Res Chem Intermed

DOI 10.1007/s11164-014-1679-5

Synthesis of (3-(naphthalen-1-yl)oxiran-2-yl)(5,6,7,8tetrahydronaphthalen-2-yl)methanone and reaction

with some nucleophiles for anticancer evaluation
Rasha S. Gouhar Eman Raafat

Received: 13 January 2014 / Accepted: 16 April 2014

Springer Science+Business Media Dordrecht 2014

Abstract (3-(Naphthalen-1-yl)oxiran-2-yl)(5,6,7,8-tetrahydronaphthalen-2-yl)methanone was prepared and allowed to react with different nucleophile agents such as
hydrazine hydrate, phenyl hydrazine, methyl hydrazine, and hydroxylamine hydrochloride to give hydroxy pyrazole 2 and hydroxy oxazole 3. Also, oxirane 1 reacted with
semicarbazide and thiosemicarbazide to give substituted pyrazole 4a,b. Also, oxirane 1
was allowed to react with carbon disulfide, glycine, substituted isothiocyanate, and
thiourea to give compounds 58, respectively. The thiopyrimidine derivative 8 was
cyclized by chloroacetic acid or ethyl bromoacetate to give thiazolidine derivative 9,
which condensed with different aldehydes to give compound 10ac. Some of these
newly synthesized compounds were evaluated as anticancer agents.
Keywords Pyrazoles
Oxazoles
Thiopyrimidine
Thiazoles
Anticancer agent

Hep-G2 cells
CaCo-2

Introduction
Recently, increasing attention has been paid to synthesis of novel tetrahydronaphthalenes for pharmacological evaluation. Many of them exhibit wide spectra of
pharmacological activities, especially those incorporated into nitrogen, oxygen, and/
or sulfur heterocycles [18].
On the other hand, many pyrazole derivatives possess hyperglycemic activity [9
11]. On the other hand, tyrosine kinase inhibitor [12, 13], many oxathiolanes, and
R. S. Gouhar (&)
Therapeutic Chemistry Department, National Research Centre, Dokki, Cairo, Egypt
e-mail: dr.rasha_gouhar@yahoo.com
E. Raafat
Pharmacology and Toxicology Department, Faculty of Pharmacy, Helwan University, Cairo, Egypt

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R. S. Gouhar, E. Raafat

oxathiazole derivatives show antitumor activity [12, 13]. In this regard, the present
work is concerned with designing and synthesizing a novel series of tetrahydronaphthalenes incorporated directly or indirectly with different biologically active
nitrogen, oxygen, and/or sulfur heterocycles, and evaluation of these newly
synthesized compounds as anticancer agents against human liver carcinoma cell line
Hep-G2 and colon carcinoma cell line CaCo-2, hoping to obtain more active and
less toxic antitumor agents.

Results and discussion

Chemistry
The key compound in this work is (3-(naphthalen-1-yl)oxiran-2-yl)(5,6,7,8tetrahydronaphthalen-2-yl)methanone (1), which was prepared from 3-(naphthalen-1-yl)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)prop-2-en-1-one and hydrogen peroxide in alkaline medium at lower temperature (1015 C). Compound 1 is
considered an interesting starting material for reaction with different nucleophilic
reagents. Treatment of 1 with hydrazine hydrate or phenyl hydrazine in absolute
ethanol gave 5-(naphthalen-1-yl)-3-(5,6,7,8-tetrahydronaphthalen-2-yl)-4,5-dihydro-1H-pyrazol-4-ol (2a) and 5-(naphthalen-1-yl)-1-phenyl-3-(5,6,7,8-tetrahydronaphthalen-2-yl)-4,5-dihydro-1H-pyrazol-4-ol (2b), respectively (Scheme 1). The
chemical structures of compounds 2a,b were confirmed by spectral data. The
infrared (IR) spectra showed a broad band at 3420 cm -1 (OH group), and mass
spectra showed a molecular ion peak at m/z of 342 for 2a and at m/z of 419 for 2b.
Also, reaction of oxirane 1 with hydroxylamine hydrochloride in boiling absolute
ethanolic sodium hydroxide gave 5-(naphthalen-1-yl)-3-(5,6,7,8-tetrahydronaphthalen-2-yl)-4,5-dihydroisoxazol-4-ol (3) (Scheme 1). The chemical structure of
oxazole derivative 3 was confirmed by IR showing a broad band at 3340
cm -1(OH) and by its molecular ion peak at m/z of 343. Moreover, reaction of
oxirane 1 with semicarbazide or thiosemicarbazide gave 4,5-dihydro-3-(1,2,3,4tetrahydronaphthalen-7-yl)-4-hydroxy-5-(naphthalen-4-yl)pyrazole-1-carboximide
(4a) and 4,5-dihydro-3-(1,2,3,4-tetrahydronaphthalen-7-yl)-4-hydroxy-5-(naphthalen-4-yl)pyrazole-1-carbothioamide (4b), respectively. The chemical structure of
carboximide 4a was confirmed by spectral data: the IR (cm-1) spectrum of 4a
revealed the presence of strong absorption bands at 3470 (OH), 3342 (NH2), and
1690 (C=O), while the mass spectrum showed a molecular ion peak at m/z of 385.
Also, the IR (cm-1) spectrum of 4b showed broad bands at 3470 cm-1 (OH) and
3265 (NH2), and the mass spectrum showed a molecular ion peak at m/z of 401,
being the base peak.
Condensation of oxirane 1 with carbon disulfide gave (1,2,3,4-tetrahydronaphthalen-6-yl)(4-(naphthalen-4-yl)-2-thioxo-1,3-oxathiolan-5-yl)methanone (5),
whose mass spectrum showed a molecular ion peak at m/z of 404 (Scheme 1).
On the other hand, cyclocondensation of oxirane 1 with glycine gave (3,4dihydro-6-hydroxy-3-(naphthalen-2-yl)-2H-1,4-oxazin-2-yl)(1,2,3,4-tetrahydronaphthalen-6-yl)methanone (6) (Scheme 2). Its structure was confirmed by the IR

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Synthesis of novel tetrahydronaphthalenes

R
N

R-NH-NH2
EtOH, reflux, 6h

Ar'

Ar
OH
(2a,b)
2a, R = H
b, R = C6H5

O
Ar'

Ar

H2O2

NH2OH.HCl

ethanolic NaOH,reflux, 8h

NaOH
O

Ar'

Ar

stirring, 2 h, r.t.

OH
(3)

Ar'

Ar
X
O
H2N
(1)

C
N
H

NH2

EtOH, reflux, 8h

NH2

Ar'

Ar
OH
(4a,b)
4a, X= O
b, X=S
O

Ar

CS2
EtOH/H2O2, reflux,2h
S

Ar'

(5)
Ar =

Ar' =

Scheme 1 Synthesis of compounds (15)

(cm-1) spectrum, which revealed the presence of strong absorption bands at 3420
(OH), 3046 (NH), and 1650 (C=O). Also, its mass spectrum showed a molecular ion
peak at m/z of 385.
Compound 1 reacted with isothiocyanate derivatives, namely cyclohexyl isothiocyanate, o-tolyl isothiocyanate, p-chlorophenyl isothiocyanate, and p-methoxyphenyl isothiocyanate, in dry pyridine to afford 3-cyclohexyl-3,4-dihydro-6-(1,2,3,4-

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R. S. Gouhar, E. Raafat

H
N

Ar'
H2N-CH2-COOH
O

EtOH, reflux, 8h

Ar

Ar'

OH

O
O

Ar

(6)
O

Ar'
R

(1)
N

R-NCS

pyridine, reflux, 8h
Ar

(7a-d)

7a, R =
b, R =
H3C

c, R =
d, R =

Ar =

Cl
OCH3

Ar' =

Scheme 2 Synthesis of compounds (6,7ad)

tetrahydronaphthalen-6-yl)-4-(naphthalen-1-yl)-1,3-oxazine-2-thione (7a), 3,4-dihydro-6-(1,2,3,4-tetrahydronaphthalen-6-yl)-4-(naphthalen-1-yl)-3-o-tolyl-1,3-oxazine2-thione (7b), 3-(4-chlorophenyl)-3,4-dihydro-6-(1,2,3,4-tetrahydronaphthalen-6-yl)4-(naphthalen-1-yl)-1,3-oxazine-2-thione (7c), and 3,4-dihydro-6-(1,2,3,4-tetrahydronaphthalen-6-yl)-3-(4-methoxyphenyl)-4-(naphthalen-1-yl)-1,3-oxazine-2-thione (7d),

respectively (Scheme 2). The chemical structures of the produced 1,3-oxazine thione
derivatives 7ad were confirmed by spectral data and elemental analysis (Scheme 2).
Compound 1 reacted with thiourea in alkaline medium to afford 5-hydroxy-4naphthalen-1-yl-6-(5,6,7,8-tetrahydronaphthalen-2-yl)-3,4-dihydropyrimidine2(1H)-thione (8) (Scheme 3). The chemical structure of 8 was confirmed by spectral
data: The IR (cm-1) spectrum of 8 revealed the presence of strong absorption bands
at 3400 (OH) and 3220 (NH), and its mass spectrum showed a molecular ion peak at
m/z of 386. Also, the chemical structure of 8 was confirmed by cyclocondensation

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Synthesis of novel tetrahydronaphthalenes

O
Ar'
Ar

S
+

H2N

ethanolic NaOH
reflux, 8h

H
N

Ar

NH2

(1)

NH

HO
Ar'
ClCH2COOH
R-CHO

(8)
ClCH2COOH

acetic cid/acetic anhydride

reflux,4h
Ar

Ar

Ar

R-CHO

N
O

Ar

acetic cid/acetic anhydride

reflux, 6h

R
O

(10a-c)

HO

Ar'

HO

Ar'

Ar'

a, R =

Ar'
(9)

F
OCH3

b, R =

OCH3

Ar =

c, R =
N
H

Ar' =

Scheme 3 Synthesis of compounds (810ac)

reaction with chloroacetic acid to give 7-(1,2,3,4-tetrahydronaphthalen-6-yl)-5(naphthalen-1-yl)-2H-thiazolo[2,3-a]pyrimidine-3,6(5H,7H)-dione (9) (Scheme 3).

The IR (cm-1) spectrum of thiazolopyrimidine derivative 9 showed strong
absorption bands at 3420 (OH) and 1,730 (C=O). Also, its mass spectrum showed
a molecular ion peak at m/z of 426.
Compound 9 was condensed with different aldehydes, namely 4-fluorobenzaldehyde, 3,4-dimethylbenzaldehyde, and indolaldehyde, to give the corresponding
2-(4-fluorobenzylidene)-7-(1,2,3,4-tetrahydronaphthalen-6-yl)-5-(naphthalen-1-yl)2H-thiazolo[2,3-a]pyrimidine-3,6(5H,7H)-dione (10a), 2-(3,4-dimethylbenzylidene)-7-(1,2,3,4-tetrahydronaphthalen-6-yl)-5-(naphthalen-1-yl)-2H-thiazolo[2,3-a]
pyrimidine-3,6(5H,7H)-dione (10b), and 2-((1H-indol-3-yl)methylene)-7-(1,2,3,4tetrahydronaphthalen-6-yl)-5-(naphthalen-1-yl)-2H-thiazolo[2,3-a]pyrimidine-3,6
(5H,7H)-dione (10c), respectively (Scheme 3). Also, compounds 10ac could be
prepared by one-pot reaction of compound 8 with chloroacetic acid and aromatic
aldehydes in glacial acetic acid and acetic anhydrides. The spectral data of
compounds 10ac prepared from compound 9 or through one-pot reaction of
compound 8 showed identical data (Scheme 3).

Biological activity
Eight of the newly synthesized compounds were selected as representative examples
to evaluate their in vitro cytotoxic activity against two different types of carcinoma

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R. S. Gouhar, E. Raafat
Table 1 In vitro anticancer activity of selected compounds against Hep-G2 and CaCo-2 cell lines
Compound

IC50 (lM)
Hep-G2 cells

CaCo-2 cells

12.52 0.220

2b

16.88 0.29

16.98 0.27
2.64 0.28

4a

16.31 0.23

10.99 0.88

20.1 0.42

29.15 1.67

7b

25.96 1.39

10.63 0.10

24.1 1.78

10.007 0.24

21.27 0.85

16.47 0.10

10c

24.09 0.60

19.65 2.33

16.2 4.1

6.90 1.01

Doxorubicin (DOX)

cell line: human liver carcinoma cells (Hep-G2) and heterogeneous human
epithelial colorectal adenocarcinoma cells (CaCo-2) using the known anticancer
drug doxorubicin (DOX) as reference standard [14]. Cytotoxic activity is
expressed as the IC50 value (the dose reducing cell survival to 50 %). According
to Table 1, regarding the Hep-G2 cell line, it is noted that all of the tested
compounds exhibited cytotoxic activity to varying degrees. The highest potency
was obtained for the starting oxirane derivative 1 with IC50 of 12.52 lM, which
was higher than that obtained for the reference drug doxorubicin (IC50 of
16.2 lM). At the same time, cytotoxic activity equipotent to doxorubicin was
achieved by the pyrazoline derivatives 2b and 4a (IC50 of 16.88 and 16.31 lM,
respectively). Replacement of the pyrazoline ring by a 1,4-oxazine ring or the
fused thiazolo[2,3-a]pyrimidine ring system (compounds 6 and 9) produced a
noticeable reduction in activity to IC50 of 20.1 and 21.27 lM, respectively. A
further remarkable reduction in cytotoxicity was observed for the derivatives
carrying 1,3-oxazine, 3,4-dihydropyrimidine, and 2-indolomethylene-thiazolo[2,3a]pyrimidine rings (compounds 7b, 8, and 10c with IC50 of 25.96, 24.1, and
24.09 lM, respectively). Regarding the CaCo-2 cell line, the data showed that
cytotoxic activity more potent than that of doxorubicin (IC50 of 6.90 lM) was
exhibited by the 2-phenylpyrazoline compound 2b (IC50 of 2.64 lM). A
noticeable decrease in cytotoxicity was observed for compounds 4a, 7b, and 8
(IC50 of 10.99, 10.63, and 10 lM, respectively). A further reduction in potency to
approximately 2.53 times less than that of the reference drug was observed for
derivatives 1, 9, and 10c (IC50 of 16.98, 16.47, and 19.65 lM, respectively).
Attachment of 1,4-oxazine moiety to tetralin ring led to a dramatic decrease in
cytotoxic potency (IC50 of 29.15 lM).
It can be noted that the tested compounds showed more potent cytotoxic activity
against the human liver carcinoma cells (Hep-G2) than against the CaCo-2 cell line.
Also, the 2-phenylpyrazoline derivative 2b exhibited dual activity against both
tested carcinoma cell lines.

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Conclusions
In this work, new derivatives of the tetrahydronaphthalene nucleus incorporated
with various heterocyclic ring systems, such as oxirane, pyrazoline, isoxazoline,
1,3-oxathiolane, oxazine, 3,4-dihydropyrimidine, and thiazolo[2,3-a]pyrimidine
rings, were synthesized. Cytotoxic activity evaluation of some of these compounds
showed that the most potent activity was exhibited by the oxirane and pyrazoline
derivatives 1, 2b, and 4a against the Hep-G2 carcinoma cell line, compared with
doxorubicin. Meanwhile, the 2-phenylpyrazoline compound 2b was the most active
derivative, even more so than the standard drug, against the CaCo-2 carcinoma cell
line. Further structural modification is required in future study to obtain new
compounds with greater potency and broader cytotoxic activity.

Experimental
All melting points were uncorrected and were taken in open capillary tubes using an
Electrothermal IA 9100 digital melting point apparatus. Elemental microanalyses
were carried out on an Elementar vario EL at the Microanalytical Laboratory,
Central Services Laboratory, National Research Center, Dokki, Cairo, Egypt, and
were found to be within 0.5 % of theoretical values. Infrared spectra were
recorded on an FT/IR 6100 Fourier-transform infrared spectrometer (Japan) on
cm-1 scale using the KBr disc technique. 1H NMR spectra were obtained using a
JEOL EX-270 NMR spectrometer and measured on the d scale using tetramethylsilane (TMS) as internal standard. Mass spectra were measured using a Finnegan
MAT SSQ-7000 mass spectrometer. The reactions were followed and the purity of
the compounds checked using thin-layer chromatography (TLC) on silica gelprecoated aluminum sheets (type 60, f254; Merck, Darmstadt, Germany), and the
spots were detected by exposure to ultraviolet (UV) lamp at k = 254 nm for a few
seconds. The chemical names given for the prepared compounds are according to
the IUPAC system.
Synthesis of (3-(naphthalen-1-yl)oxiran-2-yl)(5,6,7,8-tetrahydronaphthalen-2yl)methanone (1)
Hydrogen peroxide (9 mL, 36 %) was added dropwise to a mixture of 3-(naphthalen1-yl)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)prop-2-en-1-one (3.12 g, 10 mmol) in acetone (30 mL) and methanol (1 mL) containing sodium hydroxide (1 g) at 1015 C
with stirring for 2 h at room temperature. The solid substance was filtered off, washed
with water, dried, and crystallized from methanol to give compound 1 as white needle
crystals: yield 78 %; m.p. 117 C. 1H NMR (270 MHz, CDCl3): d = 1.72 (4 H, 2
CH2, tetrahydronaphthalene, m), 2.74 (4 H, 2 CH2, tetrahydronaphthalene, m), 4.5 (2
H, 2 CH, epoxide ring, t), 7.008.10 (10 H, m, Ph) ppm; 13C NMR (CDCl3):
d = 22.1, 32.0 (CH2, tetrahydronaphthalene), 61.2, 70.3 (CH, epoxide ring), 123.6,
126.3, 127.3, 132.4, 134.0, 134.1, 136.5, 140.4, 141.8 (aromatic, CH), 199.5 (C=O)

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R. S. Gouhar, E. Raafat

ppm. MS (EI, 70 eV): m/z (%) = 328 (7 %) [M]?; Anal. for C23H20O2 (328.40):
calcd. C, 88.43; H, 6.45; found: C, 87.93; H, 5.95.
General synthesis of 2a and 2b
A mixture of compound 1 (1.56 g, 5 mmol) and the appropriate hydrazine, namely
hydrazine hydrate or phenyl hydrazine (10 mmol), in absolute ethanol (25 mL) was
refluxed for 6 h. The solid substance formed on cooling was crystallized from
ethanol to give compounds 2a and 2b, respectively.
5-(Naphthalen-1-yl)-3-(5,6,7,8-tetrahydronaphthalen-2-yl)-4,5-dihydro-1Hpyrazol-4-ol (2a)
Yellow crystals, yield 55 %; m.p. 89 C; IR (KBr): m~ = 3420 (br, OH), 3049 (NH),
2925 (CH2, tetrahydronaphthalene) cm-1; 1H NMR (270 MHz, CDCl3): d = 1.72 (4
H, 2 CH2, tetrahydronaphthalene, m), 2.74 (4 H, 2 CH2, tetrahydronaphthalene, m),
4.00 (1 H, CH, pyrazole, d), 4.80 (1 H, CH, pyrazole, d), 7.168.20 (10 H, m, Ph) ppm;
13
C NMR (CDCl3): d = 23.1, 32.0 (CH2, tetrahydronaphthalene), 53.3 (CH, pyrazole
ring), 83.1 (COH, pyrazole ring), 124.2, 126.3, 127.3, 128.0, 130.5, 132.4, 133.1,
134.0, 138.1 (aromatic, CH), 156.1 (C=N, pyrazole ring) ppm. MS (EI, 70 eV): m/
z (%) = 342 (5 %) [M]?; Anal. for C23H22N2O (342.43): calcd. C, 80.67; H, 6.48; N,
8.18; found: C, 80.45; H, 6.04; N, 7.85.
5-(Naphthalen-1-yl)-1-phenyl-3-(5,6,7,8-tetrahydronaphthalen-2-yl)-4,5-dihydro1H-pyrazol-4-ol (2b)
Yellow crystals, yield 60 %; m.p. 78 C; IR (KBr): m~ = 3420 (br, OH), 2926 (CH2,
tetrahydronaphthalene) cm-1; 1H NMR (270 MHz, CDCl3): d = 1.72 (4 H, 2 CH2,
tetrahydronaphthalene, m), 2.74 (4 H, 2 CH2, tetrahydronaphthalene, m), 4.00 (1 H,
CH, pyrazole, d), 4.80 (1 H, CH, pyrazole, d), 6.78.10 (15 H, m, Ph) ppm; 13C
NMR (CDCl3): d = 23.1, 32.0 (CH2, tetrahydronaphthalene), 113.0, 115.1, 118.2,
126.3, 127.3, 128.0, 130.5, 132.4, 133.1, 134.0, 137.1, 140.4, 141.8 (aromatic, C
H), 125.1 (COH, pyrazole ring), 150.3 (CH, pyrazole ring), 155.1 (C=N, pyrazole
ring) ppm. MS (EI, 70 eV): m/z (%) = 342 (5 %) [M]?; Anal. for C23H22N2O
(342.43): calcd. C,80.67; H, 6.48; N, 8.18; found: C, 80.45; H, 6.04; N, 7.85.
Synthesis of 5-(naphthalen-1-yl)-3-(5,6,7,8-tetrahydronaphthalen-2-yl)-4,5dihydroisoxazol-4-ol (3)
A mixture of compound 1 (1.56 g, 5 mmol) and hydroxylamine hydrochloride
(0.35 g, 5 mmol) was stirred under reflux in ethanolic sodium hydroxide (0.5 g,
30 mL) for 8 h. The reaction mixture was cooled and poured onto water (100 mL).
The solid substance was filtered off and crystallized from methanol to give
compound 3 as yellow crystals; yield 58 %; m.p. 83 C; IR (KBr): m~ = 3340 (br,
OH), 2925 (CH2, tetrahydronaphthalene) cm-1; 1H NMR (270 MHz, CDCl3):
d = 1.72 (4 H, 2 CH2, tetrahydronaphthalene, m), 2.72 (4 H, 2 CH2,

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Synthesis of novel tetrahydronaphthalenes

tetrahydronaphthalene, m), 4.00 (1 H, CH, pyrazole, d), 4.60 (1 H, CH, pyrazole, d),
7.208.20 (10 H, m, Ph) ppm; 13C NMR (CDCl3): d = 23.1, 32.0 (CH2,
tetrahydronaphthalene), 73.1 (CH, isoxazole ring), 122.1 (COH, isoxazole ring),
123.1, 126.3, 127.3, 128.0, 129.1, 130.5, 132.4, 133.1, 134.0, 137.1, 140.4, 141.8
(aromatic, CH), 164.1 (C=N, isoxazole ring) ppm. MS (EI, 70 eV): m/z (%) = 343
(20 %) [M]?; Anal. for C23H21NO2 (343.42): calcd. C,80.44; H, 6.16; N, 4.08;
found: C, 80.19; H, 6.02; N, 3.58.
General synthesis of 4a and 4b
A mixture of compound 1 (1.56 g, 5 mmol) and the appropriate carbazide, namely
semicarbazide or thiosemicarbazide (5 mmol), in absolute ethanol (25 mL) was
refluxed for 8 h. The solid substance was filtered off and crystallized from ethanol
to give compounds 4a and 4b, respectively.
4,5-Dihydro-3-(1,2,3,4-tetrahydronaphthalen-7-yl)-4-hydroxy-5-(naphthalen-4yl)pyrazole-1-carboximide (4a)
Yellow crystals; yield 52 %; m.p. 102 C; IR (KBr): m~ = 3470 (br, OH), 3342
(NH2), 2926 (CH2, tetrahydronaphthalene), 1,690 (C=O) cm-1; 1H NMR
(270 MHz, CDCl3): d = 1.60 (4 H, 2 CH2, tetrahydronaphthalene, m), 2.85 (4 H,
2 CH2, tetrahydronaphthalene, m), 4.00 (1 H, CH, pyrazole, d), 5.00 (1 H, CH,
pyrazole, d), 7.207.80 (10 H, m, Ph) ppm; 13C NMR (CDCl3): d = 23.1, 32.0
(CH2, tetrahydronaphthalene), 50.3 (CH, pyrazole ring), 80.1 (COH, pyrazole
ring), 124.1, 126.3, 127.3, 128.0, 130.5, 132.4, 133.1, 134.0, 137.1 (aromatic, CH),
155.1 (C=O), 156.1 (C=N, pyrazole ring) ppm. MS (EI, 70 eV): m/z (%) = 385
(5 %) [M]?; Anal. for C24H23N3O2 (385.46): calcd. C, 74.78; H, 6.01; N, 10.90;
found: C, 74.67; H, 5.59; N, 10.59.
4,5-Dihydro-3-(1,2,3,4-tetrahydronaphthalen-7-yl)-4-hydroxy-5-(naphthalen-4yl)pyrazole-1-carbothioamide (4b)
Yellow crystals; yield 63 %; m.p. 130 C; IR (KBr): m~ = 3370 (br, OH), 3265
(NH2), 2926 (CH2, tetrahydronaphthalene) cm-1; 1H NMR (270 MHz, CDCl3):
d = 1.60 (4 H, 2 CH2, tetrahydronaphthalene, m), 2.85 (4 H, 2 CH2, tetrahydronaphthalene, m), 3.80 (1 H, CH, pyrazole, d), 4.00 (1 H, CH, pyrazole, d), 7.207.80
(10 H, m, Ph) ppm; 13C NMR (CDCl3): d = 22.1, 31.0 (CH2, tetrahydronaphthalene), 56.3 (CH, pyrazole ring), 81.1 (COH, pyrazole ring), 124.1, 126.3, 127.3,
128.0, 130.5, 132.4, 133.1, 134.0, 137.1 (aromatic, CH), 155.1 (C=N, pyrazole
ring), 173.1 (C=S) ppm. MS (EI, 70 eV): m/z (%) = 401 (100 %) [M]?; Anal. for
C24H23N3OS(401.52): calcd. C, 71.79; H, 5.77; N, 10.47; found: C, 71.52; H, 5.33;
N, 10.22.

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Synthesis of (1,2,3,4-tetrahydronaphthalen-6-yl)(4-(naphthalen-4-yl)-2-thioxo-1,3oxathiolan-5-yl)methanone (5)

A mixture of compound 1 (1.56 g, 5 mmol) and carbon disulfide (5 mmol) was
stirred in absolute ethanol containing hydrogen peroxide (36 %) as catalyst (1 mL),
then the reaction mixture was refluxed for 2 h. The solid substance was filtered off
after cooling and crystallized from ethanol to give compound 5 as yellow crystals;
yield 63 %; m.p. 130 C; IR (KBr): m~ = 2925 (CH2, tetrahydronaphthalene) cm-1;
1
H NMR (270 MHz, CDCl3): d = 1.60 (4 H, 2 CH2, tetrahydronaphthalene, m),
2.80 (4 H, 2 CH2, tetrahydronaphthalene, m), 4.45 (1 H, CH, pyrazole, d), 5.40 (1 H,
CH, pyrazole, d), 7.007.70 (10 H, m, Ph) ppm; 13C NMR (CDCl3): d = 23.1, 32.0
(CH2, tetrahydronaphthalene), 51.1 (CH-S, oxathiolane ring), 102.1 (CHO,
oxathiolane ring), 123.1, 126.3, 127.3, 128.0, 129.1, 130.5, 132.4, 133.1, 134.0,
137.1, 140.4 (aromatic, CH), 197.1 (C=O), 209.0 (C=S) ppm. MS (EI, 70 eV): m/
z (%) = 404 (20 %) [M]?; Anal. for C24H20O2S2 (404.54): calcd. C, 71.25; H, 4.98;
found: C, 70.98; H, 4.48.
Synthesis of (3,4-dihydro-6-hydroxy-3-(naphthalen-2-yl)-2H-1,4-oxazin-2yl)(1,2,3,4-tetrahydronaphthalen-6-yl)methanone (6)
A mixture of compound 1 (1.56 g, 5 mmol) and glycine (0.37 g, 5 mmol) was
refluxed in absolute ethanol (15 mL) for 8 h. The reaction mixture was cooled and
poured onto water (100 mL). The solid substance was filtered off and crystallized
from methanol to give compound 6 as yellow crystals; yield 73 %; m.p. 117 C; IR
(KBr): m~ = 3420 (br, OH), 3046 (NH), 2926 (CH2, tetrahydronaphthalene) cm-1;
1
H NMR (270 MHz, CDCl3): d = 1.60 (4 H, 2 CH2, tetrahydronaphthalene, m),
2.85 (4 H, 2 CH2, tetrahydronaphthalene, m), 3.60 (1 H, CH, morpholine, t), 5.10 (1
H, CH, morpholine, d), 6.00 (1 H, CH, morpholine, d), 7.107.80 (10 H, m, Ph)
ppm; 13C NMR (CDCl3): d = 23.1, 32.0 (CH2, tetrahydronaphthalene), 53.1, 58.0
(2CHN, oxazine ring), 97.1 (CHO, oxazine ring), 123.1, 126.3, 127.3, 128.0,
129.1, 130.5, 132.4, 133.1, 134.0, 137.1, 140.4 (aromatic, CH), 171.1 (lactone
C=O), 197.1 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 385 (20 %) [M]?; Anal. for
C25H23NO3(385.46): calcd. C, 77.90; H, 6.01; N, 3.63; found: C, 77.57; H, 5.79; N,
3.49.
General synthesis of 7ad
A mixture of compound 1 (1.56 g, 5 mmol) and the appropriate isocyanate, namely
cyclohexyl isothiocyanate, o-tolyl isothiocyanate, 4-chlorophenyl isothiocyanate, or
4-methoxyphenyl isothiocyanate (5 mmol), was refluxed in dry pyridine for 8 h.
After cooling, the reaction mixture was poured gradually with stirring onto cold
water (100 mL). The solid substance was filtered off and crystallized from benzene
to give compounds 7ad, respectively.

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Synthesis of novel tetrahydronaphthalenes

3-Cyclohexyl-3,4-dihydro-6-(1,2,3,4-tetrahydronaphthalen-6-yl)-4-(naphthalen-1yl)-1,3-oxazine-2-thione (7a)
Yellow crystals; yield 65 %; m.p. 115 C; IR (KBr): m~ = 2928 (CH2, tetrahydronaphthalene) cm-1; 1H NMR (270 MHz, CDCl3): d = 1.402.85 (18 H, 5 CH2,
cyclohexyl, tetrahydronaphthalene, m), 2.85 (4 H, 2 CH2, tetrahydronaphthalene,
m), 2.60 (1 H, CH, cyclohexyl, t), 4.60 (1 H, CH, morpholine, d), 7.007.70 (10 H,
m, Ph) ppm; 13C NMR (CDCl3): d = 23.1, 32.0, 28.1, 57.5 (CH2, cyclohexyl), 24.3,
33.6 (CH2, tetrahydronaphthalene), 52.1 (CHN, oxazine ring), 88.1 (=CH, oxazine
ring), 124.1, 126.3, 127.3, 128.0, 129.1, 130.5, 132.4, 133.1, 134.0, 136.1 (aromatic,
CH), 143.1 (C=S), 167.1 (=CO, oxazine ring) ppm. MS (EI, 70 eV): m/
z (%) = 453 (5 %) [M]?; Anal. for C30H31NOS (453.64): calcd. C, 79.43; H, 6.89;
N, 3.09; found: C, 79.21; H, 6.64; N, 2.59.
3,4-Dihydro-6-(1,2,3,4-tetrahydronaphthalen-6-yl)-4-(naphthalen-1-yl)-3-o-tolyl1,3-oxazine-2-thione (7b)
Yellow crystals; yield 68 %; m.p. 128 C; IR (KBr): m~ = 2928 (CH2, tetrahydronaphthalene) cm-1; 1H NMR (270 MHz, CDCl3): d = 1.60 (4 H, 2 CH2,
tetrahydronaphthalene, m), 2.30 (3 H, CH3, s), 2.85 (4 H, 2 CH2, tetrahydronaphthalene, m), 4.50 (1 H, CH, morpholine, d), 6.207.70 (14 H, m, Ph) ppm; 13C NMR
(CDCl3): d = 16.6 (CH3), 23.1, 32.0 (CH2, tetrahydronaphthalene), 54.1 (CHN,
oxazine ring), 88.1 (=CH, oxazine ring), 123.1, 126.3, 127.3, 128.0, 129.1, 130.5,
132.4, 133.1, 134.0, 137.1, 140.4 (aromatic, CH), 144.1 (C=S), 167.1 (=CO,
oxazine ring) ppm. MS (EI, 70 eV): m/z (%) = 461 (5 %) [M]?; Anal. for
C31H27NOS (461.62): calcd. C, 80.66; H, 5.90; N, 3.03; found: C, 81.10; H, 6.04; N,
3.44.
3-(4-Chlorophenyl)-3,4-dihydro-6-(1,2,3,4-tetrahydronaphthalen-6-yl)-4(naphthalen-1-yl)-1,3-oxazine-2-thione (7c)
Yellow crystals; yield 65 %; m.p. 136 C; IR (KBr): m~ = 2928 (CH2, tetrahydronaphthalene) cm-1; 1H NMR (270 MHz, CDCl3): d = 1.60 (4 H, 2 CH2,
tetrahydronaphthalene, m), 2.85 (4 H, 2 CH2, tetrahydronaphthalene, m), 4.50 (1
H, CH, morpholine, d), 6.207.70 (14 H, m, Ph) ppm; 13C NMR (CDCl3): d = 23.1,
32.0 (CH2, tetrahydronaphthalene), 54.1 (CHN, oxazine ring), 88.1 (=CH, oxazine
ring), 123.1, 126.3, 127.3, 128.0, 129.1, 130.5, 132.4, 133.1, 134.0, 137.1, 140.4
(aromatic, CH), 143.1 (C=S), 167.1 (=CO, oxazine ring) ppm. MS (EI, 70 eV): m/
z (%) = 481.5, 483.5 (Cl isotope) [M]?; Anal. for C30H24NOS (482.04): calcd. C,
74.75; H, 5.02; N, 2.91; found: C, 74.36; H, 4.84; N, 2.57.
3,4-Dihydro-6-(1,2,3,4-tetrahydronaphthalen-6-yl)-3-(4-methoxyphenyl)-4(naphthalen-1-yl)-1,3-oxazine-2-thione (7d)
Yellow crystals; yield 72 %; m.p. 143 C; IR (KBr): m~ = 2928 (CH2, tetrahydronaphthalene) cm-1; 1H NMR (270 MHz, CDCl3): d = 1.60 (4 H, 2 CH2,

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R. S. Gouhar, E. Raafat

tetrahydronaphthalene, m), 2.85 (4 H, 2 CH2, tetrahydronaphthalene, m), 3.75 (3 H,

OCH3, s), 4.50 (1 H, CH, morpholine, d), 6.207.70 (14 H, m, Ph) ppm; 13C NMR
(CDCl3): d = 23.1, 32.0 (CH2, tetrahydronaphthalene), 55.1 (CHN, oxazine ring),
57.0 (OCH3), 88.1 (=CH, oxazine ring), 115.1, 123.1, 126.3, 127.3, 128.0, 129.1,
130.5, 132.4, 133.1, 134.0, 137.1, 140.4 (aromatic, CH), 145.1 (C=S), 167.1 (=C
O, oxazine ring) ppm. MS (EI, 70 eV): m/z (%) = 477 (50 %) [M]?; Anal. for
C31H27NO2S (477.62): calcd. C, 77.96; H, 5.70; N, 2.93; found: C, 78.46; H, 6.18;
N, 3.07.
Synthesis of 5-hydroxy-4-naphthalen-1-yl-6-(5,6,7,8-tetrahydronaphthalen-2yl)-3,4-dihydropyrimidine-2(1H)-thione (8)
A mixture of compound 1 (1.56 g, 5 mmol) and thiourea (0.76 g, 10 mmol) was
refluxed in ethanolic sodium hydroxide (1 g, 30 mL) for 8 h. The reaction mixture
was cooled and poured onto water (100 mL), extracted with benzene (50 mL), then
dried with anhydrous Na2SO4. The inorganic layer was filtered off, and the mother
liquor was concentrated under reduced pressure; yellow crystals were obtained,
which recrystallized from dioxane to give compound 8 as yellow crystals; yield
75 %; m.p. 68 C; IR (KBr): m~ = 3400 (br, OH), 3220 (NH), 2926 (CH2,
tetrahydronaphthalene) cm-1; 1H NMR (270 MHz, CDCl3): d = 1.72 (4 H, 2 CH2,
tetrahydronaphthalene, m), 2.74 (4 H, 2 CH2, tetrahydronaphthalene, m), 4.60 (1 H,
CH, pyrimidine, m), 7.008.20 (10 H, m, Ph) ppm; 13C NMR (CDCl3): d = 23.1,
32.0 (CH2, tetrahydronaphthalene), 61.1 (CHN, pyrimidine ring), 123.1, 126.3,
127.3, 128.0, 129.1, 130.5, 132.4, 133.1, 134.0, 136.1 (aromatic, CH), 131.1 (=CNH, pyrimidine ring), 148.4 (=COH, pyrimidine ring), 183.1 (C=S) ppm; MS (EI,
70 eV): m/z (%) = 386 (15 %) [M]?; Anal. for C24H22N2OS (386.51): calcd. C,
74.58; H, 5.74; N, 7.25; found: C, 75.08; H, 6.24; N, 7.75.
Synthesis of 7-(1,2,3,4-tetrahydronaphthalen-6-yl)-5-(naphthalen-1-yl)-2Hthiazolo[2,3-a]pyrimidine-3,6(5H,7H)-dione (9)
A mixture of compound 8 (1.93 g, 5 mmol) with chloroacetic acid (0.96 g,
10 mmol) and anhydrous sodium acetate (3 g) was refluxed in glacial acetic acid
(30 mL)/acetic anhydride (10 mL) for 6 h. The reaction mixture was cooled and
poured gradually with stirring onto cold water (100 mL); the formed solid was
filtered off and crystallized from ethanol to give compound 9 as yellow crystals;
yield 60 %; m.p. 110 C; IR (KBr): m~ = 3418 (br, OH), 2928 (CH2, tetrahydronaphthalene), 1730 (C=O) cm-1; 1H NMR (270 MHz, CDCl3): d = 1.60 (4 H, 2
CH2, tetrahydronaphthalene, m), 2.85 (4 H, 2 CH2, tetrahydronaphthalene, m), 3.70
(2 H, CH2, thiazole, s), 6.807.50 (10 H, m, Ph) ppm; 13C NMR (CDCl3): d = 23.1,
32.0 (CH2, tetrahydronaphthalene), 32.1 (CH2, thiazole ring), 60.1 (CH, pyrimidine
ring), 87.0 (CH, pyrimidine ring), 125.1, 126.3, 127.3, 128.0, 129.1, 130.5, 132.4,
133.1, 135.0, 136.1 (aromatic, CH), 155.1 (C=N, pyrimidine ring), 173.4 (C=O,
thiazole ring), 206.1 (C=O, pyrimidine ring) ppm; MS (EI, 70 eV): m/z (%) = 426
(30 %) [M]?; Anal. for C26H22N2O2S (426.53): calcd. C, 73.21; H, 5.20; N, 6.57;
found: C, 73.56; H, 5.38; N, 6.73.

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Synthesis of novel tetrahydronaphthalenes

General synthesis of 10ac

Method A
A mixture of compound 9 (2.13 g, 5 mmol) and the appropriate aldehyde, namely
4-fluorobenzaldehyde, 3,4-dimethylbenzaldehyde or indolaldehyde (5 mmol), and
anhydrous sodium acetate (3 g) was refluxed in glacial acetic acid (30 mL)/acetic
anhydride (10 mL) for 4 h. The reaction mixture was cooled and poured gradually
with stirring onto cold water (100 mL), and the formed solid was filtered off and
recrystallized from acetic acid to give compounds 10ac, respectively.
Method B
A mixture of compound 8 (1.93 g, 5 mmol) with chloroacetic acid (0.96 g,
10 mmol) and the appropriate aldehyde, namely 4-fluorobenzaldehyde, 3,4dimethylbenzaldehyde or indolaldehyde (5 mmol), and anhydrous sodium acetate
(3 g) was refluxed in glacial acetic acid (30 mL)/acetic anhydride (10 mL) for 3 h.
The reaction mixture was cooled and poured gradually with stirring onto cold water
(100 mL), and the formed solid was filtered off and recrystallized from acetic acid
to give compounds 10ac, respectively, identical in all aspects to authentic samples.
2-(4-Fluorobenzylidene)-7-(1,2,3,4-tetrahydronaphthalen-6-yl)-5-(naphthalen-1yl)-2H-thiazolo[2,3-a]pyrimidine-3,6(5H,7H)-dione (10a) Yellow crystals; yield
65 %; m.p. 125 C; IR (KBr): m~ = 3400 (br, OH), 2926 (CH2, tetrahydronaphthalene) cm-1; 1H NMR (270 MHz, CDCl3): d = 1.60 (4 H, 2 CH2, tetrahydronaphthalene, m), 2.74 (4 H, 2 CH2, tetrahydronaphthalene, m), 6.807.80 (15 H, m, Ph)
ppm; 13C NMR (CDCl3): d = 23.1, 32.0 (CH2, tetrahydronaphthalene), 59.1 (CH,
pyrimidine ring), 87.0 (CH, pyrimidine ring), 115.2, 142.1 (C=CH, side chain),
125.1, 126.3, 127.3, 128.0, 129.1, 130.5, 132.4, 133.1, 135.0, 136.1, 162.2
(aromatic, CH), 163.1 (C=N, pyrimidine ring), 166.4 (C=O, thiazole ring), 206.1
(C=O, pyrimidine ring) ppm; MS (EI, 70 eV): m/z (%) = 532 (20 %) [M]?; Anal.
for C33H25FN2O2S (532.63): calcd. C, 74.41; H, 4.73; N, 5.26; found: C, 74.22; H,
4.23; N, 5.11.
2-(3,4-Dimethylbenzylidene)-7-(1,2,3,4-tetrahydronaphthalen-6-yl)-5-(naphthalen1-yl)-2H-thiazolo[2,3-a]pyrimidine-3,6(5H,7H)-dione (10b) Yellow crystals;
yield 68 %; m.p. 95 C; IR (KBr): m~ = 3400 (br, OH), 2926 (CH2, tetrahydronaphthalene) cm-1; 1H NMR (270 MHz, CDCl3): d = 1.60 (4 H, 2 CH2,
tetrahydronaphthalene, m), 2.74 (4 H, 2 CH2, tetrahydronaphthalene, m), 3.75 (6
H, OCH3, s), 6.807.80 (15 H, m, Ph) ppm; 13C NMR (CDCl3): d = 23.1, 32.0
(CH2, tetrahydronaphthalene), 57.1 (OCH3), 60.1 (CH, pyrimidine ring), 88.0 (CH,
pyrimidine ring), 116.2, 145.1 (C=CH, side chain), 125.1, 126.3, 127.3, 128.0,
129.1, 130.5, 132.4, 133.1, 135.0, 136.1, 150.2 (aromatic, CH), 165.1 (C=N,
pyrimidine ring), 168.4 (C=O, thiazole ring), 206.1 (C=O, pyrimidine ring) ppm;

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R. S. Gouhar, E. Raafat

MS (EI, 70 eV): m/z (%) = 574 (25 %) [M]?; Anal. for C35H30N2O4S (574.69):
calcd. C, 73.15; H, 5.26; N, 4.87; found: C, 73.40; H, 5.54; N, 5.04.
2-((1H-Indol-3-yl)methylene)-7-(1,2,3,4-tetrahydronaphthalen-6-yl)-5-(naphthalen1-yl)-2H-thiazolo[2,3-a]pyrimidine-3,6(5H,7H)-dione (10c) Yellow crystals;
yield 68 %; m.p. 95 C; IR (KBr): m~ = 3420 (br, OH), 2926 (CH2, tetrahydronaphthalene), 1740 (C=O) cm-1; 1H NMR (270 MHz, CDCl3): d = 1.60 (4 H, 2
CH2, tetrahydronaphthalene, m), 2.85 (4 H, 2 CH2, tetrahydronaphthalene, m), 5.60
(1 H, CH, pyrimidine, s), 6.807.80 (15 H, m, Ph) ppm; 13C NMR (CDCl3):
d = 23.1, 32.0 (CH2, tetrahydronaphthalene), 59.1 (CH, pyrimidine ring), 87.0 (CH,
pyrimidine ring), 122.2, 142.1 (C=CH, side chain), 110.3, 111.4, 117, 6, 122.2,
124.3, 125.1, 126.3, 127.3, 128.0, 130.5, 132.4, 133.1, 135.0, 136.1, 162.2
(aromatic, CH), 163.1 (C=N, pyrimidine ring), 166.4 (C=O, thiazole ring), 206.1
(C=O, pyrimidine ring) ppm; MS (EI, 70 eV): m/z (%) = 553 (3 %) [M]?; Anal. for
C35H27N3O2S (553.67): calcd. C, 75.92; H, 4.92; N, 7.59; found: C, 75.45; H, 4.66;
N, 7.37.
Anticancer evaluation [14] Cell culture and treatment All reagents were
handled in a sterile fume hood. Dulbeccos modified Eagles medium (DMEM)
and fetal bovine serum (FBS) were purchased from Gibco; phosphate-buffered
saline pH 7.4 (PBS) and trypsinethylenediaminetetraacetic acid (EDTA) were
obtained from Sigma-Aldrich. Alamar Blue or Resazurin (Promega, Mannheim,
Germany) reduction assay was used to assess the cytotoxicity of the studied
samples. The growth medium (DMEM with 10 % FBS, 100 U/mL penicillin, and
100 mg/L streptomycin) and Alamar Blue were stored at 48 C, while trypsin
EDTA and FBS were stored frozen at -208 C and thawed before use; PBS was
stored at room temperature. Hep-G2 and CaCo-2 were obtained from the German
Cancer Research Center (DKFZ). Cells were cultured in 50-cm2 culture flasks
(Corning) using DMEM supplemented with 10 % FBS, penicillin (100 U/mL), and
streptomycin (100 mg/mL). The culture was maintained at 37 C in an atmosphere
of 5 % CO2 and 95 % relative humidity. The cells were transferred to a new flask
every 2 days and treated with trypsinEDTA to detach them from the flask. Cells
were counted under a microscope using a hemacytometer (Hausser Scientific). Cell
solutions were diluted with growth medium to concentration of 1 9 105 cells/mL
and transferred to a 96-well plate, then treated with gradient concentrations of test
compounds.
Resazurin cell growth inhibition assay Alamar Blue or Resazurin (Promega,
Mannheim, Germany) reduction assay was used to assess the cytotoxicity of the
studied samples. The assay tests cellular viability and mitochondrial function.
Briefly, adherent cells were grown in tissue culture flasks, and then harvested by
treating the flasks with 0.025 % trypsin and 0.25 mM EDTA for 5 min. Once
detached, cells were washed and counted, and an aliquot (5 9 103 cells) was placed
in each well of a 96-well cell culture plate in a total volume of 100 lL. Cells were
allowed to attach overnight, then treated with samples. The final concentration of

123

Synthesis of novel tetrahydronaphthalenes

samples ranged from 0 to 100 lM. After 48 h, 20 lL Resazurin 0.01 % w/v

solution was added to each well, and the plates were incubated at 37 C for 12 h.
Fluorescence was measured on an automated 96-well Infinite M2000 ProTM plate
reader (Tecan, Crailsheim, Germany) using an excitation wavelength of 544 nm and
an emission wavelength of 590 nm. After 48 h incubation, plates were treated with
Resazurin solution as mentioned above. Doxorubicin was used as positive control.
Each assay was done at least three times, with two replicates each. Viability was
assessed based on comparison with untreated cells. The IC50 (on cancer cells) was
the concentration of sample required to inhibit 50 % of cell proliferation, calculated
from a calibration curve using linear regression by Microsoft Excel.

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