Spectral, DFT and X-ray diffraction studies on regioselective synthesis of thiazolo-quinazoline system

Article abstract of DOI:10.1016/j.molstruc.2017.05.109

Unsymmetrical quinazoline-3-thione 2, obtained from one pot condensation of 2-tetralone, p-chlorobenzaldehyde and thiourea in acidic medium, on reaction with α-halo acids afforded thiazolo-quinazoline derivatives 3, 7 and not their regioisomers 4 and 8 respectively. The cyclised product obtained by the reaction of thione 2 with 1,2-dibromoethane has been assigned structure 5. Condensation of thione 2 with 3-chloropropionic acid and 1,3-dibromopropane furnished thiazino-quinazoline derivatives 10 and 12 instead of their regioisomers 11 and 13 respectively. The structure of the cyclised products has been established by means of spectral data (IR, NMR and Mass). X-ray diffraction studies of a representative compound supported our claim on structural assignments. DFT studies on regioisomers further validated the claim for assigned structures. The reaction of thione 2 with 3-chloropropionc acid in presence of acetic acid yielded thiazinan-4-one 10.

Full text of DOI:10.1016/j.molstruc.2017.05.109

Journal of Molecular Structure 1145 (2017) 268e277
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Spectral, DFT and X-ray diffraction studies on regioselective synthesis
of thiazolo-quinazoline system
Deepika Gautam, Poonam Gautam, R.P. Chaudhary*
Department of Chemistry, Sant Longowal Institute of Engineering & Technology, Longowal, Sangrur, Punjab, 148106, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Unsymmetrical quinazoline-3-thione 2, obtained from one pot condensation of 2-tetralone, p-chlor-
Received 2 February 2017
Received in revised form
19 May 2017
Accepted 24 May 2017
Available online 24 May 2017
obenzaldehyde and thiourea in acidic medium, on reaction with
a-halo acids afforded thiazolo-
quinazoline derivatives 3, 7 and not their regioisomers 4 and 8 respectively. The cyclised product ob-
tained by the reaction of thione 2 with 1,2-dibromoethane has been assigned structure 5. Condensation
of thione 2 with 3-chloropropionic acid and 1,3-dibromopropane furnished thiazino-quinazoline de-
rivatives 10 and 12 instead of their regioisomers 11 and 13 respectively. The structure of the cyclised
products has been established by means of spectral data (IR, NMR and Mass). X-ray diffraction studies of
a representative compound supported our claim on structural assignments. DFT studies on regioisomers
further validated the claim for assigned structures. The reaction of thione 2 with 3-chloropropionc acid in
presence of acetic acid yielded thiazinan-4-one 10.
Keywords:
2-Tetralone
Quinazoline-thione
DFT studies
© 2017 Elsevier B.V. All rights reserved.
X-ray diffraction
Thiazino-quinazoline
1. Introduction
pharmaceutical activities. The development of new structures
which incorporate various biologically active pharmacophores in a
Substituted or fused quinazoline derivatives have proven phar-
macological significance [1]. There are enough evidences to suggest
that several of them are potentially useful medicinal agents and
others are in various stages of development [2]. Quinazoline de-
rivatives have attracted significant attraction due to their diverse
pharmacological activities such as antimicrobial [3], anti-malarial
[4], anti-inflammatory [5], antihypertensive [6], anticonvulsant
[7], anti-diabetic [8], anti-cancer [9], cholinesterase inhibition [10],
dihydrofolate reductase inhibition [11], and kinase inhibitory ac-
tivity [12]. Quinazolines also exhibit a wide variety of biological
functions like cellular phosphorylation inhibition [13], ligands for
benzodiazepine and GABA receptors in the central nervous system
[14], and some of them have acted as DNA binding agents [15].
single molecule has attracted much attention in medicinal research.
This approach encouraged us to undertake the synthesis of new
thiazolo-quinazoline and thiazino-quinazoline derivatives in
continuation to our previous work on synthesis of such skeletons
[19e21]. The regiochemistry of the cyclised products was estab-
lished by means of spectral data and verified by X-ray and DFT
studies.
2. Result and discussion
A mixture of 2-tetralone 1, 4-chloro benzaldehyde and thiourea
in glacial acetic acid on stirring at 110 ꢀC for 4 h furnished thione 2.
The characterization of this thione was done on the basis of spectral
data. The unsymmetrical thione 2, on condensation with ethyl
bromo acetate followed by cyclization of the intermediate in situ
was likely to give compound 3 or its isomer 4 or a mixture of both
depending upon mode of cyclization (Scheme 1). However, the
thione 2, when treated with ethyl bromo acetate in the presence of
anhydrous sodium acetate in absolute ethanol afforded a single
product (TLC) 3 or 4 in 82% yield. The appearance of a band at
Quazinone,
(3R)-6-chloro-3-methyl-5,10-dihydroimidazo[2,1-b]
quinazolin-2(3H)-one acts as effective PDE 3 and phospholipase
inhibitor [16]. Some of the quinazoline derivatives such as pro-
quazone,
1-isopropyl-7-methyl-4-phenylquinazoline-2(1H)-one
[17] and fluoroquazone, 4-(4-fluorophenyl)-7-methyl-1-propan-2-
yl-quinazoline-2-one [18] are well known non-steroidal anti-in-
flammatory drugs. Thiazoles are also endowed with a wide range of
1713 cmꢁ1 (C¼O) in the IR spectrum, appearance of peak at
d 170.7
(C¼O) in 13C NMR spectrum and exhibition of a quasimolecular ion
peak at m/z 367.2 (MþHþ, 100%) in the mass spectrum of the TLC-
pure product suggested the formation of thiazolidinone 3 or 4. The
* Corresponding author.
E-mail address: rpchaudhary65@gmail.com (R.P. Chaudhary).
http://dx.doi.org/10.1016/j.molstruc.2017.05.109
0022-2860/© 2017 Elsevier B.V. All rights reserved.

D. Gautam et al. / Journal of Molecular Structure 1145 (2017) 268e277
269
Scheme 1. Synthetic route to thiazolo-quinazoline derivatives.
appearance of two multiplets at
d
2.56 and
d
2.83 of two protons
Whereas the comparison of the chemical shifts of HA in the
structures 3 and 5 (or 6) is on a better footing as both structures 3
and 5 (or 6) are tetracyclic compounds. The same conclusion can
still be justifiably derived by comparing the chemical shifts of HA of
the thione 2 with that of cyclization product 3. The HA proton in
each in 1H NMR spectrum of the product have been assigned to
tetrahydronaphthalene ring of 3 or 4. A double doublet of two
protons at
d
3.94 (J ¼ 17.4 Hz and 1.7 Hz) assignable to SCH2 group
confirmed the formation of thiazolidinone ring. The IR and mass
spectral data were ambivalent on deciding the structure 3 or 4.
However, structure 3 was finally assigned to this cyclization prod-
uct in preference to the structure 4 on the basis of comparison of
chemical shift of HA proton of 3 or 4 with that of 5 or 6 as discussed
below.
thione 2 resonates at
d 5.44 whereas the downfield signal at d 6.20
(1H, s, HA) in the cyclised product supported the structure 3 in
preference to structure 4. Arylidene thiazolidinones (9a-d) were
prepared by two routes. In the first approach, thiazolidinone 3 was
condensed with aldehydes to give arylidene thiazolidinones (9a-d)
while in the second approach compound 9a was obtained directly
by heating compound 2 with chloroacetic acid and benzaldehyde.
The structure of 9a-d was established by IR and 1H NMR spectral
data. The parent thiazolidinone 3 exhibited an absorption band at
1713 cmꢁ1 (C¼O), but the unsaturation at the 2-position being
conjugated with the carbonyl group at the 3-position as in aryli-
dene thiazolidinones (9a-d) produced a bathochromic shift [22] as
expected, the carbonyl absorption band appeared at 1697 cmꢁ1 in
structure 9a. The structure of arylidene derivatives 9 has been
assigned on the basis of IR and 1H NMR spectral data. 1H NMR
The reaction of thione 2 with 1, 2-dibromoethane gave a product
which was purified by column chromatography and characterized
by its quasimolecular ion peak at m/z 353.2 (MþHþ, 100%) as a
compound which could be represented by either structure 5 or 6. In
either structure (5 or 6), the singlet at d
6.13 in its 1H NMR spectrum
integrating for one proton was assigned to HA proton. If the struc-
ture 4 is correct for the cyclization product, obtained from thione 2
and ethyl bromo acetate, and then HA would resonate in the same
region as that of structure 5 (or 6). On the other hand if the
structure 3 is correct, HA would be deshielded by the thiazolidinone
ring and consequently, HA would resonate downfield in comparison
spectra of 9a-d displayed benzylic proton at
d 7.70, 7.68, 7.65 and
to HA in 5 (or 6). The appearance of a downfield singlet at
d
6.20 for
7.73 respectively. The structure of compound 9d was confirmed by
X-ray crystallographic studies. X-ray structure of arylidene deriva-
tive 9d also supported our claim for structure 3.
HA in structure 3 (or 4) as compared to singlet at 6.13 for HA in
d
structure 5 (or 6) (Table 1) supported the structure 3 and ruled out
the structure 4 because from it such a downfield shift would not be
expected [21]. The deshielding effect is due to the magnetic
anisotropy of the C¼O group and a minor contribution from the rest
of the ring.
The downfield shift in the position of HA in 1H NMR spectrum of
the product obtained from reaction of 2 with ethyl bromo acetate
may be due to the presence of imine group in structure 4. If this is
the case, then in arylidene derivatives 9a-d, HA proton would not be

270
D. Gautam et al. / Journal of Molecular Structure 1145 (2017) 268e277
Table 1
Comparison of chemical shift (1H NMR, 400 MHz, DMSO-d6) of HA proton in structures 2, 3 and 5.
affected further because of the distant position of conjugated
carbonyl group from HA. In case of arylidene derivatives obtained
from structure 3, conjugated carbonyl system, will produce further
Thione 2, on condensation with 3-chloropropionic acid in
presence of anhydrous sodium acetate furnished a single product
(TLC) 10 or 11 in 60% yield. IR spectrum of the product displayed
carbonyl group at 1698 cmꢁ1. The mass spectrum of the product
exhibited quasimolecular ion peak at m/z 381.2 (MþHþ, 100%)
corroborated by structure 10 or 11. IR and Mass data were of little
help in deciding in favour of structure 10 and 11. The condensation
of thione 2 with 1,3-dibromopropane afforded a single product 12
or 13 (Scheme 2), which was purified by column chromatography
and characterized by appearance of quasimolecular ion peak at m/z
367.1 (MþHþ, 100%). The comparison of chemical shifts of HA pro-
ton in 10 or 11 and 12 or 13 indicates that HA proton appeared
downfield shift in position of HA in 9a-d i.e.
d 6.43, 6.36, 6.40 and
d
6.36. This downfield shift in the position of HA in arylidene de-
rivatives corroborated by structure 3 and discarded structure 4. The
structure 5 (not 6) for the product, obtained from the reaction of
compound 2 with 1, 2-dibromoethane, was assigned based upon
the analogy with structure 3.
Similarly, structure 7 was assigned to the TLC pure product
obtained from the reaction of thione 2 and 2-bromopropionic acid.
The analytical and spectral data (IR, NMR and Mass) supported
structure 7 and ruled out isomeric structure 8.
downfield at d 6.77 in (10 or 11) compared to at d 6.03 in (12 or 13).
Scheme 2. Synthesis of thiazino-quinazoline derivatives.

D. Gautam et al. / Journal of Molecular Structure 1145 (2017) 268e277
271
Scheme 3. Reaction of 1-arylidene-2-tetralone with thiourea in ethanol and HCl.
This is attributed to the anisotropy effect of C¼O group of thiazin-4-
one ring and supported structure 10. Finally, structure 10 was
assigned to product obtained from the reaction of thione 2 with 3-
chloropropionic acid. Based upon above analogy, structure 12 was
assigned to the product obtained from reaction of thione 2 with 1,3-
dibromopropane.
C(7)-C(8)-C(9) are 126.9(3) and 120.2(3) respectively, which is
consistent with the sp2 hybrid character of C9 and C8 atoms. ORTEP
diagram of 9d obtained from X-ray structure is shown in (Fig. 1).
The crystallographic data and refinement parameters of 9d are
reported in (Table 2). The selected bond parameters are listed in
(Table 3). The crystal packing diagram of 9d is shown in (Fig. 2) and
hydrogen bonding geometry is reported in (Table 4).
Crystallographic data for the structure 9d has been deposited
with the Cambridge Crystallographic Data Centre and its CCDC
Number is 1024077.
1-Arylidene-2-tetralone 14 were obtained from reaction of 2-
tetralone 1 with aromatic aldehydes in presence of acetic acid at
0e5 ꢀC. The characterization of 14 was done by spectral data.
Compound 14, on condensation with thiourea in ethanol and HCl
furnished a product which was different from the thione 2. This
product was identified as 15 (Scheme 3) and its characterization
was done by means of analytical and spectral data. IR spectrum of
2.2. Computational studies of compound 3 and regioisomer 4
15a showed a peak due to C¼N group at 1638 cmꢁ1
.
1H NMR
The molecular geometry optimization, 1H and 13C NMR spectra
calculations were performed with the Gaussian 09 W software
package [24] by using DFT methods with B3LYP (Becke three
parameter Lee-Yang-Parr) exchange correlation functional, which
combines the hybrid exchange functional of Becke [25], with the
spectrum of 15a displayed a singlet of one proton at
d
5.97 due to HA
10.05 assigned to NH
protons. Four multiplets of one proton each between 2.62e3.02
proton and two broad signals at
d 9.07 and d
d
were assigned to tetrahydronaphthalene ring. The structure of
compound 15b was similarly assigned by spectral data. The struc-
tures of 15 were further supported by their acetylation with acetic
anhydride to yield compound 16. IR spectrum of 16a displayed
peaks at 1678 cmꢁ1 and 1624 cmꢁ1 due to C¼O of amide group and
C¼N group respectively. 1H NMR spectrum of 16a showed a singlet
of three protons at
d 2.02 due to acetyl group. The structure of 16b
was similarly established.
2.1. Crystallographic study and structural description of compound
9d
X-ray diffraction measurements were performed on X Calibur
EOS OXFORD Diffractometer at 293 (2) K. The intensity data were
collected using graphite monochromatic Mo-K
a
radiation
(
l
¼ 0.71073 Å). The structure was solved by direct method using
the SHELX-97 software package [23] and refined by full-matrix
least-squares procedures on F2. All non-hydrogen atoms were
refined with anisotropic thermal parameters. The compound 9d
crystallizes in the monoclinic space group P21/n, with Z ¼ 4 and cell
parameters a ¼ 9.3092(6) Å, b ¼ 16.8078 (10) Å, c ¼ 14.6707(9) Å,,
b
¼ 102.134(5). In the compound, C(9)-O and C(7)eC(8) bond dis-
Fig. 1. ORTEP drawing indicating molecular structure and atomic labeling of the (Z)-
12-(4-chlorophenyl)-9-(4-fluorobenzylidene)-9,12-dihydro-5H-benzo[f]thiazolo[2,3-b]
quinazolin-10(6H)-one (9d).
tances of 1.208 (3) and 1.344 (4) Å, respectively, indicate the double
bond character of these bonds. The bond angles C(8)-C(9)-O and

272
D. Gautam et al. / Journal of Molecular Structure 1145 (2017) 268e277
Table 2
Crystal data and the structure refinement of (Z)-12-(4-chlorophenyl)-9-(4-
fluorobenzylidene)-9,12-dihydro-5H-benzo[f]thiazolo[2,3-b]quinazolin-10(6H)-one
(9d).
CCDC no.
1024077
C27H18ClFN2OS
472.94
Empirical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
Space group
Unit cell dimensions
a (Å)
293 (2)
0.71073 Å
Monoclinic
P21/n
9.3092(6)
b (Å)
c (Å)
16.8078(10)
14.6707(9)
90.00
102.134(5)
90.00
a
b
g
(ꢀ)
(ꢀ)
(ꢀ)
Volume (Å3)
2244.2(2)
Z
4
Density (calculated) (Mg/m3)
Absorption coefficient (mmꢁ1
Crystal size
1.400 Mg/m3
0.295 mmꢁ1
0.22 ꢂ 0.20 ꢂ 0.16 mm3
3.1294 to 29.1283
1429
)
Theta range for data collection
Reflections collected
Independent reflections
Data/restraints/parameters
Goodness-of-fit on F2
2669
5125/0/286
0.973
Fig. 2. Crystal packing diagram of 9d along c-axis.
Final R indices [I > 2
s
(I) ¼ 2591 data]
R1 ¼ 0.0629, wR2 ¼ 0.1369
R1 ¼ 0.1340, wR2 ¼ 0.1800
ꢁ0.381, 0.383
R indices (all data)
Largest diff. Peak and hole (eÅꢁ3
)
as used for geometry optimization. In order to express the chemical
shifts in ppm, the geometry of tetramethylsilane (TMS) and chlo-
roform molecules had been optimized and their 1H and 13C NMR
spectra were calculated by the same method using same basis set as
in case of the structure 3 and 4. The calculated isotropic shielding
constants si were then transformed to chemical shifts relative to
gradient-correlation functional of Lee, Yang and Parr [26]. The 6-
31G (d) basic set was used for DFT studies on isomeric pair 3/4. The
optimized configurations of compounds 3 and its isomer 4 with
atom numbering schemes are shown in (Fig. 3). The optimized
bond lengths and bond angles obtained by geometry optimization
of structure 3 and 4 are reported in (Table 5). In case of structure 3,
the optimized bond lengths of C¼O and CeS bonds in thiazolidi-
none ring are 1.242 Å and 1.833 Å, which are close to actual bond
lengths. The optimized bond angles for OeCeN and SeCeN were
observed at 124.15ꢀ and 123.77ꢀ. In case of structure 4, the opti-
mized bond lengths of C¼O and SeC in thiazolidinone ring are
1.241 Å and 1.839 Å. The optimized bond angles for CeNeC and
SeCeN were observed at 116.99ꢀ and 122.81ꢀ. It may be noted here
that slight differences in bond parameters are attributed to the fact
that theoretical calculations have been carried out for isolated
molecules in gaseous phase.
TMS by the equation, di
¼
sTMS - si. The experimental and calcu-
lated 1H and 13C NMR chemical shifts (ppm) of compounds 3 and its
isomers 4 have been reported in (Table 6). The correlation values of
proton chemical shifts are found to be 0.98318 for structure 3 and
0.97375 for its isomer 4 (Fig. 4). Similarly the correlation values of
carbon chemical shifts of 3 and 4 are found to be 0.99433 and
0.98835 (Fig. 5). The theoretical and experimental 1H and 13C data
shows good correlation for proposed structures 3. The total energy
obtained for optimized structures 3 and 4 are ꢁ1814.29 ha
and ꢁ1814.28 ha respectively. This shows structure 3 is more stable
than isomer 4.
Shielding tensors of structure 3 and 4 were computed within the
GIAO approach [27e29] applying the same methods and basic set
2.3. Antimicrobial activity of compounds 3, 5, 7 and 9
Compounds 3, 5, 7 and 9 were assayed for their in vitro anti-
microbial activities against E. coli, Bacillus, Staphylococcus and
Pseudomonas by disc diffusion method [30]. Tetracycline was used
as the reference standard in each plate. It was observed that among
all the tested compounds, compound 5 showed remarkable activity
against E. coli and Bacillus. Compound 7 showed maximum activity
against bacteria Staphylococcus and Pseudomonas. Compound 3
showed moderate activity against all the tested bacteria. Com-
pound 9a did not show any activity against E. coli and Bacillus.
Compound 9c was found to be inactive against Staphylococcus and
Pseudomonas (Table 7).
Table 3
Bond parameters of (Z)-12-(4-chlorophenyl)-9-(4-fluoro benzylidene)-9,12-
dihydro-5H-benzo[f]thiazolo[2,3-b]quinazolin-10(6H)-one (9d).
Compound 9d
Parameters
Experimental
Parameters
Experimental
Bond lengths (Å)
Bond Angles (ꢀ)
SeC(8)
SeC(10)
OeC(9)
1.753(3)
1.759(3)
1.208(3)
1.372(4)
1.390(4)
1.468(3)
1.278(4)
1.479(4)
1.344(4)
1.459(3)
1.3900
C(8)-S-C(10)
91.59(15)
116.9(2)
122.0(2)
120.9(2)
120.2(3)
123.3(3)
126.9(3)
109.7(3)
109.2(2)
126.7(3)
122.3(2)
111.0(2)
C(9)-N(1)-C(10)
C(10)-N(1)-C(11)
C(9)-N(1)-C(11)
C(7)-C(8)-C(9)
O-C(9)-N(1)
N(1)eC(10)
N(1)eC(9)
N(1)eC(11)
N(2)eC(10)
C(8)eC(9)
C(7)eC(8)
C(4)eC(7)
C(1)eC(6)
C(5)eC(6)
3. Experimental
O-C(9)-C(8)
N(1)-C(9)-C(8)
N(1)-C(11)-C(12)
N(2)-C(10)-N(1)
N(2)-C(10)-S
3.1. Instrumentations
Melting points were determined in sulphuric acid bath and are
reported uncorrected. TLC was performed on silica gel G plates
1.3900
N(1)-C(10)-S

D. Gautam et al. / Journal of Molecular Structure 1145 (2017) 268e277
273
Table 4
Hydrogen bonding geometry of compound 9d.
…
…
D-H…
Å
D-H(Å)
H
A(Å)
D
…. A(Å)
D-H A(ꢀ)
Symmetry codes
C11-H11_O
C2-H2_O
0.980
0.930
0.930
0.970
2.705
2.812
2.587
2.882
2.825
3.723
3.230
3.547
86.82
x, y, z
166.48
126.66
126.61
xþ1, þy, þz
C3-H3_S
x, y, z
C21-H21A_O
-xþ1/2, þy-1/2, -zþ1/2
Fig. 3. Optimized structures of compound 3 and its isomer 4.
Table 5
Selected calculated bond parameters of compound 3 and isomer 4.
3.2. General procedure for synthesis of thione 2
mixture of 2-tetralone (0.21 g, 0.0016 mol), p-chlor-
obenzaldehyde (0.22 g, 0.0016 mol) and thiourea (0.12 g,
0.0016 mol) in gl. acetic acid (10 mL) was heated at 110 ꢀC for 4 h.
The reaction mixture was then cooled to room temperature. The
white solid obtained was filtered, dried and recrystallized from
ethanol-DMF (3:1) mixture.
A
Compound 3
Parameters
Isomer 4
Calculated
Parameters
Calculated
Bond lengths (Å)
S(15)eC(12)
S(15)eC(16)
C(17)eN(13)
C(17)eO(18)
C(12)eN(11)
C(12)eN(13)
C(9)eN(11)
C(14)eH(20)
N(13)eC(14)
C(14)eC(19)
C(9)eC(10)
1.833
1.897
1.385
1.242
1.283
1.398
1.417
1.095
1.499
1.536
1.363
S(17)-C(12)
C(16)-S(17)
N(11)-C(15)
C(15)-O(18)
N(11)-C(12)
C(12)-N(13)
N(13)-C(14)
C(14)-H(20)
N(13)-C(14)
C(14)-C(19)
C(9)-C(10)
1.839
1.889
1.394
1.241
1.423
1.267
1.495
1.096
1.495
1.535
1.359
3.2.1. 1-(4-Chlorophenyl)-1,4,5,6-tetrahydrobenzo[f]quinazoline-
3(2H)-thione (2)
Yellow crystalline solid; yield 78%; mp 190-92 ꢀC. IR (cmꢁ1):
3208 (NH), 1548 (C¼C), 1246 (C¼S). 1H NMR (400 MHz, DMSO-d6):
d
2.44e2.52 (m, 1H, CH2), 2.58e2.64 (m, 1H, CH2), 2.84 (t, 2H, CH2,
J ¼ 7.3 Hz), 5.44 (d, 1H, HA, J ¼ 2.4 Hz), 6.83 (d, 1H, C6H5, J ¼ 7.0 Hz),
6.94e7.01 (m, 2H, C6H5), 7.06 (d, 1H, C6H5, J ¼ 6.5 Hz), 7.31 (d, 2H,
C6H5, J ¼ 6.7 Hz), 7.38 (d, 2H, C6H5, J ¼ 6.6 Hz), 9.19 (br, 1H, NH),
10.06 (br, 1H, NH). Anal. Calcd. (%) for C18H15ClN2S: C, 66.15; H, 4.63;
N, 8.57; S, 9.81. Found (%): C, 66.31; H, 4.76; N, 8.69; S, 9.96.
Bond Angles (ꢀ)
C(16)-S(15)-C(12)
C(17)-C(16)-S(15)
C(17)-N(13)-C(12)
C(17)-N(13)-C(14)
C(14)-N(13)-C(12)
S(15)-C(12)-N(13)
S(15)-C(12)-N(11)
N(13)-C(12)-N(11)
C(12)-N(11)-C(9)
N(11)-C(9)-C(10)
N(11)-C(9)-C(8)
89.80
C(12)-S(17)-C(16)
S(17)-C(16)-C(15)
C(15)-N(11)-C(12)
C(15)-N(11)-C(9))
C(14)-N(13)-C(12)
S(17)-C(12)-N(11)
S(17)-C(12)-N(13)
N(13)-C(12)-N(11)
C(12)-N(11)-C(9)
N(11)-C(9)-C(10)
N(11)-C(9)-C(8)
89.928
107.827
118.395
121.472
119.871
111.314
123.770
124.837
117.597
123.089
115.437
124.159
108.418
116.996
126.067
118.895
111.124
122.815
126.060
116.899
118.901
119.153
125.330
3.3. General procedure for synthesis of thiazolidin-4-ones 3 and 7
A mixture of thione 2 (0.16 g, 0.5 mmol), ethyl bromo acetate or
2-bromopropionic acid (0.5 mmol), anhydrous sodium acetate
(0.082 g, 1.0 mmol) in ethanol (10 mL) was heated under reflux for
5e6 h. The progress of reaction was monitored by TLC. After
completion, the volume of the reaction mixture was reduced to
half. The cooled reaction mixture was then poured in to ice cold
water and filtered the solid obtained. Recrystallization from etha-
noleDMF (3:1) mixture furnished pure compounds.
O(18)-C(17)-N(13)
O(18)-C(15)-N(11)
using pet ether-ethyl acetate (4:1) as eluent and iodine vapours as
visualizing agent. IR spectra were recorded on ABB FTIR spec-
trometer and the results are reported in cmꢁ1. 1H NMR and 13C NMR
were recorded in DMSO-d6 on a BRUKER AVANCE II 400 NMR
spectrometer using tetramethylsilane (TMS) as an internal standard
3.3.1. 12-(4-Chlorophenyl)-6,12-dihydro-5H-benzo[f]thiazolo[2,3-
b]quinazolin-10(9H)-one (3)
(chemical shift in d, ppm). Mass spectra were recorded on a WA-
Yellow solid; yield 62%; mp 102-04 ꢀC. IR (cmꢁ1): 1713 (C¼O),
TERS, Q- TOF MICROMASS (LC-MS) instrument. The elemental an-
alyses of the compounds were performed on Euro EA 3000
Elemental Analyzer. X-ray diffraction was performed on X Calibur
EOS OXFORD Diffractometer.
1612 (C¼N). 1H NMR (400 MHz, DMSO-d6):
d 2.56e2.67 (m, 2H,
CH2), 2.83e2.87 (m, 2H, CH2), 3.96 (dd,1H, SCH2, J ¼ 17.4 Hz,1.7 Hz),
6.20 (s, 1H, HA), 6.99e7.05 (m, 2H, C6H5), 7.06e7.12 (m, 2H, C6H5),
7.32 (d, 2H, C6H5, J ¼ 8.4 Hz), 7.47 (d, 2H, C6H5, J ¼ 8.4). 13C NMR

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D. Gautam et al. / Journal of Molecular Structure 1145 (2017) 268e277
Table 6
Experimental and calculated 1H NMR and 13C NMR chemical shifts of compound 3 and isomer 4.
Fig. 5. Plot of the calculated vs. experimental 13C NMR chemical shifts (ppm) of 3 and
4.
Fig. 4. Plot of the calculated vs. experimental 1H NMR chemical shifts (ppm) of 3 and 4.

D. Gautam et al. / Journal of Molecular Structure 1145 (2017) 268e277
275
Table 7
Antimicrobial activities by disc diffusion method of compounds 3, 5, 7 and 9.
Entry
Compound
Zone of inhibition (mm)
Antibacterial Activity
Bacillus
E. coli
Staphylococcus
Pseudomonas
1
2
3
4
5
6
7
3
5
7
9a
9b
9c
9d
7
8
10
12
14
10
10
e
7
8
13
12
11
e
14
10
e
13
10
e
10
8
11
15
00
8
7
11
14
00
9
24
00
12
18
00
Tetracycline
DMSO
(100 MHz, DMSO-d6)
d
: 170.7, 155.3, 139.9, 138.1, 134.7, 133.3, 131.3,
66.36; H, 4.63; N, 7.51; S, 8.68.
129.7, 128.5, 127.3, 126.1, 121.5, 111.0, 53.9, 36.2, 31.9, 28.4, 27.8, 24.2.
MS, m/z 367.2 (MþHþ, 100%). Anal. Calcd. (%) for C20H15ClN2OS: C,
65.48; H, 4.12; N, 7.64; S, 8.74. found (%): C, 65.62; H, 4.31; N, 7.81; S,
8.92.
3.5. General procedure for synthesis of arylidene derivatives 9
Arylidene derivatives 9 were prepared from two routes:
3.3.2. 12-(4-Chlorophenyl)-9-methyl-6,12-dihydro-5H-benzo[f]
thiazolo[2,3-b]quinazolin-10(9H)-one (7)
a) A mixture of thione 2 (0.13 g, 0.0004 mol), chloroacetic acid
(0.0378 g, 0.0004 mol), aromatic aldehyde (0.0004 mol), anhy-
drous sodium acetate (0.032 g, 0.0004 mol) in gl. acetic acid
(10 ml) and acetic anhydride (0.5 ml) was heated under reflux
for 6 h. Reaction mixture was kept overnight and then poured in
to ice cold water. The solid obtained was filtered, dried and
recrystallized from ethanol.
b) A mixture of thiazolidin-4-one 3 (0.0004 mol), aromatic alde-
hyde (0.0004 mol) and anhydrous sodium acetate (0.032 g,
0.0004 mol) in gl. acetic acid (10 ml) and acetic anhydride
(0.5 ml) was heated under reflux for 3 h. The reaction mixture
was then poured in to ice cold water. Filtered the solid obtained,
dried and recrystallized from ethanol.
Yellow crystalline solid; yield 68%; mp 182-84 ꢀC. IR (cmꢁ1):
1715 (C¼O), 1620 (C¼N). 1H NMR (400 MHz, DMSO-d6):
d 1.34 (d,
3H, CH3, J ¼ 7.2 Hz), 2.57e2.68 (m, 2H, CH2), 2.80e2.82 (m, 2H,
CH2), 4.28e4.30 (q, 1H, SCHCH3, J ¼ 7.2 Hz), 6.15 (s, 1H, HA),
6.99e7.07 (m, 4H, C6H5) 7.27 (d, 2H, C6H5, J ¼ 8.4 Hz), 7.42 (d, 2H,
C6H5, J ¼ 8.6 Hz). 13C NMR (100 MHz, DMSO-d6)
d: 174.1, 154, 139.9,
138.6, 134.7, 133.1, 131.4, 129.8, 128.6, 128.5, 127.3, 126.2, 121.7, 111.6,
54, 53.8, 28.4, 27.7, 18.7. MS, m/z 381.2 (MþHþ, 100%). Anal. Calcd.
(%) for: C21H17ClN2OS: C, 66.22; H, 4.50; N, 7.35; S, 8.42. Found (%):
C, 66.39; H, 4.61; N, 7.48; S, 8.53.
3.4. General procedure for synthesis of thiazinan-4-one 10
A mixture of thione 2 (0.32 g, 0.001 mol), chloropropionic acid
(0.108 g, 0.001 mol), anhydrous sodium acetate (0.16 g, 0.002 mol),
gl. acetic acid (10 ml) and acetic anhydride (0.5 ml) was heated
under reflux for 10e12 h. The progress of reaction was monitored
by TLC. After completion of the reaction, the reaction mixture was
kept overnight and then poured in to ice cold water. The solid
separated was filtered, dried and recrystallized from ethanol.
3.5.1. (Z)-9-Benzylidene-12-(4-chlorophenyl)-6,12-dihydro-5H-
benzo[f]thiazolo[2,3-b]quinazolin-10(9H)-one (9a)
Yellow solid; yield 60%; mp 98e100 ꢀC. IR (cmꢁ1): 1694 (C¼O),
1624 (C¼N). 1H NMR (400 MHz, DMSO-d6):
d 2.67e2.69 (m, 2H,
CH2), 2.86e2.89 (m, 2H, CH2), 6.43 (s, 1H, HA), 7.05e7.08 (m, 2H,
C6H5), 7.11e7.12 (m, 1H, C6H5), 7.23e7.25 (m, 1H, C6H5), 7.34e7.37
(m, 2H, C6H5), 7.45e7.51 (m,1H, C6H5), 7.53e7.57 (m, 6H, C6H5), 7.73
(s, 1H, ¼CH). Anal. Calcd. (%) for C27H19ClN2OS: C, 71.28; H, 4.21; N,
6.16; S, 7.05. Found (%): C, 71.42; H, 4.38; N, 7.02; S, 7.28.
3.4.1. 13-(4-Chlorophenyl)-6,9,10,13-tetrahydro-5H,11H-benzo[f]
[1,3]thiazino[2,3-b] quinazolin-11-one (10)
Yellow solid; yield 60%; mp 108-10 ꢀC. IR (cmꢁ1): 1698 (C¼O),
3.5.2. (Z)-12-(4-Chlorophenyl)-9-(4-methylbenzylidene)-6,12-
dihydro-5H-benzo[f] thiazolo[2,3-b]quinazolin-10(9H)-one (9b)
Orange solid; yield 78%; mp 156-58 ꢀC. IR (cmꢁ1): 1698 (C¼O),
1648 (C¼N). 1H NMR (400 MHz, DMSO-d6):
d 2.45e2.51 (m, 1H,
CH2), 2.65e2.73 (m, 1H, CH2), 2.89e2.98 (m, 2H, CH2), 3.0e3.1 (m,
4H, SCH2CH2), 6.77 (s, 1H, HA), 6.93e6.96 (m, 1H, C6H5), 7.03e7.08
(m, 2H, C6H5), 7.11e7.13 (m, 1H, C6H5), 7.30e7.36 (q, 4H, C6H5,
1612 (C¼N). 1H NMR (400 MHz, DMSO-d6):
d 2.34 (s, 3H, CH3),
2.55e2.71 (m, 2H, CH2), 2.80e2.93 (m, 2H, CH2), 6.36 (s, 1H, HA),
7.02e7.06 (m, 2H, C6H5) 7.08e7.10 (m, 1H, C6H5), 7.15e7.17 (m, 1H,
C6H5), 7.29 (t, 4H, C6H5, J ¼ 8.6 Hz), 7.4 (d, 2H, C6H5, J ¼ 8.2 Hz), 7.51
(d, 2H, C6H5, J ¼ 6.8 Hz), 7.65 (s, 1H, ¼CH). Anal. Calcd. (%) for
J ¼ 8.6, 7.4 Hz). 13C NMR (100 MHz, DMSO-d6)
d: 168.8, 151.1, 139.7,
138.0, 134.3, 133.0, 131.8, 129.2, 128.8, 127.5, 126.5, 121.4, 113.0, 61.2,
48.8, 35.4, 27.7, 21.0, 15.0. MS, m/z 381.2 (MþHþ, 100%). Anal. Calcd.
(%) for C21H17ClN2OS: C, 66.22; H, 4.50; N, 7.35; S, 8.42. Found (%): C,
C28H21ClN2OS: C, 71.71; H, 4.51; N, 5.97; S, 6.84. Found (%): C, 71.89;

276
D. Gautam et al. / Journal of Molecular Structure 1145 (2017) 268e277
H, 4.68; N, 6.09; S, 7.01.
7.31e7.35 (m, 3H, C6H5), 7.4 (d, 2H, C6H5, J ¼ 8.4 Hz), 7.49 (s,
1H, ¼CH). Anal. Calcd. (%) for C17H13ClO: C, 75.98; H, 4.88. Found
3.5.3. (Z)-12-(4-Chlorophenyl)-9-(4-methoxybenzylidene)-6,12-
dihydro-5H-benzo[f]thiazolo [2,3-b]quinazolin-10(9H)-one (9c)
Orange solid; yield 79%; mp 138-40 ꢀC. IR (cmꢁ1): 1701 (C¼O),
(%): C, 76.14; H, 5.08.
3.7.2. (E)-1-(4-Nitrobenzylidene)-3,4-dihydronaphthalen-2(1H)-
one (14b)
1628 (C¼N). 1H NMR (400 MHz, DMSO-d6):
d 2.58e2.72 (m, 2H,
CH2), 2.82e2.94 (m, 2H, CH2), 3.83 (s, 3H, OCH3), 6.4 (s, 1H, HA),
7.04e7.07 (m, 4H, C6H5), 7.11 (m, 1H, C6H5), 7.20e7.22 (m, 1H, C6H5),
7.34 (d, 2H, C6H5, J ¼ 6.7 Hz), 7.50e7.55 (m, 4H, C6H5), 7.68 (s,
1H, ¼CH). Anal. Calcd. (%) for C28H21ClN2O2S: C, 69.34; H, 4.36; N,
5.78; S, 6.61. Found (%): C, 69.53; H, 4.51; N, 5.91; S, 6.78.
Yellow solid; yield 85%; mp 120e122 ꢀC. IR (cmꢁ1): 1701 (C¼O).
1H NMR (400 MHz, DMSO-d6):
d
2.61 (t, 2H, CH2, J ¼ 6.6 Hz), 3.08 (t,
2H, CH2, J ¼ 6.5 Hz), 7.02 (t, 1H, C6H5, J ¼ 7.3 Hz), 7.13 (d, 1H, C6H5,
J ¼ 7.5 Hz), 7.26 (t, 1H, C6H5, J ¼ 7.4 Hz), 7.34 (d, 1H, C6H5, J ¼ 7.4 Hz),
7.58e7.60 (m, 3H, C6H5 & ¼ CH), 8.11 (d, 2H, C6H5, J ¼ 8.9 Hz). Anal.
Calcd. (%) for C17H13NO3: C, 73.11; H, 4.69. Found (%): C, 73.24; H,
4.88.
3.5.4. (Z)-12-(4-Chlorophenyl)-9-(4-fluorobenzylidene)-6,12-
dihydro-5H-benzo[f]thiazolo[2,3-b]quinazolin-10(9H)-one (9d)
Orange solid; yield 73%; mp 194-96 ꢀC. IR (cmꢁ1): 1697 (C¼O),
3.8. General procedure for synthesis of thiazin-3-amines 15
1632 (C¼N). 1H NMR (400 MHz, DMSO-d6):
d 2.64e2.76 (m, 2H,
CH2), 2.90e2.95 (m, 2H, CH2), 6.36 (s, 1H, HA), 7.07e7.10 (m, 4H,
C6H5), 7.20e7.31 (m, 4H, C6H5), 7.48e7.56 (m, 4H, C6H5), 7.70 (s,
1H, ¼CH). MS, m/z 473.0 (MþHþ, 100%). Anal. Calcd. (%) for
To a mixture of arylidene derivative 14 (0.0005 mol), and thio-
urea (0.038 g, 0.0005 mol) in ethanol (5.0 ml) catalytic amount of
conc. HCl (0.5 ml) was added and the mixture was refluxed for 5 h.
The solid separated on cooling was filtered, dried and recrystallized
from ethanol-DMF (3:1) mixture.
C
27H18ClFN2OS: C, 68.57; H, 3.84; N, 5.92; S, 6.78. Found (%): C,
68.72; H, 4.01; N, 6.01; S, 7.98.
3.6. General procedure for synthesis of 5 and 12
3.8.1. 1-(4-Chlorophenyl)-5,6-dihydro-1H-naphtho[2,1-d][1,3]
thiazin-3-amine (15a)
A mixture of thione 2 (0.26 g, 0.0008 mol), 1,2-dibromo ethane/
1,3-dibromo propane (0.0008 mol) in ethanol (5.0 ml) was heated
under reflux for 5 h. The volume of the reaction mixture was
reduced to half and cooled to room temperature. The reaction
mixture was poured in to ice cold water and extracted with ethyl
acetate (2 ꢂ 25 ml). Gummy solid obtained was purified with col-
umn hexane-ethyl acetate (8:2).
Light yellow solid; yield 78%; mp 206-08 ꢀC. IR (cmꢁ1): 3214,
3126 (NH), 1645 (C¼N). 1H NMR (400 MHz, DMSO-d6):
d 2.60e2.66
(m, 1H, CH2), 2.82e2.88 (m, 1H, CH2), 2.96e3.0 (m, 2H, CH2), 5.97 (s,
1H, HA), 7.07e7.14 (m, 3H, C6H5) 7.19e7.21 (m, 1H, C6H5), 7.37e7.42
(m, 4H, C6H5), 9.07 (br, 1H, NH), 10.05 (br, 1H, NH). Anal. Calcd. (%)
for C18H15ClN2S: C, 66.15; H, 4.63; N, 8.57; S, 9.81. Found (%): C,
66.31; H, 4.78; N, 8.71; S, 10.05.
3.6.1. 12-(4-Chlorophenyl)-6,9,10,12-tetrahydro-5H-benzo[f]
thiazolo[2,3-b] quinazoline (5)
3.8.2. 1-(4-Nitrophenyl)-5,6-dihydro-1H-naphtho[2,1-d][1,3]
thiazin-3-amine (15b)
Yellow solid; yield 52%; mp 178-80 ꢀC. IR (cmꢁ1): 1645 (C¼N). 1H
Green crystalline solid; yield 74%; mp 186-88 ꢀC. IR (cmꢁ1):
3208, 3115 (NH), 1646 (C¼N). 1H NMR (400 MHz, DMSO-d6):
NMR (400 MHz, DMSO-d6): d 2.61e2.66 (m,1H, CH2), 2.86e3.01 (m,
2H, CH2), 3.50e3.59 (m, 1H, CH2), 3.63e3.73 (m, 2H, NCH2),
4.25e4.31 (m, 1H, SCH2), 4.46e4.52 (m, 1H, SCH2), 6.13 (s, 1H, HA),
7.0e7.16 (m, 4H, C6H5), 7.35e7.43 (m, 3H, C6H5), 7.58 (d, 1H, C6H5,
J ¼ 7.9 Hz). MS, m/z 353.2 (MþHþ, 100%). Anal. Calcd. (%) for
d 2.62e2.68 (m,1H, CH2), 2.83e2.91 (m,1H, CH2), 2.98e3.02 (m, 2H,
CH2), 6.15 (s, 1H, HA), 7.06e7.08 (m, 1H, C6H5) 7.11e7.16 (m, 2H,
C6H5), 7.20e7.23 (m, 1H, C6H5), 7.68 (d, 2H, C6H5, J ¼ 7.1 Hz), 8.21 (d,
2H, C6H5, J ¼ 6.9 Hz), 9.15 (br, 1H, NH), 10.16 (br, 1H, NH). MS, m/z
338.1 (MþHþ, 100%). Anal. Calcd. (%) for C18H15N3O2S: C, 64.08; H,
4.48; N, 12.45; S, 9.50. Found (%): C, 64.21; H, 4.61; N, 12.68; S, 9.71.
C
20H17ClN2S: C, 68.07; H, 4.86; N, 7.94; S, 9.09. Found (%): C, 68.22;
H, 5.01; N, 8.01; S, 9.28.
3.6.2. 13-(4-Chlorophenyl)-6,10,11,13-tetrahydro-5H,9H-benzo[f]
[1,3]thiazino[2,3-b] quinazoline (12)
3.9. General procedure for synthesis of thiazin-acetamides 16
Yellow solid; yield 52%; mp 184-86 ꢀC. IR (cmꢁ1): 1645 (C¼N). 1H
A mixture of thiazin-3-amine derivative 15 (0.0004 mol),
anhydrous sodium acetate (0.0008 mol), acetic anhydride (0.5 ml)
in acetic acid (5.0 ml) was heated under reflux for 5 h. The reaction
mixture cooled to room temperature and poured in to ice cold
water. The solid obtained was filtered and recrystallized from
dichloro methane-hexane (3:1) mixture.
NMR (400 MHz, DMSO-d6):
d 2.55e2.65 (m, 2H, CH2), 2.87e2.97
(m, 5H, CH2), 3.18e3.25 (m, 2H, CH2), 3.81e3.84 (m, 1H, CH2), 6.03
(s, 1H, HA), 7.08e7.11 (m, 2H, C6H5), 7.13e7.17 (m, 2H, C6H5),
7.38e7.54 (m, 2H, C6H5), 7.62 (d, 2H, C6H5, J ¼ 8.5 Hz). MS, m/z 367.1
(MþHþ, 100%). Anal. Calcd. for: C21H19ClN2S: C, 68.75; H, 5.22; N,
7.64; S, 8.74. Found (%): C, 68.92; H, 5.41; N, 7.81; S, 8.98.
3.9.1. N-(1-(4-Chlorophenyl)-5,6-dihydro-1H-naphtho[2,1-d][1,3]
thiazin-3-yl)acetamide (16a)
3.7. General procedure for synthesis of 1-arylidene-2-tetralone 14
Yellow crystalline solid; yield 58%; mp 178-80 ꢀC. IR (cmꢁ1):
A mixture of 2-tetralone (0.05 mol) and aromatic aldehyde
(0.05 mol), glacial acetic acid (25 mL) and conc. HCl (15 mL) was
kept at 0 ꢀC for 24 h. Filtered the yellow solid obtained, washed
with petroleum ether (60e80 ꢀC) and recrystallized from ethanol.
1662 (C¼O), 1636 (C¼N). 1H NMR (400 MHz, DMSO-d6):
d 1.98 (s,
3H, CH3), 2.56e2.58 (m, 1H, CH2), 2.82e2.92 (m, 3H, CH2), 5.24 (s,
1H, HA), 6.90e6.92 (m,1H, C6H5) 6.98e7.02 (m, 2H, C6H5), 7.18e7.22
(m, 1H, C6H5), 7.4 (d, 2H, C6H5, J ¼ 8.7 Hz), 8.0 (d, 2H, C6H5,
J ¼ 8.7 Hz), 10.4 (br, 1H, NH). Anal. Calcd. for C20H17ClN2OS: C, 65.12;
H, 4.65; N, 7.59; S, 8.69. Found (%): C, 65.24; H, 4.79; N, 7.71; S, 8.81.
3.7.1. (E)-1-(4-Chlorobenzylidene)-3,4-dihydronaphthalen-2(1H)-
one (14a)
Yellow solid; yield 78%; mp 90e92 ꢀC. IR (cmꢁ1): 1696 (C¼O). 1H
3.9.2. N-(1-(4-Nitrophenyl)-5,6-dihydro-1H-naphtho[2,1-d][1,3]
thiazin-3-yl) acetamide (16b)
NMR (400 MHz, DMSO-d6):
CH2, J ¼ 6.5 Hz), 7.02e7.06 (m, 1H, C6H5), 7.19e7.25 (m, 2H, C6H5),
d
2.56 (t, 2H, CH2, J ¼ 3.5 Hz), 3.03 (t, 2H,
Orange crystalline solid; yield 60%; mp 154-56 ꢀC. IR (cmꢁ1):

D. Gautam et al. / Journal of Molecular Structure 1145 (2017) 268e277
277
1666 (C¼O), 1638 (C¼N). 1H NMR (400 MHz, DMSO-d6):
d 2.0 (s, 3H,
(2009) 3046;
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3637;
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N. Loaec, L. Meijer, T. Besson, Molecules 19 (2014) 15546.
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CH3), 2.53e2.56 (m, 1H, CH2), 2.84e2.98 (m, 3H, CH2), 5.27 (s, 1H,
HA), 6.92e6.94 (m, 1H, C6H5) 7.02e7.07 (m, 2H, C6H5), 7.14e7.16 (m,
1H, C6H5), 7.46 (d, 2H, C6H5, J ¼ 8.7 Hz), 8.12 (d, 2H, C6H5, J ¼ 8.7 Hz),
11.06 (br, 1H, NH). Anal. Calcd. for C20H17N3O3S: C, 63.31; H, 4.52; N,
11.07; S, 8.45. Found (%): C, 63.54; H, 4.78; N, 11.21; S, 8.61.
Appendix A. Supplementary data
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Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.molstruc.2017.05.109.
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