Catalyst-free Synthesis of Tetrahydroacenaphtho[1,2-b]indolone Derivatives via One-pot Four-component Reaction

Article abstract of DOI:10.1002/jhet.3167

A simple and efficient one-pot synthesis of tetrahydroacenaphtho[1,2-b]indolone derivatives via four-component reaction of 5,5-dimethylcyclohexane-1,3-dione (dimedone), arylamines, acenaphthoquinone, and active methylene compounds under catalyst-free conditions is described. The reactions were carried out under mild conditions using ethanol as solvent. Advantages of this method include simple experimental and workup procedure, readily available starting materials, and high yields.

Full text of DOI:10.1002/jhet.3167

Month 2018
Catalyst-free Synthesis of Tetrahydroacenaphtho[1,2-b]indolone Deriva-
tives via One-pot Four-component Reaction
*
Mohammad Bayat
and Zeinab Amiri
Department of Chemistry, Faculty of Science, Imam Khomeini International University, Qazvin, Iran
*
E-mail: bayat_mo@yahoo.com; m.bayat@sci.ikiu.ac.ir
Received December 24, 2017
DOI 10.1002/jhet.3167
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
A simple and efficient one-pot synthesis of tetrahydroacenaphtho[1,2-b]indolone derivatives via four-
component reaction of 5,5-dimethylcyclohexane-1,3-dione (dimedone), arylamines, acenaphthoquinone,
and active methylene compounds under catalyst-free conditions is described. The reactions were carried
out under mild conditions using ethanol as solvent. Advantages of this method include simple experimental
and workup procedure, readily available starting materials, and high yields.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
structurally interesting compounds. Recently, several
methods for the synthesis of functionalized nitrogen-
containing heterocycles and acenaphtho[1,2-b]indole
derivatives have been reported [21]. Zhang and
coworker reported synthesis of tetrahydroacenaphtho[1,2-
b]indolone derivatives by using L-proline as catalyst [22].
Multicomponent reactions have emerged as an efficient
and powerful tool in modern synthetic organic chemistry
because of their valued features. Multicomponent
reactions, leading to interesting heterocyclic scaffolds,
are particularly useful for the construction of diverse
chemical libraries of “drug-like” molecules [1,2].
Heterocyclic compounds are of great importance in the
discovery of pharmaceutical reagents, organic synthesis,
and synthetic materials [3,4]. Nitrogen-containing
heterocycles, in particular, are one of the most significant
classes of heterocycles because of their molecular
functions and wide spectrum of biological activities [5].
These heterocycles are able to insert into DNA and
disrupt undesirable cellular processes [6], which result
in this wide range of biological properties that include
antitumor [7], antibacterial [8], antiparasitic [9],
antiviral [10], antifungal [11], and anti-HIV activities
[12]. Between these heterocycles, the indole unit is one
of the most important and profuse nitrogen-containing
heterocycles in medicinal agents and natural products.
Compounds containing an indole moiety display a
wide range of biological activities including antitumor,
antiviral, and anti-inflammatory activities [13–17]. The
indole unit is also an important skeleton in organic
and medicinal chemistry [18–20]. Therefore, the
preparation of polycyclic indole moiety could
RESULTS AND DISCUSSION
The reaction between arylamines, 5,5-dimethylcyclohexane-
1,3-dione (dimedone), under melt condition at 80°C for
10 min led to enaminone 1, and then addition of
acenaphthoquinone 2 and barbituric acid 3 in ethanol at
reflux for 2 h led to tetrahydroacenaphtho[1,2-b]indolone
derivatives 4a-p, in high yields (Scheme 1).
The effects of solvents and catalyst were evaluated for
this model reaction, and the results are summarized in
(Table 1).
Initially, this reaction was carried out in EtOH at
room temperature without the addition of catalyst. In
this case, target compound 4a was observed but with
low yield (Table 1, entry 1). When Et3N/para-
toluenesulfonic acid (p-TSA) was added to the mixture
respectively at room temperature and reflux, the
product was observed with low yield. But when this
reaction was employed in EtOH at reflux without
catalyst, we found that the reaction swiftly reached
completion within 2 h to give the desirable product 4a
potentially lead to
a
series of biologically and
© 2018 Wiley Periodicals, Inc.

M. Bayat and Z. Amiri
Vol 000
Scheme 1. Synthesis of the tetrahydroacenaphtho[1,2-b]indolone
derivatives 4.
in excellent yield (Table 1, entry 4). Next, with catalyst
p-TSA and without catalyst in different solvents such as
MeOH, CH3CN and H2O were employed (Table 1,
entries 5–11), and results show that except CH3CN in
reflux with p-TSA and MeOH without catalyst that
failed the others, almost all were successful but with
low yields. As a result, EtOH was determined to be the
appropriate solvent. In refluxing EtOH, reaction not only
occurred over a shorter period of time but also provided
a higher yield than that obtained by using any of the
other examined solvents such as MeOH, CH3CN, and
H2O (Table 1, entries 5–11). Accordingly, it could be
concluded that the best reaction condition is catalyst free
in EtOH at reflux. In these experiments, procedure is
very simple and the products do not require further
purification. Then a mixture of 4 and without any
catalytic at 80°C for about 2 h under refluxing ethanol
conditions led to the formation of tetrahydroacena
phtho[1,2-b]indolone derivatives 4 in excellent yields
(Scheme 1). The yields were excellent without formation
of any side products, and products are obtained in very
good purity (Table 2).
