X-ray, NMR and DFT studies on benzo[h]thiazolo[2,3-b]quinazoline derivatives

Article abstract of DOI:10.1016/j.molstruc.2013.06.038

4-Phenyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione 3, obtained by the condensation of 2-Benzylidene-3,4-dihydronapthalen-1(2H)-one 2 with thiourea, on reaction with chloroacetic acid and 1,2-dibromoethane furnish compounds 4 and 5 and not their p

Full text of DOI:10.1016/j.molstruc.2013.06.038

Journal of Molecular Structure 1049 (2013) 189–197
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
X-ray, NMR and DFT studies on benzo[h]thiazolo[2,3-b]quinazoline
derivatives
⇑
Richa Gupta, R.P. Chaudhary
Department of Chemistry, Sant Longowal Institute of Engineering and Technology, Longowal (Sangrur), Punjab 148 106, India
h i g h l i g h t s
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Loss of acetyl group of 2-acetyl-1-tetralone in alkaline medium.
Regiochemistry of cyclocondensation established by 1H NMR spectroscopy.
Theoretical NMR data gives the best fit with experimental values.
A close agreement between X-ray and theoretical data has been observed.
HOMO, LUMO and Zero point energies have been calculated.
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 March 2013
Received in revised form 14 June 2013
Accepted 16 June 2013
Available online 24 June 2013
4-Phenyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione 3, obtained by the condensation of
2-Benzylidene-3,4-dihydronapthalen-1(2H)-one 2 with thiourea, on reaction with chloroacetic acid
and 1,2-dibromoethane furnish compounds 4 and 5 and not their possible isomers 7 and 8 respectively.
The regiochemistry of the cyclized products and their structure is established by elemental analysis, 1H
NMR, 13C NMR, IR and mass spectral data. Density functional theory (DFT) calculations have been carried
out for compounds 4, 5 and their isomers 7 and 8 with Jaguar version 6.5112 using B3LYP density
functional method and 6-31G⁄⁄ basis set. X-ray diffraction technique indicates that compound 4
crystallizes in the triclinic space group P-1, with Z = 2 and cell parameters a = 6.3404 (11) Å, b = 9.997
Keywords:
4-Thiazolidinone
Arylidene derivatives
Spectral data
(3) Å, c = 13.560 (2) Å,
a = 107.532(19)°, b = 94.108(14)°, c
= 97.469(17)°. 1H and 13C NMR of compounds
4, 5, 7 and 8 have been calculated and correlated with experimental results. 2-Arylidene derivatives of 4
were obtained by two routes and their structure was established by spectral data. The lowest energy
optimized geometry of the compound 4 in gas phase is consistent with that obtained by X-ray
crystallographic studies.
X-ray diffraction data
DFT
Ó 2013 Elsevier B.V. All rights reserved.
1. Introduction
enzyme [1] and also non-nucleoside inhibitors of HIV RT [2] and
HIV-1 integrase inhibitors [3]. Its derivatives have demonstrated
The remarkable ability of heterocyclic nuclei to serve as both
biomimetics and active pharmacophores has largely contributed
to their unique value as traditional key elements of numerous
drugs. 4-Thiazolidinone and its derivatives extensively present in
natural products, are well known heterocyclic compounds with
tremendous structural as well as pharmacological importance.
The historical importance of thiazolidine derivative, i.e., the devel-
opment of penicillin which shows the presence of thiazoline ring.
There has been substantial interest in the chemistry of thiazoli-
din-4-one ring systems because of wonder nucleus is well reputed
for a spectrum of biological activities. 4-Thiazolidinones also inhi-
bit the biosynthesis of the peptidoglycan by interacting with MurB
significant pharmacological activities like antimicrobial [4], anti-
cancer [5], anti-HIV [6], antitumor [7], anti-convulsant [8], antidi-
abetic [9], antihistaminic [10], nimeticidal [11], anti-inflammatory
[12], anti-tubercular [13].
Tetralone is a keto derivative of tetralin, which is a tetrahydro-
genated form of naphthalene. 1-Tetralone and its various deriva-
tives have proven utility in the synthesis of numerous
biologically active products and play a major role in medicinal
chemistry and development of pharmaceuticals [14]. For example,
one of the major commercial pharmaceutical agents, sertraline
((+)-cis-(1S,4S)-1-methylamino-4-(3,4-dichlorophenyl) tetralin),
an antidepressant known under the trade name Zoloft, is a compet-
itive inhibitor of synaptosomal serotonin uptake [15].
In view of the wide spectrum activities of condensed 4-thiazo-
lidinones it was thought worthwhile to undertake the synthesis of
⇑
Corresponding author. Tel.: +91 1672 253206; fax: +91 1672 280057.
E-mail address: rpchaudhary65@gmail.com (R.P. Chaudhary).
0022-2860/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2013.06.038

190
R. Gupta, R.P. Chaudhary / Journal of Molecular Structure 1049 (2013) 189–197
Table 2
heterocyclic systems in which 4-thiazolidinone nucleus is fused to
another biologically active heterocyclic ring. The product is ex-
pected synergically more biologically active. In continuation to
our research on condensed 4-thiazolidinones [16,17], we report
in this paper the synthesis of fused thiazolo-quinazoline system
in which 4-thiazolidinone nucleus is fused with benzo[h]quinazo-
line moiety to yield two novel heterocyclic systems as 7-phenyl-
Selected bond lengths and bond angles of the optimized compound 5.
Sr. No.
Bond lengths (Å)
Bond angles (°)
Entry
Calculated
Entry
Calculated
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
C16 H36
C15 H33
C16 C15
N12 C15
C13 N12
C11 N12
C9 C11
1.11
1.11
1.52
1.47
1.46
1.47
1.49
1.52
1.49
1.45
1.26
1.85
1.82
1.11
H36 C16 H35
H36 C16 C15
H34 C15 H33
C10 N14 C13
N12 C13 N14
N14 C13 S17
C13 N12 C11
N12 C11 H18
C13 S17 C16
C19 C11 H18
C9 C10 N14
H32 C8 H31
C7 C8 C9
109.4
109.4
109.4
115.0
126.0
126.0
108.0
107.5
91.8
109.3
120.0
109.4
109.5
109.4
7,10-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-9(6H)-one
4
and 7-Phenyl-6,7,9,10-tetrahydro-5H-benzo[h]thiazolo[2,3-b]qui-
nazoline 5. The regiochemistry of the cyclocondensation reaction
of an unsymmetrical thione with bifunctional compounds is stud-
ied and the structure of regioisomers is established by spectral,
computational and X-ray diffraction data.
C8 C7
C9 C8
N14 C10
C13 N14
S17 C13
C16 S17
C11 H18
2. Computational studies
H30 C7 H29
The molecular geometry optimization and 1H and 13C NMR
spectra calculations were performed with the Jaguar software
package version 6.5112 by using DFT methods with B3LYP (Becke
three parameter Lee–Yang–Parr) exchange correlation functional,
which combines the hybrid exchange functional of Becke [18], with
the gradient-correlation functional of Lee, Yang and Parr [19]. The
6-31G⁄⁄ basis set was used for calculations in the gas phase of the
structures 4, 5 and their isomers 7 and 8 respectively.
A DFT calculation was carried out to predict the geometry of the
molecules. The actual and optimized bond lengths and bond angles
obtained by X-ray crystallographic study as well as by geometry
optimization at B3LYP/6-31G⁄⁄ level of theory of structure 4 are re-
ported in Table 1. In case of X-ray structure of compound 4, the ob-
served bond lengths of C@O, SAC and CAN bonds in five membered
thiazolidinone ring are 1.213 Å, 1.799 Å and 1.398 Å respectively.
The calculated bond lengths, through DFT method, of C@O, SAC
and CAN bonds of same thiazolidinone ring of isomer 4 are
1.208 Å, 1.812 Å and 1.462 Å respectively, which are very close to
the actual values. From Table 1, it is clear that actual CAC and
CAH bond lengths are also in close agreement with calculated val-
ues. The calculated bond angles for CASAC, OACAN and OACAC
bond angles in five membered ring of isomer 4 are 91.9°, 122.6°
and 122.5° respectively, which are close to corresponding actual
angles obtained from X-ray. The actual values of above bond angles
are 92.8°, 123.5° and 124.1° respectively. In case of compound 5,
the calculated SAC and CAN bond lengths in five membered ring
are 1.85 Å and 1.47 Å (Table 2) respectively. The CASAC bond angle
in compound 5 is 91.8°. The bond lengths and angles data shows
the structural similarity in compounds 4 and 5. On this basis struc-
ture 5 is assigned to product obtained from the reaction of thione 3
and 1,2-dibromoethane. It was noted here that slight differences in
bond parameters are attributed to the fact that the experimental
results belong to solid phase and theoretical calculations belong
to gaseous phase. Despite slight variations observed in the geomet-
ric parameters, the general agreement is good and the theoretical
calculations support the solid-state structure. The Ortep diagram
obtained from crystal structure of 4 and optimized configurations
of structures 4, 5 and their isomers 7 and 8 with atom numbering
schemes are shown in Figs. 1 and 2.
Shielding tensors of structure 4, 5, 7 and 8 were evaluated by
using B3LYP functional with basis set given above. In order to ex-
press the chemical shifts in ppm, the geometry of tetramethylsil-
ane (TMS) and chloroform molecules had been optimized and
then their 1H and 13C NMR spectra were calculated by the same
method using same basis set as in case of the calculations on struc-
tures 4, 5, 7 and 8. The shielding of TMS is 32.3379 for 1H NMR and
202.8593 for 13C NMR. The calculated isotropic shielding constants
Table 1
Selected X-ray and calculated bond lengths and bond angles of compound 4.
S. No.
Bond length (Å)
Entry
Bond angle (°)
X-ray
Calculated
Entry
X-ray
Calculated
1.
2.
3.
4.
5.
6.
7.
8.
