A microwave-assisted, facile, regioselective Friedl?nder synthesis and antitubercular evaluation of 2,9-diaryl-2,3-dihydrothieno-[3,2-b]quinolines

Article abstract of DOI:10.1016/j.ejmech.2009.11.011

A series of 2,9-diaryl-2,3-dihydrothieno[3,2-b]quinolines have been synthesized regioselectively by Friedl?nder annulation of 5-aryldihydro-3(2H)-thiophenones and 2-aminobenzophenones in the presence of trifluoroacetic acid in good yields under microwave irradiation at 100?°C. The 2,9-diaryl-2,3-dihydrothieno[3,2-b]quinolines were screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug resistant M. tuberculosis (MDR-TB). Among the 17 compounds screened, 7-chloro-2-(2,4-dichlorophenyl)-9-phenyl-2,3-dihydrothieno-[3,2-b]quinoline and 7-chloro-2-(3-nitrophenyl)-9-phenyl-2,3-dihydrothieno[3,2-b]quinoline display maximum activity with MIC of 0.90 and 0.95?μM against MTB and MDR-TB respectively.

Full text of DOI:10.1016/j.ejmech.2009.11.011

European Journal of Medicinal Chemistry 45 (2010) 682–688
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
A microwave-assisted, facile, regioselective Friedla¨nder synthesis and
antitubercular evaluation of 2,9-diaryl-2,3-dihydrothieno-[3,2-b]quinolines
,
b
Kamaraj Balamurugan a, Veerappan Jeyachandran a, Subbu Perumal a , Thimmappa H. Manjashetty ,
*
Perumal Yogeeswari b, Dharmarajan Sriram b
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai – 625021, Tamil Nadu, India
b Medicinal Chemistry & Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science – Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad –
500 078, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 2,9-diaryl-2,3-dihydrothieno[3,2-b]quinolines have been synthesized regioselectively by
Friedla¨nder annulation of 5-aryldihydro-3(2H)-thiophenones and 2-aminobenzophenones in the pres-
ence of trifluoroacetic acid in good yields under microwave irradiation at 100 ꢀC. The 2,9-diaryl-2,3-
dihydrothieno[3,2-b]quinolines were screened for in vitro antimycobacterial activity against Mycobac-
terium tuberculosis H37Rv (MTB) and multi-drug resistant M. tuberculosis (MDR-TB). Among the 17
compounds screened, 7-chloro-2-(2,4-dichlorophenyl)-9-phenyl-2,3-dihydrothieno-[3,2-b]quinoline
and 7-chloro-2-(3-nitrophenyl)-9-phenyl-2,3-dihydrothieno[3,2-b]quinoline display maximum activity
Received 23 September 2009
Received in revised form
31 October 2009
Accepted 4 November 2009
Available online 14 November 2009
Keywords:
Friedla¨nder annulation
Thienoquinoline
with MIC of 0.90 and 0.95
m
M against MTB and MDR-TB respectively.
Ó 2009 Elsevier Masson SAS. All rights reserved.
5-Aryldihydro-3(2H)-thiophenone
2-Aminobenzophenone
Antimycobacterial activity
Mycobacterium tuberculosis
Multi-drug resistant Mycobacterium
tuberculosis
1. Introduction
side chain of the quinoline derivative (TMC207) to the quinoline
ring) and one variable aryl ring, incorporating all the encircled
portions of the diarylquinoline and thienoindoles (Scheme 1) and
screen them for antimycobacterial activities. Retrosynthesis points
to the readily available starting materials 5-aryldihydro-3(2H)-
thiophenone 1 [18] and 2-aminobenzophenone 2, which upon
Quinolines constitute an important class of heterocycles as the
quinoline structural unit is prevalent in naturally occurring quin-
oline alkaloids, therapeutics and synthetic analogues with impor-
tant biological activities [1] such as antimalarial [2], antiasthmatic
[3], antidiabetic [4], antibacterial [5], in vitro antifungal [6], anti-
viral [7], anti-inflammatory [8], immunosuppressive [9], HIV-1
integrase inhibitory [10], anti-breast cancer [11] and anti-
proliferative activities [12]. Sulfur-containing fused quinolines, in
particular, thienoquinolines display significant biological and
pharmacological activities [13–16]. The quinoline derivative, TMC
207 (Fig. 1), possessing a new mechanism of action, is in phase 2
clinical trials with very promising activity against MDR-TB [17]. Our
recent studies on hybrid heterocycles with indole, thiophene/
dihydrothiophene sub-structures (Fig. 2) display significant anti-
mycobacterial activities [18]. This prompted the synthesis of thie-
noquinolines, with one phenyl ring (with a shift in its position from
Friedla¨nder reaction could furnish the thienoquinolines
(Scheme 1).
3
This study forms a part of our research programme embarked on
the construction of novel heterocycles [19] and/or their screening
for antimycobacterial activities [20]. It is to be noted that tuber-
culosis (TB) has become an important world-wide public health
problem with one-third of the world’s population infected by the
TB bacillus resulting in a death toll of 2 million, mostly from
developing countries [21]. The pathogenic synergy of tuberculosis
with HIV [22] enhances the overall incidence of TB in HIV-positive
patients by 50 times relative to the rate for HIV-negative individ-
uals [23]. The emergence of multi-drug resistant tuberculosis
(MDR-TB) and extensively drug resistant tuberculosis (XDR-TB)
further aggravates the problems associated with TB treatment and
render the development of new drugs and strategies to efficiently
treat this disease imperative.
