m, 1H, H ), 7.61 (d, J=7.9 Hz, 1H, H ), 7.73–7.82 (m, 2H, H ),
5
′
4′
8, 9
7
1
3
1
.86–7.88 (m, 1H, H ), 7.99–8.02 (m, 1H, H ), 8.28 (d, J=3.8 Hz, 1H. H ), 8.49 (s,
7 10 6′
1
3
H, H ), 9.91 (s, 1H, NH); C NMR (DMSO-d , 75 MHz) δ 26.5 (CH ), 29.0 (C ),
2
′
6
3
3
7
2.0 (CH), 32.1 (C ), 50.1 (C ), 109.8 (C ), 117.9 (C ), 123.5 (C ), 125.6 (C ),
4
2
12a
11a
5′
25.9 (C ), 130.4 (C ), 131.8 (C ), 133.3 (C ), 134.7 (C ), 135.4 (C ), 138.8
1
0
6a
10a
8
9
4′
(
C ), 141.0 (C ), 147.3 (C ), 149.2 (C ), 150.1 (C ), 179.3 (C , C═O), 181.9 (C ,
5
a
3′
4a
6′
2′
6
11
1
3

S. Kamalifar, H. Kiyani
C═O), 194.6 (C , C═O of dimedone moiety). Anal. Calcd. For C H NO (%): C,
1
19 13
3
7
5.24; H, 4.32; N, 4.62; Found: C, 75.22; H, 4.30; N, 4.62.
Results and discussion
2
-Amino-1,4-naphthoquinone (2) was synthesized as the brown crystalline mate-
rial from the commercially available 1,4-naphthoquinone and sodium azide in
aqueous acetic acid at 40 °C for 2 h according to the method reported in the lit-
erature [77]. A series of 12-substituted-3,3-dimethyl-3,4,5,12-tetrahydrobenzo[b]
acridine-1,6,11(2H)-triones, 1,4-naphthoquinone fused with 7,7-dimethyl-4,6,7,8-
tetrahydroquinolin-5(1H)-ones, (4a–k) were synthesized from an equimolar mix-
ture of aromatic aldehydes (1a–k) with 2-amino-1,4-naphthoquinone (2) and
5
,5-dimethylcyclohexane-1,3-dione, dimedone, (3) via the one-pot 3-MCR of in
EtOH as a green solvent under reꢀux conditions (Scheme 1). The initial attempt
began with the 3-MCR of benzaldehyde (1a, 1 mmol), 2-amino-1,4-naphthoquinone
(
2, 1 mmol), and dimedone (3, 1 mmol) in EtOH without adding any catalyst or
additives. The reaction was subjected to reꢀux conditions, and thin-layer chroma-
tography (TLC) analysis revealed that the reaction was completed within 3 h. After
workup, the desired product 3,3-dimethyl-12-phenyl-3,4,5,12-tetrahydrobenzo[b]
acridine-1,6,11(2H)-trione (4a) was isolated in 90% yield. The temperature reaction
was altered to understand the eꢂect of temperature on the reaction yield and reaction
time. Satisfactory results were not obtained from this study. The inꢀuence of the
solvent on the reaction time and product yield was also screened in the MCR of ben-
zaldehyde (1a), A-1,4-NQ (2), and dimedone (3) using several solvents such as etha-
nol, water, dichloromethane, and acetonitrile under reꢀux conditions. The results are
presented in Table 1. Among the diꢂerent solvents explored, EtOH was found to
be an excellent choice of the solvent. Under reꢀuxing ethanol, to show the versatil-
ity of this 3-MCR, a set of 12-substituted-3,3-dimethyl-3,4,5,12-tetrahydrobenzo[b]
acridine-1,6,11(2H)-triones was synthesized by changing the structure of aromatic
aldehydes. Substituted benzaldehydes containing electron-donating (–Me, –OMe,
OH, OEt) and electron-withdrawing groups (–F, Cl, NO –CF ) as well as a heter-
2
3
oaromatic aldehyde (pyridine-3-carbaldehyde) were employed. In all experiments,
Table 1 Screening of the
Entry
Solvent (5 mL)
EtOH
Time (h)
Isolated
solvent eꢂect on the synthesis
of 3,3-dimethyl-12-phenyl-
yields (%)
3
,4,5,12-tetrahydrobenzo[b]
1
2
3
4
3
3.5
4
90
50
60
60
acridine-1,6,11(2H)-trione (4a)
H O
2
CH Cl
2
2
CH CN
4
3
The reaction was implemented using benzaldehyde (1a, 1 mmol),
2
1
-amino-1,4-naphthoquinone (2,
1 mmol), and dimedone (3,
mmol) under reꢀux temperature of the solvent
1
3

An expeditious and green one-pot synthesis of…
the reaction proceeds eꢃciently under the same reaction conditions, and the corre-
sponding heterocyclic products were obtained in 80–95% isolated yields.
The structural conꢁrmation of numerous synthesized heterocyclic compounds
has been done based on the corresponding analytical and spectroscopic data anal-
1
ysis. For example, in the proton nuclear magnetic resonance ( H NMR) of com-
pound 4b, CH protons showed two separate singlets at δ 0.89 and 1.02 ppm.
3
H
CH proton signals of synthesized heterocycles were observed in a range of δ
3
H
0
.86–1.14 ppm. The protons of CH at the position C4 of dimedone moiety appeared
2
2
at δ 2.04 and 2.22 ppm as two separate doublets with J =16.1 Hz and 16.2 Hz
H
HH
2
because of geminal coupling [78]. Two doublets at δ 2.54 ( J =17.6 Hz) and
H
HH
2
2
.66 ( J =17.5 Hz) were attributed to CH protons of the position C2 of dime-
HH 2
1
done ring. In the H NMR spectra of other synthesized compounds, the dimedone
moiety signals also appeared in the same region, i.e., from 2.04 to 2.72 ppm. The
spectrum displayed a singlet at δ 3.63 ppm, which indicates the presence of a meth-
H
oxy group. It is noteworthy that compounds 4c and 4d contain the methoxy groups
and their corresponding proton signals appeared at δ 3.63 and 3.66 ppm for 4c,
H
and δ 3.55 (p-OCH ) and 3.67 (m-OCH ) ppm, respectively. In other heterocyclic
H
3
3
compounds that do not contain the methoxy group, these signals are not seen. Fur-
thermore, in compounds 4e and 4f containing hydroxyl group instead of a methoxy
in para-position, the resonances of the OH protons were determined as singlets at
δ 9.12 and 8.65 ppm, respectively. A singlet at δ 5.10 ppm, integrating for one
H
H
hydrogen, is owing to CH (H-12) of 1,4-dihydropyridine scaꢂold. The character-
istic singlet in the range from 5.05 to 5.28 ppm for CH of 1,4-dihydropyridine sec-
1
tion was present in the H NMR spectra of all the target compounds. The protons
of ortho-position (H-3′, 5′) and meta-position (H-2′, 6′) of p-methoxyphenyl ring
showed two doublets centered at δ 6.74 (2H, J=8.5 Hz), 7.14 (2H, J=8.5 Hz),
H
respectively. Resonated multiplet signal at δ 7.52–7.81 ppm and two doublets at δ
H
H
7
.87 (J=7.2 Hz) and 7.98 (J=7.7 Hz) ppm, integrating for four protons, were attrib-
uted to 1,4-NQ hydrogens [40] in the desired compound. The resonance of the NH
proton signal belonging to the 1,4-dihydropyridine nucleus was found as a singlet
signal at δ 9.79 ppm. Also, singlet signals observed in the downꢁeld region, rang-
H
ing from 9.71 to 9.98 ppm, each with integrating for one hydrogen and characteristic
of NH proton conꢁrmed the formation of 1,4-dihydropyridine ring in the all hetero-
cyclic compounds.
1
3
The C NMR spectrum of compound 4b showed a peak from the two methyl-
group carbons (3-CH ) at 26.5 ppm. The two methylene carbon signals at δ 32.1
3
C
(
4-CH ) and 50.2 (2-CH ) ppm, the signal at δ 29.1 ppm (C-3), and a carbonyl
2
2
C
signal at δ 194.7 ppm suggested a dimedone moiety in the molecule. The corre-
C
sponding chemical shift of the p-methoxy group was observed at δ 54.9 ppm. Two
C
signals, observed at 179.6 and 182.0 ppm, were assigned to the carbonyl groups
of 1,4-naphthoquinone moiety. The chemical shifts of the carbonyl functional
groups at the position C11 are higher than those of C6, which can be attributed to
the resonance eꢂect between nitrogen and the carbonyl groups at C-11 [75, 76].
The expected resonance signals for other carbons were detected in the range of δ
C
1
10.6–157.6 ppm. The NMR data, except for the aryl and heteroaryl rings on posi-
tion C4 of 1,4-dihydropyridine moiety, were similar to those of compound 4b.
1
3

S. Kamalifar, H. Kiyani
The plausible mechanism of the reaction is outlined in Scheme 2. The reaction
possibly starts with a keto-enol tautomerization of dimedone (3), and the reaction of
generated enol (5) with the aldehydes (1) via the Knoevenagel condensation to give
the corresponding α,β-unsaturated dicarbonyl intermediates 6. Michael addition
between 2-amino-1,4-naphthoquinone (2) and intermediates 6 aꢂords the Michael
adducts 7. The tautomerization of 7 gives intermediate 8 with a 1° amine group
which is then converted into the desired 1,4-naphthoquinone fused with 4-substi-
tuted 7,7-dimethyl-4,6,7,8-tetrahydroquinolin-5(1H)–one polyheterocyclic com-
pounds (4a–k) through intramolecular nucleophilic cyclization.
Conclusions
In summary, the green and expeditious synthesis of a series of new 12-aryl/het-
eroaryl-3,3-dimethyl-tetrahydrobenzo[b]acridine-1,6,11(2H)-trione
derivatives
from aromatic aldehydes, 2-amino-1,4-naphthoquinone, and dimedone via 3-CR
approach has been described. Among several solvents tested in this reaction, the
best results were obtained when ethanol was employed as the reaction medium.
Scheme 2 Possible mechanism for the synthesis of 12-substituted-3,3-dimethyl-tetrahydrobenzo[b]acrid-
ine-1,6,11(2H)-trione (4a–k)
1
3

An expeditious and green one-pot synthesis of…
Structural elucidation of the newly synthesized fused tetracyclic compounds con-
taining substituents at position 4 of 1,4-dihydropyridine ring was implemented uti-
lizing recorded spectroscopic data analysis. The simplicity of operation under mild
conditions, simple workup and puriꢁcation process, inexpensiveness, atom econ-
omy, convenience, the use of ethanol as an environmentally benign solvent, and very
good-to-high yields make this approach attractive for the synthesis of a variety of
such heterocyclic compounds.
Acknowledgements The authors are thankful to Damghan University Research Council for ꢁnancial sup-
port of this study.
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