S1 C3
S1 C2
1.743(5)
1.799(5)
1.269(5)
1.422(6)
1.367(5)
1.398(5)
1.483(6)
1.213(5)
0.98
0.97
0.97
1.510(7)
0.97
0.97
1.404(6)
1.506(6)
0.97
0.97
1.528(6)
1.327(6)
1.856
1.812
1.260
1.456
1.462
1.462
1.470
1.208
1.113
1.113
1.113
1.509
1.113
1.113
1.523
1.497
1.113
1.113
1.497
1.337
C3 S1 C2
C3 N2 C6
C1 N1 C3
C1 N1 C4
C3 N1 C4
N2 C3 N1
N2 C3 S1
N1 C3 S1
C5 C6 N2
N2 C6 C10
N1 C4 C5
N1 C4 C15
N1 C4 H4
C1 C2 S1
S1 C2 H2A
S1 C2 H2B
H2A C2 H2B
O1 C1 N1
O1 C1 C2
N1 C1 C2
92.8(2)
116.5(4)
116.3(4)
122.3(4)
121.4(4)
125.9(4)
123.0(4)
111.1(3)
123.7(4)
115.4(4)
109.1(4)
111.0(4)
108.2
91.9
115.0
124.0
108.0
108.0
126.0
126.0
111.4
120.0
120.0
108.6
111.5
107.5
107.3
111.4
111.4
109.4
122.6
122.5
118.0
N2 C3
N2 C6
N1 C1
N1 C3
N1 C4
O1 C1
C4 H4
C7 H7A
C7 H7B
C2 C1
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
C2 H2A
C2 H2B
C7 C8
106.9(3)
110.3
110.3
C5 C4
C8 H8A
C8 H8B
C15 C4
C5 C6
108.6
123.5(5)
124.1(5)
112.4(4)

R. Gupta, R.P. Chaudhary / Journal of Molecular Structure 1049 (2013) 189–197
191
Fig. 1. Ortep diagram obtained from X-ray of 7-phenyl-7,10-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazolin-9(6H)-one (4).
Compound 4
Compound 7
Compound 5
Compound 8
Fig. 2. Optimized geometry of compounds 4, 5 and their isomers 7, 8 respectively.
r
i were then transformed to chemical shifts relative to TMS by the
A comparison of experimental and calculated 1H and 13C NMR
chemical shifts (ppm) of compounds 4, 5 and their isomers 7, 8
have been reported in Tables 3–6. It is evident from the calculated
equation
di ¼ rTMS
ꢁ
ri

192
R. Gupta, R.P. Chaudhary / Journal of Molecular Structure 1049 (2013) 189–197
Table 3
Experimental and calculated 1H NMR chemical shifts (ppm) of the title compound 4 and its isomer 7.
Structure 4
Structure 7
Entry
Expt.
NMR
Calc.
shield
Calc.
NMR
Averaged
NMR
Entry
Calc.
shield
Calc.
NMR
Averaged
NMR
H15
H26
H27
H28
H29
H30
H31
H32
H33
H34
H35
H36
H37
H38
H39
H40
5.59
27.18
24.70
25.59
25.60
23.97
29.45
29.58
30.11
29.88
24.76
24.80
24.80
24.82
24.57
28.27
28.12
5.50
8.16
7.20
7.20
8.94
3.08
2.95
2.38
2.62
8.10
8.06
8.05
8.03
8.3
H19
H26
H27
H28
H29
H30
H31
H32
H33
H36
H37
H38
H39
H40
H34
H35
28.19
24.81
24.83
25.04
25.72
30.38
29.62
30.80
31.06
24.77
24.74
24.83
24.81
24.68
29.10
29.21
4.43
8.05
8.02
7.8
7.87
7.36
7.73
7.07
2.09
2.90
1.64
1.36
8.08
8.12
8.02
8.04
8.18
3.46
3.34
2.76
2.62
2.18
1.94
7.82
3.95
8.10
4.43
8.08
3.40
4.35
4.51
Table 4
Experimental and calculated 13C NMR chemical shifts (ppm) of the compound 4 and its isomer 7.
Structure 4
Structure 7
Entry
Expt. NMR
Calc. shield
Calc. NMR
Entry
Calc. shield
Calc. NMR
C5
C7
C11
C13
C22
C23
142
27
58
154
170
31
70.48
176.83
148.52
56.41
44.05
174.23
140.13
27.56
57.53
155.02
168.1
30.32
C5
C7
C11
C13
C17
C16
93.26
175.57
155.42
61.98
49.60
177.26
116.02
28.90
50.23
149.12
162.23
27.11
Table 5
Experimental and calculated 1H NMR chemical shifts (ppm) of the optimized compound 5 and its isomer 8.
Structure 5
Structure 8
Entry
Expt.
NMR
Calc.
Calc.
Averaged
Entry
Calc.
Calc.
Averaged
shield
NMR
NMR
shield
NMR
4.65
7.6
NMR
H18
H25
H26
H27
H28
H29
H30
H31
H32
H33
H34
H35
H36
H37
H38
H39
H40
H41
5.25
27.24
25.39
25.41
25.55
24.49
29.17
28.93
29.97
30.11
28.92
28.98
29.25
28.89
24.79
25.02
25.45
25.32
25.46
5.44
7.42
7.4
H15
H25
H26
H27
H28
H29
H30
H31
H32
H40
H41
H38
H39
H33
H34
H35
H36
H37
27.98
25.22
25.17
25.05
25.55
29.07
29.45
30.39
30.27
29.11
29.02
29.44
29.50
25.41
25.32
25.43
25.24
25.03
7.65
7.78
7.25
3.48
3.08
2.07
2.2
6.88
7.61
7.57
7.25
8.38
3.38
3.64
2.52
2.37
3.64
3.58
3.29
3.68
8.06
7.82
7.36
7.5
2.84
2.55
2.96
3.63
3.51
2.44
3.61
3.48
3.28
2.13
3.44
3.54
3.1
3.49
3.06
3.03
7.4
7.5
7.38
7.58
7.81
7.49
7.62
7.53
7.35
1H NMR of 4, HA appears at d 5.50, which is very close to the exper-
imental value of d 5.59. The correlation values of proton chemical
shifts are found to be 0.9889 for structure 4 and 0.9565 for its iso-
mer 7 (Fig. 3). The correlation between the calculated and experi-
mental 1H NMR of compound 5 is 0.9618 as compared to 0.9265
value of structure 8 (Fig. 5). In 13C NMR of isomer 4, carbonyl
carbon appears at d 170 as compared to the calculated value 168.1,
whereas in isomer 7 the calculated value is 162.23 (Table 5). The
correlation values of carbon chemical shifts of 4 and 7 are found
to be 0.9996 and 0.9778 respectively (Fig. 4). Similarly 13C chemi-
cal shift correlation values of 5 and its isomer 8 are found to be
0.9825 and 0.9184 (Fig. 6) respectively. It may be noted that there

R. Gupta, R.P. Chaudhary / Journal of Molecular Structure 1049 (2013) 189–197
193
Table 6
Experimental and calculated 13C NMR chemical shifts (ppm) of the compound 5 and its isomer 8.
Structure 5
Structure 8
Entry
Expt. NMR
Calc. shield
Calc. NMR
Entry
Calc. shield
Calc. NMR
C3
C8
C13
C15
C16
137
27
164
52
74.16
174.51
50.19
153.71
175.03
136.23
30.01
161.6
52.03
29.47
C3
C8
C13
C24
C23
82.54
181.64
54.62
139.08
186.67
127.36
22.48
156.91
67.51
17.15
45
is large deviation in correlation values of isomers 7 and 8. Based
upon comparison of experimental and theoretical NMR studies,
1H and 13C data shows good correlations for proposed structures
4 and 5.
The total energy, energy of highest occupied molecular orbitals
and energy of lowest unoccupied molecular orbitals for structures
4, 5, 7 and 8 are obtained theoretically and listed in Table 7. The
highest occupied molecular orbitals (HOMOs) are mainly localized
on the five membered thiazolidinones ring of compound 4, which
indicates that five membered ring is most active part of the mole-
cule. Compound 4, therefore condense with aldehydes to furnish 5-
benzylidene derivatives 6. Similar situation exists in compound 5.
The molecular orbital surface for HOMO of compounds 4 and 5 are
reported as Supplementary material (Figs. S1 and S2). Stationary
points for all the molecules 4, 5, 7 and 8 were verified by the fre-
quency calculations. Since there was no negative frequency, the as-
signed geometry to the molecules is considered to be energy
B3LYP/6-31G**
R2 (Structure 4)= 0.9889
Structure 4
Structure 7
R2 (Structure 7)= 0.9565
9
8
7
6
5
4
3
2
1
Structure 5
Structure 8
B3LYP/6-31G**
R2 (structure 5)= 0.9618
R2 (Structure 8)= 0.9265
8
7
6
5
4
3
2
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
Experimental 1H NMR Shifts (ppm)
Experimental 1H NMR Shifts (ppm)
Fig. 3. Plot of the calculated vs. the experimental 1H NMR chemical shifts (ppm).
Fig. 5. Plot of the calculated vs. the experimental 1H NMR chemical shifts (ppm).
B3LYP/6-31G**
Structure 5
Structure 8
Structure 4
Structure 7
R2 (Structure 4)= 0.9996
B3LYP/6-31G**
180
160
140
120
100
80
180
R2 (Structure 5)= 0.9825
R2 (Structure 8)= 0.9184
R2 (Structure 7)= 0.9778
160
140
120
100
80
60
60
40
40
20
20
0
20
40
60
80
100
120
140
160
180
20
40
60
80
100
120
140
160
180
Experimental 13C NMR Shifts (ppm)
Experimental 13C NMR Shifts (ppm)
Fig. 4. Plot of the calculated vs. the experimental 13C NMR chemical shifts (ppm).
Fig. 6. Plot of the calculated vs. the experimental 13C NMR chemical shifts (ppm).

194
R. Gupta, R.P. Chaudhary / Journal of Molecular Structure 1049 (2013) 189–197
Table 7
Theoretically computed energies for structures 4, 5, 7 and 8.
Sr. No.
Parameters
Structure 4
Structure 7
Structure 5
Structure 8
1.
2.
3.
4.
HOMO Energy (kcal/mol)
LUMO Energy (kcal/mol)
Zero Point Energy (kcal/mol)
Total Energy (kcal/mol)
ꢁ177.56
59.52
212.85
ꢁ163.42
62.75
214.22
ꢁ164.99
67.51
222.73
ꢁ162.53
68.03
227.19
ꢁ845556.25
ꢁ845528.86
ꢁ799497.75
ꢁ799432.38
minimum. The calculated total energy of compound
4
is
4-Phenyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thi-
one (3): Brown solid, yield: 82%; m.p: 232–34 °C. IR (cmꢁ1): 1196
(C@S), 1558 (C@C), 3155 (NH). 1H NMR (DMSO-d6, 400 MHz): d
1.91–1.97 (m, 1H, CH2), 2.11–2.17 (m, 1H, CH2), 2.63–2.68 (m,
1H, CH2), 2.73–2.78 (m, 1H, CH2), 4.97 (s, 1H, HA), 7.11–7.36 (m,
8H, ArAH), 7.57–7.59 (m, 1H, ArAH), 8.85 (br, 1H, NH), 9.15 (br,
1H, NH). MS: m/z = 293 (M + 1)+ (100%). Anal. Calc. for C18H16N2S
(292): C 73.97, H 5.48, N 9.59, S 10.96; found: C 73.89, H 5.41, N
9.65, S 10.89.
ꢁ845556.25 kcal/mol and its isomer 7 is ꢁ845528.86 kcal/mol.
This shows the compound 4 is more stable by 1.18 eV than its iso-
mer 7. The total energy of compound 5 is ꢁ799497.75 kcal/mol and
isomer 8 is ꢁ799432.38 kcal/mol. This indicates compound 5 is
stable by an amount of 2.81 eV.
3. Experimental
3.1. General
3.2.3. Procedure for synthesis of 7-phenyl-7,10-dihydro-5H-
benzo[h]thiazolo[2,3-b]quinazolin-9(6H)-one (4)
Melting points were determined in sulfuric acid bath and are
uncorrected. TLC was performed on silica gel G plates using pet
ether-ethylacetate (4:1) as irrigant and iodine vapors as visualizing
agent. IR spectra were recorded on ABB FTIR spectrometer and the
A mixture of compound 3 (2.92 g, 0.01 mol), chloroacetic acid
(0.94 g, 0.01 mol), anhyd. sodium acetate (0.82 g, 0.01 mol) and
absolute ethanol (20 ml) was heated under reflux for 5 h. The reac-
tion mixture was cooled to room temperature and then poured
into water. The solid obtained, was filtered, washed well with
water. Crystallization from ethanol gave light brown crystals of
compound 4.
7-Phenyl-7,10-dihydro-5H-benzo[h]thiazolo[2,3-b]quinazo-
lin-9(6H)-one (4): Brown crystals, yield: 80%; m.p: 182–84 °C. IR
(cmꢁ1): 1728 (C@O), 1643 (C@N). 1H NMR (DMSO-d6, 400 MHz):
d 1.89–2.00 (m, 1H, CH2), 2.11–2.26 (m, 1H, CH2), 2.59–2.66 (m,
1H, CH2), 2.71–2.81 (m, 1H, CH2), 3.90–4.01 (dd, J = 12.56, 17.24,
2H, SCH2), 5.59 (s, 1H, HA), 7.06–7.36 (m, 8H, ArAH), 7.81–7.83
(d, J = 7.52 Hz, 1H, ArAH). 13C NMR (DMSO-d6, 100 MHz): d 170,
154, 142, 139, 135, 134, 132, 128, 127, 126, 122, 121, 114, 110,
99, 59, 58, 31, 27, 26, 24. MS: m/z = 333 (M + 1)+ (100%). Anal. Calc.
for C20H16N2SO (332): C 72.29, H 4.82, N 8.43, S 9.64; found: C
72.21, H 4.88, N 8.52, S 9.56.
results are reported in cmꢁ1 1H NMR and 13C NMR were recorded
.
in DMSO-d6 on a BRUKER ADVANCE II 400 NMR spectrometer
using tetramethylsilane (TMS) as an internal standard (chemical
shift in d, ppm). Mass spectra were recorded on a TOF MS
ES + 1.38e4 instrument. The elemental analysis of compounds
was performed on a Carlo Erba-1108 elemental analyzer. X-ray dif-
fraction was performed on X Calibur EOS OXFORD Diffractometer.
The structures were optimized by molecular mechanics using PM3
method based on Hyperchem with version 7.5 packages.
3.2. Synthesis
3.2.1. Procedure for the synthesis of 2-benzylidene-3,4-
dihydronapthalen-1(2H)-one (2)
A mixture of 2-acetyl-1-tetralone 1 (1.88 g, 0.01 mol) and benz-
aldehyde (1.06 g, 0.01 mol) in aq. sodium hydroxide (1.0 g NaOH in
20 ml water) was heated under reflux for 3 h. The reaction mixture
was cooled at room temperature and neutralized with dil. HCl. The
solid, thus obtained was filtered, washed with water and finally
crystallized from ethanol to furnish shinning brown crystals.
2-Benzylidene-3,4-dihydronapthalen-1(2H)-one (2): Brown
crystals, yield: 90%; m.p: 112–14 °C. IR (cmꢁ1): 1705 (C@O). 1H
NMR (DMSO-d6, 400 MHz): d 2.93–2.97 (t, J = 6.08 Hz, 2H, CH2),
3.12–3.16 (t, J = 6.88 Hz, 2H, CH2), 7.24–7.26 (m, 1H, ArAH),
7.33–7.51 (m, 7H, ArAH), 7.87 (s, 1H, CH), 8.12–8.14 (d,
J = 6.56 Hz, 1H,=CH). MS: m/z = 235 (M + 1)+ (100%). Anal. Calc.
for C17H14O (234): C 87.18, H, 5.98; found: C 87.10, H 5.90.
3.2.4. Procedure for synthesis of 7-phenyl-6,7,9,10-tetrahydro-5H-
benzo[h]thiazolo[2,3-b]quinazoline (5)
Compound 5 was obtained by stirring a mixture of thione 3
(2.92 g, 0.01 mol) and 1,2-dibromoethane (5.0 ml) at 110 °C for
4 h. The crude solid, thus separated, was purified by column chro-
matography using pet ether: ethyl acetate (4:1) to give compound
5 as light yellow solid.
7-Phenyl-6,7,9,10-tetrahydro-5H-benzo[h]thiazolo[2,3-b]
quinazoline (5): Yellow solid, yield: 60%. m.p: 136–38 °C. IR
(cmꢁ1): 1651 (C@N).1H NMR (DMSO-d6, 400 MHz): d 2.54–2.56
(m, 2H, CH2), 2.81–2.87 (m, 2H, CH2), 2.95–2.98 (t, J = 5.88 Hz,
2H, NCH2), 3.61–3.65 (t, J = 7.40 Hz, 2H, SCH2), 5.25 (s, 1H, HA),
6.84–6.92 (m, 4H, ArAH), 7.10–7.14 (m, 1H, ArAH), 7.25–7.27 (d,
J = 7.44 Hz, 2H, ArAH), 7.46–7.49 (m, 2H, ArAH). 13C NMR
(DMSO-d6, 100 MHz): d 164, 137, 135, 129, 128, 127, 126, 125,
121, 113, 62, 52, 45, 27, 26, 23, 8. MS: m/z = 319 (M + 1)+ (100%).
Anal. Calc. for C20H18N2S (318): C 75.47, H 5.66, N 8.81, S 10.06;
found: C 75.40, H 5.72, N 8.89, S 10.12.
3.2.2. Procedure for synthesis of 4-phenyl-3,4,5,6-
tetrahydrobenzo[h]quinazoline-2(1H)-thione (3)
Compound 2 (2.34 g, 0.01 mol), and thiourea (0.76 g, 0.01 mol)
in ethanolic potash (1.0 g KOH in 20 ml ethanol) was heated under
reflux for 4 h, and kept overnight. The volume was reduced to half,
and the concentrate poured into ice-cold water. The solid, thus ob-
tained, was filtered, washed well with water and finally crystal-
lized from DMF to give compound 3.
3.2.5. Procedure for synthesis of arylidene derivatives (6a–c)
Arylidene derivatives were prepared by two routes:
Compound 3 was also obtained directly by the reaction of 2-
acetyl-1-tetralone
1 (1.88 g, 0.01 mol), benzaldehyde (1.06 g,
(i) A mixture of thiazolidinone 4 (0.332 g, 0.001 mol), substi-
tuted aldehydes (0.001 mol), anhy. sodium acetate
(0.082 g, 0.001 mol) and gl. acetic acid (10 ml) was heated
under reflux for 4 h. The reaction mixture was cooled to
0.01 mol), and thiourea (0.76 g, 0.01 mol) in alc. KOH (1.0 g KOH
in 20 ml ethanol) under refluxing for 4 h. The solid obtained, was
filtered, washed well with water and crystallized from DMF to
yield brown solid.

R. Gupta, R.P. Chaudhary / Journal of Molecular Structure 1049 (2013) 189–197
195
room temperature and poured into water. The solid thus
obtained was filtered and washed well with water and
finally crystallized from DMF and ethanol with ratio 1:1 to
gave compounds 6a–c.
the reaction of 2-acetyl-1-tetralone, beazaldehyde and thiourea.
The unsymmetrical thione 3 on reaction with chloroacetic acid
may yield compound 4 [21,22] or its isomer 7 or both. In the liter-
ature the compound 7, the isomer of 4 is either not considered [21]
or the derivatives of compound 4 are reported [22]. But we have
established the structure of 4 by comparing its NMR data with
compound 5. The structure 4 is further confirmed by X-ray diffrac-
tion and DFT studies. There are possibly three methods to establish
the structure of a compound. Firstly by its unambiguous synthesis,
secondly by its transformation to the product of known regiochem-
istry. Both these methods are tedious and follow circuitry routes. In
the third method 1H NMR spectroscopy is used to establish the
structure of cyclized product. In this paper we make use of 1H
NMR spectral data to decide the structure of the cyclized regioi-
somers, which in fact is well supported by X-ray crystallography
and DFT studies.
The thione 3 when treated with chloroacetic acid in the pres-
ence of anhyd. sodium acetate and absolute ethanol afforded a sin-
gle product (TLC) 4 or 7 in 80% yield (Scheme 2). The appearance of
a band at 1728 cmꢁ1 (C@O) in the IR spectrum, appearance of peak
at d 170 (C@O) in 13C NMR spectrum and exhibition of a molecular
ion peak at m/z 333 (100%) in the mass spectrum of the TLC – pure
product suggested that the cyclization had indeed taken place. The
IR and mass spectral data were of little help in deciding in favor of
either structure 4 or 7. However, the structure 4 was finally as-
signed to this cyclization product in preference to the structure 7
on the basis of 1H NMR spectral data.
The reaction of compound 3 with 1,2-dibromoethane gave a
product which was purified by column chromatography and char-
acterized by its molecular ion peak at m/z 319 (100%) as a com-
pound which could be represented by either structure 5 or 8. In
either structure (5 or 8), the singlet at d 5.25 in its 1H NMR spec-
trum integrating for one proton was assignable to HA. If the struc-
ture 7 is correct for the cyclization product, obtained from thione 3
and chloroacetic acid, then HA will resonate in the same region as
that of structure 5 (or 8). On the other hand if the structure 4 is cor-
rect, HA will be deshielded by the thiazolidinone ring and conse-
quently, HA will resonate downfield in comparison to HA in 5 (or
8). The appearance of a downfield singlet at d 5.59 for HA in 1H
NMR of the TLC pure product as compared to singlet at d 5.25 for
HA in structure 5 (or 8) supported the structure 4 and ruled out
the structure 7 from which such a downfield shift would not be ex-
pected. The deshielding effect is due to the magnetic anisotropy of
the C@O group with a minor contribution from the rest of the ring.
Although the comparison of the chemical shifts of HA in the
structures 4 and 5 (or 8) is on a better footing, on the basis that
both structures 4 and 5 (or 8) are tetracyclic compounds. Finally
the structure of 4 was confirmed by single crystal X-ray crystallo-
graphic data. The crystals for X-ray were grown from ethyl alcohol
by slow evaporation process at room temperature. Arylidene thia-
(ii) A mixture of thione 3 (0.292 g, 0.001 mol), chloroacetic acid
(0.094 g, 0.001 mol) and substituted aldehydes (0.001 mol)
and anhyd. sodium acetate (0.082 g, 0.001 mol) in gl. acetic
acid (10 ml) and acetic anhydride (1 ml) was refluxed for
3–4 h. A similar work up as in (i) gave compound 6a–c.
The melting points of the compound remained undepressed
when mixed with the compound obtained by method (i).
10-Benzylidene-7-phenyl-7,10-dihydro-5H-benzo[h]thiazolo
[2,3-b]quinazolin-9(6H)-one 6a: Yellow solid, yield: 70%; m.p:
212–14 °C. IR (cmꢁ1): 1705 (C@O), 1589 (C@N). 1H NMR (DMSO-
d6, 400 MHz): d 2.01 (m, 1H, CH2), 2.29 (m, 1H, CH2), 2.66 (m,
1H, CH2), 2.68 (m, 1H, CH2), 5.80 (s, 1H, HA), 7.10–7.57 (m, 13H,
ArAH), 7.66 (s, 1H, HB), 7.84 (m, 1H, ArAH). Anal. Calc. for
C27H20N2SO (420): C 77.14, H 4.76, N 6.67, S 7.62; found:
C 77.22, H 4.82, N 6.58, S, 7.69.
(E)-10-(4-Methoxybenzylidene)-7-phenyl-7,10-dihydro-5H-
benzo[h]thiazolo[2,3-b]quinazolin-9(6H)-one 6b: Yellow nee-
dles, yield: 65%. m.p: 202–04 °C. IR (cmꢁ1): 1705 (C@O), 1589
(C@N). 1H NMR (DMSO-d6, 400 MHz): d 1.95 (m, 1H, CH2), 2.30
(m, 1H, CH2), 2.61 (m, 1H, CH2), 2.65 (m, 1H, CH2), 3.82 (s, 3H,
OCH3), 5.80 (s, 1H, HA), 7.05–7.39 (m, 10H, ArAH), 7.51–7.54 (d,
J = 8.80 Hz, 2H, ArAH), 7.61 (m, 1H, HB), 7.81–7.82 (d, J = 6.84 Hz,
1H, ArAH). Anal. Calc. for C28H22N2SO2 (450): C 74.67, H 4.89, N
6.22, S 7.11. found: C 74.58, H 4.82, N 6.30, S 7.19.
(E)-10-(4-Chlorobenzylidene)-7-phenyl-7,10-dihydro-5H-
benzo[h]thiazolo[2,3-b]quinazolin-9(6H)-one 6c: Yellow solid,
yield: 66%; m.p: 238–40 °C. IR (cmꢁ1): 1705 (C@O), 1589 (C@N).
1H NMR (DMSO-d6, 400 MHz): d 1.94–2.03 (m, 1H, CH2), 2.26–
2.35 (m,1H, CH2), 2.61–2.69 (m, 1H, CH2), 2.76–2.80 (m, 1H,
CH2), 5.82 (s, 1H, HA), 7.10–7.42 (m, 8H, ArAH), 7.53–7.60 (m,
4H, ArAH), 7.66 (m, 1H, HB), 7.82–7.84 (d, J = 7.72 Hz, 1H, ArAH).
Anal. Calc. for C27H19N2SOCl (454.5): C 71.29, H 4.18, N 6.16, S
7.04. Found: C 71.22, H 4.08, N 6.72, S 7.13.
4. Results and discussion
2-Acetyl-1-tetralone on condensation with benzaldehyde in
alkaline medium was expected to yield compound 9. On the con-
trary, the product obtained was identified as 2-benzylidene-1-tet-
ralone 2 [20] from its melting point and spectral data. The
proposed mechanism and the formation of compound 2 are de-
picted in Scheme 1. To the best of our knowledge compound 9 is
not reported in the literature. Efforts were made to synthesize
compound 9 but we did not succeed. Compound 2 on reaction with
thiourea gave thione 3, which can also be obtained directly from
O
O
O
O
O
O
C CH3
O
C CH3
C CH2
C6H5
OH
C H
C6H5
C
H
H
OH
-H
1
O
-CH3COOH
CHC6H5
2
Scheme 1. Base catalyzed condensation of 2-acetyl-1-tetralone with benzaldehyde.

196
R. Gupta, R.P. Chaudhary / Journal of Molecular Structure 1049 (2013) 189–197
S
S
O
N
N
O
HA
Ph
N
N
COCH=CHPh
HA
Ph
9
7
8
PhCHO
NaOH
S
S
O
N
N
HA
O
NH
PhCHO
HN
ClCH2CO2H
HA
Ph
COCH3
Ph
H2NCSNH2
alc.KOH
4
1
3
ArCHO
gl.HOAc
ClCH2CO2H,
ArCHO
H2NCSNH2
alc.KOH
CHPh
BrCH2CH2Br
S
PhCHO
NaOH
CHB-Ar
O
S
O
N
N
N
N
H
HA
Ph
A
2
Ph
(a) Ar= C6H5
6
5
(b) Ar= p-C6H4OMe
(c) Ar= p-C6H4Cl
Scheme 2. Synthesis of benzo[h]thiazolo[2,3-b]quinazoline derivatives.
zolidinones (6a–c) were prepared by two routes. In the first ap-
proach, the thiazolidinone 4 was condensed with aldehydes to give
arylidene thiazolidinones (6a–c) while in the second approach
compound 6a was obtained directly by heating compound 3 with
chloroacetic acid and benzaldehyde. The structures 6a–c were
established by IR and 1H NMR spectral data. The parent thiazolid-
inone 4 exhibited an absorption band at 1728 cmꢁ1 (C@O), but the
unsaturation at the 2-position being conjugated with the carbonyl
group at the 3-position as in arylidene thiazolidinones (6a–c) pro-
duced a bathochromic shift [23] as expected, the carbonyl absorp-
tion band appeared at 1705 cmꢁ1 in structure 6a–c respectively.
The downfield shift in the position of HA in 1H NMR of the product
obtained from reaction of 3 with chloroacetic acid may be due to
the presence of adjacent imine group in structure 7. If this is the
case, then in arylidene derivatives 6a–c HA proton will not be af-
fected further because of absence of conjugation of imine system
as evident from the structure of isomer 7. In case of arylidene
derivatives obtained from isomer 4, form conjugated carbonyl sys-
tem, which produces further downfield shift in position of HA in
6a–c i.e. d 5.80, 5.80 and d 5.82 respectively. This corroborates with
structure 4 and discards structure 7. The structure 5 (not 8) for the
product, obtained from the reaction of compound 3 with 1,2-dibro-
moethane, was assigned based upon the analogy with structure 4
and high degree correlation between the experimental and calcu-
lated 1H and 13C NMR spectra.
least-squares procedures on F2. All non-hydrogen atoms were re-
fined with anisotropic thermal parameters. The compound 4 crys-
tallizes in the triclinic space group P-1, with Z = 2 and cell
parameters a = 6.3404 (11) Å, b = 9.997 (3) Å, c = 13.560 (2) Å,
a
= 107.532(19)°, b = 94.108(14)°, c = 97.469(17)°. In the com-
pound, the C1O1 and C3N2 bond distances of 1.213 (5) and 1.269
(5) Å, respectively, indicate the double character of these bonds,
and are consistent with the corresponding values obtained theoret-
ically. The bond angles N2C3S1 and O1C1N1 are 123.0° (4) and
123.5° (5) respectively, which is consistent with the sp2 hybrid
character of C3 and C1 atoms. The crystallographic data and refine-
ment parameters of 4 are reported in Table S1 of Supplementary
material.
Crystallographic data for the structure reported in this paper
has been deposited with the Cambridge Crystallographic Data Cen-
ter and its CCDC No. is 926603.
6. Conclusion
Acetyl group is lost during an alkaline condensation of aldehyde
with 2-acetyl-1-tetralone. The structure of cyclized product is
established by spectral data. X-ray data and DFT calculations using
B3LYP and 6-31G⁄⁄ basis set supported the predicted cyclized
structure. Zero point energy favors the formation of the assigned
structure.
5. Crystallographic study and structural description
Acknowledgments
X-ray diffraction measurements were performed on X Calibur
EOS OXFORD Diffractometer at 293 (2) K. The intensity data were
One of the authors RG is thankful to the authorities of Sant
Longowal Institute of Engineering and Technology, Longowal for
providing financial assistance. The facilities provided by SLIET
authorities are gratefully acknowledged.
collected using graphite monochromated MoK
a radiation
(k = 0.71073 Å). The structure was solved by direct method using
the SHELX-97 software package [24] and refined by full-matrix

R. Gupta, R.P. Chaudhary / Journal of Molecular Structure 1049 (2013) 189–197
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