Synthesis and antitubercular evaluation of novel dibenzo[b,d]furan and 9-methyl-9H-carbazole derived hexahydro-2H-pyrano[3,2-c]quinolines via Povarov reaction

Article abstract of DOI:10.1016/j.ejmech.2011.06.014

A series of novel hexahydro-2H-pyrano[3,2-c]quinoline analogues derived from dibenzo[b,d]furan and 9-methyl-9H-carbazole has been synthesized in very good yields through SnCl₂·2H₂O catalyzed one-pot Povarov reaction (imino-Diels-Alder reaction). The imines generated in situ from dibenzo[b,d]furan-2-carbaldehyde or 9-methyl-9H-carbazole-3-carbaldehyde and aromatic amines, were reacted with 3,4-dihydro-2H-pyran in a diasteroselective manner in acetonitrile at RT. These synthesized isomeric pyranoquinoline analogues have been evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (MTB) by agar dilution method. Among the 23 compounds screened, 5-(dibenzo[b,d]furan-2-yl)-9-fluoro-3,4,4a,5,6,10b- hexahydro-2H-pyrano[3,2-c]quinoline 4f, 5-(dibenzo[b,d]furan-2-yl)-9-fluoro-3,4, 4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline 5f and 9-fluoro-5-(9-methyl-9H- carbazol-3-yl)-3,4,4a,5,6,10b-hexa hydro-2H-pyrano[3,2-c]quinoline 7f (MIC 3.13 μg/mL) were resulted as most active antitubercular agents.

Full text of DOI:10.1016/j.ejmech.2011.06.014

European Journal of Medicinal Chemistry 46 (2011) 4827e4833
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and antitubercular evaluation of novel dibenzo[b,d]furan
and 9-methyl-9H-carbazole derived hexahydro-2H-pyrano[3,2-c]quinolines
via Povarov reaction
,
a
a
b
Srinivas Kantevari a , Thirumal Yempala , Govardhan Surineni , Balasubramanian Sridhar ,
*
Perumal Yogeeswari c, Dharmarajan Sriram c
a Organic Chemistry Division-II, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Centre for X-ray crystallography, Indian Institute of Chemical Technology, Hyderabad 500 007, India
c Medicinal Chemistry and Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar,
Hyderabad 500078, 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 novel hexahydro-2H-pyrano[3,2-c]quinoline analogues derived from dibenzo[b,d]furan and 9-
methyl-9H-carbazole has been synthesized in very good yields through SnCl2$2H2O catalyzed one-pot
Povarov reaction (imino-DielseAlder reaction). The imines generated in situ from dibenzo[b,d]furan-2-
carbaldehyde or 9-methyl-9H-carbazole-3-carbaldehyde and aromatic amines, were reacted with 3,4-
dihydro-2H-pyran in a diasteroselective manner in acetonitrile at RT. These synthesized isomeric pyr-
anoquinoline analogues have been evaluated for their in vitro antimycobacterial activity against Myco-
bacterium tuberculosis H37Rv (MTB) by agar dilution method. Among the 23 compounds screened, 5-
(dibenzo[b,d]furan-2-yl)-9-fluoro-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline 4f, 5-(dibenzo
[b,d]furan-2-yl)-9-fluoro-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline 5f and 9-fluoro-5-(9-
Received 24 March 2011
Received in revised form
10 June 2011
Accepted 10 June 2011
Available online 1 July 2011
Keywords:
Pyranoquinoline
Imino-DielseAlder reaction
Povarov reaction
Dibenzofuran
methyl-9H-carbazol-3-yl)-3,4,4a,5,6,10b-hexa hydro-2H-pyrano[3,2-c]quinoline 7f (MIC 3.13
mg/mL)
were resulted as most active antitubercular agents.
Carbazole
Mycobacterium tuberculosis
Ó 2011 Elsevier Masson SAS. All rights reserved.
1. Introduction
been more than 40 years since a new tubercular drug discovered
[10,11]. The worsening situation has prompted WHO to declare
tuberculosis as a global public health crisis [8]. The challenge of
meeting all these facts necessitated an urgent need for develop-
ment of fast acting new antitubercular drugs with diverse and
unique structural features.
The natural product inspired, structurally diverse new mole-
cules play a major role in drug discovery [12]. Quinoline alkaloids
such as graveolinine and kokusagine (Fig. 1) isolated from Lunasia
amara and synthetic analogue TMC-207 exhibited significant
in vitro antitubercular activity against M. tuberculosis H37Rv [13].
SAR studies direct that the presence of phenyl or substituted phenyl
group at C- 2 position of quinoline nucleus enhances MTB inhibi-
tory activity. Also noticed in synthetically derived analogues such
as EMD 534085, L-689560, Veprisine and Flindersine (Fig. 1), tet-
rahydroquinoline moiety is key for their pharmacological proper-
ties [14e16]. On the other hand, in the development of
antitubercular agents, benzofurobenzopyran analogues were
described to show very good in vitro as well in vivo antitubercular
activity [17,18]. We therefore envisaged that re-engineering the
Tuberculosis (TB) has become more prevalent chronic disease in
the world today than any other time in human history [1]. The
pathogen Mycobacterium tuberculosis (MTB) responsible for TB uses
different strategies to survive in a variety of host lesions and
invades immune surveillances [2e7]. It claims over two million
lives each year and dwells hidden in as many as two billion people.
It is anticipated that by 2020, one billion people will be new
infected; over 125 million people will get sick and over 30 million
will die of tuberculosis if control is not further strengthened [8]. In
addition, emergence of its new virulent forms like multi drug
resistant (MDR-TB) and extremely drug resistant (XDR-TB) further
fuelled epidemic nature of TB [9]. Among immuno-compromised
individuals such as those infected with HIV, on anti-tumour
necrosis or with diabetics, the resurgence of TB is alarming due to
the development of pathogenic synergy [2e5]. Furthermore, it has
* Corresponding author. Tel.: þ91 4027191437; fax: þ91 4027198933.
E-mail addresses: kantevari@gmail.com, kantevari@yahoo.com (S. Kantevari).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.06.014

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S. Kantevari et al. / European Journal of Medicinal Chemistry 46 (2011) 4827e4833
Scheme 1. Synthesis of dibenzo[b,d]furan-2-carbaldehyde 1 and 9-methyl-9H-carba-
zole-3-carbaldehyde 2.
prepared from dibenzo[b,d]furan and 9-methyl-9H-carbazole
respectively using standard formylation conditions [21]. For
example, the reaction dibenzo[b,d]furan with a,a-dichloromethyl
methyl ether, SnCl4 at room temperature in dichloromethane
(Scheme 1) gave the required dibenzo[b,d]furan-2-carbaldehyde 1
in 84% yield. Similarly 9-methyl-9H-carbazole was also formylated
to give 9-methyl-9H-carbazole-3-carbaldehyde 2 in 80% yield. Both
the products 1 and 2 were fully characterized by 1H and 13C NMR
spectral analysis.
Fig. 1. Bioactive quinoline alkaloids.
Since the pioneering work of Povarov [22], BF3-etherate has
been the most commonly used catalyst for the construction of
tricyclic tetrahydroquinoline ring systems. Later investigations on
this reaction led to the development of several methods and cata-
lysts [23]. On the basis of our previous work [19,24], initially, efforts
were focussed on the condensation of dibenzo[b,d]furan-2-
carbaldehyde 1 with 4-bromoaniline and 3,4-dihydro-2H-pyran
in presence of SnCl2$2H2O as Lewis acid catalyst under imino-
DielseAlder reaction conditions (Scheme 2). After series of exper-
iments, the reaction proceeded efficiently in acetonitrile at room
temperature for 5.5 h to give the products 4e and 5e in 67%
combined yield. Both the isomers 4e and 5e was separated by silica
gel column chromatography. The cis and trans isomeric structures
Fig. 2. Re-engineering antitubercular agents.
bioactive fragments by coupling dibenzo[b,d]furan or 9-methyl-9H-
carbazole to tetrahydroquinoline nucleus could deliver a new
scaffold with better antimycobacterial activity (Fig. 2). With our
continued interest in developing new antimycobacterial agents
[19,20], we planned to synthesize and evaluate hexahydro-2H-
pyrano[3,2-c]quinolines derived hybrid heterocycles. We report
herein an efficient diasteroselective one-pot synthesis of novel
dibenzo[b,d]furan and 9-methyl-9H-carbazole derived hexahydro-
2H-pyrano[3,2-c]quinolines 4aef, 5aef, 6aeb, 6def and 7aef
through SnCl2$2H2O catalyzed Povarov reaction (imino-Diel-
seAlder reaction). The imines generated in situ from dibenzo[b,d]
furan-2-carbaldehyde or 9-methyl-9H-carbazole-3-carbaldehyde
and aromatic amines, were reacted with 3,4-dihydro-2H-pyran in
a diasteroselective manner in acetonitrile at RT. Screening all the
isomeric hexahydro-2H-pyrano[3,2-c]quinolines 4aef, 5aef, 6aeb,
6def and 7aef for their in vitro antimycobacterial activity against
M. tuberculosis H37Rv (MTB) resulted three compounds 4f, 5f and
7f as most active antitubercular agents.
for the respective compounds 4e and 5e was assigned from 1H, 13
C
NMR and mass spectroscopic data and single crystal X-ray crys-
tallographic analysis (Fig. 3). In the 1H NMR spectrum, the most
distinctive parameter for structural assignment is the scalar
coupling constant between H-4a and H-5 protons. The cis isomer
4e has smaller coupling constant J(Hꢀ4a, H-5) ¼ 5.2 Hz and J(Hꢀ4a, H-
¼ 2.2 Hz consistent with the cis orientation of the hydrogen
10)
atoms H-4a, H-5 and H-10b. In the trans isomer 5e, the value of
J(Hꢀ4a, H-5)¼ 10.4 Hz is large and indicative of the anti orientation of
H-4a and H-5. The smaller coupling constant J(H-4a, H-10) ¼ 0.75 in
the product 5e reveal the cis fusion of pyran and quinoline rings.
These 1H NMR observations are comparable with the literature
described analogous structures [25,26]. Further to these NMR
assignments, single crystal X-ray analysis of 4e was unambiguously
confirmed the cis oriented molecular structure (Scheme 2, Fig. 3).
Further to extend the scope of Povarov reaction, dibenzo[b,d]
furan-2-carbaldehyde 1 and 9-methyl-9H-carbazole-3-carbaldehyde
2 were reacted with different aromatic amines 3aef and 3,4-dihydro-
2H-pyran in presence of SnCl2$2H2O in acetonitrile under optimized
2. Results and discussion
2.1. Chemistry
The starting substrates for the study, dibenzo[b,d]furan-2-
carbaldehyde 1 and 9-methyl-9H-carbazole-3-carbaldehyde 2 was
Scheme 2. Synthesis of isomeric 5-(dibenzo[b,d]furan-2-yl)-9-bromo-3,4,4a,5,6,10b-hexahydro-2H-pyrano [3,2-c] quinoline 4e and 5e.

S. Kantevari et al. / European Journal of Medicinal Chemistry 46 (2011) 4827e4833
4829
Table 1
Synthesis of cis and trans isomeric hexahydro-2H-pyrano[3,2-c]quinolines 4aef,
5aef, 6aeb, 6def and 7aef.
Entry Aldehyde Amine
R
Time Product Cis/trans Over all m.p (ꢁC)
(h)
Ratio
yield (%)a
82
1
1
1
1
1
1
1
2
2
2
2
2
2
3a
3b
3c
3d
3e
3f
H
3.5
4a
5a
4b
5b
4c
5c
4d
5d
4e
5e
4f
1:2.5
132
156
112
154
Syrup
136
56
2
CH3 3.5
1:3
1:1
6:5
1:1
10:9
1:1
1:1
e
68
72
66
67
56
64
82
30
47
40
35
3
OCH3
Cl
4
4
5.5
5.5
5
138
50
5
Br
140
Syrup
174
Syrup
142
150
142
e
Fig. 3. ORTEP representation of 4e with thermal displacement ellipsoids drawn at the
30% probability.
6
F
5f
7
3a
3b
3c
3d
3e
3f
H
4
6a
7a
6b
7b
6c
7c
6d
7d
6e
7e
6f
conditions (Scheme 3). All the reactions proceeded well and cis and
trans isomeric hexahydro-2H-pyrano[3,2-c]quinolines 4aef, 5aef,
6aeb, 6def and 7aef were obtained in good yields (Table 1). In the
8
CH3
OCH3
Cl
4
9
6
130
130
122
122
112
135
122
condensation of 9-methyl-9H-carbazole-3-carbaldehyde
2 with
10
11
12
6
2:3
3:2
1:1
4-methoxyaniline 3c and 3,4-dihydro-2H-pyran, the reaction was
sluggish and only trans isomer 7c was isolated. All the isomeric
products 4aef, 5aef, 6aeb, 6def and 7aef were fully characterized
by 1H, 13C NMR and mass spectroscopic data. The cis isomeric struc-
tures for the compounds 4aef, 6aeb, 6def and trans isomeric
structures for the compounds 5aef, 7aef was assigned from scalar
coupling constant between H-4a and H-5 protons in the 1H NMR
spectra. These cis/trans assignments for all these compounds
were also compared with literature described aryl substituted
analogous derivatives of isomeric hexahydro-2H-pyrano[3,2-c]quin-
olines [16,25e27].
Br
6
F
6
7f
a
Isolated yield.
three compounds 4f, 5f and 7f are found to be equally active as
ethambutol. All other compounds are also found to show moderate
activity against M. tuberculosis H37Rv (MTB), though all the 23
compounds were less potent than another anti-TB drug isoniazid.
Structural correlations of the new isomeric hexahydro-2H-pyr-
ano[3,2-c]quinolines 4aef, 5aef, 6aeb, 6def and 7aef with respect
to their antitubercular activity reveal that trans isomeric analogues
5d, 5e, 7a and 7def are better placed to show potent activity by two
folds than the corresponding cis isomeric analogues. For example,
2.2. Pharmacology
All the synthesized isomeric hexahydro-2H-pyrano[3,2-c]quin-
olines 4aef, 5aef, 6aeb, 6def and 7aef was screened for their
in vitro antimycobacterial activity against M. tuberculosis H37Rv
(MTB) by agar dilution method [28]. The minimum inhibitory
concentration (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 triplicate at 7.40
pH. The MICs of the synthesized compounds 4aef, 5aef, 6aeb,
6def and 7aef along with the standard drugs for comparison are
depicted in Table 2. Twenty three new isomeric compounds
screened have showed in vitro activity against MTB with MIC
Table 2
Antimycobacterial activities of isomeric hexahydro-2H-pyrano[3,2-c]quinolines
4aef, 5aef, 6aeb, 6def and 7aef.
Entry
Product
logP/ClogPa
MIC (mg/mL)
1
2
3
4
5
6
7
8
4a
5a
4b
5b
4c
5c
4d
5d
4e
5e
4f
5f
6a
7a
6b
7b
7c
6d
7d
6e
7e
6f
7f
3.92/5.04
3.92/5.04
4.42/5.539
4.42/5.539
3.81/5.14
3.81/5.14
4.49/6.055
4.49/6.055
4.76/6.205
4.76/6.205
4.09/5.48
4.09/5.48
4.1/4.93
4.1/4.93
4.58/5.43
4.58/5.43
3.97/5.03
4.65/5.95
4.65/5.95
4.93/6.10
4.93/6.10
4.25/5.38
4.25/5.38
e
25.0
25.0
12.5
12.5
12.5
12.5
25.0
6.25
12.5
6.25
3.13
3.13
ranging from 3.13 to 25.0
pyrano[3,2-c]quinolines examined, five compounds 4e, 5d, 6f, 7d
and 7e inhibited MTB with MIC of 6.25 g/mL and three compounds
4f, 5f and 7f inhibited MTB with MIC 3.13 g/mL. When compared
to one of the first line anti-TB drug ethambutol (MIC 3.13 g/mL),
mg/mL. Among all the hexahydro-2H-
m
m
9
m
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
25.0
12.5
25.0
25.0
25.0
12.5
6.25
25.0
6.25
6.25
3.13
0.1
0.2
3.13
Isoniazid
Rifampicin
Ethambutol
e
e
Scheme 3. synthesis of cis and trans isomeric hexahydro-2H-pyrano[3,2-c]quinolines
4aef, 5aef, 6aeb, 6def and 7aef.
a
Calculated using Chemdraw Ultra 12.0.

4830
S. Kantevari et al. / European Journal of Medicinal Chemistry 46 (2011) 4827e4833
cis isomer of 5-(Dibenzo [b,d]furan-2-yl)-9-chloro-3,4,4a,5,6,10b-
hexahydro-2H-pyrano[3,2-c]quinoline 4d exhibited MIC of 25 g/
mL, where as its trans isomer showed MIC of 6.25 g/mL. The result
appropriate solvent mixture needed for elution of compounds. The
crude residue of products was applied on silica gel column as neat or
as a concentrated solution. The products were eluted in appropriate
solvent mixture by applying air pressure. The eluted fractions were
collected and evaporated under reduced pressure. Yields refer to
chromatographically and spectroscopically homogeneous materials
unless otherwise stated. Appropriate names for all the new
compounds were given with the help of ChemBioOffice 12.0; 2010.
Ten fold serial dilutions of each test compound/drug were
prepared and incorporated into Middlebrook 7H11 agar medium
with OADC Growth Supplement. Inoculum of M. tuberculosis H37Rv
was prepared from fresh Middlebrook 7H11 agar slants with OADC
Growth Supplement adjusted to 1 mg/mL (wet weight) in Tween 80
(0.05%) saline diluted to 10ꢀ2 to give a concentration of approxi-
m
m
clearly revealed that the appropriate isomeric structural orienta-
tion of hexahydro-2H-pyrano[3,2-c]quinoline is necessary to
exhibit MTB activity. Similarly isomeric derivatives 4e and 5e
(entries 9 & 10); 6a and 7a (entries 13 & 14); 6d and 7d (entries 18 &
19); 6e and 7e (entries 20 & 21) and 6f and 7f (entries 22 & 23) in
Table 2 also exhibited difference in MTB activity with respect their
structural orientation. Among all the hexahydro-2H-pyrano[3,2-c]
quinolines, compounds derived with 4-fluoroaniline are more
active than the respective all other derivatives (entries 11, 12 and
23, Table 2). Also noticed that hexahydro-2H-pyrano[3,2-c]quino-
lines derived with 4-chloroaniline (3d), 4-bromoaniline (3e) and 4-
fluoroaniline (3f) are more active than the unsubtituted (3a),
methyl (3b) or methoxy (3c) derivatives of hexahydro-2H-pyrano
[3,2-c]quinolines. All these results reveal that moderate liphophilic
nature along with halo substituents is needed for hexahydro-2H-
pyrano[3,2-c]quinolines to be active against M. tuberculosis H37Rv
(MTB) and among them fluoro analogues with trans geometry are
structurally better correlates and showed better activity.
mately 107 cfu/mL. A 5
mL amount of bacterial suspension was
spotted into 7H11 agar tubes containing 10-fold serial dilutions of
drugs per mL. The tubes were incubated at 37 ꢁC, and final readings
were recorded after 28 days. The minimum inhibitory concentra-
tion (MIC) is defined as the minimum concentration of compound
required to give complete inhibition of bacterial growth. This
method is similar to that recommended by the National Committee
for Clinical Laboratory Standards for the determination of MIC in
triplicate.
3. Conclusion
In conclusion, we have synthesized a series of new hexahydro-
2H-pyrano[3,2-c]quinolines derived from dibenzo[b,d]furan and 9-
methyl-9H-carbazole 4aef, 5aef, 6aeb, 6def and 7aef in very
good yields through SnCl2$2H2O catalyzed one-pot Povarov reac-
tion (imino-DielseAlder reaction). The imines generated in situ
from dibenzo[b,d]furan-2-carbaldehyde or 9-methyl-9H-carbazole-
3-carbaldehyde and aromatic amines, were reacted diaster-
oselectively with 3,4-dihydro-2H-pyran in acetonitrile at RT. All
these new isomeric pyranoquinoline analogues have been evalu-
ated for their in vitro antimycobacterial activity against M. tuber-
culosis H37Rv (MTB) by agar dilution method. Among the 23
isomeric compounds screened, 5-(dibenzo[b,d]furan-2-yl)-9-
fluoro-3,4,4a,5,6,10b-hexahydro-2H-pyrano [3,2-c] quinoline 4f,
5-(dibenzo[b,d]furan-2-yl)-9-fluoro-3,4,4a,5,6,10b-hexahydro-2H-
pyrano [3,2-c] quinoline 5f and 9-fluoro-5-(9-methyl-9H-carbazol-
3-yl)-3,4,4a,5,6,10b-hexa hydro-2H-pyrano [3,2-c] quinoline 7f
4.1. Synthesis of dibenzo[b,d]furan-2-carbaldehyde 1
To a solution of dibenzo[b,d]furan (5.0 g, 29.7 mmol) in
dichloromethane (100 mL) was added SnCl4 (5.14 mL, 44.6 mmol)
followed by dichloromethyl methyl ether (4.03 mL, 44.6 mmol) at
room temperature. After stirring for 40 min, the reaction mixture
was quenched with 1N HCl (100 ml). The organic layer was sepa-
rated, washed with water (20 mL), sat. NaHCO3 solution (20 mL),
Brine solution (25 mL), dried over anhydrous sodium sulphate and
rotary evaporated to dryness. Crude residue thus obtained was
purified over silica gel column chromatography (Hexane: ethyl
acetate, 99: 1) gave dibenzo[b,d]furan-2-carbaldehyde 1 (4.9 g,
84%) as pale yellow solid. m.p. 62 ꢁC 1H NMR (300 MHz, CDCl3)
d
10.07 (s, 1H),8.41 (s, 1H), 7.96 (d, J ¼ 8.3 Hz, 2H), 7.62 (d, J ¼ 8.3 Hz,
1H), 7.56(d, J ¼ 8.0 Hz, 1H), 7.48 (t, J ¼ 7.2 Hz, 1H), 7.36 (t, J ¼ 7.5 Hz,
1H). 13C NMR (75 MHz, CDCl3)
191.2, 159.5, 156.7, 131.8,
d
(MIC 3.13
agents.
m
g/mL) were resulted as most active antitubercular
129.0,128.1,124.9,124.06, 123.4, 122.8, 120.9, 112.1, 111.8.
4.2. Synthesis of 9-methyl-9H-carbazole-3-carbaldehyde 2
4. Experimental section
To a solution of 9-methyl-9H-carbazole (5.3 g, 29.7 mmol) in
dichloromethane (100 mL) was added SnCl4 (5.14 mL, 44.6 mmol)
followed by dichloromethyl methyl ether (4.03 mL, 44.6 mmol) at
room temperature. After stirring for 45 min, the reaction mixture
was quenched with 1N HCl (100 ml). The organic layer was sepa-
rated, washed with water (20 mL), sat. NaHCO3 solution (20 mL),
Brine solution (25 mL), dried over anhydrous sodium sulphate and
rotary evaporated to dryness. Crude residue thus obtained was
purified over silica gel column chromatography (Hexane: ethyl
Melting points were measured with a Fischer-Johns melting
point apparatus and are uncorrected. Optical rotations were recor-
ded with JASCO P2000 polarimeter at 25 ꢁC. IR spectra were recor-
ded as neat liquids or KBr pellets and absorptions are reported in
cmꢀ1. NMR spectra were recorded on 300 (Bruker) and 500 MHz
(Varian) spectrometers in appropriate solvents using TMS as
internal standard or the solvent signals as secondary standards and
the chemical shifts are shown in
d scales. Multiplicities of NMR
signals are designated as s (singlet), d (doublet), t (triplet), q
(quartet), br (broad), m (multiplet, for unresolved lines), etc. 13C
NMR spectra were recorded on 75 and 125 MHz spectrometers.
High-resolution mass spectra were obtained by using ESI-QTOF
mass spectrometry. All the experiments were monitored by
analytical thin layer chromatography (TLC) performed on silica gel
GF254 pre-coated plates. After elution, plate was visualized under
UV illumination at 254 nm for UV active materials. Further visuali-
zation was achieved by staining with PMA and charring on a hot
plate. Silica gel finer than 200 mesh was used for column chroma-
tography. The chromatography column was loaded with slurry of
silica gel prepared in hexane. It was then equilibrated with the
acetate, 99: 1) gave 9-methyl-9H-carbazole-3-carbaldehyde
(4.89 g, 80%) as pale green solid. m.p. 74 ꢁC 1H NMR (300 MHz,
CDCl3)
9.90 (s, 1H), 8.28 (s, 1H), 7.93 (d, J ¼ 7.7 Hz, 1H), 7.79 (d,
J ¼ 8.4 Hz, 1H), 7.42(t, J ¼ 7.9 Hz, 1H), 7.26e7.14 (m, 3H), 3.65 (s, 3H).
13C NMR (75 MHz, CDCl3)
191.7, 144.3, 141.5, 128.3, 127.0, 126.6,
2
d
d
123.6, 122.8, 122.7, 120.4, 120.2, 109.0, 108.5, 29.2.
4.3. General procedure for the preparation of hexahydro-2H-pyrano
[3,2-c]quinolines 4aef, 5aef, 6aeb, 6def and 7aef
To a mixture of SnCl2$2H2O (20 mol %) and anhydrous Na2SO4
(0. 2 g) in acetonitrile (4 mL), was added dibenzo[b,d]furan-2-

S. Kantevari et al. / European Journal of Medicinal Chemistry 46 (2011) 4827e4833
4831
carbaldehyde 1or 9-methyl-9H-carbazole-3-carbaldehyde2(1 mmol)
and aromatic amine 3aef(1 mmol) at room temperature. After 15 min,
3,4-dihydro-2H-pyran (1 mmol) was added and continued stirring at
RT. The progress of the reaction was monitored by TLC. After
completion, the reaction mixture was concentrated under reduced
pressure, CHCl3 (25 mL) and water (10 mL) was added, chloroform
layerwasseparated,washedwithbrinesolution, driedoveranhydrous
Na2SO4 and concentrated to dryness. Crude residue thus obtained was
purifiedoversilicagelcolumnchromatography(hexane:ethylacetate,
97: 3) gave pure hexahydro-2H-pyrano [3,2-c] quinolines 4aef, 5aef,
6aeb, 6def and 7aef.
J ¼ 9.0 Hz, 1H), 6.58(d, J ¼ 9.0 Hz, 1H), 5.31 (d, J ¼ 5.2 Hz, 1H), 4.41(s,
1H), 4.27 (t, J ¼ 6.7 Hz, 1H), 3.77(s, 1H), 3.69 (s, 3H), 2.38e2.14(m,
2H), 1.79e1.40 (m, 4H). 13C NMR(75 MHz, CDCl3)
d 156.4, 155.4,
142.0,135.9,130.8,128.7,127.1,126.8,125.9,124.0,122.6,120.6,119.6,
118.6, 114.8, 114.4, 111.6, 111.5, 72.9, 60.8, 59.5, 55.7, 39.4, 29.6, 25.3.
IR(neat) 3291, 2925, 2857, 1731, 1508, 1452, 1247, 1192, 1120, 1073,
1031, 815, 744 cmꢀ1. MS (ESI) m/z 386[M þ H]þ; HRMS (ESI) Calcd
for C25H24NO3: 386.1756, found: 386.1759.
5c: Black solid. m.p 136 ꢁC; 1H NMR (300 MHz, CDCl3) 7.98(s,
1H), 7.91 (d, J ¼ 7.9 Hz, 1H), 7.57e7.48(m, 2H),7.47e7.39(m, 1H),
7.31(t, J ¼ 7.1 Hz, 1H),6.79e6.54(m, 3H), 6.47 (d, J ¼ 8.6 Hz, 1H),
4.80(d, J ¼ 10.5 Hz, 1H), 4.36(d, J ¼ 2.8 Hz, 1H), 4.20e3.87(m, 2H),
3.76 (s, 3H),3.72(s, 1H),2.19e2.10(m, 1H),2.07e1.97(m, 1H),
1.96e1.81 (m, 1H), 1.73e1.57(m, 1H), 1.55e1.42(m, 1H). 13C NMR
4.3.1. 5-(Dibenzo[b,d]furan-2-yl)-3,4,4a,5,6,10b-hexahydro-2H-
pyrano[3,2-c]quinoline
4a: Light yellow solid. m.p 132 ꢁC; 1H NMR (300 MHz, CDCl3)
(75 MHz, CDCl3) d 156.5, 155.8, 139.0,137.0, 127.2, 126.8, 124.5, 124.0,
d
8.01e7.87 (m, 2H),7.58e7.49 (m, 2H),7.48e7.36 (m, 3H), 7.31 (t,
122.7, 121.4, 120.6, 119.7, 116.9, 116.3, 115.5, 114.8, 111.7, 111.5,
74.8,68.5, 55.6, 55.1, 39.5, 29.7, 24.2. IR(KBr) 3384, 2923, 2851, 1729,
1507, 1447, 1258, 1203, 1074, 1037, 819, 745 cmꢀ1. MS (ESI) m/z 386
[M þ H]þ; HRMS (ESI) Calcd for C25H24NO3: 386.1756, found:
386.1750.
J ¼ 7.5 Hz, 1H), 7.05 (t, J ¼ 7.3 Hz, 1H), 6.77(t, J ¼ 7.1 Hz, 1H), 6.58 (d,
J ¼ 7.7 Hz, 1H), 5.32 (d, J ¼ 5.4 Hz, 1H), 4.83(d, J ¼ 2.0 Hz, 1H),
3.97e3.81(br, 1H), 3.62e3.51 (m, 1H), 3.50e3.34 (m, 1H),
2.34e2.11(m, 1H),1.72e1.39 (m,4H). 13C NMR (75 MHz, CDCl3)
d
156.5, 155.2, 145.0, 135.6, 130.7, 128.0, 127.6,127.2, 125.9,124.0,
122.7, 120.6, 119.9, 118.6, 118.5, 114.4, 111.7, 111.7, 111.3, 72.5, 60.5,
59.3, 39.3, 29.7, 25.4. IR(KBr) 3364, 3049, 2930, 2853, 1603, 1475,
1253, 1193, 1070, 1027, 834, 749 cmꢀ1. MS (ESI) m/z 356[M þ H]þ;
HRMS (ESI) Calcd for C24H21NO2: 356.1650, found: 356.1660.
5a: White solid. m.p. 156 ꢁC; 1H NMR (300 MHz, CDCl3)
4.3.4. 5-(Dibenzo[b,d]furan-2-yl)-9-chloro-3,4,4a,5,6,10b-
hexahydro-2H-pyrano [3,2-c] quinoline
4d: Yellow solid. m.p 56 ꢁC; 1H NMR (300 MHz, CDCl3)
d
8.02e7.90(m, 2H), 7.70e7.30 (m, 6H), 7.01(dd, J ¼ 2.6,8.4 Hz, 1H),
6.54(d, J ¼ 8.4 Hz,1H), 5.26 (d, J ¼ 5.4 Hz,1H), 4.81(d, J ¼ 2.07 Hz,1H),
3.92(br,1H), 3.67e3.52(m,1H), 3.49e3.33 (m,1H),2.40e1.93(m, 3H),
d
8.00e7.85(m,2H), 7.62e7.37(m, 4H), 7.36e7.26 (m,1H), 7.18(d,
J ¼ 7.3 Hz, 1H), 7.05 (t, J ¼ 7.3 Hz, 1H), 6.68 (t, J ¼ 7.3 Hz, 1H), 6.49 (d,
J ¼ 7.9 Hz, 1H), 4.83 (d, J ¼ 10.7 Hz, 1H), 4.36(s, 1H), 4.19e3.95 (m,
2H), 3.70 (t, J ¼ 10.7 Hz, 1H), 2.19e2.01(m, 2H), 1.97e1.75(m, 1H),
1.71e1.54 (m, 1H), 1.53e1.39 (m, 1H). 13C NMR (75 MHz, CDCl3)
1.62e1.35 (m, 2H). 13C NMR (75 MHz, CDCl3)
d 156.5, 155.5, 143.6,
135.2,129.1,128.2,128.0,127.3,127.2,125.8,123.5,122.9,121.0,120.6,
118.5,115.7,111.7,111.4, 72.4, 60.8, 59.2, 38.9, 29.6, 25.2. IR (KBr) 3361,
3050, 2925, 2853, 1689, 1595, 1475, 1193, 1084, 810, 749 cmꢀ1. MS
(ESI) m/z 390 [M þ H]þ; HRMS (ESI) Calcd for C24H21NO2Cl :
390.1260, found: 390.1256.
d
156.6, 155.8, 144.7, 136.9, 131.0, 129.4, 127.3, 126.8, 124.5, 124.0,
122.7, 120.7,119.7, 117.6, 114.2, 111.7, 111.6, 110.9, 74.7, 68.7, 54.7, 39.4,
29.7, 24.2. IR(KBr) 3394, 2937, 2844, 1606, 1480, 1441, 1304, 1259,
1188, 1030, 838, 746 cmꢀ1. MS (ESI) m/z 356[M þ H]þ; HRMS (ESI)
Calcd for C24H21NO2: 356.1650, found: 356.1662.
5d: Light blue solid. m.p 138 ꢁC; 1H NMR (500 MHz, CDCl3)
d
7.98e7.88(m, 2H), 7.59e7.50(m, 2H), 7.49e7.40(m, 2H), 7.32(t,
J ¼ 7.0 Hz, 1H), 7.19 (d, J ¼ 2.3 Hz, 1H), 7.02(dd, J ¼ 2.3, 8.5 Hz),
6.44(d, J ¼ 8.3 Hz, 1H), 4.81(d, J ¼ 10.6 Hz, 1H), 4.34(d, J ¼ 2.6 Hz,
1H), 4.16e4.03(br m, 2H), 3.75e3.62(m, 1H), 2.33e2.22(m, 1H),
2.15e2.06(m, 1H), 1.93e1.80(m, 2H), 1.40e1.32 (m, 1H). 13C
4.3.2. 5-(Dibenzo[b,d]furan-2-yl)-9-methyl-3,4,4a,5,6,10b-
hexahydro-2H-pyrano [3,2-c] quinoline
4b: Light red solid. m.p 112 ꢁC; 1H NMR (300 MHz, CDCl3)
NMR(75 MHz, CDCl3) d 156.5, 155.8, 143.3, 136.4, 130.8, 130.4, 129.2,
d
8.06e7.91(m, 2H), 7.68e7.41 (m, 5H), 7.37e7.27 (m, 1H), 6.87(d,
127.3, 126.7, 124.5, 123.8, 122.7, 121.9, 120.6, 119.6, 115.3, 111.7, 111.6,
74.0, 62.8, 54.7, 39.0, 29.6, 25.3. IR(KBr) 3395, 3022, 2925, 2849,
1728,1603, 1486,1302, 1261,1186, 1058, 811, 747 cmꢀ1. MS (ESI) m/z
390 [M þ H]þ; HRMS (ESI) Calcd for C24H21NO2Cl: 390.1260, found:
390.1268.
J ¼ 7.5 Hz, 1H), 6.51(d, J ¼ 8.3 Hz, 1H), 5.29 (d, J ¼ 5.2 Hz, 1H),4.79 (d,
J ¼ 2.2 Hz, 1H), 3.72e3.52(m, 1H), 3.50e3.32(m, 1H), 2.29(s, 3H),
2.27e1.95(m, 4H), 1.70e1.39 (m, 2H). 13C NMR (75 MHz, CDCl3)
d
156.5, 155.5, 142.7, 135.8, 131.4, 130.9, 128.7, 127.8, 127.2, 125.9,
122.7, 120.6, 119.9, 118.6, 115.5, 114.6, 111.7, 111.3, 72.8, 60.7, 59.4,
39.4, 29.6, 25.4, 20.6. IR(KBr) 3368, 3051, 2925, 2854, 1613, 1502,
1448, 1191, 1074, 816, 753 cmꢀ1. MS (ESI) m/z 370[M þ H]þ; HRMS
(ESI) Calcd for C25H24NO2: 370.1807, found: 370.1821.
4.3.5. 5-(Dibenzo[b,d]furan-2-yl)-9-bromo-3,4,4a,5,6,10b-
hexahydro-2H-pyrano [3,2-c] quinoline
4e: Light red solid. m.p 50 ꢁC; 1H NMR (300 MHz, CDCl3)
5b: Light yellow solid. m.p 154 ꢁC; 1H NMR (300 MHz, CDCl3)
7.98(s, 1H), 7.94e7.87 (m, 1H),7.58e7.38(m, 4H), 7.30 (t,J ¼ 8.4 Hz,
1H),7.02(s br, 1H), 6.91e6.85 (m, 1H),6.42(d, J ¼ 8.1 Hz, 1H), 4.80 (d,
J ¼ 10.7 Hz, 1H), 4.33 (d, J ¼ 2.6 Hz, 1H), 4.26e3.81(m, 2H),
3.76e3.63(m,1H),2.25(s, 3H),2.22(s,1H),2.18e2.05(m,1H),1.95e1.79
(m,1H),1.71e1.56(m,1H),1.52e1.37 (m,1H).13C NMR(75 MHz, CDCl3)
d
8.03e7.90(m, 2H), 7.69e7.28 (m, 6H), 7.14 (dd, J ¼ 2.2,8.3 Hz, 1H),
6.48(d, J ¼ 8.3 Hz, 1H), 5.28 (d, J ¼ 5.2 Hz, 1H), 4.81 (d, J ¼ 2.2 Hz,
1H), 3.92(br, 1H), 3.65e3.56 (m, 1H), 3.53e3.38 (m, 1H), 2.34e2.12
(m, 2H), 1.79e1.41 (m, 3H). 13C NMR (75 MHz, CDCl3)
d 156.5, 155.5,
144.1, 135.1, 130.8, 130.1, 129.1.128.1, 127.3, 125.8, 123.5, 122.7, 121.0,
120.6, 118.5,116.1,111.7,111.4, 72.3, 60.8, 59.2, 38.8, 29.6, 25.2. IR KBr
3376, 2927, 2855, 1692, 1595, 1480, 1194, 1084, 814, 752 cmꢀ1. MS
(ESI) m/z 434[M þ H]þ; HRMS (ESI) Calcd for C24H21 NO2Br:
434.0755, found: 434.0745.
d
156.4, 155.8, 142.4, 136.9, 131.1,130.1, 129.7, 127.2, 126.9, 126.8, 122.7,
120.7, 120.6, 119.8, 115.2, 114.3, 111.7, 111.5, 74.7, 68.8, 54.8, 39.5, 29.6,
24.1, 21.9. IR(KBr) 3325,3165, 2923, 2849,1655,1613,1564,1507,1444,
1255, 1073, 813, 784 cmꢀ1. MS (ESI) m/z 370[M þ H]þ; HRMS (ESI)
Calcd for C25H24NO2: 370.1807, found: 370.1822.
5e: Light yellow solid. m.p 140 ꢁC; 1H NMR (500 MHz, CDCl3)
8.01e7.87(m, 2H), 7.62e7.39(m, 4H),7.36e7.28(m, 2H), 7.15(d,
d
J ¼ 8.3 Hz, 1H), 6.40(d, J ¼ 8.5 Hz, 1H),4.80 (d, J ¼ 10.4 Hz, 1H),
4.34(d, J ¼ 0.75 Hz, 1H), 4.18e4.04 (br, 2H), 3.69 (t, J ¼ 10.1 Hz, 1H),
2.30e2.05(m,2H), 1.92e1.81(m, 1H), 1.76e1.68 (m, 1H),
4.3.3. 5-(Dibenzo[b,d]furan-2-yl)-9-methoxy-3,4,4a,5,6,10b-
hexahydro-2H-pyrano [3,2-c] quinoline
4c: Thick syrup; 1H NMR (300 MHz, CDCl3)
d
8.02e7.82(m, 2H),
1.61e1.52(m,1H). 13C NMR(75 MHz, CDCl3)
d
156.4, 155.7, 143.6,
7.73e7.63 (m, 1H), 7.58e7.39(m, 4H), 7.36e7.255 (m, 1H), 6.72(d,
136.3, 133.2, 131.9, 127.2, 126.6, 124.4, 123.7, 122.7, 122.3, 120.5,

4832
S. Kantevari et al. / European Journal of Medicinal Chemistry 46 (2011) 4827e4833
119.5, 115.7, 111.6, 111.5, 110.6, 73.9, 62.7, 54.6, 38.9, 30.5, 25.3.
IR(KBr) 3389, 2932, 2853, 1601,1486, 1259, 1195, 1073, 967, 811,
751 cmꢀ1. MS (ESI) m/z 434[M þ H]þ.
137.8, 132.6, 130.0, 128.4, 127.1, 126.6, 125.7, 122.7, 120.5, 119.5,118.8,
115.1, 114.1, 113.9, 112.9, 74.9, 68.8, 54.9, 41.0, 39.4, 29.2, 24.1,21.9.
IR(KBr)3404, 2927, 2857, 1622, 1505, 1460, 1254, 1065, 813,
748 cmꢀ1. MS (ESI) m/z 381[M ꢀ H]þ; HRMS Calcd for C26H26N2O
381.2050; found 381.2050.
4.3.6. 5-(Dibenzo[b,d]furan-2-yl)-9-fluoro-3,4,4a,5,6,10b-
hexahydro-2H-pyrano [3,2-c] quinoline
7b: White solid. m.p 142 ꢁC; 1H NMR (500 MHz, CDCl3)
d 8.10 (t,
4f: Thick syrup; 1H NMR (300 MHz, CDCl3)
d
8.04e7.75(m, 2H),
7.71e7.21(m, 6H), 6.92e6.71 (m, 1H), 6.62e6.42 (br s, 1H),
5.27(d, 3.7 Hz, 1H), 4.78(s, 1H), 4.39(s, 1H), 4.15e3.71
(m,1H),3.65e3.34(m, 1H), 2.32e1.92(m, 1H), 1.69e1.25(m, 4H). 13C
NMR(75 MHz, CDCl3) 156.5, 155.0, 141.2, 135.5, 128.2, 127.8, 127.3,
J ¼ 7.8 Hz, 1H), 8.50(d, J ¼ 7.8 Hz, 1H), 7.95(d, J ¼ 8.7 Hz,
1H),7.55e7.46 (m, 1H), 7.44e7.35(m, 1H), 7.34e7.28(m, 1H), 7.20(t,
J ¼ 7.8 Hz, 1H), 7.00(s, 1H), 6.85(d, J ¼ 7.8 Hz, 1H), 6.42(d, J ¼ 7.8 Hz,
1H),4.82(d, J ¼ 10.7 Hz, 1H), 4.33(d, J ¼ 1.9, 1H), 4.12(d, J ¼ 9.7 Hz,
1H), 3.90(s, 3H), 3.87(s, 1H), 3.75e3.62(m, 1H), 2.30e2.20(m, 3H),
J
¼
d
126.6, 125.9, 122.7, 120.6, 119.6, 118.6, 115.1, 114.8, 113.8, 111.7, 111.4,
72.5, 60.8, 59.4, 39.0, 29.6, 25.2. IR(neat) 3360, 2925, 2853, 1692,
1603, 1506, 1450, 1249, 1194, 1085, 1062, 809, 750 cmꢀ1. MS (ESI) m/
z 374 [M þ H]þ; HRMS (ESI) Calcd for C24H21NO2F: 374.1556, found:
374.1567.
2.15(d,
1.49e1.35(m, 1H), 1.31e1.19(m, 1H). 13C NMR (75 MHz, CDCl3)
156.6, 155.6, 142.6, 136.9, 131.1, 130.0, 1 28.4, 127.1, 126.6, 126.4,
122.7, 120.5, 120.2, 119.5, 115.1, 114.1, 112.9, 74.9, 68.8, 54.9, 41.0,
39.2, 29.2, 24.1, 21.9. IR(KBr)3422, 2925, 2854, 1725, 1624, 1505,
1463, 1255, 1125, 1075, 1031, 809, 746 cmꢀ1. MS (ESI) m/z 383
[M þ H]þ; HRMS Calcd for C26H26N2O 383.2289; found 382.2289.
J
¼
12.6, 1H), 1.95e1.85(m, 1H), 1.68e1.55(m, 1H),
d
5f: Light blue solid. m.p 174 ꢁC; 1H NMR (300 MHz, CDCl3)
d
7.99e7.87(m, 2H), 7.58e7.50(m, 2H), 7.49e7.39(m, 2H),
7.36e7.28(m, 1H), 6.93 (dd, J ¼ 3.0, 8.8 Hz, 1H), 6.81 (td, J ¼ 3.0,
8.8 Hz, 1H), 6.50e6.41 (m, 1H), 4.79(d, 10.7 Hz, 1H),
J
¼
4.3.9. 9-Methoxy-5-(9-methyl-9H-carbazol-3-yl)-3,4,4a,5,6,10b-
hexahydro-2H-pyrano[3,2-c]quinoline
4.34(d, J ¼ 2.8 Hz, 1H), 4.16e3.92 (m, 2H), 3.75e3.63(m, 1H),
2.24e2.23(m, 1H), 2.17e2.07(m, 1H),1.96e1.78 (m, 1H), 1.72e1.56
7c: White solid. m.p 103 ꢁC; 1H NMR (300 MHz, CDCl3)
d 8.05 (t,
(m, 1H),1.54e1.41(m, 1H). 13C NMR (75 MHz, CDCl3)
d
156.5, 155.8,
J ¼ 10.5 Hz, 2H), 7.51e7.40 (m, 2H), 7.35(t, 2H), 7.20(t,J ¼ 8.3 Hz, 1H),
6.80(d, J ¼ 2.26 Hz, 1H), 6.75e6.65(m, 1H), 6.48(d, J ¼ 8.3 Hz, 1H),
4.82(d, J ¼ 11.3 Hz, 1H), 4.40(d, J ¼ 3.0 Hz, 1H),4.15 (d, J ¼ 11.3 Hz,
1H), 3.90(s, 3H), 3.76(s, 3H),3.71(s, 1H), 2.38e2.30(m, 1H),
2.2e2.1(m, 1H), 2.02e1.98(m, 2H), 1.70e1.68(m, 1H), 1.65e1.55(m,
141.1, 136.5, 127.3, 126.7, 124.5, 123.9, 122.7, 120.6, 119.6, 116.8, 116.5,
116.2, 115.0, 111.7, 111.6, 110.7, 74.2, 68.7, 54.9, 39.1, 29.6, 23.9.
IR(KBr) 3389, 2924, 2850, 1741, 1601, 1500, 1474,1255, 1186, 1077,
1056, 811, 746 cmꢀ1. MS (ESI) m/z 374 [M þ H]þ; HRMS (ESI) Calcd
for C24H21 NO2F: 374.1556, found: 374.1571.
1H).13C NMR (75 MHz, CDCl3)
d 156.5, 155.2, 139.2, 136.7, 125.7,
124.5, 123.1, 121.4, 120.2, 119.5, 118.8, 116.8, 115.9, 115.5, 114.9, 108.4,
108.3, 74.9, 68.8, 55.9, 55.2, 41.1, 39.4, 29.6,24.1. IR(KBr)3422, 2924,
2853, 1710, 1626, 1503, 1461, 1249, 1152,1039, 810, 745 cmꢀ1. MS
(ESI) m/z 399[M þ H]þ; HRMS Calcd for C26H26N2O2 399.2041;
found 399.2041.
4.3.7. 5-(9-Methyl-9H-carbazol-3-yl)-3,4,4a,5,6,10b-hexahydro-
2H-pyrano[3,2-c]quinoline
6a: Syrup. 1H NMR (300 MHz, CDCl3)
d 8.30 (s, 1H), 8.15(d,
J ¼ 8.4 Hz, 1H), 8.08e8.00 (m, 1H), 7.75(d, J ¼ 8.1 Hz, 1H), 7.65(t,
J ¼ 7.7 Hz, 1H),7.45e7.32(m, 1H), 7.30e7.23 (m, 1H), 7.10(d,
J ¼ 6.9 Hz, 2H), 6.72e6.67(m, 1H), 6.60e6.52(m, 1H), 5.00(d,
J ¼ 5.4 Hz, 1H), 4.40(d, J ¼ 2.2 Hz, 1H), 3.91(s, 3H), 3.85(s, 1H),
4.3.10. 9-Chloro-5-(9-methyl-9H-carbazol-3-yl)-3,4,4a,5,6,10b-
hexahydro-2H-pyrano[3,2-c]quinoline
3.68e3.52(m, 1H),3.5e3.4(m, 1H), 2.35(t,
J
¼
8.1 Hz, 1H),
6d: White solid. m.p 130 ꢁC; 1H NMR (300 MHz, CDCl3)
d 8.20 (s,
1.80e1.65(m, 2H), 1.60e1.40(m,2H). 13C NMR(75 MHz, CDCl3)
157.0, 156.5, 144.9, 136.1, 130.0, 128.8, 127.8, 126.8, 126.2, 125.8,
1H), 8.10e8.00 (m, 1H), 7.90(s, 1H), 7.70(d, J ¼ 2.2 Hz, 1H),
7.65e7.55(m, 1H), 7.50e7.35 (m, 2H), 7.20(t, J ¼ 7.5 Hz, 1H), 7.10(d,
J ¼ 3.0 Hz, 1H), 6.37(t, J ¼ 6.8 Hz, 1H), 4.90(d, J ¼ 5.2 Hz, 1H),4.41(d,
J ¼ 3.7 Hz, 1H),3.90(s, 3H), 3.85e3.75(m, 1H), 3.60(t, J ¼ 6.0 Hz, 1H),
3.44(t, J ¼ 6.7 Hz, 1H), 2.30 (t, J ¼ 8.3 Hz, 1H), 2.09e1.92(m, 1H),
d
122.5, 120.4, 119.8, 117.6, 114.0, 111.6, 108.5, 108.1, 73.6, 66.9, 53.9,
40.2, 39.1, 29.2, 24.0. IR(neat) 3358, 2933, 2858, 1607, 1490, 1396,
1256, 1124, 1064, 930, 751 cmꢀ1 .MS (ESI) m/z 367[M ꢀ H]þ; HRMS
Calcd for C25H24N2O 367.1810; found 367.1825.
1.60e1.35(m, 3H).13C NMR (75 MHz, CDCl3)
d 156.5, 155.1, 143.2,
7a: White solid. m.p 142 ꢁC; 1H NMR (300 MHz, CDCl3)
d
8.15 (s,
134.9, 129.8, 129.4, 128.1, 127.7, 126.0, 125.0, 123.0, 121.7,120.5, 119.7,
118.6, 114.6, 108.1, 107.7, 73.4, 60.8, 53.9, 40.0, 39.1, 28.7, 28.5.
IR(KBr) 3384, 2923, 2853, 1599, 1485, 1322, 1251, 1124, 1058, 807,
740. cm-1. MS (ESI) m/z 401[M ꢀ H]þ; HRMS Calcd for C25H23N2OCl
401.1422; found 401.1420.
1H), 8.08 (d, J ¼ 7.5 Hz, 1H), 7.52e7.45(m, 1H), 7.43e7.40(m,1H),
7.38e7.30 (s, 2H), 7.23e7.15(m, 2H), 7.05(t, J ¼ 7.5 Hz, 1H), 6.66(t,
J ¼ 6.79 Hz, 1H), 6.50(d, J ¼ 7.5 Hz, 1H), 4.87(d, J ¼ 11.3 Hz, 1H),
4.40(d, J ¼ 3.0 Hz, 1H), 4.14(d, J ¼ 12.8 Hz, 2H), 3.88(s, 3H), 3.67(t,
J ¼ 11.3 Hz, 1H), 2.3e2.1(m, 1H), 1.98e1.8(m, 1H), 1.70e1.55(m, 1H),
1.50e1.40(m, 1H), 1.39e1.25(m, 1H) .13C NMR (75 MHz, CDCl3)
7d: White solid. m.p 122 ꢁC; 1H NMR (300 MHz, CDCl3)
d
8.11e8.00 (m, 2H),7.95(d, J ¼ 8.3 Hz, 1H) 7.51e7.43(m, 2H),
d
156.3, 155.1, 144.9, 137.0, 131.0, 129.3, 125.8, 125.4, 124.7, 122.8,
7.42e7.34(m, 3H), 7.21e7.13(m, 1H), 7.05(d, J ¼ 7.1 Hz, 1H), 6.42 (d,
J ¼ 8.3 Hz,1H), 4.80(d, J ¼ 11.3 Hz,1H), 4.31(s,1H), 4.09(d, J ¼ 9.0 Hz,
1H), 3.87 (s, 3H), 3.67(t, J ¼ 9.8 Hz, 1H), 2.14e1.99(m, 1H),
1.68e1.41(m, 1H), 1.30e1.25(m, 4H). 13C NMR (75 MHz, CDCl3)
122.4, 120.2, 119.5, 117.2, 114.0, 110.9, 108.4, 108.3, 74.8, 68.5, 54.8,
40.2, 39.2, 29.6, 24.1,. IR(KBr) 3373, 3048, 2924, 2852, 1604, 1476,
1361, 1251, 1074, 746 cmꢀ1. MS (ESI) m/z 369[M þ H]þ; HRMS Calcd
for C25H24N2O 369.1966; found 369.1973.
d
156.1, 155.1, 144.9, 135.3, 132.6, 131.8, 130.0, 127.2, 126.7, 126.4,
125.0, 123.8, 122.7, 120.6, 120.3, 112.9, 109.0, 108.6, 74.4, 63.7, 54.1,
40.4, 39.0, 29.6, 27.1. IR(KBr) 3446, 2923, 2855, 1672, 1590, 1466,
1365, 1314, 1243,1118, 1067, 713 cmꢀ1. MS (ESI) m/z 403[M þ H]þ;
HRMS Calcd for C25H23N2OCl 403.1437; found 403.1437.
4.3.8. 9-Methyl-5-(9-methyl-9H-carbazol-3-yl)-3,4,4a,5,6,10b-
hexahydro-2H-pyrano [3,2-c] quinoline
6b: White solid. m.p 150 ꢁC; 1H NMR (300 MHz, CDCl3)
d
8.25(s,1H), 8.04(t, J ¼ 6.7 Hz, 1H), 7.90(s, 1H), 7.60 (d, J ¼ 8.3 Hz,
1H), 7.50e7.33(m, 2H), 7.15 (s,1H), 7.00(s,1H), 6.77(t, J ¼ 7.5 Hz,1H),
6.30(d, J ¼ 7.5 Hz, 1H), 4.92(d, J ¼ 5.2 Hz, 1H), 4.35(d, J ¼ 3.0 Hz, 1H),
3.90 (s, 3H), 3.60e3.50(m, 1H),3.35(t, J ¼ 6.7 Hz, 1H), 2.60(s, 2H),
2.34(t, J ¼ 7.5 Hz, 1H), 2.23(d, J ¼ 10.7 Hz, 4H), 1.75e1.60(m, 1H),
4.3.11. 9-Bromo-5-(9-methyl-9H-carbazol-3-yl)-3,4,4a,5,6,10b-
hexahydro-2H-pyrano [3,2-c] quinoline
6e: White solid. m.p 122 ꢁC; 1H NMR (300 MHz, CDCl3)
d 8.30 (s,
1H), 8.20e7.90 (m, 1H), 7.80e7.61(m, 2H), 7.50e7.38(m, 4H),7.10(d,
J ¼ 9.0 Hz, 1H), 6.30(d, J ¼ 8.30 Hz, 1H), 4.90(d, J ¼ 6.0 Hz, 1H),
1.50e1.30(m, 1H).13C NMR (75 MHz, CDCl3)
d 156.3, 155.6, 142.6,

S. Kantevari et al. / European Journal of Medicinal Chemistry 46 (2011) 4827e4833
4833
3.88(s, 3H), 3.80(s, 1H), 3.65(t, J ¼ 6.0 Hz, 2H), 3.45(t, J ¼ 6.0 Hz, 1H),
2.35(t, J ¼ 7.5 Hz, 1H), 2.10e1.92(m, 1H), 1.73e1.64(m, 1H),
spectra of all the new compounds. CCDC 793281 (for 4e) contain
the crystallographic data and can be obtained free of charge from
the Cambridge Crystallographic Data centre via www.ccdc.cam.ac.
uk/data_request/cif.
1.60e1.50(m, 2H). 13C NMR (75 MHz, CDCl3)
d 156.3, 155.1, 143.5,
136.7,134.9, 130.7, 130.4, 128.8, 126.5, 125.9, 123.9, 122.7, 121.8,
120.8, 120.4, 115.6, 109.4, 108.2, 108.1, 72.9, 62.5, 62.4, 41.2, 35.8,
29.6, 25.3. IR(KBr) 3415, 2922, 2853, 1711, 1594, 1470, 1255, 1062,
810, 744 cmꢀ1. MS (ESI) m/z 448[Mþ2]þ.
7e: White solid. m.p 112 ꢁC; 1H NMR (300 MHz, CDCl3)
Appendix. Supplementary data
d
8.20e7.96 (m, 2H), 7.53e7.40 (m, 2H), 7.39e7.32(m, 1H),
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.ejmech.2011.06.014.
7.24e7.15(m, 2H), 7.05 (t, J ¼ 7.1 Hz, 1H), 6.66(t, J ¼ 7.3 Hz, 1H),
6.49(d, J ¼ 7.9 Hz, 1H), 4.88(d, J ¼ 10.9 Hz, 1H), 4.38 (d, J ¼ 2.4 Hz,
1H), 4.12 (d,J ¼ 9.8 Hz, 1H), 3.87(s, 3H), 3.71(t, J ¼ 11.5 Hz, 1H),
2.24e2.10(m, 1H), 2.04e1.80(m, 1H), 1.71e1.54(m, 1H),
1.43e1.23(m, 2H) .13C NMR (100 MHz, CDCl3)
d 154.6, 152.2, 143.4,
References
134.8130.6, 130.4, 129.9, 128.8, 128.5, 126.2, 125.8, 122.8, 120.8,
120.3, 119.2, 119.0, 108.6, 108.5, 72.8, 62.1, 61.6, 41.7, 35.7, 29.5, 25.3.
IR(KBr) 3449, 2926, 2854, 1631,1599,1488,1250, 1125,1072,
750 cmꢀ1. MS (ESI) m/z 445[M ꢀ H]þ; HRMS Calcd for C25H23N2OBr
445.0915 found 445.0924.
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4.3.12. 9-Fluoro-5-(9-methyl-9H-carbazol-3-yl)-3,4,4a,5,6,10b-
hexahydro-2H-pyrano [3,2-c] quinoline
6f: White solid. m.p 135 ꢁC; 1H NMR (300 MHz, CDCl3)
d 8.28 (d,
J ¼ 6.4 Hz, 1H), 8.18e8.02(m, 1H), 7.95(d, J ¼ 6.9 Hz, 1H), 7.70(d,
J ¼ 6.7 Hz, 2H), 7.50e7.35(m, 3H), 7.20 (t, J ¼ 7.7 Hz, 2H), 4.98(d,
J ¼ 6.2 Hz, 1H),3.97(s, 3H), 3.90(s, 1H), 3.65(t, J ¼ 6.2 Hz, 1H), 3.45(t,
J ¼ 6.2 Hz, 2H), 2.10(t, J ¼ 7.7 Hz,1H),1.80e1.70(m, 2H),1.60e1.45(m,
2H). 13C NMR (75 MHz, CDCl3)
d 156.1, 155.4, 142.8, 135.3, 129.6,
127.9, 126.5, 125.9, 122.5, 120.8, 120.5, 119.2, 119.1, 115.9, 115.2, 113.7,
111.6, 111.5, 72.2, 61.8, 59.7, 40.2, 38.6, 29.6, 22.5. IR(KBr) 3449,
2924, 2853, 1724, 1601, 1490, 1462,1254, 1219, 1065 cmꢀ1. MS (ESI)
m/z 385 [M ꢀ H] þ; HRMS Calcd for C25H23N2OF 385.1716; found
385.1722.
7f: White solid. m.p 122 ꢁC; 1H NMR (300 MHz, CDCl3)
d 8.04 (m,
1H), 7.43(t, J ¼ 7.9 Hz, 2H), 7.34(m, 2H), 7.24e7.12(m, 2H), 7.01 (d,
J ¼ 8.5 Hz,1H),6.43(d, J ¼ 8.6 Hz,1H), 4.83 (d, J ¼ 10.7 Hz, 1H),4.33(s,
1H), 4.09(d, J ¼ 10.7, 1H), 3.88(s, 3H), 3.68(t, J ¼ 10.0 Hz,
1H),2.47e1.78(m, 4H), 1.75e1.48(m, 2H). 13C NMR (75 MHz, CDCl3)
d
156.6, 154.0. 141.1, 136.8, 128.0, 125.1, 124.8, 123.6, 122.5, 120.0,
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Authors (SK, TY and GS) are thankful to Dr. J. S. Yadav, Director
and Dr. V. V. N. Reddy, Head, Organic Chemistry Division-II, IICT,
Hyderabad for their continuous support and financial assistance
from MLP projects. TY (SRF) and GS (JRF) are thankful to CSIR for
fellowship.
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Appendix. Supplementary data
Supplementary data associated with this article can be found in
online version. Copies of 1H, 13C NMR and mass (ESI-MS and HRMS)