* Corresponding author. Tel./fax: þ91 452 2459845.
E-mail address: subbu.perum@gmail.com (S. Perumal).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.11.011

K. Balamurugan et al. / European Journal of Medicinal Chemistry 45 (2010) 682–688
683
NMe2
HO
NMe2
HO
R
Ph
Ph
S
Ar
Br
Br
N
N
OMe
N
OMe
Fig. 1. Quinoline derivative, TMC 207.
Thienoindoles
Diarylquinoline TMC 207
Design concept
2. Chemistry
In the present work, the synthesis of a series of 2,9-diaryl-2,3-
dihydrothieno[3,2-b]quinolines 3 was initially investigated under
thermal conditions by heating a mixture of 5-aryldihydro-3(2H)-
thiophenone 1, [18] 2-aminobenzophenone 2 and trifluoroacetic
acid (Scheme 2) in a 1:1:1.5 M ratio on an oil bath at 100 ꢀC for 2–
2.5 h in the absence of solvent. After completion of the reaction
(TLC) and work up, the product 3 was isolated in a pure form by
column chromatography.
Ph
R'
S
R
N
R = Ar; R' = H, Cl
Diarylthienoquinolines3
This reaction was further investigated under solvent-free
microwave irradiation with a view to rendering it efficient since
reactions under microwave irradiation, in general, enhance the
yield of the product besides accelerating the reactions, minimizing
the decomposition of the reactants and/or products and affording
enhanced selectivity relative to the thermal reactions [24]. Conse-
quently, in the present study, the synthesis of 2,9-diaryl-2,3-dihy-
drothieno[3,2-b]quinolines (Table 1; Scheme 2) was performed by
reacting a 1:1:1.5 M ratio of 5-aryldihydro-3(2H)-thiophenone 1, 2-
aminbenzophenone 2 and trifluoroacetic acid under solvent-free
microwave irradiation at 100 ꢀC. These reaction conditions were
optimized by varying the amount of catalyst and temperature
(Table 2). Typically, a mixture of 5-aryldihydro-3(2H)-thiophenone
1, 2-aminoaryl ketone 2 and trifluoroacetic acid (1:1:1.5 mmol) in
a sealed vial was irradiated in a focused microwave oven at 100 ꢀC
at 40 W power level with 1 bar pressure at high absorption level for
30 min. After completion of the reaction (TLC), the product 3 was
isolated. This reaction proceeded more rapidly and afforded better
yields (65–98%) of 3 than the thermal reaction (Table 1).
It is pertinent to note that the Friedla¨nder reaction of o-ami-
nobezophenone and 5-phenyldihydro-3(2H)-thiophenone 1a in
the presence of HCl at 120 ꢀC was previously reported to afford 2,9-
diphenyl-2,3-dihydrothieno[3,2-b]quinoline, 3a, as the only
compound in this series, in 75% yield [25]. Generally, Friedla¨nder
reactions are performed by heating either an aqueous or alcoholic
solution of reactants under reflux in the presence of a catalyst or
a mixture of the reactants at high temperatures (150–220 ꢀC)
without catalyst [26]. Different catalysts, viz. base [27], Brønsted
acids [28], Lewis acid [29], inorganic salt [30], and ionic liquid [31]
have been employed to effect this reaction. However, most of the
previous methods employ harsh reaction conditions and/or
expensive catalysts, encounter work up difficulties and afford low
yields of the product. However, in the present work, the reaction in
presence of trifluoroacetic acid results in a significantly better yield,
viz. 80% from thermal and 98% from microwave reaction than 75%
reported for 3a in the presence of HCl under thermal conditions.
Although two regioisomeric thienoquinolines 3 and 30 are
possible in this reaction (Scheme 3) as the 5-aryldihydro-3(2H)-
Retrosynthesis
O
S
R'
R
Ph
+
NH2
O
Scheme 1. Design concept and retrosynthesis of diarylthienoquinolines 3.
thiophenone 1 is unsymmetrical, the reaction furnishes only 3,
whose structure is in accord with the NMR spectroscopic data as
described for a representative example, 3k. The 1H NMR spectrum
of 3k has two doublets of doublets and one triplet corresponding to
the AMX spin system of the CH–CH2 part of the thiene ring of 3k.
The diastereotopic 3-CH2 hydrogens appear as doublets of doublets
at 3.78 ppm (J ¼ 16.7 and 8.3 Hz) and 3.90 ppm (16.7 and 8.3 Hz).
These protons showed HMBCs with C-3a, C-8b, C-2 and C-10
respectively at 162.7, 135.6, 50.2 and 136.2 ppm. The H-2 appears as
a 1H triplet at 5.05 ppm (J ¼ 8.3 Hz), which shows HMBCs (Fig. 3)
with the C-3a at 162.7 ppm, C-3 at 45.7 ppm and both C-20 and C-60
at 129.0 ppm. Thus 3 could be readily distinguished from its
regioisomer 30, since the latter should give two singlets for the
methine hydrogens of the thiene ring. The structure of the thie-
noquinolines 3 was further confirmed by a single crystal X-ray
crystallographic study of 3f (Fig. 4) [32].
The regioselectivity of the reaction could be rationalized by the
mechanism depicted in Scheme 3. Presumably, the transformation
is triggered by the condensation of 1 and 2 affording the imine 4,
which tautomerises to furnish the enamine 5, whose subsequent
annulation affords 3. The observed regioselectivity is ascribable to
the stabilization of the enamine 5 by conjugative interaction of the
enamine function with sulfur, which is not possible for the regioi-
someric enamine 50 (Scheme 3). Probably, enamine intermediate 5
alone (and not 50) is formed in this reaction that gives only 3. That
O
R
Ph
COOEt
O
R'
S
R'
Ar
Ph
NH2
S
CF3COOH
+
R
MW, 100 0C
R
Ar
S
NH2
N
S
N
H
S
2
1
3
Fig. 2. Structure of hybrid heterocycles with antimycobacterial activities.
Scheme 2. Synthesis of 2,9-diaryl-2,3-dihydrothieno[3,2-b]quinolines 3.

684
K. Balamurugan et al. / European Journal of Medicinal Chemistry 45 (2010) 682–688
Table 1
Yields and antimycobacterial activities of 3.
Compd.
R
R0
Reaction time (min)
Thermala (100 ꢀC)
Yield of 3 (%)
MIC (
MTB
mM)
MWb (100 ꢀC)
Thermalc
MWc
MDR-TB
d
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
C6H5
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
120
120
120
150
150
120
150
180
120
120
150
120
120
150
150
180
150
120
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
80
62
74
68
49
61
58
82
85
78
67
70
65
60
70
81
85
73
98
85
87
82
60
75
70
90
93
98
80
78
78
65
76
88
93
90
36.82
35.36
16.72
8.76
32.76
3.82
8.39
4.06
32.09
16.71
8.07
–
–
–
–
d
p-MeC6H4
p-ClC6H4
p-FC6H4
d
d
d
p-PriC6H4
o,p-Cl2C6H3
o-ClC6H4
m-O2NC6H4
1-naphthyl
C6H5
–
15.30
d
-
8.14
d
–
–
–
d
d
p-MeC6H4
p-ClC6H4
p-FC6H4
o,p-Cl2C6H3
o-ClC6H4
m-O2NC6H4
1-naphthyl
H
3.82
3.98
0.90
3.82
3.82
3.98
1.76
1.91
0.95
1.86
d
3q
3r
29.48
–
–
d
d
–
Isoniazid
Rifampicin
Ciprofloxacin
Ethambutol
0.36
0.12
4.71
7.64
11.38
3.80
37.73
61.18
a
Heated on an oil bath at 100 ꢀC.
b
c
Microwave irradiation programmed at 100 ꢀC, 1 bar, 40 W with high absorption level.
Isolated yield after column chromatography.
Not tested.
d
the regioselectivity does not arise from steric effect due to inter-
action between the aryl rings of the quinoline and the sulfur
heterocyclic rings of 30 is evident from the fact that even in the case
of the Friedla¨nder reaction of unsubstituted dihyrothiophen-3(2H)-
one, where no steric effect can be expected from the other
regioisomer of type 30, the regioisomer of the type 3, viz. 3r alone is
formed.
chloro-2-(2,4-dichlorophenyl)-9-phenyl-2,3-dihydrothieno[3,2-
b]quinoline (3n) is the most active compound with MIC of 0.90
against MTB. This compound 3n is 5 and 8 times more active than
ciprofloxacin and ethambutol respectively, while 3 and 8 times less
active than isoniazid and rifampicin respectively.
m
M
Subsequently, seven compounds (3f, 3h, 3l–3p) of high activity
against MTB were evaluated against MDR-TB. These compounds
inhibited MDR-TB with MIC ranging from 0.95 to >15.30
1). All the seven compounds were found to be more active, 4–64.4
times than ethambutol (MIC: 61.18 M). Six compounds (3h, 3l,
3m–3p) with MIC of 8.14, 3.82, 3.98, 1.76, 1.91 and 0.95
respectively displayed greater activity against MDR-TB than the
anti-TB drug isoniazid (MIC: 11.38 M), while three compounds
3n–3p with MIC of 1.76, 1.91 and 0.95 M are more potent against
MDR-TB than rifampicin (MIC: 3.80 M). 7-chloro-2-(3-nitro-
phenyl)-9-phenyl-2,3-dihydrothieno-[3,2-b]quinoline 3p dis-
played maximum activity in vitro with MIC of 0.95 M against
mM (Table
3. Biological results and discussion
m
m
M
All the thienoquinolines 3a–3q were screened for their in vitro
antimycobacterial activity against MTB and MDR-TB by agar dilu-
tion method. The MIC is defined as the minimum concentration of
the compound required to completely inhibit the bacterial growth.
The determination of MIC values was performed in duplicate at 7.40
pH. The MDR-TB clinical isolate was resistant to isoniazid, rifam-
picin, ethambutol and ciprofloxacin. The MICs of the synthesized
compounds and standard drugs are listed in Table 1.
m
m
m
m
MDR-TB, being 40, 12 and 4 times more potent than ciprofloxacin,
isoniazid and rifampicin respectively.
A clear trend that emerges from the antimycobacterial activity
data of the thienoquinolines against both MTB and MDR-TB is that
In the first phase of screening against MTB, all the compounds
showed promising in vitro activity against MTB with MIC in the
range of 0.90–36.82
mM. Seven compounds (3f, 3h, 3l, 3m–3p) with
MIC of 3.82, 4.06, 3.82, 3.98, 0.90, 3.82 and 1.86
m
M were more
potent than first line anti-TB drug, ethambutol (MIC: 7.64 mM). 7-
4''
Table 2
Optimization of the microwave reaction by varying the amount of TFA and
temperature.
3''
2''
5''
6''
S.No.
Temperature
(ꢀC)
Molar equiv.
of TFA
Irradiation
Yield
(%)b
Time (min)a
1''
1
2
3
4
5
6
7
100
100
100
100
60
0.2
0.5
1.0
1.5
1.5
1.5
1.5
30
30
30
38
45
80
98
60
62
78
1
8
9
6'
5'
3'
Cl
8a
8b
S
7
H
1'
30
2
CH3
150
120
60
4'
6
4a
3a
80
90
N
4
3
2'
H
5
H
a
Maximum power of 40 W at very high absorption level was employed.
Isolated yield after purification by column chromatography.
b
Fig. 3. Selected HMBCs in 3k.

K. Balamurugan et al. / European Journal of Medicinal Chemistry 45 (2010) 682–688
685
5. Experimental
The melting points were measured in open capillary tubes
and are uncorrected. The 1H, 13C and the 2D NMR spectra were
recorded on a Bruker (Avance) 300 MHz NMR instrument using
TMS as internal standard and CDCl3 as solvent. Chemical shifts
are given in parts per million
(d-scale) and the coupling
constants are given in Hertz. Silica gel-G plates (Merck) were
used for TLC analysis with a mixture of petroleum ether (60–
80 ꢀC) and ethyl acetate as eluent. Elemental analyses were
performed on a Perkin Elmer 2400 Series II Elemental CHNS
analyzer. Microwave reactions have been carried out in a Biotage
Microwave synthesizer.
5.1. General procedure for synthesis of 2,9-diaryl-2,3-
dihydrothieno[3,2-b]quinolines (3)
Fig. 4. ORTEP diagram of 3f.
Conventional method: a mixture of 5-aryltetrahydro-3-thio-
phenone 1 (1 mmol), 2-aminobenzophenone 2 (1 mmol) and
trifluoroacetic acid (1.5 mmol) was heated on an oil bath under
solvent-free conditions with stirring at 100 ꢀC for the time given
in Table 1. After completion of the reaction as indicated by TLC,
the reaction mixture was neutralized by the addition of an
aqueous NaHCO3 solution, the product was filtered and washed
with water (2 ꢁ 10 ml). The crude product was purified by a short
column chromatography on silica gel employing ethyl acetate-
petroleum ether (1:4 v/v) as eluent to obtain pure thienoquino-
line 3.
the thienoquinolines with chlorine at the 7-position displayed
significantly greater activity than the corresponding unsub-
stituted compounds. It is found that the thienoquinolines with
electron withdrawing groups like halogen or nitro group in the
phenyl ring of the thiophene ring of 3 showed better activity than
that with electron donating groups like alkyl. Disubstitution in the
phenyl ring enhances the activity many-fold relative to
monosubstitution.
4. Conclusion
Under microwave irradiation: a mixture of 5-aryltetrahydro-3-
thiophenone (1 mmol), 2-aminobenzophenone (1 mmol) and tri-
flouroacetic acid (1.5 mmol) was taken in a 10 ml quartz vial, sealed
and placed in a Biotage microwave oven. The vial was subjected to
microwave irradiation, programmed at 100 ꢀC, 40 W, 1 bar pressure
and very high absorption level for the time given in Table 1. After
a period of 1–2 min, the temperature reached a plateau, 100 ꢀC, and
remained constant. After gas jet cooling to room temperature
(3 min), the reaction mixture was neutralized with NaHCO3,
extracted with CH2Cl2 (2 ꢁ 5 mL), dried over MgSO4 and concen-
trated in vacuo to give the crude product which was purified as
done for the thermal reaction.
In conclusion, a facile regioselective synthesis of 2,9-diaryl-2,3-
dihydrothieno[3,2-b]quinolines by the Friedla¨nder annulation of 2-
aminobenzophenones with 5-aryldihydro-3(2H)-thiophenones in
the presence of triflouroacetic acid is described under thermal as
well as solvent-free microwave irradiation with higher yields being
realised from the latter. These 2,9-diaryl-2,3-dihydrothieno[3,2-
b]quinolines also displayed good in vitro antimycobacterial activity
against both MTB and MDR-TB. The synthesis of a library of
compounds belonging to the thieno[3,2-b]quinoline motif to
facilitate in depth structure-activity investigations is currently
underway in our research group.
R'
H
:
R'
H
O
H2N
HN
b
H
:
a
N
- H2O
Ph
O
O
H
a
+
R'
S
O
R
Ph
R
S
S
Ph
H
R
4
2
1
5
b
X
R'
R'
R'
R'
Ph
N
H
-H2O
N
N
Ph
X
O
Ph
NH
5'
Ph
R
S
OH
R
S
R
S
R
S
H
6
3
3'
Scheme 3. Proposed mechanism for the regioselective formation of 3.

686
K. Balamurugan et al. / European Journal of Medicinal Chemistry 45 (2010) 682–688
5.1.1. 2,9-Diphenyl-2,3-dihydrothieno[3,2-b]quinoline (3a)
Paleyellow solid; Yield: 98%, m.p.156–157 ꢀC; 1H NMR (300 MHz,
CDCl3) dH: 3.89 (m, 2H, 3-CH2), 5.07 (t,1H, J ¼ 8.1 Hz, H-2), 7.25–7.34
(m, 3H, Ar-H), 7.43–7.51 (m, 8H, Ar-H), 7.62 (t, 2H, J ¼ 8.6 Hz, Ar-H),
8.02 (d, 1H, J ¼ 8.1 Hz, Ar-H); 13C NMR (75 MHz, CDCl3) dC: 45.7, 50.3,
124.5,126.4,126.6,127.1,127.9,128.5,128.7,128.9,129.0,134.0,136.8,
138.6, 140.7, 146.4, 162.2. Anal. Calcd for C23H17NS: C, 81.38; H, 5.05;
N, 4.13%. Found C, 81.44; H, 5.12; N, 4.19%.
5.1.7. 2-(2-Chlorophenyl)-9-phenyl-2,3-dihydrothieno[3,2-
b]quinoline (3g)
Pale yellow solid; Yield: 70%, m.p.121–122 ꢀC; 1H NMR (300 MHz,
CDCl3) dH: 3.82 (dd, 1H, J ¼ 16.8, 8.1 Hz, H-3), 4.10 (dd, 1H, J ¼ 16.8,
8.1 Hz, H-3), 5.46 (dd,1H, J ¼ 8.1, 5.4 Hz, H-2), 7.11–7.18 (m, 2H, Ar-H),
7.29–7.63 (m, 8H, Ar-H), 7.68 (d, 1H, J ¼ 8.1 Hz, Ar-H), 8.13 (d, 1H,
J ¼ 8.1 Hz, Ar-H); 13C NMR (75 MHz, CDCl3) dC: 43.8, 45.4, 124.3,
126.2, 126.3, 127.0, 127.1, 127.7, 128.4, 128.6, 128.7, 128.8, 129.4, 133.0,
133.1, 136.5, 138.8, 138.9, 146.3, 161.7. Anal. Calcd for C23H16ClNS: C,
73.88; H, 4.31; N, 3.75%. Found C, 73.94; H, 4.36; N, 3.83%.
5.1.2. 2-(4-Methylphenyl)-9-phenyl-2,3-dihydrothieno[3,2-
b]quinoline (3b)
Pale yellow solid; Yield: 85%, m.p.136–137 ꢀC; 1H NMR (300 MHz,
CDCl3) dH: 2.30 (s, 3H, CH3), 3.80 (dd, 1H, J ¼ 16.5, 8.5 Hz, H-3), 3.91
(dd, 1H, J ¼ 16.5, 8.5 Hz, H-3), 5.04 (t, 1H, J ¼ 8.5 Hz, H-2), 7.11 (d, 2H,
J ¼ 7.8 Hz, Ar-H), 7.31 (d, 2H, J ¼ 7.8 Hz, Ar-H), 7.38–7.63 (m, 8H, Ar-H),
8.11 (d, 1H, J ¼ 8.7 Hz, Ar-H); 13C NMR (75 MHz, CDCl3) dC: 21.1, 45.8,
50.2, 124.6, 126.4, 126.6, 127.0, 127.9, 128.5, 128.8, 128.9, 129.1, 129.4,
134.2,136.8,137.6,137.7,138.5,146.4,162.3. Anal. Calcd for C24H19NS:
C, 81.55; H, 5.42; N, 3.96%. Found C, 81.62; H, 5.47; N, 4.01%.
5.1.8. 2-(3-Nitrophenyl)-9-phenyl-2,3-dihydrothieno[3,2-
b]quinoline (3h)
Pale yellow solid; Yield: 90%, m.p.153–154 ꢀC; 1H NMR (300 MHz,
CDCl3) dH: 3.82 (dd, 1H, J ¼ 16.7, 8.0 Hz, H-3), 4.06 (dd, 1H, J ¼ 16.7,
8.0 Hz, H-3), 5.14 (t,1H, J ¼ 8.0 Hz, H-2), 7.42–7.68 (m, 8H, Ar-H), 7.78
(d, 1H, J ¼ 7.8 Hz, Ar-H), 8.06 (d, 1H, J ¼ 8.1 Hz, Ar-H), 8.14–8.17 (m,
1H, Ar-H), 8.34 (d,1H, J ¼ 1.8 Hz, Ar-H); 13C NMR (75 MHz, CDCl3) dC
:
45.7, 49.1, 122.3, 122.9, 124.7, 126.6, 126.7, 128.2, 128.7, 129.0, 129.9,
132.9, 133.2, 136.6, 139.2, 143.3, 146.7, 148.3, 161.0. Anal. Calcd for
C23H16N2O2S: C, 71.85; H, 4.19; N, 7.29%. Found C, 71.91; H, 4.23; N,
7.34%.
5.1.3. 2-(4-Chlorophenyl)-9-phenyl-2,3-dihydrothieno[3,2-
b]quinoline (3c)
Pale yellow solid; Yield: 87%, m.p.174–175 ꢀC; 1H NMR (300 MHz,
CDCl3) dH: 3.74 (dd, 1H, J ¼ 16.8, 8.1 Hz, H-3), 3.93 (dd, 1H, J ¼ 16.8,
8.1 Hz, H-3), 4.99 (t, 1H, J ¼ 8.1 Hz, H-2), 7.25 (d, 2H, J ¼ 8.4 Hz, Ar-H),
7.33 (d, 2H, J ¼ 8.4 Hz, Ar-H), 7.39–7.62 (m, 8H, Ar-H), 8.01 (d, 1H,
J ¼ 8.4 Hz, Ar-H); 13C NMR (75 MHz, CDCl3) dC: 45.7, 49.5, 124.6,
126.5, 126.6, 128.0, 128.5, 128.6, 128.9, 129.0, 133.5, 133.6, 136.7, 138.8,
139.4, 146.5, 161.7. Anal. Calcd for C23H16ClNS: C, 73.88; H, 4.31; N,
3.75%. Found C, 73.92; H, 4.35; N, 3.79%.
5.1.9. 2-(1-Naphthyl)-9-phenyl-2,3-dihydrothieno[3,2-b]quinoline (3i)
Pale yellow solid; Yield: 93%, m.p.194–195 ꢀC; 1H NMR (300 MHz,
CDCl3) dH: 4.06–4.21 (m, 2H, 3-CH2), 5.84 (t,1H, J ¼ 7.5 Hz, H-2), 7.41–
7.71 (m,11H, Ar-H), 7.79 (t, 2H, J ¼ 8.1 Hz, Ar-H), 7.90 (d,1H, J ¼ 7.8 Hz,
Ar-H), 8.13 (d,1H, J ¼ 8.4 Hz, Ar-H); 13C NMR (75 MHz, CDCl3) dC: 44.1,
45.8, 122.8, 123.5, 124.5, 125.4, 125.8, 126.4, 126.5, 126.6, 127.9, 128.4,
128.5,128.7,128.9,129.0,130.9,133.7,133.9,136.2,136.7,139.0,146.5,
162.3. Anal. Calcd for C27H19NS: C, 83.26; H, 4.92; N, 3.60%. Found C,
83.30; H, 4.88; N, 3.64%.
5.1.4. 2-(4-Fluorophenyl)-9-phenyl-2,3-dihydrothieno[3,2-
b]quinoline (3d)
Pale yellow solid; Yield: 82%, m.p.162–163 ꢀC; 1H NMR (300 MHz,
CDCl3) dH: 3.81 (dd, 1H, J ¼ 16.7, 8.1 Hz, H-3), 3.98 (dd, 1H, J ¼ 16.7,
8.1 Hz, H-3), 5.08 (t, 1H, J ¼ 8.1 Hz, H-2), 7.03 (t, 2H, J ¼ 7.5 Hz, Ar-H),
7.42–7.68 (m, 10H, Ar-H), 8.06 (d, 1H, J ¼ 8.1 Hz, Ar-H); 13C NMR
(75 MHz, CDCl3) dC: 46.0, 49.6, 115.5, 115.8, 124.6, 126.5, 126.6, 128.0,
128.6, 128.7, 128.8,128.9,129.0, 133.7,136.6,136.8,138.7,146.5,161.9.
Anal. Calcd for C23H16FNS: C, 77.28; H, 4.51; N, 3.92%. Found C, 77.34;
H, 4.57; N, 3.95%.
5.1.10. 7-Chloro-2,9-diphenyl-2,3-dihydrothieno[3,2-b]quinoline (3j)
Pale yellow solid; Yield: 98%, m.p. 179–180 ꢀC; 1H NMR
(300 MHz, CDCl3) dH: 3.79 (dd, 1H, J ¼ 16.8, 8.3 Hz, H-3), 3.91 (dd,
1H, J ¼ 16.8, 8.3 Hz, H-3), 5.06 (t, 1H, J ¼ 8.3 Hz, H-2), 7.24–7.34 (m,
3H, Ar-H), 7.40–7.57 (m, 8H, Ar-H), 7.93 (d, 1H, J ¼ 8.7 Hz, Ar-H); 13C
NMR (75 MHz, CDCl3) dC: 45.7, 50.4, 123.4, 127.1, 127.4, 128.0, 128.6,
128.9, 129.0, 130.4, 132.4, 135.4, 136.2, 137.6, 140.4, 144.8, 162.6.
Anal. Calcd for C23H16ClNS: C, 73.88; H, 4.31; N, 3.75%. Found C,
73.94; H, 4.36; N, 3.82%.
5.1.5. 2-(4-Isopropylphenyl)-9-phenyl-2,3-dihydrothieno[3,2-
b]quinoline (3e)
5.1.11. 7-Chloro-2-(4-methylphenyl)-9-phenyl-2,3-
Paleyellow solid; Yield: 60%, m.p.125–126 ꢀC; 1H NMR (300 MHz,
CDCl3) dH: 1.26 (d, 6H, J ¼ 6.9 Hz, 2CH3), 2.91 (septet, 1H, J ¼ 6.9 Hz,
CH), 3.86 (dd, 1H, J ¼ 16.6, 9.0 Hz, H-3), 3.96 (dd, 1H, J ¼ 16.6, 8.4 Hz,
H-3), 5.10 (t,1H, J ¼ 8.4 Hz, H-2), 7.21 (d, 2H, J ¼ 8.4 Hz, Ar-H), 7.40 (d,
2H, J ¼ 8.4 Hz, Ar-H), 7.46–7.62 (m, 6H, Ar-H), 7.65 (t, 2H, J ¼ 8.4 Hz,
dihydrothieno[3,2-b]quinoline (3k)
Pale yellow solid; Yield: 80%, m.p. 115–116 ꢀC; 1H NMR
(300 MHz, CDCl3) dH: 2.32 (s, 3H, CH3), 3.78 (dd, 1H, J ¼ 16.7, 8.3 Hz,
H-3), 3.90 (dd, 1H, J ¼ 16.7, 8.3 Hz, H-3), 5.05 (t, 1H, J ¼ 8.3 Hz, H-2),
7.12 (d, 2H, J ¼ 7.8 Hz, Ar-H), 7.31 (d, 2H, J ¼ 8.1 Hz, Ar-H), 7.44–7.64
(m, 7H, Ar-H), 7.94 (d, 1H, J ¼ 9.0 Hz, Ar-H); 13C NMR (75 MHz,
CDCl3) dC: 21.1, 45.7, 50.2, 123.4, 127.0, 127.4, 128.3, 128.5, 128.8,
129.0, 129.4, 130.4, 132.3, 135.6, 136.2, 137.4, 137.5, 137.8, 144.8,
162.7. Anal. Calcd for C24H18ClNS: C, 74.31; H, 4.68; N, 3.61%. Found
C, 74.36; H, 4.73; N, 3.65%.
Ar-H), 8.07 (d, 1H, J ¼ 8.4 Hz, Ar-H); 13C NMR (75 MHz, CDCl3) dC
:
23.9, 33.7, 45.8, 50.2, 124.6, 126.4, 126.6, 126.8, 127.1, 127.9, 128.5,
128.7, 128.9, 129.1, 134.2, 136.8, 137.9, 138.5, 146.4, 148.7, 162.4. Anal.
Calcd for C26H23NS: C, 81.85; H, 6.08; N, 3.67%. Found C, 81.91; H,
6.14; N, 3.71%.
5.1.6. 2-(2,4-Dichlorophenyl)-9-phenyl-2,3-dihydrothieno[3,2-
b]quinoline (3f)
5.1.12. 7-Chloro-2-(4-chlorophenyl)-9-phenyl-2,3-
dihydrothieno[3,2-b]quinoline (3l)
Pale yellow solid; Yield: 75%, m.p.164–165 ꢀC; 1H NMR (300 MHz,
CDCl3) dH: 3.69 (dd, 1H, J ¼ 16.8, 8.4 Hz, H-3), 4.03 (dd, 1H, J ¼ 16.8,
8.4 Hz, H-3), 5.33 (dd,1H, J ¼ 8.4, 5.1 Hz, H-2), 7.06–7.13 (m,1H, Ar-H),
7.34–7.48 (m, 7H, Ar-H), 7.60 (t, 2H, J ¼ 7.5 Hz, Ar-H), 8.02 (d, 1H,
J ¼ 8.1 Hz, Ar-H); 13C NMR (75 MHz, CDCl3) dC: 43.9, 45.1,124.5,126.5,
126.6, 127.5, 127.8, 128.1, 128.2, 128.5, 128.6, 128.8, 129.0, 129.4, 132.8,
133.9, 136.5, 137.4, 139.3, 146.5, 161.5. Anal. Calcd for C23H15Cl2NS: C,
67.65; H, 3.70; N, 3.43%. Found C, 67.70; H, 3.74; N, 3.48%.
Pale yellow solid; Yield: 78%, m.p. 119–120 ꢀC; 1H NMR
(300 MHz, CDCl3) dH: 3.71 (dd, 1H, J ¼ 16.8, 8.1 Hz, H-3), 3.90 (dd,
1H, J ¼ 16.8, 8.1 Hz, H-3), 5.00 (t, 1H, J ¼ 8.1 Hz, H-2), 7.25 (d, 2H,
J ¼ 8.4 Hz, Ar-H), 7.32 (d, 2H, J ¼ 8.4 Hz, Ar-H), 7.40–7.56 (m, 7H, Ar-
H), 7.92 (d, 1H, J ¼ 9.0 Hz, Ar-H); 13C NMR (75 MHz, CDCl3) dC: 45.6,
49.5, 123.4, 127.4, 128.5, 128.7, 128.9, 129.0, 130.4, 132.5, 133.7, 135.0,
136.0,137.8,139.1,144.9,162.1. Anal. Calcd for C23H15Cl2NS: C, 67.65;
H, 3.70; N, 3.43%. Found C, 67.74; H, 3.78; N, 3.48%.

K. Balamurugan et al. / European Journal of Medicinal Chemistry 45 (2010) 682–688
687
5.1.13. 7-Chloro-2-(4-fluorophenyl)-9-phenyl-2,3-
Acknowledgements
dihydrothieno[3,2-b]quinoline (3m)
Pale yellow solid; Yield: 78%, m.p. 158–159 ꢀC; 1H NMR
(300 MHz, CDCl3) dH: 3.77 (dd, 1H, J ¼ 16.8, 8.3 Hz, H-3), 3.94 (dd,
1H, J ¼ 16.8, 8.3 Hz, H-3), 5.07 (t, 1H, J ¼ 8.3 Hz, H-2), 7.02 (t, 2H,
J ¼ 8.4 Hz, Ar-H), 7.39–7.61 (m, 8H, Ar-H), 7.97 (d, 1H, J ¼ 9.0 Hz, Ar-
H); 13C NMR (75 MHz, CDCl3) dC: 45.8, 49.6,115.5,115.8,123.4,127.4,
128.7,128.8,128.9,129.0,130.4,132.5,135.1,136.1,136.2,136.3,137.7,
144.9,162.2. Anal. Calcd for C23H15ClFNS: C, 70.49; H, 3.86; N, 3.57%.
Found C, 70.52; H, 3.94; N, 3.64%.
S.P. thanks the Department of Science and Technology, New
Delhi, for funding for a major research project (No. SR/S1/OC-70/
2006) and for funds under (i) IRHPA program for funds for the
purchase of a high resolution NMR spectrometer and (ii) FIST
program and the University Grants Commission, New Delhi, for (i)
funds under the DRS and ASIST programs and (ii) for funding for
a major research project [F. No. 36-155/2008(SR)].
Appendix. Supporting information
5.1.14. 7-Chloro-2-(2,4-dichlorophenyl)-9-phenyl-2,3-
dihydrothieno[3,2-b]quinoline (3n)
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.ejmech.2009.11.011.
Pale yellow solid; Yield: 65%, m.p. 145–146 ꢀC; 1H NMR
(300 MHz, CDCl3) dH: 3.72 (dd, 1H, J ¼ 17.1, 8.5 Hz, H-3), 4.06 (dd,
1H, J ¼ 17.1, 8.5 Hz, H-3), 5.40 (dd, 1H, J ¼ 8.5, 5.4 Hz, H-2), 7.17–7.20
(m, 1H, Ar-H), 7.41–7.60 (m, 9H, Ar-H), 7.97 (d, 1H, J ¼ 8.7 Hz, Ar-H);
13C NMR (75 MHz, CDCl3) dC: 43.9, 45.3, 123.5, 127.4, 127.7, 128.2,
128.6, 128.9, 129.0, 129.6, 129.9, 130.4, 132.7, 134.0, 134.1, 134.4,
136.0, 137.5, 138.4, 144.9, 161.9. Anal. Calcd for C23H14Cl3NS: C,
62.39; H, 3.19; N, 3.16%. Found C, 62.46; H, 3.25; N, 3.23%.
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5.1.16. 7-Chloro-2-(3-nitrophenyl)-9-phenyl-2,3-
dihydrothieno[3,2-b]quinoline (3p)
Pale yellow solid; Yield: 88%, m.p. 160–161 ꢀC; 1H NMR
(300 MHz, CDCl3) dH: 3.79 (dd, 1H, J ¼ 16.8, 8.0 Hz, H-3), 4.03 (dd,
1H, J ¼ 16.8, 8.0 Hz, H-3), 5.15 (t, 1H, J ¼ 8.0 Hz, H-2), 7.44–7.61 (m,
7H, Ar-H), 7.77 (d, 1H, J ¼ 7.5 Hz, Ar-H), 7.96 (d, 1H, J ¼ 7.5 Hz, Ar-H),
8.13–8.16 (m, 1H, Ar-H), 8.32 (d, 1H, J ¼ 1.5 Hz, Ar-H); 13C NMR
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129.0, 129.1, 129.9, 130.5, 132.6, 133.2, 134.3, 135.9, 138.1, 143.0,
145.0, 148.3, 161.4. Anal. Calcd for C23H15ClN2O2S: C, 65.95; H, 3.61;
N, 6.69%. Found C, 66.01; H, 3.69; N, 6.74%.
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J ¼ 7.5 Hz, H-2), 7.41–7.63 (m, 10H, Ar-H), 7.75 (d, 1H, J ¼ 7.2 Hz, Ar-
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J ¼ 8.7 Hz, Ar-H), 8.10 (d, 1H, J ¼ 8.1 Hz, Ar-H); 13C NMR (75 MHz,
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128.6, 128.9, 129.0, 129.1, 130.5, 130.9, 132.4, 133.9, 135.2, 135.9,
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4.28; N, 3.30%. Found C, 76.53; H, 4.25; N, 3.28%.
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5.1.18. 7-Chloro-9-phenyl-2,3-dihydrothieno[3,2-b]quinoline (3r)
Pale yellow solid; Yield: 90%, m.p. 138–139 ꢀC; 1H NMR
(300 MHz, CDCl3) dH: 3.34 (t, 2H, J ¼ 7.5 Hz, CH2, CH2), 3.58 (t, 2H,
J ¼ 7.5 Hz, CH2), 7.39–7.57 (m, 5H, Ar-H), 7.90 (d, 1H, J ¼ 8.7 Hz, Ar-
H); 13C NMR (75 MHz, CDCl3) dC: 29.4, 37.4, 123.2, 127.1, 128.4, 128.7,
128.8, 128.9, 130.3, 132.2, 135.3, 136.3, 137.7, 144.5, 163.5. Anal. Calcd
for C17H12ClNS: C, 68.56; H, 4.06; N, 4.70%. Found C, 68.63; H, 4.12;
N, 4.77%.
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