Table 1
Synthesis of the tetrahydroacenaphtho[1,2-b]indolone derivatives under
different conditionsa.
Temperature
(°C)
Time
(h)
Yield
(%)b
Entry
Solvent
Catalyst
1
2
3
4
5
6
7
8
EtOH
EtOH
EtOH
EtOHc
MeOH
CH3CN
CH3CN
CH3CN
H2O
r.t.
80
r.t.
80
65
80
80
r.t.
80
80
r.t.
—
p-TSA
Et3N
—
—
—
p-TSA
—
—
p-TSA
—
15
6
12
2
6
6
40
45
55
95
Trace
58
—
55
54
35
Plausible mechanism for the formation of
tetrahydroacenaphtho[1,2-b]indolone
derivatives
is
proposed in Scheme 2. The structures of products were
deduced from their IR and 1H and 13C NMR spectra.
The mass spectra of these products displayed molecular
ion peaks at the appropriate m/z values. The present
procedure has the advantage that not only the reaction
is performed under neutral conditions but also the
reactants can be mixed without any activation or
modification. The simplicity of the present procedure
makes it an interesting alternative to complex multistep
approaches.
6
12
10
10
15
9
10
11
H2O
H2O
25
aDimedone (1 mmol), 4-methoxyaniline (1 mmol), acenaphthoquinone
(1 mmol), and N,N-dimethylbarbituric acid (1 mmol), solvent 5 mL.
bYield of isolated 4a.
cThe best condition.
Table 2
Compounds 4a-p.
Entry
Product
R
X
Y
Time (h)
Yields (%)
Mp (°C)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4-OCH3
4-H
4-Cl
O
O
O
O
O
O
S
CH
3
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
93
89
91
92
90
92
91
89
91
93
92
91
90
93
91
89
244–245
257–258
258–259
255–256
217–218
265–266
237–238
237–239
227–229
229–230
260–261
246–247
238–240
180–182
280–281
254–256
CH
3
CH
3
4-Br
CH
3
4-NO2
2-CH3
4-OCH3
4-Cl
4-H
4-Br
4-OCH3
4-Cl
4-H
2-Cl
3-Cl
CH
3
CH
3
H
H
H
H
H
H
H
S
9
S
10
11
12
13
14
15
16
S
O
O
O
O
O
O
CH
3
CH
3
3,4-Cl
CH
3
Reagents and conditions: 1–3 (1 mmol), EtOH (5 mL), 80°C, catalyst free.
Isolated yield based on arylamines and barbituric acids.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Catalyst-free Synthesis of Tetrahydroacenaphtho[1,2-b]indolone Derivatives
Scheme 2. Proposed mechanism for the synthesis of tetrahydroacenaphtho[1,2-b]indolone derivatives.
CONCLUSIONS
solvent-free condition for 10 min at 80°C, then
acenaphthoquinone 2 (0.182 g, 1 mmol), and 1,3-
dimethylbarbituric acid 3 (0.156 g, 1 mmol) in EtOH
(5 mL) was added and was heated at reflux for 2 h. The
progress of the reaction was monitored by TLC using
EtOAc/n-hexane (1 : 1) as eluent. After reaction
completion, the solid was washed with ethanol (5 mL) to
In summary, we have described a facile and highly
efficient route for the synthesis of novel
tetrahydroacenaphtho[1,2-b]indolone derivatives via four-
component reaction between aniline derivatives,
dimedone, acenaphthoquinone, and barbiturates in
ethanol at reflux. Advantages of this route include
catalyst-free reaction conditions, short reaction time,
simple workup procedure, and excellent yields. In this
method, reactants can be mixed without any activation or
modification.
obtain the product 4a.
5-(6bS,11bR)-6b-Hydroxy-7-(4-methoxyphenyl)-9,9-
dimethyl-11-oxo-7,8,9,10,11,11b-hexahydro-6bH-
acenaphtho[1,2-b]indol-11b-yl)-1,3-dimethylpyrimidine-
2,4,6(1H,3H,5H)-trione (4a).
Gray solid, yield, (93%).
Mp: 244–246°C, IR (KBr), νmax: 3424, 3051, 2951,
1685, 1563, 1510, 1445, 1248, 1148, 789, 671,
602 cmÀ1. H NMR (300 MHz, DMSO-d6) δ: 0.77 (s, 3
H, CH3), 1.06 (s, 3 H, CH3), 1.64–2.07 (m, 4 H, 2CH2),
1
EXPERIMENTAL
2.70 (s, 3 H, N-CH3), 3.10 (s, 3 H, N-CH3), 3.71 (s, 3 H,
General. All of the chemicals used in this work were
purchased from Merck and Aldrich Chemical
Companies. Melting points were measured on an
Electrothermal 9100 apparatus. IR spectra were
measured with Bruker Tensor 27 spectrometer;
2
O-CH3), 5.02 (s, 1 H, OH), 6.46 (d, JHH = 6 Hz, 1 H,
3
CH), 6.96 (s, 3 H, Ar), 7.29 (t, JHH = 8 Hz, 1 H, Ar),
3
2
7.45 (t, JHH = 8 Hz, 1 H, Ar), 7.62 (d, JHH = 8 Hz, 2
H, Ar), 7.69 (d, JHH = 8 Hz, 2 H, Ar). 13C NMR
2
(75 MHz, DMSO-d6) δ: 28.6, 29.9, 33.7, 37.1, 50.8,
55.8, 66.9, 114.6, 119.5, 125.3, 127.1, 128.6, 131.2,
131.3, 136.1, 152.3, 159.1, 167.1, 189.8 (C═O). Anal.
