Enaminone as building blocks in organic chemistry: A novel route to polyfunctionally 2-substituted 5,6,7,8-tetrahydronaphthalenes and their antiviral evaluation

Article abstract of DOI:10.1002/jhet.1080

The enaminone reacts with different reagents to afford anilino, aroylpyridine, 1,3,5-tri-tetrahydronaphthoyl-benzene, pyridine, 2,3,6-trisubstituted pyridines, pyrazole, pyrido[1,2-a]benzimidazole, and hydrazone derivatives, and. The antiviral evaluation of some selected new products showed promising antiviral activity against human adenovirus 7 and human rotavirus Wa strain.

Full text of DOI:10.1002/jhet.1080

Month 2013
Enaminone as Building Blocks in Organic Chemistry: A Novel Route to
Polyfunctionally 2‐Substituted 5,6,7,8‐Tetrahydronaphthalenes and Their
Antiviral Evaluation
a
b
a
*
Nehal A. Hamdy, Waled M. El‐Senousy and Issa M. I. Fakhr
aApplied Organic Chemistry Department, National Research Centre, Dokki 12622, Cairo, Egypt
bEnteric Viruses Laboratory, Centre of Excellence for Advanced Sciences, National Research Centre, Dokki 12622, Cairo,
Egypt
*
E-mail: drnehalhamdy63@hotmail.com
Received May 3, 2011
DOI 10.1002/jhet.1080
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
CH3
S
N
CO2C2H5
NH
H
CN
N
N
15
17
13
O
H
N
N
O
N
H
N
CN
21
20
The enaminone 2 reacts with different reagents to afford anilino, aroylpyridine, 1,3,5‐tri‐tetrahydronaphthoyl‐
benzene, pyridine, 2,3,6‐trisubstituted pyridines, pyrazole, pyrido[1,2‐a]benzimidazole, and hydrazone
derivatives 4, 6, 8, 9, 11, 13, 15, 17, 20, and 21. The antiviral evaluation of some selected new products
showed promising antiviral activity against human adenovirus 7 and human rotavirus Wa strain.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
readily obtainable inexpensive starting materials for
biological screening program in our laboratory, we report
here on the behavior of the versatile hitherto E‐3‐(N,N‐
dimethylamino)‐1‐(5,6,7,8‐tetrahydronaphthalen‐2‐yl)
prop‐2‐en‐1‐one 2 and its utility as a building block for the
synthesis of the target compounds for antiviral screening.
Adenovirus 7 belongs to the Adenoviridae family. It contains
a linear, double‐stranded DNA about 30,000–42,000 nucleo-
tides long. It has icosahedral morphology and no envelope. This
virus spreads rapidly among people living in close proximity,
such as military barracks, hospital wards, and chronic‐care
facilities. Adenovirus 7 causes acute respiratory disease,
pharyngoconjunctival fever, conjunctivitis, and gastroenteritis.
Rotaviruses have been detected in water, wastewater,
and biosolids. These viruses are extremely resistant to
environmental stress due to the presence of a double
icosahedral shell. Rotavirus Wa strain was chosen as a
representative example of the Reoviridae, because it is of
human origin and is cultured on MA104 cell line. Rotavi-
ruses are the first causes of gastroenteritis in children
worldwide [16]. So, our goal is to find effective anti-
adenovirus and rotavirus compounds.
Enaminone derivatives are highly reactive intermediates
and extensively received a considerable attention in the syn-
thesis of a wide variety of biologically active heterocyclic sys-
tems [1–3]. Tetralines (tetrahydronaphthalene derivatives) are
of increasing interest since many of these compounds play a
vital role in the biological and pharmacological activities, be-
cause of their biological potentialities; for example, as potent
agonists for D2‐type receptors [4], for the treatment of
Alzheimer’s disease [5], cardiovascular diseases [6], and as
a preventer of dopamine‐induced cell death [7]. On the other
hand, the importance of the pyridine ring in the chemistry has
been greatly realized because of its presence as a substructure
in many natural products of therapeutically importance, in-
volved in oxidation–reduction processes. The potent biologi-
cal activity of various vitamins and drugs [8–11] is
primarily contributed to the presence of a pyridine ring
in their molecular make‐up. In addition to various thera-
peutic applications, the importance of pyridines in the pre-
parative organic chemistry cannot be ignored.
Therefore, in continuation to our previous interest [12–15]
in the synthesis of a variety of heterocyclic systems from a
© 2013 HeteroCorporation

N. A. Hamdy, W. M. El-Senousy, and I. M. I. Fakhr
Vol 000
Scheme 2
RESULTS AND DISCUSSION
O
O
NH4OAc
AcOH
Chemistry. The versatile hitherto E‐3‐(N,N‐dimethylamino)‐
1‐(5,6,7,8‐tetrahydronaphthalen‐2‐yl)prop‐2‐en‐1‐one (2)
was prepared by the treatment of 2‐acetyl tetralin (1)
with dimethylformamide‐dimethyl acetal (DMF‐DMA)
in refluxing dry toluene. The structure of the isolated
product was confirmed by elemental analysis and spectral
N
NMe2
R
R
R
Me2N
O
R
6
5
1
data. For example, its H‐NMR spectrum displayed two
AcOH
singlets at δ 2.87, 3.10 ppm due to N,N‐dimethyl protons
and two doublets at δ 5.76 and 7.65 ppm (J = 12.2 Hz) due
to olefinic protons, in addition to an aromatic multiplet at
the region δ 7.05–7.58 ppm and a multiplet at the region δ
1.71, 2.72 ppm for 4CH2 tetrahydronaphthalene. The value
of the coupling constant (J = 12.2 Hz) for the ethylenic
protons indicates that the enaminones 2 exists all in the E‐
configuration. The reaction of 2 with o‐phenylenediamine
afforded products of condensation via elimination of
dimethylamine. This was assigned Z structure 4 rather than
R
O
2
R
O
- 3 Me2NH
NMe2
R
Me2N
R
R
O
R
O
O
NMe2
O
8
7
1
N
1
AcOH
/ NH4OAc
E structure 3 based on H‐NMR spectrum, which revealed
signals for E olefinic protons at δ 6.08 and δ 7.78 ppm (J =
7.5 Hz). The predominance of this form may be due to the
fixation by hydrogen bonding (Scheme 1) [17].
9
R =
Refluxing of compound 2 in acetic acid/ammonium
acetate afforded the pyridine derivative 6 (Scheme 2). This
was assumed to be formed via initial addition of two
molecules of 2 yielding intermediate 5 that was cyclized by
the action of ammonia into 6 [18]. In a trial to isolate the in-
termediate 5, enaminone 2 was refluxed in acetic acid alone;
however, under this condition the tri‐tetrahydronaphthoyl‐
benzene derivative 8 was the only isolable product. It is most
likely that intermediate 5 reacted swiftly with a third
molecule of 2 yielding the intermediate 7 that loses three
molecules of dimethylamine yielding the final product 8.
The structures of compounds 6 and 8 were confirmed
by 1H‐NMR, MS, and IR spectra. In addition, when
enaminone 2 reacted with 2‐acetyl tetralin (1) in acetic
acid/ammonium acetate, afforded the pyridine derivative
9, its structure was confirmed by H‐NMR, MS spectra.
IR spectrum of the compound showed the disappear-
ance of the carbonyl group (Scheme 2).
1
The reaction of compound 2 with acetyl acetone in
refluxing acetic acid in the presence of ammonium acetate
yielded the product that might be formulated as the pyri-
dine derivative 11, which was confirmed by 1H‐NMR,
MS, and IR spectra. It is believed that 10 is an intermediate
(Scheme 3).
Similar to the behavior of 2 toward acetyl acetone, it was
reacted with cyanothioacetamide to yield 13 (Scheme 3).
Structure of compound 13 is preferred over possible
4‐tetrahydronaphthalene pyridine structures based on
1H‐NMR spectrum, which revealed pyridyl hydrogen
resonances as doublets signals with J = 8.40 Hz.
Isomeric 4‐tetrahydronaphthalene pyridine should show
lower coupling constants J = 4–6 Hz [19].
Scheme 1
In addition, enaminone 2 was reacted smoothly with
ethyl acetoacetate in refluxing acetic acid in the presence
of ammonium acetate to yield the product that was formu-
1
lated as pyridine derivative 15, based on H‐NMR spec-
trum, which indicated pyridyl H‐5 and H‐4 as two
doublets at δ 8.03 and 8.18 ppm with J = 8.4 Hz. If these
were for H‐3 and H‐2, one would expect J = 4–6 Hz [19]
(Scheme 3).
The reactivity of enaminone 2 toward some nitrogen
nucleophiles was investigated. Thus, treatment of com-
pound 2 with hydrazine hydrate, in refluxing ethanol, gave
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Enaminone as Building Blocks in Organic Chemistry: A Novel Route to Polyfunctionally
2-Substituted 5,6,7,8-Tetrahydronaphthalenes and Their Antiviral Evaluation
Scheme 3
CH3
COCH3
COCH3
N
NH4OAc
COCH3
COCH3
COCH3
O
R
11
10
S
CN
H
N
CSNH2
CN
H2NSC
O
CN
NH4OAc
2
R
13
12
CH3
CO2Et
O
N
MeOC
O
CO2Et
CO2Et
NH4OAc
15
14
R =
the product 17 (Scheme 4). The formation of 17 was
assumed to take place via Michael‐type addition of the
amino group of hydrazines to the enamine double bond
in compound 2 to form the nonisolable acyclic intermedi-
ate 16, which readily undergoes intramolecular cyclization
into the pyrazole derivative 17 via loss of dimethylamine
and water molecules. The chemical structure of 17 was
established on the basis of elemental analysis and spectral
data of the isolated reaction product for example, the
appearance of NH at 3218 cm−1 and disappearance of the
carbonyl group in IR spectrum, also its 1H‐NMR spectrum
revealed D2O exchangeable signal at δ 12.76 ppm due to
NH proton in addition to the presence of three doublet sig-
nals at δ 6.57, 7.02, 7.44 ppm and one singlet at δ 7.61
ppm due to pyrazol and aromatic protons.
On the other hand, heating equimolar amounts of
compound 2 and benzimidazoleacetonitrile 18, in ethanol
in the presence of a catalytic amount of piperidine resulted
in the formation of a single pure product 20 (as examined
by TLC). The structure of the isolated product was identified
as 3‐(5,6,7,8‐tetrahydronaphthalen‐2‐yl)‐benz[4,5]imidazo
[1,2‐a]pyridine‐4‐carbonitrile (20) on the basis of its elemen-
tal analysis, IR, MS ,1H–NMR, and 13C‐NMR spectral data.
For example, IR spectrum of compound 20 showed a nitrile
absorption band at 2227 cm−1, whereas its 1H‐NMR
spectrum displayed nine aromatic signals at the region
δ 6.69–8.30 ppm.
Similar to the established behavior of enaminones towards
aromatic diazonium salts [20, 21], enaminone 2 was coupled
with benzene diazonium chloride to yield the
phenylhydrazino derivative 21 as major reaction product
[22, 23]. The chemical structure of compound 21 was
established on the basis of its elemental analysis, IR, MS,
1
1H‐NMR, and 13C‐NMR spectral data. H NMR revealed
two signals at δ 9.54 and 9.98 ppm for a total of one proton,
which indicated that the product exist in DMSO solution as
mixtures of the anti form 21 and syn form 22. The antiform
generally predominated; this observation is also in accor-
dance with that reported [24]. On the other hand, if there is
no intramolecular hydrogen bonding, the aldehyde proton is
expected at around 11 ppm according to Al‐Matar et al. [22].
Antiviral screening. The nontoxic dose for all the samples
was 0.1 mg/mL either on Hep2 or MA104 cell lines. Some
samples did not show effect on either adenovirus 7 or
human rotavirus Wa strain. Those samples are 4, 6, 8, 9,
and 11. Four samples showed antiviral effect on
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

N. A. Hamdy, W. M. El-Senousy, and I. M. I. Fakhr
Vol 000
Scheme 4
H
H
H
:
N
N
N
NH
O
-Me2NH
-H2O
NH2NH2
NMe2
16
17
H
N
NMe2
CN
H
N
-Me2NH
-H2O
N
N
2
18
N
N
O
NC
CN
20
19
O
H
N
CHO
PhN=NCl
O
H
O
N
H
N
N
21
22
adenovirus type 7 and five samples showed antiviral effect
on human rotavirus Wa strain ranged from 90 to 99%
Tables 1 and 2. The CC50 ranged from 0.21 to 0.26 mg/
mL on MA104 cell line and ranged from 0.23 to 0.28 mg/
mL on Hep 2 cell line Tables 3 and 4.
It obvious that the best antiviral activity against adeno-
virus 7 and human rotavirus Wa strain was gained by
the compounds 13, 15, 17, 20, and 21. These results can
be returned to the attachment of the respective
thioxopyridine, pyridine, pyrazole benzimidazo pyridine,
and/or phenylhydrazino ring systems to tetralin nucleus.
These moieties may either affect the viral DNA or viral
protein. In addition, the inhibition of viral adsorption to
the host cells or interruptions of the viral life cycles
are all other possibilities. In our screening for antiviral
activity of the tested compounds, it has been noted that
compound 17 did not show any effect on adenovirus 7,
and this may be returned to that compound 17 could affect
only the RNA of rotavirus.
CONCLUSION
Some tested compounds 13, 15, 17, 20, 21 showed
antiviral effect against adenovirus 7 and human rotavirus
Wa strain, which may be promising compounds as anti‐
adenovirus 7 and human rotaviruses.
Table 1
Table 2
Minimal nontoxic dose and anti‐rotavirus Wa strain activity of tested
materials on MA104 cells determined by the end‐point titration technique.
Minimal nontoxic dose and anti‐adenovirus type 7 activity of tested
materials on Hep2 cells determined by the end‐point titration technique.
Tested materials
Viral reduction factor
Tested materials
Viral reduction factor
4
6
1
1
4
6
1
1
8
1
8
1
9
1
9
1
11
17
13
15
20
21
1
11
17
13
15
20
21
1
1
10
10
10
10
10
10
10
102
102
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Enaminone as Building Blocks in Organic Chemistry: A Novel Route to Polyfunctionally
2-Substituted 5,6,7,8-Tetrahydronaphthalenes and Their Antiviral Evaluation
Table 3
E‐3‐(N,N‐Dimethylamino)‐1‐(5,6,7,8‐tetrahydronaphthalen‐
2‐yl)prop‐2‐en‐1‐one (2). To a mixture of 2‐acetyl tetralin
(1; 1.74 g, 10 mmol) in dry toluene (50 mL), DMF‐DMA (1.34
g, 10 mmol) was added, and the mixture was refluxed for 5 h.
The solvent was evaporated, and the residual reddish brown
viscous liquid was taken in ether. The resulting yellow crystals
were collected by filtration, washed thoroughly with ether, dried
and finally recrystallized from EtOH to afford compound 2 as
yellow crystals in 58% yield, mp 70–72°C; IR (KBr) (ν, cm−1):
1634 (C═O); 1H‐NMR (DMSO‐d6): δ (ppm) 1.71 (m, 4H,
aliphatic 2CH2 of tetrahydronaphthalene), 2.72 (m, 4H, aliphatic
2CH2 of tetrahydronaphthalene), 2.87 (s, 3H, CH3), 3.10 (s, 3H,
CH3), 5.76 (d, 1H, J = 12.2 Hz, -CO-CH═), 7.05–7.58 (m, 3H
Ar‐H), 7.65 (d, 1H, J = 12.2 Hz, ═CH-N-); 13C‐NMR (DMSO‐
d6): δ (ppm) 20.12, 20.13 (2CH3), 22.48, 22.597, 28.70, 28.75
(4CH2), 90.93 (CO-CH═), 124.25, 127.67, 128.44, 136.17,
137.52, 139.62 (aromatic‐C), 153.63 (═CH-N-), 185.70 (C═O);
MS m/z (%): 229 (M+, 92.4), 212 (99.0), 159 (43.5), 98 (100),
70 (74.5). Anal. calcd for C15H19NO (229.32): required C,
78.56; H, 8.35; N, 6.11; found C, 78.24; H, 8.03; N, 6.28.
(Z)‐3‐(2‐Aminophenylamino)‐1‐(5,6,7,8‐tetrahydronaphthalen‐
2‐yl)‐prop‐2‐en‐1‐one (4). A mixture of enaminone 2 (2.29 g,
0.01 mol) and o‐phenylenediamine (1.08 g, 0.01 mol) in dry
ethanol (30 mL) was refluxed for 8 h. The solvent was partially
removed, and the obtained precipitate was filtered off and
recrystallized from ethanol to give compound 4.
Anti‐rotavirus Wa strain activity of tested materials on MA104 Cells de-
termined by the MTT method.
Tested
materials
CC50
IC50
(mg/mL)
Therapeutic
index
(mg/mL)
4
6
8
9
11
17
13
15
20
21
0.23
0.21
0.26
0.24
0.24
0.23
0.21
0.25
0.22
0.23
ND
ND
ND
ND
ND
0.053
0.057
0.051
0.047
0.045
ND
ND
ND
ND
ND
ND
4.21
4.9
4.68
5.11
ND: not done.
Table 4
Anti‐adenovirus type 7 strain activities of tested materials on Hep2 cells
determined by the MTT method.
Tested
materials
CC50
(mg/mL)
IC50
(mg/mL)
Therapeutic
index
4
6
8
9
11
17
13
15
20
21
0.26
0.24
0.28
0.26
0.27
0.24
0.23
0.27
0.24
0.25
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
3.89
4.82
4.44
4.46
Yield (83%); m.p. 148–150°C; IR spectrum (KBr, ν, cm−1): 3381,
3331, 3132 (NH2, NH), 2925 (CH alicyclic), 1640 (CO); 1H‐NMR
(DMSO‐d6, δ ppm): 1.75 (m, 4H, 2CH2 of tetrahydronaphthalene),
2.77 (m, 4H, 2CH2 of tetrahydronaphthalene), 4.81 (d, 2H, NH2,
exchangeable with D2O), 6.08 (d, J = 7.50 Hz, 1H, CH═),
6.61–7.74 (m, 7H, Ar‐H), 7.79 (d, J = 7.50 Hz, 1H, CH═),
11.96 (br, 1H, NH, D2O exchangeable); MS m/z (%): 292
(M+, 43), 291 (M+‐1, 62), 159 (80) and 119 (100); Anal.
calcd for C19H20N2O (292.38): required C, 78.05; H, 6.89;
N, 9.58; found C, 78.28; H, 6.87; N, 9.57.
ND
0.059
0.056
0.054
0.056
ND: not done.
(5,6,7,8‐Tetrahydronaphthalen‐2‐yl)‐6‐[(5,6,7,8‐tetrahydrona-
phthalen‐2‐yl)‐pyridin‐3‐yl)]‐methanone (6). A mixture of enaminone
2 (2.29 g, 0.01 mol) and ammonium acetate (0.77g, 0.01 mol) was
refluxed in glacial acetic acid (20 mL) for 1h, then left to cool. The
separated solid was filtered off and recrystallized from ethanol‐DMF
to give compound 6.
Yield (81%); m.p. 132–134°C; IR spectrum (Biorad FTS, ν, cm−1):
2930 (CH alicyclic), 1651 (CO), 1587 (C═N); 1H‐NMR (DMSO‐d6, δ
ppm) : 1.77 (m, 8H, 4CH2 of tetrahydronaphthalene), 2.79 (m, 8H,
4CH2 of tetrahydronaphthalene), 7.19–7.26 (m, 2H, Ar‐H), 7.53 (d, J
= 13.50 Hz, 2H, Ar‐H), 7.87 (d, J = 9.22 Hz, 2H, Ar‐H), 8.06–8.19
(m, 2H, Ar‐H,), 9.07 (s, 1H, pyridyl H‐2); MS m/z (%): 368 (M++1,
100), 367 (M+, 30); Anal. calcd for C26H25NO (367.50): required C,
84.98; H, 6.86; N, 3.81; found C, 84.96; H, 6.54; N, 3.95.
EXPERIMENTAL
Chemistry. All melting points were uncorrected and measured
using an Electro‐thermal IA 9100 apparatus (Shimadzu, Japan).
Microanalytical data were performed by Vario El‐Mentar
apparatus (Shimadzu, Japan), National Research Centre, Cairo,
Egypt. IR spectra were recorded on a Biorad FTS 155 FT‐IR
spectrophotometer (ICB‐IR Service Centre, Pozzuoli, Naples,
Italy) or recorded as potassium bromide pellets on a Perkin‐Elmer
1650 Spectrophotometer, National Research Centre, Cairo, Egypt.
1H‐NMR experiments were conducted at ICB‐NMR Service
Centre (Pozzuoli, Naples, Italy) and were acquired in DMSO,
(shifts are referenced to the solvent signal) on
a Bruker
Avance‐400 operating at 400 MHz, and/or 1H‐NMR spectra
were determined in DMSO‐d6 at 300 MHz (1H‐NMR) and at
75 MHz (13C‐NMR) on a Varian Mercury VX 300 NMR
spectrometer using TMS as an internal standard (Faculty of
Science, Cairo University, Cairo, Egypt). Mass spectra were
carried out on an ion‐trap MS instrument in EI mode at 70
ev (ICB‐IR Service Centre, Pozzuoli, Naples, Italy) or
1,3,5‐Tri‐2‐(5,6,7,8‐Tetrahydronaphtholyl)benzene (8).
Compound 2 (2.29 g, 0.01 mol) was refluxed in glacial acetic acid
(20 mL) for 4 h, then left to cool. The separated solid was filtered
off and recrystallized from glacial acetic acid to afford compound 8.
Yield (89%); m.p. 158–160°C; IR spectrum (Biorad FTS, ν, cm−1):
2931 (CH alicyclic), 1659 (3CO), 1604 (C═C); 1H‐NMR (DMSO‐d6,
δ ppm): 1.75 (m, 12H, 6 CH2 of tetrahydronaphthalene), 2.78 (m, 12H,
6CH2 of tetrahydronaphthalene), 7.25 (d, J = 7.60 Hz, 3H, Ar‐H), 7.53
(s, 3H, Ar‐H), 7.55 (s, 3H, Ar‐H), 8.18 (d, J = 9.0 Hz, 3H, Ar‐H); MS
m/z (%): 552 (M+, 8), 159 (100); Anal. calcd for C39H36O3 (552.72):
required C, 84.75; H, 6.57; found C, 84.87; H, 6.55.
determined
on
Shimadzu
GCMS‐QP‐1000EX
mass
spectrometer at 70 ev (Cairo University, Cairo, Egypt).
Compounds 1 and 18 were prepared according to the reported
methods [25,26].
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

N. A. Hamdy, W. M. El-Senousy, and I. M. I. Fakhr
Vol 000
2,6‐Bis‐(5,6,7,8‐tetrahydronaphthalen‐2‐yl)‐pyridine (9). A
mixture of compound 2 (2.29 g, 0.01 mol), acetyl tetralin 1
(1.74 g, 0.01 mol), and ammonium acetate (0.77 g, 0.01 mol)
was refluxed in glacial acetic acid (30 mL) for 1 h. The
precipitated solid was isolated by filtration and recrystallized
from ethanol to afford compound 9.
3‐(5,6,7,8‐Tetrahydronaphthalen‐2‐yl)‐1H‐pyrazole (17). To
a solution of enaminone 2 (2.29 g, 0.01 mol) in dry ethanol (30
mL), hydrazine hydrate (2 mL, 80%) was added, and the reaction
mixture was refluxed for 4 h. The separated solid after cooling was
filtered off and recrystallized from ethanol to afford compound 17.
Yield (69%); m.p. 62–64°C; IR spectrum (KBr, ν, cm−1): 2925
(CH alicyclic), 3218 (NH); 1H‐NMR spectrum (DMSO‐d6, δ
ppm): 1.75 (m, 4H, 2CH2 of tetrahydronaphthalene), 2.75
(m, 4H, 2CH2 of tetrahydronaphthalene), 6.57 (d, J = 2.3 Hz,
1H, pyrazole‐4‐CH), 7.02 (d, J = 7.65 Hz, 1H, Ar‐H), 7.44 (d,
J = 7.65, 2H, Ar‐H+ pyrazole 5‐CH), 7.61 (s, 1H, Ar‐H), 12.76
(s, 1H, NH, exchangeable with D2O); MS m/z (%): 198 (M+, 73),
170 (100); Anal. calcd for C13H14N2 (198.27): required C, 78.75;
H, 7.12; N, 14.13; found C, 78.61; H, 7.22; N, 14.42.
3‐(5,6,7,8‐Tetrahydronaphthalen‐2‐yl)‐benz[4,5]imidazo[1,2‐
a]pyridine‐4‐carbonitrile (20). To a mixture of enaminone 2
(0.573 g, 0.025 mol) and 1H‐benzimidazole‐2‐acetonitrile
18 (0.393 gm, 0.025 mol) in dry ethanol (30 mL), piperidine
(0.3 mL) was added, and the reaction mixture was refluxed for
12 h. The precipitated product was filtered off, washed with
ethanol dried. Recrystallized from DMF afforded compound 20.
Yield (83%); m.p. 236–238°C; IR spectrum (KBr, ν, cm−1):
2925 (CH alicyclic), 2227 (CN), 1593 (C═N); 1H‐NMR (DMSO‐
d6, δ ppm) : 1.84 (m, 4H, 2CH2 of tetrahydronaphthalene), 2.88
(m, 4H, 2CH2 of tetrahydronaphthalene), 6.69 (d, J = 8.40 Hz,
1H, Ar‐H), 6.91 (d, J = 7.50 Hz, 1H, Ar‐H), 7.11–7.53 (m, 5H,
Ar‐H), 7.91 (d, J = 8.40 Hz, 1H, Ar‐H), 8.30 (d, J = 7.20 Hz, 1H,
Ar‐H); 13C‐NMR (DMSO‐d6): δ (ppm): 22.41, 22.51, 28.67,
28.72 (4CH2), 119.61 (CN), 111.41, 114.65, 115.77, 121.30,
125.29, 126.01, 128.70, 129.57, 130.02, 137.81, 137.84, 139.69,
144.28, 146.30, 146.50 (Aromatic‐C). MS m/z (%): 323
(M+, 100); Anal. calcd for C22H17N3 (323.40): required C, 81.71;
H, 5.30; N, 12.99; found C, 81.52; H, 5.45; N, 13.97.
3‐Oxo‐2‐(phenylhydrazino)‐3‐(5,6,7,8‐tetrahydronaphthalen‐
2‐yl)‐propionaldehyde (21). A cold solution of benzene diazonium
salt (0.01 mol) was prepared by a solution of sodium nitrite (0.01 mol
in 3 mL water) to a cold solution of aniline with stirring. The resulting
solution of benzene diazonium salt was added to a cold solution of
enaminone 2 (2.29 g, 0.01 mol) in dry ethanol (50 mL) containing
sodium acetate. The reaction mixture was stirred for 30 min at
room temperature and the formed solid was filtered off, washed
with water, and recrystallized from ethanol to give compound 21.
Yield (76%); m.p. 82–84°C; IR spectrum (KBr, ν, cm−1): 2921 (CH
alicyclic), 3130 (NH) 1646 (CH═O), 1631 (CO); 1H‐NMR spectrum
(DMSO‐d6, δ ppm): 1.74 (m, 4H, 2CH2 of tetrahydronaphthalene),
2.76 (m, 4H, 2CH2 of tetrahydronaphthalene), 7.09–7.62 (m, 8H, Ar‐
H), 9.54,9.98 (s, 1H, CHO), 11.96,14.20 (s, 1H, NH, exchangeable
with D2O); 13C‐NMR (DMSO‐d6): δ (ppm): 22.37, 22.53, 28.77,
28.88 (4CH2), 116.65, 123.30, 125.71, 126.13, 127.31, 128.26,
129.19, 130.88, 137.81, 137.84, 138.53, 141.42 (Aromatic‐C),
143.85 (C═N), 188.28, 188.46, 189.99, 191.91 (CO). MS m/z (%):
306 (M+, 85), 186 (100%); Anal. Calcd. for C19H18N2O2 (306.37): re-
quired C, 74.49; H, 5.92; N, 9.14; found C, 74.21; H, 5.99; N, 9.35.
Yield (66%); m.p. 140–142°C; IR spectrum (Biorad FTS, ν,
1
cm−1): 2936 (CH alicyclic), 1590 (C═N); H‐NMR (DMSO‐d6,
δ ppm): 1.75 (m, 8H, 4CH2 of tetrahydronaphthalene), 2.77
(m, 8H, 4CH2 of tetrahydronaphthalene), 7.16–8.14 (m, 9H,
Ar‐H); MS m/z (%): 339 (M+, 20), 208 (37), 159 (100); Anal.
calcd for C25H25N (339.48): required C, 88.45; H, 7.42; N,
4.13; found C, 88.21; H, 7.44; N, 4.35.
1‐[2‐Methyl‐6‐(5,6,7,8‐tetrahydronaphthalen‐2‐yl)‐pyridin‐
3‐yl]‐ethanone (11). To a solution of enaminone 2 (2.29 g, 0.01
mol) and ammonium acetate (1 g, 0.01 mol) in glacial acetic acid
(30 mL), acetyl acetone (1 g, 0.01 mol) was added, and the reaction
mixture was refluxed for 2 h, cooled, poured onto ice‐water. The
separated solid was filtered off and recrystallized from ethanol to
afford compound 11.
Yield (81%); m.p. 104–106°C; IR spectrum (KBr, ν, cm−1): 2926
1
(CH alicyclic), 1646 (CO), 1581 (C═N); H‐NMR (DMSO‐d6, δ
ppm): 1.78 (m, 4H, 2CH2 of tetrahydronaphthalene), 2.59 (s, 3H,
COCH3), 2.69 (s, 3H, CH3), 2.80 (m, 4H, 2CH2 of
tetrahydronaphthalene), 7.21 (d, J = 7.80 Hz, 1H, Ar‐H), 7.51 (s,
1H, Ar‐H), 7.87 (d, J = 7.50 Hz, 1H, Ar‐H), 8.09 (d, J = 8.10 Hz,
1H, pyridyl H‐5), 8.91 (d, J = 8.10 Hz, 1H, pyridyl H‐4); MS m/z
(%): 265 (M+, 86), 250 (100); Anal. calcd for C18H19NO (265.36): re-
quired C, 81.48; H, 7.22; N, 5.28; found C, 81.34; H, 7.41; N, 5.13.
(5,6,7,8‐Tetrahydronaphthalen‐2‐yl)‐2‐thioxohydropyridine‐
3‐carbonitrile (13). To a stirred suspension of 2 (2.29 g, 0.01 mol)
and ammonium acetate (1 g, 0.01 mol) in glacial acetic acid (10 mL),
cyanothioacetamide (1 g, 0.01 mol) was added, and the reaction
mixture was refluxed for 1 h then allowed to cool. The separated
solid was filtered off and recrystallized from ethanol to afford
compound 13. Yield (73%); m.p. 202–204°C; IR spectrum
1
(KBr, ν, cm−1): 3193 (NH), 2928 (CH alicyclic), 2219 (CN); H‐
NMR (DMSO‐d6,
δ
ppm): 1.75 (m, 4H, 2CH2 of
tetrahydronaphthalene),
2.77 (m, 4H, 2CH2 of
tetrahydronaphthalene), 7.19 (d, J = 7.20 Hz, 1H, Ar‐H), 7.49 (d,
J = 7.20 Hz, 1H, Ar‐H), 7.93 (s, 1H, Ar‐H), 8.19 (d, J = 8.40 Hz,
1H, pyridyl H‐5), 8.59 (d, J = 8.40 Hz, 1H, pyridyl H‐4), 12.00 (s,
1H, NH, exchangeable with D2O); MS m/z (%): 266 (M+, 100);
Anal. calcd for C16H14N2S (266.37): required C, 72.15; H, 5.30;
N, 10.52; S, 12.03; found C, 72.14; H, 5.34; N, 10.49; S, 12.23.
2‐Methyl‐6‐(5,6,7,8‐tetrahydronaphthalen‐2‐yl)‐nicotinic acid
ethyl ester (15). To a solution of enaminone 2 (0.573 g, 0.025
mol) and ammonium acetate (0.385 g, 0.005 mol) in glacial acetic
acid (10 mL), ethyl acetoacetate (0.325 g, 0.025 mol) was added,
and the reaction mixture was refluxed for 1 h, then the solvent
was evaporated under reduced pressure, and the residue was
recrystallized from ethanol to give compound 15.
Yield (88%); m.p. 92–94°C; IR spectrum (Biorad FTS, ν,
1
cm−1): 2924 (CH alicyclic), 1719 (CO), 1586 (C═N); H‐NMR
Cytotoxicity assay. All samples (100 mg) were dissolved in
500 μL of ethanol or acetic acid. Cell monolayers Hep2 and
MA104 (obtained from The Holding Company for Biological
Products & Vaccines VACSERA, Egypt) were trypsinized,
washed with culture medium and plated in a 96‐well flat
bottomed plate with 5 × 103 cells per well for both cell lines.
After 24 h incubation, each diluted (Greiner‐Bio one, Germany)
tested materials (10‐fold dilutions of decontaminated samples
(DMSO‐d6, δ ppm) : 1.32 (t, 3H, J = 7.2 Hz, CH3), 1.74
(m, 4H, 2CH2 of tetrahydronaphthalene), 2.73 (s, 3H, CH3),
2.77 (m, 4H, 2CH2 of tetrahydronaphthalene), 4.31 (q, 2H,
OCH2), 7.23 (d, J = 7.4 Hz, 1H,), 7.81–7.87 (m, 2H, Ar‐H),
8.03 (d, J = 8.40 Hz, 1H, pyridyl H‐5), 8.18 (d, J = 8.40 Hz,
1H, pyridyl H‐4); MS m/z (%): 295 (M+, 40), 225 (100); Anal.
calcd for C19H21NO2 (295.38): required C, 77.26; H, 7.17; N,
4.74; found C, 77.49; H, 7.15; N, 4.42.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Enaminone as Building Blocks in Organic Chemistry: A Novel Route to Polyfunctionally
2-Substituted 5,6,7,8-Tetrahydronaphthalenes and Their Antiviral Evaluation
which 12 μL of 100x of antibiotic, antimycotic mixture was added
to 500 μL of each sample) was added to the appropriate wells, and
the plates were incubated for a further 48 h at 37°C in a
humidified incubator with 5% CO2. The supernatants were
removed from the wells, and cell viability was evaluated using
microscopic examination trypan blue and using the MTT
technique [27–29]. The results are obtained from triplicate
assays with at least five extract concentrations. The percentage
of cytotoxicity is calculated as [(A − B)/A] × 100, where A and
B are the OD492 of untreated and of treated cells, respectively.
Antiviral testing. The in vitro antiviral screening method was
used to estimate the inhibition of the cytopathic effect (CPE) of the
pure compounds on MA104 and HEP‐2 cell monolayers infected
with rotavirus Wa strain (ATCC VR‐2018, obtained by Prof. Dr.
Albert Bosch, University of Barcelona, Spain) and adenovirus type
7 (obtained by Dr. Ali Fahmy, VACSERA, EGYPT) using the
end‐point titration technique (EPTT) [30]. Confluent monolayers of
MA104 and HEP‐2 cells were grown in 96‐well microtiter plates,
which were infected with serial 10‐fold dilutions of a rotavirus Wa
strain and adenovirus type 7 suspensions, respectively. The viruses
were allowed to adsorb for 60 min at 37°C, after which serial
twofold dilutions of the test compounds in maintenance medium,
supplemented with 2% serum and antibiotics, were added. The
plates were incubated at 37°C, and the viral cytopathic effect was
recorded by light microscopy after 2–8 days. Virus suspensions are
characterized by their virus titers, which are expressed as the
smallest amount of virus capable of producing a reaction in the
host cells. The antiviral activity is expressed as a reduction factor
(RF), being the ratio of the viral titers in the virus control and in
the presence of the maximal nontoxic dose of test substance.
Chimica Biomolecolare Consiglio Nazionale delle Ricerche via
Campi Flegrei, Pozzuoli, Naples, Italy for IR, NMR, and Mass
measurements of the new compounds. Sincere thankful and
grateful to Prof. Dr. Guido Cimino, Dr. Margrita Givengi, and
Dr. Maria Letizia Ciavatta for their valuable help.
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Acknowledgments. This work was supported by the National
Research Center, Cairo, Egypt. We are grateful to Istituto di
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet