Synthesis of novel 12-aryl-8,9,10,12-tetrahydrobenzo[a]xanthene-11-thiones and evaluation of their biocidal effects

Article abstract of DOI:10.1016/j.ejmech.2012.10.025

Novel 12-aryl-8,9,10,12-tetrahydrobenzo[a]xanthene-11-thiones have been synthesized in high yields by treatment of the corresponding oxo analogs with Lawesson's reagent. The structure has been confirmed by X-ray analysis. The compounds were tested for in

Full text of DOI:10.1016/j.ejmech.2012.10.025

European Journal of Medicinal Chemistry 58 (2012) 470e477
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis of novel 12-aryl-8,9,10,12-tetrahydrobenzo[a]xanthene-11-thiones and
evaluation of their biocidal effects
,
a
a
b
c
Jitender M. Khurana a , Devanshi Magoo , Komal Aggarwal , Nisha Aggarwal , Rajesh Kumar ,
*
Chitra Srivastava d
a Department of Chemistry, University of Delhi, Delhi 110 007, India
b Centre for Mycorrhizal Research, Biotechnology and Bioresources Division, The Energy and Resources Institute, India Habitat Centre, Lodhi Road, New Delhi 110 003, India
c Division of Agricultural Chemicals, Indian Agricultural Research Institute, Pusa Campus, New Delhi 110 012, India
d Division of Entomology, Indian Agricultural Research Institute, Pusa Campus, New Delhi 110 012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel 12-aryl-8,9,10,12-tetrahydrobenzo[a]xanthene-11-thiones have been synthesized in high yields by
treatment of the corresponding oxo analogs with Lawesson’s reagent. The structure has been confirmed
by X-ray analysis. The compounds were tested for in vitro antifungal activity against Rhizoctonia bata-
ticola, Sclerotium rolfsii, Fusarium oxysporum and Alternaria porii. The compounds exhibited moderate to
good activity against all pathogens. Insecticidal activity of these compounds against Spodoptera litura was
observed to be comparable to commercial pyrethroid insecticide, cypermethrin. The urease inhibitory
activity has also been studied.
Received 12 May 2012
Received in revised form
9 October 2012
Accepted 16 October 2012
Available online 25 October 2012
Keywords:
Ó 2012 Elsevier Masson SAS. All rights reserved.
Tetrahydrobenzo[a]xanthene-11-thiones
Lawesson’s reagent
Antifungal activity
Insecticidal activity
Urease activity
1. Introduction
[11]. We have endeavored to develop new and efficient synthetic
routes for scaffold manipulation of bioactive compounds [12]. In
Xanthene derivatives have a wide utility range in laser tech-
nology [1], dyes [2], pH sensitive fluorescent materials [3], and are
also reported to exhibit a broad spectrum of pharmaceutical activ-
ities [4e6]. Further, thio analogs of xanthones and related systems
have received considerable attention due to the importance of such
structural motifs in biology and photochemistry [7]. Also, it can be
indubitably stated that thiocarbonyl compounds are valued not only
for their rich and varied chemistry but also for their usefulness in
pharmaceutical, polymer, pesticide and herbicide industries [8].
Several bioactive thio compounds, have already been reported for
their antifungal activity [9] and insecticidal activity [10]. Therefore,
the objective of the present work was to prepare new thio deriva-
tives of xanthenes and to study their biological activity. Recently, we
have reported the synthesis of a series of 12-aryl-8,9,10,12-tetra-
view of the importance of thioxanthene derivatives, we decided to
explore the possibility of synthesizing thio analogs of the reported
xanthene polycycles [11] by replacing the cyclohexenone moiety by
the corresponding cyclohexenethione and evaluate their antifungal,
insecticidal, insect growth regulatory and urease inhibitory activi-
ties to develop broad spectrum pesticidal molecules.
2. Results and discussion
2.1. Chemistry
The starting compounds, 12-aryl-8,9,10,12-tetrahydrobenzo[a]
xanthene-11-ones were synthesized as outlined in Scheme 1. The
transformation of carbonyl compounds to their thio analogs can be
achieved by application of many reagents [13]. The thionation of
synthesized xanthene-11-ones was attempted with P4S10 and
Lawesson’s reagent (2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadipho
sphetane 2,4-disulfide) using 12-(4-chloro-phenyl)-9,9-dimethyl-
8,9,10,12-tetrahydro-benzo[a]xanthen-11-one as the model
substrate. A series of experiments established that 2.2 mol of
Lawesson’s reagent per mole of the xanthene-11-one (1a) was
hydrobenzo[a]xanthene-11-ones by the condensation of b-naph-
thol and aromatic aldehydes with cyclic 1,3-dicarbonyl compounds
in presence of pTSA under neat conditions and also in ionic liquid
* Corresponding author. Tel.: þ91 11 2766772; fax: þ91 1 27667624.
E-mail addresses: jmkhurana1@yahoo.co.in, jmkhurana@chemistry.du.ac.in
(J.M. Khurana).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2012.10.025

J.M. Khurana et al. / European Journal of Medicinal Chemistry 58 (2012) 470e477
471
R'
O
O
R'
[bmim]BF4 / Neat
pTSA
OH
CHO
R
R'
O
R
O
R'
1a-n
R' = CH3, H
Scheme 1.
required to obtain the optimum yield (85%) of the desired 12-(4-
chlorophenyl)-9,9-dimethyl-8,9,10,12-tetrahydrobenzo[a]xanthen-
11-thione in dry toluene under reflux conditions. However,
employing P4S10 to synthesize the target compound did not lead to
satisfactory results despite several manipulations involving molar
ratios, solvents and temperature. Using the optimized reaction
conditions, thionation of a series of xanthene-11-ones (1aen)
reflecting structural variation was examined.
Variously substituted xanthene-11ones (1aen) reacted
smoothly with Lawesson’s reagent in boiling toluene to give the
corresponding novel xanthenes-11-thiones (2aen) in good to
excellent yields in short reaction time (Scheme 2). The results are
summarized in Table 1. Compounds 2aen are stable solids whose
structures were established by IR, 1H, and 13C NMR spectroscopies,
mass spectrometry and elemental analysis. The structure of 2j has
also been confirmed by a single crystal X-ray analysis [14] (Fig. 1).
The thiocarbonyl double bond of compound 2j has been assigned
based on spectral data. IR spectrum of thioxanthene (2j) showed
C]S stretch at 1581 cmꢀ1 while the C]O stretch of the corre-
sponding xanthene (1j) appeared at 1651 cmꢀ1. In 13C NMR spec-
trum of compound 1j, carbon of carbonyl functionality appeared at
2.4. Insecticidal and insect growth regulatory activity
Compounds 2aen were also evaluated for insecticidal activity as
well as insect growth regulatory activity against lepidopteran insect
pest namely, Spodoptera litura (third instar larvae) at 0.1% dose by
both contact and feeding method (Tables 3 and 4) [16] (Figs. 3 and
4). Most of the compounds showed moderate to good insecticidal
activity with feeding method whereas low mortality was observed
when treated through topical method (i.e. through direct pene-
tration on the insects). The insecticidal activity of few compounds
was comparable to that of cypermethrin, a commercial pyrethroid
insecticide when tested at a 0.1% dose. The compound with R ¼ 3-
BrC6H4 was more active in comparison to the compounds having
R ¼ H as insecticidal agent. Most of the compounds revealed high
activity as insect growth regulator. Compound with 3-bromo
substitution was found to be most effective with 100% growth
inhibition index at 0.1% dose. Compound with 4-NO2 and without
substitution (compounds 2n and 2d) also revealed higher activity
(% growth inhibition index ¼ 80 and 75). The percentage of larvae
that reached to pupa or adult stage decreased considerably as life
cycle progresses. Some of them resulted in abnormal pupae or
adults.
d
196.8 while in corresponding thioxanthene (2j) disappearance of
carbon of carbonyl functionality occurred and carbon of thio-
carbonyl functionality appeared at 230. X-ray data of compound
d
2.5. Urease inhibitory activity
2j reveals important information about the thiocarbonyl double
bond as the bond length of the carbonyl double bond of xanthene
All the compounds were tested for urease inhibitory activity at 1%
dose. The urease inhibitory activity observed with the test
compounds was ranged from ꢀ8 to 47% during 9e27 h of incubation.
The best performer was compound 2k (R ¼ H) with 47 and 22%
urease inhibition (Fig. 5). A perusal of activity data along with SAR
revealed that better activity was observed with compounds
substituted with aryl group having electron donating groups espe-
cially at para position, compounds, 2a and 2e. Increase in the aryl
ring did not result in any significant change in the urease inhibitory
activity. Results for the soil incubation study are reported in Table 5.
ꢀ
was 1.223 A while the observed bond length of the thiocarbonyl
ꢀ
double bond of 2j was 1.634 A.
2.2. Biology
These thiones (2ae2n) were then tested for antifungal, insec-
ticidal, insect growth regulatory and urease inhibitory activities.
2.3. In vitro antifungal activity
All the synthesized compounds were screened for antifungal
activity against four soil borne fungi, namely, Rhizoctonia bataticola
(RB), Sclerotium rolfsii (SR), Fusarium oxysporum (FO), and Alternaria
porii (AP) by the poisoned food technique [15] and their calculated
ED50 values are reported in Table 2. All the compounds showed low
to moderate activity against all pathogens (Fig. 2). Maximum
activity was observed against A. porii (ED50 ranges from 135 to
3. Conclusion
In summary, we have synthesized a novel series of 12-aryl-
8,9,10,12-tetrahydrobenzo[a]xanthene-11-thiones and studied
their insecticidal, antifungal and urease activity. The spectroscopic
analyses and X-ray analysis confirmed the structures of these
compounds. The in vitro antifungal activity of these compounds
revealed that the 2-bromo and 2-naphthyl derivatives were more
active among all the xanthene-11-thiones. Insecticidal activity data
670
mg/mL). Compounds with 2-bromo and 2-naphthyl substitu-
tions showed better antifungal activity than rest of the compounds.
R'
O
R'
R'
O
R
R'
Lawesson's Reagent
Toluene/Reflux
O
S
R
1a-n
(R' = CH3, H)
2a-j (R'=CH3); 2k-n (R'=H)
Scheme 2.

472
J.M. Khurana et al. / European Journal of Medicinal Chemistry 58 (2012) 470e477
Table 1
anhydrous toluene (15 mL) was placed in a 100 mL round bottomed
flask mounted over a magnetic stirrer. The reaction mixture was
refluxed for 30e90 min (Table 1). The progress of the reaction was
monitored by TLC using petroleum ether:ethyl acetate (90:10).
After completion, the solvent was evaporated under reduced
pressure. The residue was purified by silica gel (100e200 mesh)
column chromatography eluting with petroleum ether:ethyl
acetate (99:1).
Synthesis of 12-aryl-8,9,10,12-tetrahydrobenzo[a]xanthene-11-thiones.
Compound no.
R
R0
Product
Time
(min)
Yield
(%)
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
4-ClC6H4
3-BrC6H4
4-FC6H4
C6H5
4-(CH3)C6H4
4-(OCH3)C6H4
2-(OCH3)C6H4
3-(OCH3),4-(OH)C6H3
2-Naphthyl
2-Thiophenyl
C6H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
45
45
45
45
40
40
40
50
60
35
60
60
60
90
85
86
88
85
80
78
77
82
88
87
80
78
80
85
4.3. In vitro antifungal activity
The antifungal activity of the compounds was evaluated in vitro
using a food poison technique [15].
2-BrC6H4
3-ClC6H4
4-(NO2)C6H4
H
H
H
4.4. In vitro insecticidal activity
The biological assay was conducted against third-instar larvae of
S. litura (7 ꢁ 1 day old) using the feeding method and topical
treatment [16].
have shown that the synthesized compounds have a significant
insecticidal activity against the tested microorganisms.
4.4.1. Feeding method
4. Experimental
The castor leaf was dipped in a 0.1% solution of synthesized
compounds for 2 s and then air-dried. Moist filter paper was placed
in glass Petri plates (9 cm diameter) on which treated leaf disks
were kept. Larvae of S. litura prestarved for 4 h were released
individually into each Petri plates. Thirty replications were kept for
each treatment. Solvent was used as control. Mortality was
observed after 24 h.
4.1. General
All the chemicals used were purchased from SigmaeAldrich and
used as received. Thin layer chromatography was used to monitor
reaction progress. Column chromatography was performed using
100e200 mesh silica gel and appropriate mixture of petroleum
ether/ethyl acetate for elution. Melting points were determined on
a Tropical Labequip apparatus and are uncorrected. IR (KBr) spectra
were recorded on PerkineElmer FTIR spectrophotometer and the
values are expressed as nmax cmꢀ1. Mass spectral data were recor-
ded on a Waters micromass LCT Mass Spectrometer and on JEOL-
AccuTOF JMS-T100 mass spectrometer having a DART source. The
1H NMR and 13C NMR spectra were recorded on Bruker Spectrospin
spectrometer and Jeol JNM ECX-400P at 300 MHz and 400 MHz,
respectively using TMS as an internal standard. The chemical shift
4.4.2. Topical treatment
The 0.1% stock solution of various compounds was prepared in
dichloromethane. 2
mL of each compound was applied on the
ventral side of the S. litura larvae. Ten treated larvae were released
in glass bottles, and fresh tender castor leaves were given as food.
Each treatment was kept in triplicate, and solvent was used as
control. Mortality was observed after 24 h.
4.5. Insect growth regulatory activity (IGR)
values are recorded on
Hertz.
d scale and the coupling constants (J) are in
The IGR activity of the above synthesized compounds was
evaluated against S. litura following the test procedure. Third Instar
larvae (S. litura) reared on the artificial diet was used for IGR
activity. The 0.1% stock solution of test compounds was prepared
using appropriate solvent. Newly moulted pre-weighed (30e
40 mg) 3rd instar larvae were treated through leaf dip method
with different concentrations of the compounds. Individual leaves
were placed on moistened pieces of filter paper in Petri dishes. The
leaves were then sprayed with the test solution and allowed to dry.
The dishes were infested with ten third-instar larvae. Each treat-
ment was performed in triplicate. Controls were treated with
carrier solvent alone. After 24 h treated larvae were observed for
larval weight, larval mortality, percentage pupation, deformed
pupae, larvalepupal and pupaleadult intermediates, percentage
adult emergence and deformed adults and the same were recorded.
4.2. General procedure for the synthesis of tetrahydrobenzo[a]
xanthene-11-thione derivatives
A mixture of 12-aryl-8,9,10,12-tetrahydrobenzo[a]xanthene-11-
one (0.3 g, 0.77 mmol), Lawesson’s reagent (0.68 g, 1.69 mmol) and
4.6. Urease inhibitory activity
The above synthesized compounds were also evaluated for their
effect on urease inhibition at a 1% dose according to the following
method.
4.6.1. Soil
The soil for in vitro incubation experiments was collected from
the farm of the Institute. A composite soil sample was collected in
bulk from the cultivated fields of known history from a depth of 0e
Fig. 1. ORTEP of compound 9,9-dimethyl-12-thiophen-2yl-8,9,10,12-tetrahydro-benzo
[a]xanthenes-11-thione (2j) with atoms represented as 50% thermal probability
ellipsoid.

J.M. Khurana et al. / European Journal of Medicinal Chemistry 58 (2012) 470e477
473
Table 2
In vitro antifungal activities of 2ae2n thiones.
Compound no.
Antifungal activity
RB
SR
FO
AP
ED50
(
m
g/mL)
Chi square
ED50
(m
g/mL)
Chi square
ED50
(
mg/mL)
Chi square
ED50
(
m
g/mL)
Chi square
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
334.01
475.42
345.03
570.39
489.24
478.49
484.26
566.75
243.92
589.64
437.50
285.85
380.35
554.62
4.36
0.44
4.04
2.54
1.76
0.47
3.84
2.87
1.66
4.23
5.35
2.96
1.06
1.04
4.69
1.23
280.43
478
3.55
1.71
0.72
4.32
4.75
4.45
2.37
2.48
3.93
1.87
2.29
3.36
3.59
2.89
1.01
245.46
309.57
260.25
325.52
410.45
278.98
335.56
438.39
188.56
375.27
287.20
148.47
320.23
357.60
20.56
0.70
1.71
0.72
4.32
5.40
2.11
3.40
4.51
5.33
5.69
2.29
3.36
5.32
2.89
1.56
310.74
320.89
198.65
335.72
385.32
405.61
418.48
432.85
165.37
456.20
209.90
135.80
268.20
212.00
25.54
0.42
1.44
2.89
3.98
2.54
2.41
5.03
4.03
4.23
2.54
4.00
3.41
1.88
2.65
1.23
358.22
525.29
320.87
365.40
324.38
670.34
198.75
456.78
500.30
225.46
425.65
670.41
12.96
Hexaconazole
RB e Rhizoctonia bataticola; SR e Sclerotium rolfsii; FO e Fusarium oxysporium; AP e Alternaria porii; ED50 is an average of four replicates and its standard deviation (ꢁ) ranged
from ꢁ0.44 to ꢁ5.03; Chi square for heterogeneity (tabular value at 0.05 level) ¼ 5.991 (degrees of freedom ¼ 3).
15 cm following a standard sampling procedure. The physical and
chemical characteristics of the soil were as follows: sand, 60.8%;
clay, 20.5%; and slit, 18.7%; pH 7.9 (soil/water 1:2.5); EC at 25 ꢂC,
0.35 d Smꢀ1; organic carbon, 0.50%; available N, 55.72 mg kgꢀ1 of
soil; nitrate-N, 12.9 mg kgꢀ1 of soil; nitrite-N, traces; and
ammonium-N, 5.6 mg kgꢀ1 of soil. It was air-dried at room
temperature, ground, and passed through a 2 mm sieve. The soil
was thoroughly mixed before use.
thoroughly. In all of the treatments including control, the same
volume of acetone was added. After thorough mixing, 10 mg of
urea-N (200 mg of urea-N kgꢀ1 of soil) in aqueous solution was
added and mixed thoroughly. Distilled water was added to each
beaker to maintain the moisture at 50% water-holding capacity of
the soil. The controls were similarly processed with urea alone at
200 mg kgꢀ1 urea-N level without adding any test inhibitor. All of
the beakers were accurately weighed, labeled, and kept at
25 ꢁ 1 ꢂC with 98% relative humidity in an incubator. Soil moisture
was maintained by adding distilled water every day after taking
the difference of weight if necessary.
4.6.2. Experiment
The experiments were conducted following
a completely
randomized design (CRD) with three replicates. The test chemicals
were tested at a 1% dose of applied urea-N along with a urea alone
control. The samples were incubated in 100 mL capacity plastic
beakers (50 g of air-dried soil was taken per beaker). A calculated
amount of the test chemical (0.1 mg for 1% dose of applied urea-N,
respectively) in acetone was added to each beaker and mixed
4.6.3. Sampling and estimation of urea-N from the soil samples
The soil samples (5 g) were withdrawn after 9 and 27 h of
incubation and extracted with 1 M aqueous sodium sulfate (50 mL)
solution containing 2.5 mg of phenyl mercuric acetate to stop the
urea hydrolysis after extraction. The soil with extracting solution
was shaken for an hour on a reciprocal shaker. The soil samples
were filtered and estimated for urea-N following the Douglas and
Bremner method [17]. The contents of urea-N were obtained from
the standard curves and expressed in milligrams per kilogram.
Table 3
Insecticidal activities against Spodoptera litura at 0.1% through both contact and
feeding technique.
Compound no.
Insect mortality (S. litura)
Contact
Stomach
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
30
30
10
20
10
0
15
0
0
40
10
40
20
20
10
30
10
80
10
30
90
60
70
ea
100
0
10
50
30
0
Cypermethrin
Aza
100
Fig. 2. In vitro antifungal activities of selected compounds. Columns represent ED50 mg/
mL of selected compounds against RB e Rhizoctonia bataticola; SR e Sclerotium rolfsii;
FO e Fusarium oxysporium; AP e Alternaria porii.
ea
a
Not applicable.

474
J.M. Khurana et al. / European Journal of Medicinal Chemistry 58 (2012) 470e477
Table 4
IGR (insect growth regulator) activities of 2ae2n thiones against Spodoptera litura at
0.1%.
Compound % Mortality % Abnormal % Abnormal % Normal % Growth
no.
larva/dead
larva
pupa/dead
pupa
adult
inhibition
index
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
40
50
0
50
30
10
30
10
0
15
40
0
30
50
10
50
50
0
10
10
20
0
20
0
0
20
20
10
20
0
0
30
0
70
100
50
75
50
40
60
30
30
35
50
25
60
80
50
35
50
60
40
70
70
65
50
75
40
20
15
10
20
10
20
10
20
10
5
10
20
5. Spectral data
Fig. 4. IGR (insect growth regulator) activities of 2ae2n thiones. Columns represent
the % growth inhibition index of 2ae2n against Spodoptera litura at 0.1%.
5.1. 12-(4-Chloro-phenyl)-9,9-dimethyl-8,9,10,12-tetrahydro-benzo
[a]xanthene-11-thione (2a)
Pink solid, yield: 85%, m.p.: 184e186 ꢂC, 1H NMR (400 MHz,
1H, J ¼ 16.8 Hz, CH2CO), 2.83 (d, 1H, J ¼ 16.8 Hz, CH2CO), 6.10 (s, 1H,
ArCH), 7.02e7.08 (m, 1H, AreH), 7.15 (d, 1H, J ¼ 8.1 Hz, AreH), 7.26
(d, 1H, J ¼ 8 Hz, AreH), 7.36e7.44 (m, 3H, AreH), 7.48e7.53 (m, 1H,
AreH), 7.84e7.87 (d, 2H, J ¼ 8.7 Hz, AreH), 8.08 (d, 1H, J ¼ 8.4 Hz,
CDCl3)
d
: 0.83 (s, 3H, CMe),1.03 (s, 3H, CMe), 2.67 (d,1H, J ¼ 16.8 Hz,
CH2CO), 2.75 (d, 1H, J ¼ 16.8 Hz, CH2CO), 2.82 and 2.84 (AB system,
2H, J ¼ 16.8 Hz, CHa.CHbCMe2), 6.12 (s, 1H, ArCH), 7.18 (d, 2H,
J ¼ 8.8 Hz, AreH), 7.33(d, 2H, J ¼ 8.8 Hz, AreH), 7.41e7.54 (m, 3H, Are
H), 7.90 (d, 2H, J ¼ 8.8 Hz, AreH), 8.11 (d,1H, J ¼ 8 Hz, AreH); 13C NMR
AreH); 13C NMR (75 MHz, CDCl3)
d: 26.43, 28.81, 33.19, 37.49, 42.94,
61.01, 116.93, 117.78, 122.16, 123.30, 123.51, 125.19, 127.24, 128.12,
128.60, 129.05, 129.41, 130.98, 131.63, 132.12, 146.31, 146.86, 161.53,
(100 MHz, CDCl3) d: 26.25, 28.86, 33.02, 37.12, 42.87, 60.95, 116.96,
123.39, 125.27, 127.27, 128.20, 128.69, 129.04, 130.71, 142.95, 146.28,
230.36 (C]S); IR (KBr, cmꢀ1
)
nmax ¼ 2958.31, 1585.75, 1368.93,
162.69, 231.5 (C]S); IR (KBr, cmꢀ1
)
nmax ¼ 2920.38,1579.42,1369.40,
1219.12, 1187.01; MS (FAB): m/z ¼ [M]þ 449, 451 [M þ 2]þ.
1221.22, 1186.88; MS (ESI): m/z ¼ [M þ H]þ 405, 407 [M þ 2]þ.
5.2. 12-(3-Bromo-phenyl)-9,9-dimethyl-8,9,10,12-tetrahydro-benzo
5.3. 12-(4-Fluoro-phenyl)-9,9-dimethyl-8,9,10,12-tetrahydro-benzo
[a]xanthene-11-thione (2b)
[a]xanthene-11-thione (2c)
Pink solid, yield: 86%, m.p.: 140 ꢂC, 1H NMR (300 MHz, DMSO-
Pink solid, yield: 88%, m.p.: 140 ꢂC, 1H NMR (400 MHz, CDCl3)
d:
d6) d: 0.81 (s, 3H, CMe), 0.99 (s, 3H, CMe), 2.68 (s, 2H, CH2), 2.76 (d,
0.97 (s, 3H, CMe), 1.13 (s, 3H, CMe), 2.69 (d, 1H, J ¼ 18.3 Hz, CH2CO),
Fig. 3. Insecticidal activities of compounds 2ae2n. Columns represent the % inhibition
of compounds 2ae2n against Spodoptera litura at 0.1% through both contact and
feeding technique.
Fig. 5. Urease inhibitory activity of selected compounds. Columns represent the %
inhibition of selected compounds during 9e27 h of incubation.

J.M. Khurana et al. / European Journal of Medicinal Chemistry 58 (2012) 470e477
475
Table 5
1H, ArCH), 6.70 (d, 2H, J ¼ 8.8 Hz, AreH), 7.24 (d, 2H, J ¼ 8.8 Hz, Are
H), 7.43e7.50 (m, 2H, AreH), 7.53e7.57 (m, 1H, AreH), 7.88e7.92
(m, 2H, AreH), 8.15 (d, 1H, J ¼ 8 Hz, AreH); 13C NMR (100 MHz,
Urease inhibitory activity of 2ae2n thiones.
Compound
no.
R
R0
9 h %
Inhibition
27 h %
Inhibition
CDCl3):
d
¼ 25.48, 28.46, 32.84, 36.28, 41.79, 54.85, 60.44, 113.32,
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
4-ClC6H4
3-BrC6H4
4-FC6H4
C6H5
4-(CH3)C6H4
4-(OCH3)C6H4
2-(OCH3)C6H4
3-(OCH3),4-(OH)C6H3
2-Naphthyl
2-Thiophenyl
C6H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
35
15
ꢀ3
5
33
5
24
ꢀ6
1
4
47
1
6
1
18
6
0
116.98, 118.33, 123.05, 123.32, 125.19, 127.33, 128.70, 128.98, 129.80,
130.28, 131.23, 136.23, 146.38, 157.53, 162.68, 231.15 (C]S); IR (KBr,
cmꢀ1): nmax ¼ 2961.25, 1578.88, 1508.55, 1369.27, 1250.98, 1220.23,
1186.47; MS (ESI): m/z ¼ [M þ H]þ 401.2, 403.2 [M þ 2]þ.
5
12
ꢀ4
6
12
3
ꢀ8
22
ꢀ2
2
5.7. 12-(2-Methoxy-phenyl)-9,9-dimethyl-8,9,10,12-tetrahydro-
benzo[a]xanthene-11-thione (2g)
Pink solid, yield: 77%, m.p.: 220e222 ꢂC, 1H NMR (400 MHz,
2-BrC6H4
3-ClC6H4
4-(NO2)C6H4
H
H
H
CDCl3)
d
: 0.96 (s, 3H, CMe), 1.12 (s, 3H, CMe), 2.69 (d, 1H, J ¼ 18.3 Hz,
CH2CO), 2.77 (d, 1H, J ¼ 18.3 Hz, CH2CO), 2.84 and 2.86 (AB system,
2H, J ¼ 16.8 Hz, CHaCHbCMe2), 3.79 (s, 3H, OMe), 6.40 (s, 1H, ArCH),
6.71 (d, 1H, J ¼ 8 Hz), 6.78e6.83 (m, 1H), 7.01e7.05 (m, 1H), 7.26e
7.30 (m, 1H, AreH), 7.34e7.38 (m, 1H, AreH), 7.45e7.49 (m, 2H,
AreH), 7.68e7.75 (m, 2H, AreH), 8.44 (d, 1H, J ¼ 8 Hz); 13C NMR
ꢀ1
2.77 (d, 1H, J ¼ 18 Hz, CH2CO), 2.85 and 2.87 (AB system, 2H,
J ¼ 16.8 Hz, CHaCHbCMe2), 6.29 (s,1H, ArCH), 6.82e6.87 (m, 2H, Are
H), 7.35e7.54 (m, 5H, AreH), 7.76e7.82 (m, 2H, AreH), 8.14 (d, 1H,
(100 MHz, CDCl3):
d
¼ 26.04, 29.07, 32.89, 34.34, 43.05, 55.30, 61.25,
111.29, 116.61, 117.91, 120.06, 122.98, 124.14, 124.65, 126.67, 127.71,
J ¼ 8.4 Hz, AreH); 13C NMR (100 MHz, CDCl3)
d: 25.40, 28.39, 32.80,
128.23, 131.42, 132.28, 147.20, 156.92, 162.06, 230.27 (C]S); IR (KBr,
cmꢀ1
)
nmax ¼ 2932.75, 1572.18, 1373.82, 1220.95, 1185.92; MS (ESI):
36.40, 41.76, 60.35, 114.55, 114.83, 116.97, 117.75, 122.92, 125.26,
127.43, 128.72, 129.16, 130.16, 130.53, 130.64, 131.22, 140.21, 146.26,
158.75, 161.97, 162.53, 230.59 (C]S); IR (KBr, cmꢀ1):
nmax ¼ 2924.23, 1579.91, 1368.42, 1220.78, 1185.93; MS (FAB): m/
z ¼ [M þ H]þ 389, 391 [M þ 2]þ.
m/z ¼ [M þ H]þ 401.2, 403.2 [M þ 2]þ.
5.8. 12-(4-Hydroxy-3-methoxy-phenyl)-9,9-dimethyl-8,9,10,12-
tetrahydro benzo[a]xanthene-11-thione (2h)
5.4. 9,9-Dimethyl-12-phenyl-8,9,10,12-tetrahydro-benzo[a]
Pink solid, yield: 82%, m.p.: 182e184 ꢂC, 1H NMR (400 MHz,
xanthene-11-thione (2d)
CDCl3) d: 0.96 (s, 3H, CMe), 1.11 (s, 3H, CMe), 2.63 (s, 2H, CH2CMe2),
2.81 (d, 1H, J ¼ 16.8 Hz, CH2CO), 2.95 (d, 1H, J ¼ 16.8 Hz, CH2CO),
3.82 (s, 3H, OMe), 5.39 (s, 1H, OH), 6.23 (s, 1H, ArCH), 6.645 (d, 1H,
J ¼ 8 Hz, AreH), 6.72e6.74 (m, 1H, AreH), 7.06e7.07 (m, 1H, AreH),
7.34 (d, 1H, J ¼ 8.8 Hz, AreH), 7.38e7.42 (m, 1H, AreH), 7.48e7.50
(m, 1H, AreH), 7.73e7.80 (m, 2H, AreH), 8.17 (d, 1H, J ¼ 8 Hz, Are
Pink solid, yield: 85%, m.p.: 128 ꢂC, 1H NMR (300 MHz, DMSO-
d6)
d
: 0.86 (s, 3H, CMe), 1.06 (s, 3H, CMe), 2.75 (d, 2H, J ¼ 6 Hz,
CH2), 2.85 (s, 2H, CH2), 6.16 (s, 1H, ArCH), 7.02 (d, 1H, J ¼ 7.5 Hz,
AreH), 7.13e7.18 (m, 2H, AreH), 7.34 (d, 2H, J ¼ 7.8 Hz, AreH),
7.42e7.56 (m, 3H, AreH), 7.92 (d, 2H, J ¼ 9 Hz, AreH), 8.17 (d,
H); 13C NMR (100 MHz, CDCl3)
d: 26.28, 28.86, 33.07, 37.11, 42.94,
1H, J ¼ 8.4 Hz, AreH); 13C NMR (75 MHz, CDCl3)
d: 26.40, 28.28,
55.89, 61.09, 112.38, 113.91, 116.77, 121.83, 123.51, 124.99, 126.96,
128.47, 128.56, 131.25, 131.59, 136.46, 143.70, 145.88, 146.94, 161.22,
231.40 (C]S); IR (KBr, cmꢀ1): nmax ¼ 3473.31 (eOH), 2925.31,
1583.43, 1508.61, 1369.74, 1271.39, 1216.31, 1184.15; MS (ESI): m/
z ¼ [M þ H]þ 417.2, 419.2 [M þ 2]þ.
33.12, 37.74, 42.97, 61.09, 116.86, 118.68, 123.55, 124.14, 125.03,
126.18, 127.04, 127.92, 128.24, 128.48, 128.68, 129.27, 131.16, 131.61,
144.14, 161.34, 230.49 (C]S); IR (KBr, cmꢀ1): nmax ¼ 2956.82,
1579.51, 1369.55, 1219.63, 1186.56; MS (ES): m/z ¼ [M]þ 370.85,
372.85.
5.9. 9,9-Dimethyl-12-naphthalen-2-yl-8,9,10,12-tetrahydro-benzo
5.5. 12-(4-Methyl-phenyl)-9,9-dimethyl-8,9,10,12-tetrahydro-
[a]xanthene-11-thione (2i)
benzo[a]xanthene-11-thione (2e)
Pink solid, yield: 88%, m.p.: 162 ꢂC, 1H NMR (300 MHz, DMSO-
d6) d: 0.78 (s, 3H, CMe), 0.99 (s, 3H, CMe), 2.71e2.72 (m, 2H,
Pink solid, yield: 80%, m.p.: 162e164 ꢂC, 1H NMR (400 MHz,
CDCl3)
d
: 0.97 (s, 3H, CMe), 1.11 (s, 3H, CMe), 1.58 (s, 3H, ArMe),
CH2CO), 2.78 (s, 2H, CH2), 6.27 (s, 1H, ArCH), 7.30e7.38 (m, 4H, Are
H), 7.45e7.48 (m, 2H, AreH), 7.60e7.65 (m, 2H, AreH), 7.74 (d, 1H,
J ¼ 12 Hz, AreH), 7.82e7.86 (m, 3H, AreH), 8.20 (d, 1H, J ¼ 8.4 Hz,
2.58e2.69 (m, 2H, CH2), 2.80 (d, 1H, J ¼ 16.8 Hz, CH2CO), 2.94 (d, 1H,
J ¼ 16.8 Hz, CH2CO), 6.25 (s, 1H, ArCH), 6.94 (d, 2H, J ¼ 8 Hz, AreH),
7.26e7.40 (m, 4H, AreH), 7.47e7.51 (m, 1H, AreH), 7.71e7.77 (m,
2H, AreH), 8.19 (d, 1H, J ¼ 8.7 Hz, AreH); 13C NMR (100 MHz,
AreH); 13C NMR (75 MHz, CDCl3)
d: 26.38, 28.84, 33.09, 37.91,
42.98, 61.09, 116.85, 118.42, 123.54, 123.85, 125.02, 125.43, 125.71,
127.05, 127.24, 127.35, 127.68, 127.94, 128.29, 128.46, 128.79, 131.18,
CDCl3):
d
¼ 20.96, 26.43, 28.84, 33.11, 37.30, 42.93, 61.07, 116.82,
118.82, 123.53, 124.21, 124.96, 126.97, 128.44, 128.52, 128.63, 129.07,
131.11, 131.77, 135.59, 141.32, 146.72, 161.25, 231.53 (C]S); IR (KBr,
cmꢀ1): nmax ¼ 2918.00, 1579.52, 1369.18, 1218.35, 1184.67; MS (ESI):
m/z ¼ [M þ H]þ 385.2, 387.2 [M þ 2]þ.
131.62, 131.96, 132.99, 141.43, 146.85, 161.31, 230.48; IR (KBr, cmꢀ1
)
nmax ¼ 2926.16, 1577.02, 1369.47, 1220.31, 1185.54; MS (FAB): m/
z ¼ [M þ H]þ 421, 423 [M þ 2]þ.
5.10. 9,9-Dimethyl-12-thiophen-2yl-8,9,10,12-tetrahydro-benzo[a]
5.6. 12-(4-Methoxy-phenyl)-9,9-dimethyl-8,9,10,12-tetrahydro-
xanthenes-11-thione (2j)
benzo[a]xanthene-11 thione (2f)
Pink solid, yield: 87%, m.p.: 145e147 ꢂC, 1H NMR (400 MHz,
CDCl3) d: 1.02 (s, 3H, CH3), 1.11 (s, 3H, CH3), 2.59 and 2.61 (AB
Pink solid, yield: 78%, m.p.: 148e152 ꢂC, 1H NMR (400 MHz,
CDCl3)
d
: 0.87 (s, 3H, CMe), 1.06 (s, 3H, CMe), 2.63 and 2.64 (AB
system, 2H, J ¼ 18.3 Hz, CHaCHbCO), 2.83 (d, 1H, J ¼ 16.8 Hz, CH2CO),
3.03 (d, 1H, J ¼ 16.8 Hz, CH2CO), 6.66 (s, 1H, ArCH), 6.69e6.71 (m,
2H, AreH), 6.96e6.97 (m, 1H, AreH), 7.33 (d, 1H, J ¼ 8 Hz, AreH),
system, 2H, J ¼ 18.3 Hz, CHaCHbCMe2), 2.82 (d, 1H, J ¼ 16.8 Hz,
CH2CO), 2.94 (d, 1H, J ¼ 16.8 Hz, CH2CO), 3.59 (s, 3H, OMe), 6.10 (s,

476
J.M. Khurana et al. / European Journal of Medicinal Chemistry 58 (2012) 470e477
7.40e7.44 (m, 1H, AreH), 7.50e7.54 (m, 1H, AreH), 7.76e7.82 (m,
2H, AreH), 8.14 (d,1H, J ¼ 8.8 Hz, AreH); 13C NMR (100 MHz, CDCl3)
Acknowledgment
d
: 26.40, 28.92, 32.47, 33.01, 42.84, 60.79, 117.92, 123.39, 123.68,
DM, NA and KA thank UGC and CSIR respectively, New Delhi,
India for the grant of Senior and Junior Research Fellowships.
123.88, 125.16, 125.62, 127.19, 128.45, 128.89, 131.03, 131.49, 147.18,
147.48, 161.91, 231.58 (C]S); IR (KBr, cmꢀ1): nmax ¼ 2918.83,
1581.32,1370.69, 1215.93,1186.64; MS (ESI): m/z ¼ [M þ H]þ 377.15,
379.15 [M þ 2]þ.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2012.10.025.
5.11. 12-Phenyl-8,9,10,12-tetrahydro-benzo[a]xanthene-11-thione
(2k)
References
Pink solid, yield: 80%, m.p.: 110 ꢂC, 1H NMR (300 MHz, DMSO-d6)
: 1.23e1.29 (m, 2H, CH2), 1.89e2.18 (m, 2H, CH2), 2.74e3.14 (m, 2H,
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d
CH2), 6.24 (s, 1H, ArCH), 7.03e7.30 (m, 3H, AreH), 7.35e7.58 (m, 5H,
AreH), 7.93e7.03 (m, 2H, AreH), 8.16e8.19 (d, 1H, J ¼ 8 Hz, AreH);
13C NMR (75 MHz, CDCl3)
d: 21.81, 29.51, 37.64, 47.46, 116.78, 118.75,
123.56, 125.05, 125.52, 126.22, 127.06, 128.00, 128.47, 128.69,
129.25, 131.17, 131.62, 144.45, 146.87, 162.60, 231.17 (C]S); IR (KBr,
cmꢀ1): nmax ¼ 2925.13, 157.63, 1372.32, 1232.16, 1176.34; MS (FAB):
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[8] R.J. Cremlyn, An Introduction to Organosulfur Chemistry, John Wiley & Sons,
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Pink solid, yield: 78%, m.p.: 190 ꢂC, 1H NMR (300 MHz, DMSO-
d6) d: 1.86e2.04 (m, 2H, CH2), 2.88e2.89 (m, 2H, CH2), 3.04e3.10
(m, 2H, CH2), 6.30 (s, 1H, ArCH), 6.96e7.01 (m, 1H, AreH), 7.22e
7.27 (m, 1H, AreH), 7.37e7.61 (m, 5H, AreH), 7.92 (d, 2H,
J ¼ 9 Hz, AreH), 8.42 (d, 1H, J ¼ 8.4 Hz, AreH); 13C NMR (75 MHz,
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CDCl3) d: 21.68, 29.63, 39.29, 47.94, 116.79, 117.04, 123.14, 124.00,
124.92, 126.79, 126.87, 128.03, 128.47, 129.17, 131.56, 134.19, 134.49,
142.29, 147.19, 163.05, 231.01 (C]S); IR (KBr, cmꢀ1
)
nmax ¼ 2922.65,
1571.95, 1371.33, 1236.85, 1178.21. MS (FAB): m/z ¼ [M þ H]þ 421,
423 [M þ 2]þ.
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derivatives incorporating benzothiazole moiety, Der Pharmacia Lettre
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2
Pink solid, yield: 80%, m.p.: 174 ꢂC, 1H NMR (300 MHz, DMSO-d6)
: 1.89e2.01 (m, 2H, CH2), 2.84e2.91 (m, 2H, CH2), 3.0e3.1 (m, 2H,
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dazoline-2-thiones and 1,3-dihydro-1,3-diaryl-2-thioxopyrimidine-4,6(2H,5H)-
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(2002) 2520e2524;
d
CH2), 6.22 (s,1H, ArCH), 7.09 (d,1H, J ¼ 9 Hz, AreH), 7.16e7.22 (t,1H,
J ¼ 7.8 Hz, AreH), 7.28e7.31 (d, 1H, J ¼ 9 Hz, AreH), 7.36 (s, 1H, Are
H), 7.44e7.60 (m, 3H, AreH), 7.93 (d, 2H, J ¼ 9 Hz, AreH), 8.14 (d,1H,
J ¼ 9 Hz, AreH); 13C NMR (75 MHz, CDCl3)
d: 21.75, 29.69, 37.39,
47.39, 116.81, 117.89, 123.30, 124.88, 125.17, 126.52, 127.21, 127.66,
128.56, 129.01, 129.15, 130.99, 131.63, 133.90, 146.32, 146.91, 162.77,
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dihydro-4-oxo-5H-pyrano[2,3-d]pyrimidines, Heterocycles 68 (2006) 1885e
1892;
231.02 (C]S); IR (KBr, cmꢀ1
)
nmax ¼ 2927.30, 1573.21, 1368.62,
1224.58, 1172.00; MS (FAB): m/z ¼ [M þ H]þ 377, 379 [M þ 2]þ.
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b]isoquinoline-1,5-diones by in situ desulfurization, Chem. Heterocycl. Compd
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phthalazine-triones by catalytic H2SO4 in watereethanol or ionic liquid, Tetra-
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5.14. 12-(4-Nitro-phenyl)-8,9,10,12-tetrahydro-benzo[a]xanthene-
11-thione (2n)
Pink solid, yield: 85%, m.p.: 198 ꢂC,1H NMR (300 MHz, DMSO-d6):
d
¼ 0.77e0.81 (m,1H, CH2),1.17 (d,1H, J ¼ 15.9 Hz, CH2),1.82e1.95 (m,
2H, CH2), 2.79e2.84 (m, 2H, CH2), 6.27 (s,1H, ArCH), 7.37e7.42 (m,1H,
AreH), 7.45e7.52 (m, 2H, AreH), 7.56 (d, 2H, J ¼ 8.4 Hz, AreH), 7.85e
7.89 (m, 2H, AreH), 7.94 (d, 2H, J ¼ 8.4 Hz, AreH), 8.06 (d, 1H,
J ¼ 8.1 Hz, AreH); 13C NMR (75 MHz, CDCl3)
d: 21.76, 29.51, 37.74,
(i) J.M. Khurana, B. Nand, P. Saluja, DBU: a highly efficient catalyst for one-
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benzo[g]chromenes in aqueous medium, Tetrahedron 60 (2010) 5637e
5641.
47.35, 116.83, 117.11, 122.97, 123.34, 124.25, 125.39, 127.45, 128.75,
129.48, 130.14, 130.82, 131.68, 146.21, 146.89, 151.59, 163.13, 231.02
(C]S); IR (KBr, cmꢀ1
)
nmax ¼ 2927.36, 1579.13, 1513.13, 1345.71,
1230.67, 1107.66; MS (FAB): m/z ¼ [M þ H]þ 388, 390 [M þ 2]þ.

J.M. Khurana et al. / European Journal of Medicinal Chemistry 58 (2012) 470e477
477
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