Calcd for C33H31N3O6 (565.62): C, 70.07; H, 5.52; N,
7.43. Found C, 70.5; H, 5.2; N, 7.8. MS (EI) m/z (%):
565 (M+, 0.2), 547 (9), 409 (17), 393 (35), 325 (100),
absorbencies are reported in cmÀ1
spectra were measured with
.
1H and 13C NMR
Bruker DRX-300
a
AVANCE spectrometer at 299.87 MHz. NMR spectra
were obtained in solutions of DMSO-d6. Mass spectra
were recorded on an Agilent Technologies 5975C VL
MSD with Tripe-Axis Detector mass spectrometer
operating at an ionization potential of 70 eV.
278 (20), 265 (13), 41 (10).
5-(6bS,11bR)-6b-Hydroxy-9,9-dimethyl-11-oxo-7-phenyl-
7,8,9,10,11,11b-hexahydro-6bH-acenaphtho[1,2-b]indol-11b-
yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (4b).
General procedure for the synthesis of product 4a.
Typical procedure for preparation of 5-(6bS,11bR)-6b-
hydroxy-7-(4-methoxyphenyl)-9,9-dimethyl-11-oxo-7,8,9,
10,11,11b-hexahydro-6bH-acenaphtho[1,2-b]indol-11b-yl)
-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (4a): A
mixture of 4-methoxyaniline (0.123 g, 1 mmol), 5,5-
dimethylcyclohexane-1,3-dione (0.140 g, 1 mmol), under
Gray solid, yield, (89%). Mp: 257–259°C, IR (KBr),
ν
max: 3409, 2946, 2883, 2659, 1680, 1557, 1431, 1369,
1
1275, 1141, 1032, 787, 706, 598, 459 cmÀ1. H NMR
(300 MHz, DMSO-d6) δ: 0.79 (s, 3 H, CH3), 1.08 (s, 3
H, CH3), 1.66–2.21 (m, 4 H, 2CH2), 2.8 (s, 3 H, N-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Bayat and Z. Amiri
Vol 000
CH3), 3.1 (s, 3 H, N-CH3), 5.02 (s, 1 H, OH), 6.46 (d,
3 H, N-CH3), 4.86 (s, 1 H, OH), 7.48–7.64 (m, 7 H,
2
2JHH = 6 Hz, 1 H, CH), 6.38 (s, 1 H, Ar), 7.03 (s, 2
ArH, CH), 7.79 (d, JHH = 6 Hz, 2 H, Ar), 9.15 (s, 1 H,
3
H, Ar), 7.29 (t, JHH = 6 Hz, 1 H, Ar), 7.41–7.49 (m,
Ar). 13C NMR (75 MHz, DMSO-d6) δ: 28.6, 28.9, 33.7,
37.2, 48.5, 51.1, 56.5, 65.6, 105.3, 119.5, 120.0, 123.2,
126.3, 128.0, 128.8, 135.7, 139.1, 152.3, 166.8, 193.6
(C═O). Anal. Calcd for C32H28N4O7 (580.59): C, 66.20;
2
3 H, Ar), 7.62 (d, JHH = 6 Hz, 2 H, Ar), 7.68 (d,
2JHH = 6 Hz, 2 H, Ar). 13C NMR (75 MHz,
DMSO-d6) δ: 27.7, 28.6, 30.0, 33.9, 37.2, 49.0, 50.8,
67.0, 105.3, 119.3, 120.1, 122.7, 125.3, 127.0, 128.3,
128.6, 129.5, 129.9, 131.2, 136.1, 136.7, 152.3, 167.1,
190.4 (C═O). Anal. Calcd for C33H29N3O5 (535.59): C,
71.76; H, 5.46; N, 7.85. Found C, 71.4; H, 5.8; N, 7.6.
MS (EI) m/z (%): 535 (M+, 73), 443 (10), 380 (100),
296 (36), 215 (12), 187 (13), 151 (19), 117 (15), 83
H, 4.86; N, 9.65. Found C, 66.8; H, 4.5; N, 9.3.
5-(6bS,11bR)-6b-Hydroxy-9,9-dimethyl-11-oxo-7-(o-tolyl)-
7,8,9,10,11,11b-hexahydro-6bH-acenaphtho[1,2-b]indol-11b-
yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (4f).
Gray powder, yield, (92%). Mp: 265–266°C, IR (KBr),
ν
max: 3412, 2954, 1679, 1557, 1437, 1373, 1275, 1146,
787, 595 cmÀ1 1H NMR (300 MHz, DMSO-d6) δ:
.
(87), 42 (17).
0.71 (s, 3 H, CH3), 1.12 (s, 3 H, CH3), 1.46–1.97 (m,
4 H, 2CH2), 2.27 (s, 3 H, ο-CH3), 2.74 (s, 3 H, N-
CH3), 3.12 (s, 3 H, N-CH3), 5.02 (s, 1 H, OH), 6.38
5-(6bS,11bR)-7-(4-Chlorophenyl)-6b-hydroxy-9,9-dimethyl-
11-oxo-7,8,9,10,11,11b-hexahydro-6bH-acenaphtho[1,2-b]
indol-11b-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione
(4c). Gray powder, yield, (91%). Mp: 258–259°C, IR
2
(s, 1 H, CH), 6.81 (d, JHH = 6 Hz, 1 H, Ar), 7.18 (t,
3JHH = 6 Hz, 1 H, Ar), 7.36–7.49 (m, 3 H, Ar), 7.63
(KBr), νmax: 3417, 2943, 1679, 1560, 1488, 1435, 1276,
1
1144, 792, 600 cmÀ1. H NMR (300 MHz, DMSO-d6) δ:
2
2
(d, JHH = 6 Hz, 2 H, Ar), 7.76 (d, JHH = 6 Hz, 2 H,
Ar). 13C NMR (75 MHz, DMSO-d6) δ: 28.5, 29.7,
33.6, 33.7, 36.6, 36.8, 49.1, 50.9, 67.0, 105.3, 119.1,
120.1, 122.7, 125.2, 126.5, 127.2, 128.8, 129.4, 131.0,
131.1, 131.3, 131.8, 132.3, 134.3, 134.9, 136.5, 138.1,
152.3, 167.0, 190.0 (C═O). Anal. Calcd for
C33H31N3O5 (549.62): C, 72.11; H, 5.69; N, 7.65.
0.80 (s, 3 H, CH3), 1.08 (s, 3 H, CH3), 1.67–2.23 (m, 4
H, 2CH2), 2.86 (s, 3 H, N-CH3), 3.12 (s, 3 H, N-CH3),
2
5.06 (s, 1 H, OH), 6.45 (d, JHH = 6 Hz, 1 H, CH), 7.07
3
(s, 1 H, Ar), 7.29 (t, JHH = 6 Hz, 1 H, Ar), 7.44–7.50
2
(m, 3 H, Ar), 7.62 (d, JHH = 6 Hz, 2 H, Ar), 7.69 (d,
2JHH = 6 Hz, 1 H, Ar), 7.81 (s, 1 H, Ar). 13C NMR
(75 MHz, DMSO-d6) δ: 28.6, 30.1, 33.9, 37.0, 49.0,
50.8, 67.0, 87.2, 108.3, 119.2, 122.7, 125.4, 127.1, 128.4,
128.6 (2 C), 129.5, 131.2, 131.5 (2 C), 132.7, 136.5,
136.7, 152.3, 167.3, 190.4 (C═O). MS (EI) m/z (%): 571
(M++1, 23), 570 (M+, 23), 569 (M+À1, 60), 415 (25),
414 (64), 330 (23), 294 (10), 191 (18), 150 (30), 83
Found C, 72.5; H, 5.2; N, 7.4.
5-(6bS,11bR)-6b-Hydroxy-7-(4-methoxyphenyl)-9,9-
dimethyl-11-oxo-7,8,9,10,11,11b-hexahydro-6bH-
acenaphtho[1,2-b]indol-11b-yl)-2-thioxodihydropyrimidine-
4,6(1H,5H)-dione (4g). Gray powder, yield, (91%). Mp:
237–238°C, IR (KBr), νmax: 3158, 2943, 1693, 1548,
1
1513, 1429, 1338, 1244, 1157, 782, 600 cmÀ1. H NMR
(100), 42 (18).
(300 MHz, DMSO-d6) δ: 0.79 (s, 3 H, CH3), 1.10 (s, 3
H, CH3), 1.59–2.14 (m, 4 H, 2CH2), 3.77 (s, 3 H, O-
CH3), 5.02 (s, 1 H, OH), 6.46 (s, 1 H, CH), 6.93 (s, 4 H,
Ar), 7.24 (s, 3 H, Ar), 7.44–7.57 (m, 3 H, Ar), 7.63–7.69
(m, 2 H, Ar), 8.02 (s, 1 H, Ar), 11.64 (s, 1 H, NH), 11.97
(s, 1 H, NH). 13C NMR (75 MHz, DMSO-d6) δ: 27.9,
30.2, 33.9, 37.1, 48.6, 50.9, 55.7, 104.7, 114.5, 119.5,
122.3, 124.9, 126.7, 128.7, 129.1, 131.2, 136.3, 158.9,
160.4, 166.5, 189.2 (C═O). Anal. Calcd for
C31H27N3O5S (553.63): C, 67.25; H, 4.92; N, 7.59.
5-(6bS,11bR)-7-(4-Bromophenyl)-6b-hydroxy-9,9-dimethyl-
11-oxo-7,8,9,10,11,11b-hexahydro-6bH-acenaphtho[1,2-b]
indol-11b-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione
(4d).
Gray powder, yield, (92%). Mp: 255–256°C, IR
(KBr), νmax: 3538, 3051, 2956, 1690, 1613, 1424, 1369,
1
1274, 1208, 1144, 788, 670 cmÀ1. H NMR (300 MHz,
DMSO-d6) δ: 0.80 (s, 3 H, CH3), 1.09 (s, 3 H, CH3),
1.67–2.24 (m, 4 H, 2CH2), 2.83 (s, 3 H, N-CH3), 3.12 (s,
3 H, N-CH3), 5.11 (s, 1 H, OH), 6.45 (s, 1 H, CH), 7.00
(s, 2 H, Ar), 7.29 (s, 1 H, Ar), 7.46–7.85 (m, 6 H, Ar). 13C
NMR (75 MHz, DMSO-d6) δ: 27.6, 28.6, 30.0, 34, 37.0,
49.3, 50.8, 66.9, 105.4, 119.2, 121.3, 122.7, 125.4, 127.1,
128.7, 131.2, 131.8 (2 C), 132.5(2 C), 136.0, 152.3,
167.1, 190.4 (C═O). MS (EI) m/z (%): 615 (M+, 44), 458
(40), 359 (15), 294 (16), 150 (20), 83 (100), 42 (20).
5-(6bS,11bR)-6b-Hydroxy-9,9-dimethyl-7-(4-nitrophenyl)-11-
oxo-7,8,9,10,11,11b-hexahydro-6bH-acenaphtho[1,2-b]indol-
11b-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (4e).
Found C, 67.7; H, 4.5; N, 7.3.
5-(6bS,11bR)-7-(4-Chlorophenyl)-6b-hydroxy-9,9-dimethyl-
11-oxo-7,8,9,10,11,11b-hexahydro-6bH-acenaphtho[1,2-b]
indol-11b-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (4h).
Gray
powder, yield, (89%). Mp: 237–238°C, IR (KBr), νmax
:
3378, 3173, 2957, 2882, 2694, 1716, 1548, 1436, 1392,
1
1315, 1203, 1149, 964, 790, 737, 599 cmÀ1. H NMR
(300 MHz, DMSO-d6) δ: 0.79 (s, 3 H, CH3), 1.12 (s, 3
H, CH3), 1.62–2.25 (m, 4 H, 2CH2), 5.04 (s, 1 H, OH),
Gray powder, yield, (90%). Mp: 217–218°C, IR (KBr),
2
2
6.45 (d, JHH = 6 Hz, 1 H, CH), 7.05 (d, JHH = 6 Hz, 2
ν
max: 3415, 3010, 2943, 1679, 1561, 1486, 1434, 1374,
3
1276, 1143, 792, 599 cmÀ1 1H NMR (300 MHz,
.
H, Ar), 7.25 (t, JHH = 6 Hz, 1 H, A), 7.46 (d,
2JHH = 6 Hz, 3 H, Ar), 7.58–7.68 (m, 4 H, Ar), 8.22 (s, 1
DMSO-d6) δ: 0.75 (s, 3 H, CH3), 1.14 (s, 3 H, CH3),
2.02–2.25 (m, 4 H, 2CH2), 2.80 (s, 3 H, N-CH3), 3.09 (s,
H, Ar), 11.67 (s, 1 H, NH), 11.98 (s, 1 H, NH). 13C
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Catalyst-free Synthesis of Tetrahydroacenaphtho[1,2-b]indolone Derivatives
NMR (75 MHz, DMSO-d6) δ: 19.0, 27.7, 30.3, 34.2, 37.1,
48.7, 51.0, 56.5, 67.2, 104.9, 105.0, 115.2, 118.0, 119.2,
119.7, 122.5, 125.1, 126.8, 128.8, 129.5, 131.3, 132.5,
135.9, 136.2, 141.1, 145.2, 159.4, 166.5, 190.5 (C═O).
Anal. Calcd for C30H24ClN3O4S (558.05): C, 64.57; H,
4.33; N, 7.53. Found C, 65.1; H, 4.8; N, 7.2.
5-(6bS,11bR)-6b-Hydroxy-9,9-dimethyl-11-oxo-7-phenyl-
7,8,9,10,11,11b-hexahydro-6bH-acenaphtho[1,2-b]indol-11b-
37.1, 39.1, 47.9, 51.0, 55.8(2C), 66.4, 104.9, 111.7,
114.5, 119.3, 119.6, 122.2, 124.9, 126.8, 128.7, 129.2,
131.2, 136.3, 141.5, 146.7, 151.4, 158.9, 160.2, 168.5,
168.7, 189.9 (C═O).
5-(6bS,11bR)-7-(4-Chlorophenyl)-6b-hydroxy-9,9-dimethyl-
11-oxo-7,8,9,10,11,11b-hexahydro-6bH-acenaphtho[1,2-b]
indol-11b-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (4l).
Gray
powder, yield, (91%). Mp: 246–247°C, IR (KBr), νmax
3219, 3100, 2953, 2867, 1713, 1567, 1492, 1427, 1136,
788, 673, 600, 508 cmÀ1 1H NMR (300 MHz,
:
yl)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (4i).
Gray
powder, yield, (91%). Mp: 227–229°C, IR (KBr), νmax
:
.
3374, 3284, 3050, 2951, 1796, 1701, 1500, 1407, 1268,
DMSO-d6) δ: 0.81 (s, 3 H, CH3), 1.11 (s, 3 H, CH3),
1.60–2.06 (m, 4 H, 2CH2), 4.93 (s, 1 H, OH), 6.41 (d,
1
1163, 1015, 875, 784, 600 cmÀ1. H NMR (300 MHz,
2
DMSO-d6) δ: 0.79 (s, 3 H, CH3), 0.81 (s, 3 H, CH3),
1.08 (s, 3 H, CH3), 1.12 (s, 3 H, CH3), 1.81–2.41 (m, 8
H, 4CH2), 4.68 (s, 1 H, OH), 4.67 (s, 1 H, OH),6.51–
6.73 (m, 3 H, ArH, 2CH), 7.28–7.91 (m, 21 H, Ar), 8.80
(s, 1 H, Ar), 9.32 (s, 1 H, Ar), 9.51 (s, 1 H, NH), 9.69 (s,
1 H, NH), 11.56 (s, 1 H, NH), 11.78 (s, 1 H, NH). 13C
NMR (75 MHz, DMSO-d6) δ: 26.3, 27.2, 29.4, 30.1,
34.0, 35.4, 36.6, 37.8, 50.3, 50.4, 56.5, 57.3, 65.9, 67.1,
110.1, 112.9, 113.0, 113.4, 120.4, 120.5, 121.7, 122.2,
124.8, 125.1, 127.2, 127.9, 128.2, 128.4, 128.9, 129.4,
129.7, 130.3, 131.6, 131.7, 135.7, 135.8, 135.9, 136.1,
136.2, 137.5, 140.0, 142.8, 163.8, 164.1, 166.7, 167.7,
2JHH = 6 Hz, 1 H, CH), 7.06 (d, JHH = 6 Hz, 2 H, Ar),
3
2
7.25 (t, JHH = 6 Hz, 1 H, Ar), 7.46 (d, JHH = 6 Hz, 3
2
H, Ar), 7.58 (d, JHH = 6 Hz, 3 H, Ar), 7.66 (d,
2JHH = 6 Hz, 3 H, Ar), 8.08 (s, 1 H, Ar), 10.56 (s, 1 H,
NH), 10.92 (s, 1 H, NH). 13C NMR (75 MHz,
DMSO-d6) δ: 27.6, 30.4, 31.2, 34.2, 37.1, 39.1, 47.9,
49.2, 50.8, 66.5, 105.1, 112.8, 119.1, 119.6, 122.3, 125.1,
126.8, 128.8, 129.5, 131.3, 132.3, 136.0, 141.2, 146.5,
151.3, 159.3, 168.4, 168.7, 190.5 (C═O). Anal. Calcd for
C30H24ClN3O5 (541.98): C, 66.48; H, 4.46; N, 7.75.
Found C, 66.0; H, 4.9; N, 7.5.
5-((6bS,11bR)-6b-Hydroxy-9,9-dimethyl-11-oxo-7-phenyl-
7,8,9,10,11,11b-hexahydro-6bH-acenaphtho[1,2-b]indol-11b-
171.9, 172.5, 181.0, 181.7, 191.3 (C═O), 191.5 (C═O).
5-(6bS,11bR)-7-(4-Bromophenyl)-6b-hydroxy-9,9-dimethyl-
11-oxo-7,8,9,10,11,11b-hexahydro-6bH-acenaphtho[1,2-b]
indol-11b-yl)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione
yl)pyrimidine-2,4,6(1H,3H,5H)-trione (4m).
Gray powder,
yield, (90%). Mp: 238–240°C, IR (KBr), νmax: 3401,
3016, 2956, 2864, 1708, 1557, 1490, 1424, 1272, 1127,
1026, 779, 669, 600 cmÀ1
.
1H NMR (300 MHz,
(4j).
Gray powder, yield, (93%). Mp: 229–230°C, IR
(KBr), νmax: 3375, 3204, 3047, 2956, 2358, 1716, 1547,
DMSO-d6) δ: 0.81 (s, 3 H, CH3), 1.12 (s, 3 H, CH3),
1.60–2.25 (m, 4 H, 2CH2), 4.94 (s, 1 H, OH), 6.36 (d,
2JHH = 6 Hz, 1 H, CH), 7.02 (s, 1 H, Ar), 7.20 (s, 1 H,
Ar), 7.37–7.49 (m, 3 H, Ar), 7.56–7.69 (m, 3 H, Ar),
7.99 (s, 1 H, Ar), 10.55 (s, 1 H, NH), 10.92 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6) δ: 19.0, 27.7, 30.4, 34.1,
37.3, 39.1, 47.9, 51.0, 56.5, 66.5, 105.1, 112.4, 119.1,
119.6, 122.3, 125.0, 126.7, 128.0, 128.7, 129.4, 129.7,
131.2, 136.2, 137.0, 146.7, 151.4, 159.6, 168.5, 168.7,
1489, 1436, 1393, 1315, 1149, 791, 736, 676, 599 cmÀ1
.
1H NMR (300 MHz, DMSO-d6) δ: 0.78 (s, 3 H, CH3),
1.05 (s, 3 H, CH3), 1.63–2.26 (m, 4 H, 2CH2), 5.04 (s, 1
2
H, OH), 6.44 (d, JHH = 6 Hz, 1 H, CH), 6.99 (d,
2JHH = 6 Hz, 2 H, Ar), 7.25–7.58 (m, 2 H, Ar), 7.60–
7.67 (m, 5 H, Ar), 8.23 (s, 1 H, Ar), 11.67 (s, 1 H, NH),
11.99 (s, 1 H, NH). 13C NMR (75 MHz, DMSO-d6) δ:
19.0, 27.7, 30.3, 31.2, 34.2, 37.1, 48.0, 51.0, 56.5, 67.0,
104.9, 112.5, 119.2, 119.7, 121.0, 122.5, 125.1, 126.8,
128.7, 131.2, 131.6, 132.5, 136.2, 136.4, 141.8, 146.4,
190.2 (C═O).
5-(6bS,11bR)-7-(2-Chlorophenyl)-6b-hydroxy-9,9-dimethyl-
11-oxo-7,8,9,10,11,11b-hexahydro-6bH-acenaphtho[1,2-b]
indol-11b-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione
(4n). Gray powder, yield, (93%). Mp: 180–182°C, IR
159.3, 166.5, 166.7, 190.4 (C═O).
5-(6bS,11bR)-6b-Hydroxy-7-(4-methoxyphenyl)-9,9-
dimethyl-11-oxo-7,8,9,10,11,11b-hexahydro-6bH-
acenaphtho[1,2-b]indol-11b-yl)pyrimidine-2,4,6(1H,3H,5H)-
trione (4k). Gray powder, yield, (92%). Mp: 260–261°C,
(KBr), νmax: 3377, 3052, 2958, 2880, 1683, 1610,
1
1426, 1374, 1273, 1210, 1146, 783, 669, 615 cmÀ1. H
IR (KBr), νmax: 3403, 3211, 3096, 2963, 2873, 2742, 1700,
NMR (300 MHz, DMSO-d6) δ: 0.75 (s, 3 H, CH3),
1.11 (s, 3 H, CH3), 1.96–2.19 (m, 4 H, 2CH2), 2.78 (s,
3 H, N-CH3), 3.08 (s, 3 H, N-CH3), 4.86 (s, 1 H, OH),
7.54–7.79 (m, 11 H, ArH, CH), 9.16 (s, 1 H, Ar). 13C
NMR (75 MHz, DMSO-d6) δ: 19.0, 28.4, 28.6, 28.9,
33.7, 37.2, 48.4, 51.0, 56.5, 65.6, 119.5, 119.9, 123.2,
126.2, 128.0, 128.8, 131.2, 135.7, 140.8, 152.3, 166.7,
193.6 (C═O). Anal. Calcd for C32H28ClN3O5 (570.03):
C, 67.42; H, 4.95; N, 7.37. Found C, 67.8; H, 5.4;
N, 7.2.
1552, 1506, 1425, 1286, 1137, 1028, 837, 782, 672,
1
601 cmÀ1. H NMR (300 MHz, DMSO-d6) δ: 0.79 (s, 3
H, CH3), 1.11 (s, 3 H, CH3), 1.58–2.25 (m, 4 H, 2CH2),
3.77 (s, 3 H, O-CH3), 4.91 (s, 1 H, OH), 6.43 (d,
2JHH = 6 Hz, 1 H, CH), 6.93 (s, 2 H, Ar), 7.25 (t,
3
3JHH = 6 Hz, 1 H, Ar), 7.44 (t, JHH = 6 Hz, 2 H, Ar),
2
7.58 (d, JHH = 6 Hz, 1 H, Ar), 7.63–7.72 (m, 3 H, Ar),
7.88 (s, 1 H, Ar), 10.53 (s, 1 H, NH), 10.91 (s, 1 H, NH).
13C NMR (75 MHz, DMSO-d6) δ: 27.8, 30.3, 31.2, 34.0,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Bayat and Z. Amiri
Vol 000
[3] (a) Sunderhaus, J. D.; Dockendorff, C.; Martin, S. F. Org Lett
2007, 9, 4223; (b) Li by-Muller, F.; Constantieux, T.; Rodriguez, J. J Am
Chem Soc 2005, 127, 17176; (c) Hulme, C.; Gore, V. Curr Med Chem
2003, 10, 51.
[4] Garuti, L.; Roberti, M.; Pizzirani, D. Mini-Rev Med Chem
2007, 7, 481.
5-(6bS,11bR)-7-(3-Chlorophenyl)-6b-hydroxy-9,9-dimethyl-
11-oxo-7,8,9,10,11,11b-hexahydro-6bH-acenaphtho[1,2-b]
indol-11b-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione
(4o). Gray powder, yield, (91%). Mp: 280–281°C, IR
(KBr), νmax: 3413, 2950, 2709, 1670, 1558, 1430,
1
1376, 1275, 1143, 1038, 784, 726, 674, 596 cmÀ1. H
[5] Denny, W. A. Med Chem Rev 2004, 1, 257.
[6] Belmont, P.; Dorange, I. Expert Opin Ther Pat 2008, 18, 1211.
[7] (a) Oppegard, L. M.; Ougolkov, A. V.; Luchini, D. N.; Schoon,
R. A.; Goodell, J. R.; Kaur, H.; Billadeau, D. D.; Ferguson, D. M.; Hiasa, H.
Eur J Pharmacol 2009, 602, 223; (b) Goodell, J. R.; Ougolkov, A. V.;
Hiasa, H.; Kaur, H.; Remmel, R.; Billadeau, D. D.; Ferguson, D. M. J
Med Chem 2008, 51, 179.
[8] (a) Wainwright, M. J Antimicrob Chemother 2001, 47, 1.
[9] (a) Chauhan, P. M.; Srivastava, S. K. Curr Med Chem 2001, 8,
1535; (b) Di Giorgio, C.; Shimi, K.; Boyer, G.; Delmas, F.; Galy, J. P. Eur
J Med Chem 2007, 42, 1277.
[10] Taraporewala, I. B. Tetrahedron Lett 1991, 32, 39.
[11] Patel, N. A.; Sruthi, S. C.; Patel, R. D.; Patel, M. P. Phosphorus
Sulfur Silicon Relat Elem 2008, 183, 2191.
[12] Lee, Y.; Hyun, S.; Kim, H. J.; Yu, J. Angew Chem Int Ed 2008,
47, 134. Angew Chem 2008, 120, 140.
NMR (300 MHz, DMSO-d6) δ: 0.81 (s, 3 H, CH3),
1.11 (s, 3 H, CH3), 1.67–2.32 (m, 4 H, 2CH2), 2.80 (s,
3 H, N-CH3), 3.12 (s, 3 H, N-CH3), 5.10 (s, 1 H, OH),
6.39 (s, 1 H, CH), 6.90 (s, 1 H, Ar), 7.26–7.67 (m, 8
H, Ar), 7.91 (s, 1 H, Ar). 13C NMR (75 MHz,
DMSO-d6) δ: 27.5, 28.6, 30.2, 34.1, 37.0, 50.9, 66.9,
106.2, 113.4, 119.1, 120.1, 122.6, 125.5, 127.1, 128.2,
128.4, 128.7, 129.3, 131.0, 131.2, 133.5, 136.0, 138.4,
152.3, 167.1, 190.6 (C═O). Anal. Calcd for
C32H28ClN3O5 (570.03): C, 67.42; H, 4.95; N, 7.37.
Found C, 70.0; H, 4.5; N, 7.1.
5-(6bS,11bR)-7-(3,4-Dichlorophenyl)-6b-hydroxy-9,9-
dimethyl-11-oxo-7,8,9,10,11,11b-hexahydro-6bH-
acenaphtho[1,2-b]indol-11b-yl)-1,3-dimethylpyrimidine-
[13] Michaudel, Q.; Thevenet, D.; Baran, P. S. J Am Chem Soc
2012, 134, 2547.
[14] Iglesias, A.; Alvarez, R.; Lea, A. R.; Muniz, K. Angew Chem
Int 2012, 51, 2225.
2,4,6(1H,3H,5H)-trione (4p).
Gray solid, yield, (89%).
[15] Fan, R.; Li, W.; Pu, D.; Zhang, L. Org Lett 2009, 11, 1425.
[16] Davies, H. M. L.; Long, M. S. Angew Chem Int Ed 2005,
44, 3518.
[17] Davies, H. M. L. Angew Chem Int Ed 2006, 45, 6422.
[18] Fuchs, J. R.; Funk, R. L. Org Lett 2005, 7, 677.
[19] Chen, W. L.; Cai, Y. F.; Fu, X.; Liu, X. H.; Liu, L. L.; Feng, X.
M. Org Lett 2011, 13, 4910.
[20] Thirumurugan, P.; Perumal, P. T. Tetrahedron 2009, 65, 7620.
[21] (a) Huang, X.; Zhang, T. -X. J Org Chem 2010, 75, 506; (b)
Neochoritis, C. G.; Eleftheriadis, N.; Tsiantou, A.; Stephanidou-Stephanatou,
J.; Tsoleridis, C. A. Synlett 2013, 24, 2768; (c) Ma, Z. -D.; Day, C. S.;
Bierbach, U. J Org Chem 2007, 72, 5387; (d) Lartia, R.; Bertrand, H.;
Teulade-Fichou, M. P. Synlett 2006, 8, 610; (e) Rogness, D. C.; Larock,
R. C. J Org Chem 2010, 75, 2289; (f) Goel, A.; Singh, S. P.; Kumar, A.;
Kant, R.; Maulik, P. R. Org Lett 2009, 11, 5122.
Mp: 254–256°C, IR (KBr), νmax: 3363, 2946, 2700,
1678, 1563, 1466, 1425, 1370, 1271, 1198, 1134, 1030,
.
787, 738, 672, 602 cmÀ1 1H NMR (300 MHz,
DMSO-d6) δ: 0.82 (s, 3 H, CH3), 1.10 (s, 3 H, CH3),
1.70–2.35 (m, 4 H, 2CH2), 2.79 (s, 3 H, N-CH3), 3.12 (s,
3 H, N-CH3), 5.12 (s, 1 H, OH),6.46 (s, 1 H, CH), 6.96
(s, 1 H, Ar), 7.30–7.67 (m, 7 H, Ar), 7.98 (s, 1 H, Ar).
13C NMR (75 MHz, DMSO-d6) δ: 19.0, 27.5, 28.2, 28.6,
28.7, 30.3, 34.1, 36.9, 48.9, 50.9, 56.5, 66.9, 105.2,
119.1, 120.1, 121.7, 122.8, 125.5, 127.2, 128.7, 128.9,
129.8, 130.7, 131.1, 131.3, 131.4, 131.7, 132.7, 136.0,
137.1, 152.3, 167.0, 190.9 (C═O). Anal. Calcd for
C32H27Cl2N3O5 (604.48): C, 63.58; H, 4.50; N, 6.95.
Found C, 64.1; H, 4.9; N, 6.5.
[22] Zhang, J. J.; Feng, X.; Liu, X. C.; Huang, Z. B.; Shi, D. Q. Mol
Div77ers 2014, 18, 727.
SUPPORTING INFORMATION
REFERENCES AND NOTES
Additional Supporting Information may be found online
in the supporting information tab for this article.
[1] Shi, F.; Xiao-Ning, Z.; Zhang, G.; Ma, N.; Jiang, B.; Tu, S.
Bioorg Med Chem Lett 2011, 21, 7119.
[2] Fu, L.; Shi, Q.; Shi, Y.; Jiang, B.; Tu, S. ACS Comb Sci 2013,
15, 135.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet