Synthesis of biologically active pyridoimidazole/imidazobenzothiazole annulated polyheterocycles using cyanuric chloride in water

Article abstract of DOI:10.1039/c4ra03415e

An efficient and mild protocol for rapid access to N-fused polyheterocycles via Pictet-Spengler type 6-endo cyclization using cyanuric chloride in an aqueous reaction medium has been developed. The protocol was successfully applied to a wide range of compounds including aryl/heteroaryl aldehydes (8a-o), ketones (10a-e), an electron-rich metallocene aldehyde (8e) and indoline-2,3-diones (12a-c) using cyanuric chloride (15-20 mol%) with tetra-n-butylammonium bromide (TBAB) (2.0 eq.) as an additive at 80-90 °C to give a good to excellent yield (66-92%) of polyheterocycles. Some of the synthesized compounds were found to exhibit antiplasmodial activity against chloroquine-sensitive (CQ-S) 3D7 and chloroquine-resistant (CQ-R) K1 strains of Plasmodium falciparum. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra03415e

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Synthesis of biologically active pyridoimidazole/
imidazobenzothiazole annulated polyheterocycles
using cyanuric chloride in water†
Cite this: RSC Adv., 2014, 4, 26757
Anand Kumar Pandey,a Rashmi Sharma,a Awantika Singh,b Sanjeev Shukla,b
Kumkum Srivastava, Sunil K. Puri, Brijesh Kumar and Prem M. S. Chauhan
c
c
b
a
*
An efficient and mild protocol for rapid access to N-fused polyheterocycles via Pictet–Spengler type 6-
endo cyclization using cyanuric chloride in an aqueous reaction medium has been developed. The
protocol was successfully applied to a wide range of compounds including aryl/heteroaryl aldehydes
(8a–o), ketones (10a–e), an electron-rich metallocene aldehyde (8e) and indoline-2,3-diones (12a–c)
using cyanuric chloride (15–20 mol%) with tetra-n-butylammonium bromide (TBAB) (2.0 eq.) as an
additive at 80–90 ꢀC to give a good to excellent yield (66–92%) of polyheterocycles. Some of the
synthesized compounds were found to exhibit antiplasmodial activity against chloroquine-sensitive
(CQ-S) 3D7 and chloroquine-resistant (CQ-R) K1 strains of Plasmodium falciparum.
Received 15th April 2014
Accepted 28th May 2014
DOI: 10.1039/c4ra03415e
www.rsc.org/advances
annulated dipyridoimidazoles (Glu-P1 and Glu-P2) (Fig. 1,
panels I and II) exhibit anti-cancer activity,8 pyridino[1,2-a]-
Introduction
imidazo[5,4-b]-indole (Fig. 1, panel III) is a well known anti-
hypertensive agent,9 and dihydropyrano imidazopyridine
(Fig. 1, panel IV) is a potassium-competitive acid blocker used
for treatment of gastroesophageal reux disease.10 Further-
more, the privileged benzothiazole motif has been recently
functionalized by formation of rings (i.e., annulations) with
other pharmacophores to prepare pharmaceutically important
scaffolds11 such as the arylimidazo-benzothiazole derivative
YM-201627 (Fig. 1, panel V) for the treatment of solid tumours.12
Racemic spirotetrahydro b-carboline-based spiroazepineindole
has also been recently shown to exhibit antiplasmodial activity
(Fig. 1, panel VI).13
Research involving reactions in aqueous media, including
syntheses of organic heterocycles in water, has been growing
tremendously in the past few decades in order to satisfy envi-
ronmental concerns.1 Water as a universal solvent has great
impact, as it is environmentally acceptable, non-ammable and
economical. Organic reactions in water have become exciting
and/or essential research endeavors. Indeed, industry prefers to
use water as a solvent rather than conventional toxic organic
solvents. Although most inorganic reactions can be carried out
using water as a solvent, it is not the preferred solvent for
organic reactions because of poor solubility of most organic
compounds in water.2 To overcome the solubility problem,
micellar catalysis has been found to be very helpful to allow
utilization of aqueous media for carrying out several organic
transformations.3
In the present work we report the use of privileged PI and
IBT structures along with Pictet–Spengler-type cyclizations in
As small organic scaffolds, polyheterocycles are invaluable
structural motifs with many applications in the pharmaceu-
tical4 and material sciences.5 The pyridoimidazole (PI) and
imidazobenzothiazole (IBT) substructures are found in several
drugs and biologically active molecules.6,7 For example, the
aMedicinal and Process Chemistry Division, CSIR-Central Drug Research Institute,
Lucknow, 226031, India. E-mail: premsc58@hotmail.com; prem_chauhan_2000@
yahoo.com; Fax: +91-522-2771941; Tel: +91-0522-2771940 ext. 4659; +91-0522-
2771940 ext. 4660
bSophisticated Analytical Instrument Facility, CSIR-Central Drug Research Institute,
Lucknow, 226031, India
cDivision of Parasitology, CSIR-Central Drug Research Institute, Lucknow, 226031,
India
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra03415e
Fig. 1 Several biologically active fused polyheterocycles.
RSC Adv., 2014, 4, 26757–26770 | 26757
This journal is © The Royal Society of Chemistry 2014

View Article Online
RSC Advances
Paper
aqueous medium to produce a moderate to good yield of
biologically relevant polyheterocycles (Fig. 2). The Pictet–
Spengler reaction is one of the most powerful strategies for
constructing C–C bonds. Previously, the Pictet–Spengler
reaction has been performed using strong Brønsted acids
such as triuoroacetic acid (TFA) and methanesulfonic acid,
which tend to result in diminished yields, lead to long reac-
tion times, create difficulties in work-up and/or require the
use of conventional solvents.14–16 We chose cyanuric chloride
as in our previous work17,18 and in research reported in the
literature19 it was found to be effective in several trans-
formations. Although there are some reports of the Pictet–
Spengler reaction using only water as the medium,20 the use
of the combination of water with cyanuric chloride for such
transformations has not been reported in the literature. The
reaction of cyanuric chloride with water produces HCl and
cyanuric acid, which could be useful in carrying out the
organic reactions under mild conditions while at the same
time producing metal-free, non-volatile and essentially non-
toxic side products that should encourage its application in
medicinal chemistry.
Very recently, Sawant et al. developed a similar cyanuric
chloride-promoted Pictet–Spengler cyclisation, but in dimethyl
sulfoxide (DMSO) and with limited examples (Fig. 2).21 In
contrast, we present an extensive polyheterocyclic library with
skeletal diversity using a relatively mild and “green” protocol by
employing a range of oxo-substrates, such as aryl aldehydes,
acetophenones and indoline-2,3-diones. Furthermore, for the
rst time we focus on using imidazo[1,2-a]benzothiazole as a
substrate for such a transformation. It is worth mentioning that
compounds bearing pyrido[1,2-a]imidazole annulations have
been demonstrated to possess a variety of pharmacological
properties.9 Therefore, we speculated that this skeleton, upon
fusion with aryl quinolone, may generate signicant interest
regarding its biological activity.22
Results and discussion
The modied Pictet–Spengler reaction is a two-step process,
where an aryl amine and an oxo-substrate rst react to give an
imine as an intermediate followed by a 6-endo intramolecular
cyclization to provide the cyclic product. In the present work the
desired aryl amines 6 and 7 (see Scheme 1) were prepared in a
mild two-step procedure from 2-amino azines 1 and 2, respec-
tively. Previously, however, synthon 6 was generally synthesized
by bromination of 2-nitroacetophenone under harsh condi-
tions.16 Condensation with 1-(2,2-dibromovinyl)-2-nitroben-
zene23 (3) gives intermediates 4 and 5,24 which upon reduction
with Fe powder/acetic acid provides the desired PI substrates 6
and 7 in good yields.
The Pictet–Spengler reaction between pyridoimidazole aryl-
amine (6) and benzaldehyde (8a) was further explored to iden-
tify the optimal reaction conditions. Several Brønsted acids
were evaluated as catalysts at various temperatures in organic
and aqueous media (Table 1). Out of all Brønsted acids in
different solvents (entries 1–5) screened, cyanuric chloride (20
mol%) in CH3CN (entry 5) seemed promising, therefore, further
renement was limited to varying the solvents and temperature.
Comparison of entries 5 and 7 suggests that increasing the
polarity of an aprotic solvent may increase reaction yield, but
upon replacing the aprotic solvent, DMSO, with the protic
solvent, water, a slight drop in yield was observed (entry 8).
Interestingly, further improvement of yield, ease of handling
(without inert conditions) and reaction time was found upon
using cyanuric chloride (15 mol%) as the reagent, water as the
solvent, and a stoichiometric amount of TBAB as an additive
(entry 9), which prompted us to further optimise the reaction
conditions in aqueous media. Increasing the amount of cya-
nuric chloride to 20 mol% and of TBAB to 2 eq. was found to be
benecial in terms of reaction yield and time (entry 10).
However, a further increase of TBAB to 3 eq. was not of signif-
icant benet (entry 11). Replacing the TBAB with other additives
Fig. 2 Comparison of our Pictet–Spengler cyclisation strategy with previous work. TBAB ¼ tetra-n-butylammonium bromide.
26758 | RSC Adv., 2014, 4, 26757–26770
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
Scheme 1 Synthesis of proposed IP substrates for Pictet–Spengler type cyclization.
was found to decrease effectiveness (compare entries 10, 12 and
The optimized reaction condition (Table 1, entry 10) was
13). A slight increase in cyanuric chloride loading to 30 mol% applied to an array of aromatic/heteroaromatic (HetAr) alde-
was also not benecial (entry 14). As predicted, the reaction did hydes appended with various substituents (8a–o, Table 2).
not work at all without cyanuric chloride (entry 15). Thus, a Neither steric nor electronic factors had a signicant impact on
survey of different reaction conditions (compare entries 9, 10, the reaction time and/or yield (products 9a–s). Furthermore, the
14) identied 20 mol% cyanuric chloride with 2.0 eq. TBAB to be organometallic and heteroaromatic aldehydes 8e and 8n also
the optimum conditions (entry 10). The use of p-toluenesulfonic participated in a similar way, producing good yields of
acid (PTSA) in place of cyanuric chloride under otherwise opti- compounds 9e and 9r, respectively.
mized conditions provided the aromatic polycyclic product but
Interestingly, less reactive aromatic/HetAr ketone elec-
the yield was poor (entry 16). To further validate our assumption trophiles also successfully participated in the Pictet–Spen-
that we had reached an optimized condition, we ran the same gler reaction (Table 3), with slightly improved reaction
reaction with TBAB (2.0 eq.) in water but with cyanuric acid conditions [15 mol% cyanuric chloride with 2.0 eq. of TBAB
(20 mol%) in place of cyanuric chloride, which led to the poly- at 80 ꢀC in water (compare with Table 1, entry 10)] to produce
heterocycles (9a) in a similar yield but with a prolonged reaction the high yields (82–88%) of polyheterocycles 11a–f shown in
time (entry 17).
Table 3.
Table 1 Table for the optimisation of the reaction conditions for a Pictet–Spengler reactiona
Entry
Reagent (mol%)
Additive (eq.)
Solvent
Temp (ꢀC)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
TFA (500)
PTSA (20)
CH3COOH
CH3SO3H (100)
—
—
—
—
—
—
—
—
DCM
Toluene
Neat
EtOH
CH3CN
THF
DMSO
H2O
H2O
H2O
H2O
H2O
H2O
70
120
90
90
85
75
90
90
90
90
90
90
90
90
90
90
90
6
5
5
5
3
3
2.0
3.0
2.0
1.5
1.5
2.0
2.0
1.5
4
34
46
54
45
56
52
68
62
73
82
83
71
67
76
nre
46
79
Cyanuric chloride (20)
Cyanuric chloride (20)
Cyanuric chloride (20)
Cyanuric chloride (15)
Cyanuric chloride (15)
Cyanuric chloride (20)
Cyanuric chloride (20)
Cyanuric chloride (20)
Cyanuric chloride (20)
Cyanuric chloride (30)
9
TBAB (1.0)
TBAB (2.0)
TBAB (3.0)
TMAIc (1.0)
Al2O3 (1.0)
TBAB (2.0)
TBAB (2.0)
TBAB (2.0)
TBAB (2.0)
10
11
12
13
14
15
16
17
H2O
H2O
H2O
H2O
d
—
PTSA (20)
Cyanuric acid (20)
3
3.0
a
Reaction conditions: substrate 6 (0.5 mmol), substrate 8a (0.5 mmol), reagent (20 mol%), additive (2.0 eq.), solvent (0.64 M) at 90 ꢀC for 1.5 h.
b
c
d
e
Isolated yield. Tetramethylammonium iodide.
Reaction without cyanuric chloride. No reaction. DCM: dichloromethane; THF:
tetrahydrofuran.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 26757–26770 | 26759

View Article Online
RSC Advances
Paper
Table 2 Scope of the reaction with different aromatic and heteroaromatic aldehydesa
Entry
Ar/HetAr aldehyde
X
Yieldb (%)
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
9o
9p
9q
9r
Benzaldehyde (8a)
H
H
H
H
82
90
82
77
75
82
92
77
82
86
83
86
75
78
72
79
83
82
87
4-Nitrobenzaldehyde (8b)
4-Flourobenzaldehyde (8c)
4-Methoxybenzaldehyde (8d)
Ferrocene aldehyde (8e)
H
Benzaldehyde (8a)
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
4-Nitrobenzaldehyde (8b)
2-Nitrobenzaldehyde (8f)
3-Nitrobenzaldehyde (8g)
4-Cyanobenzaldehyde (8h)
4-Isopropylbenzaldehyde (8i)
4-Bromobenzaldehyde (8j)
4-(N,N-Dimethylamino)benzaldehyde (8k)
4-Methoxybenzaldehyde (8d)
4-Hydroxybenzaldehyde (8l)
3,4,5-Trimethoxybenzaldehyde (8m)
4-Flourobenzaldehyde (8c)
Pyridine-4-aldehyde (8n)
1-Naphthaldehyde (8o)
9s
a
Reaction conditions: 6 or 7 (0.5 mmol), Ar/HetAr aldehyde (8a–o) (0.5 mmol), cyanuric chloride (20 mol%), TBAB (2.0 eq.), H2O (0.64 M) at 90 ꢀC for
b
1.5 h. Isolated yield.
Table 3 Reactions with different aromatic/HetAr ketonesa
Entry
Ar/HetAr ketones
X
Yieldb (%)
11a
11b
11c
11d
11e
11f
Acetophenone (10a)
H
H
H
H
CH3
H
82
86
82
84
88
83
1-(4-Nitrophenyl)ethanone (10b)
1-(4-Methoxyphenyl)ethanone (10c)
1-(4-Bromophenyl)ethanone (10d)
Acetophenone (10a)
1-(Thiophen-2-yl)ethanone (10e)
a
Reaction conditions: 6 or 7 (0.5 mmol), Ar/HetAr ketones (10a–e) (0.5 mmol), cyanuric chloride (15 mol%), TBAB (2.0 eq.), H2O (0.64 M) at 80 ꢀC for
b
1.5 h. Isolated yield.
26760 | RSC Adv., 2014, 4, 26757–26770
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
The spirooxindole core has great importance for medicinal releases hydrochloric acid and cyanuric acid.18,26 The generated
chemistry and is found in several natural products such as HCl as well as cyanuric acid (23a) (entry 17, Table 1) may acti-
spirotryprostatins A and B,25a horsline,25b rhynchophylline,25c vate the imine 23b, converting it to the quaternized imine salt
and marcfortine A.25d Therefore, spirooxiindole-fused azapoly- 23c to facilitate 6-endo intramolecular cyclisation to provide
cycles were prepared using our method, starting with indole- 23d. When this intermediate 23d is an acetophenone (11a)
2,3-dione (12a) and its analogues (12b,c). Cyanuric chloride or indole-2,3-dione (13a), its deprotonation would afford the
gave moderate to good yields (66–72%, Table 4) of the spi- polycylic product, but when the intermediate is an aromatic
rofused cyclic frameworks 13a–d.
aldehyde, its deprotonation and aerial oxidation would lead to
Preparation of tricyclic imidazobenzothiazoles 19 and 20 the aromatised polyheterocycle (9a).
(Scheme 2), novel substrates for the Pictet–Spengler reaction,
was analogous to the preparation of 6 and 7, and carried out
Biological activity
under the previously optimized reaction condition (Scheme 1).
These substrates were successfully transformed into their
respective polycyclic systems 21a–f with good yields as shown in
Table 5.
In addition, substrate 19 was condensed with different
electron-decient or electron-rich aromatic ketones and 10a–c
with cyanuric chloride to obtain their corresponding poly-
heterocycles 22a–c (Table 6).
A plausible mechanism for the formation of the poly-
heterocycles is proposed in Fig. 3. The rate-determining step of
the Pictet–Spengler reaction is the conversion of the imine
intermediate to the cyclised product by a 6-endo intramolecular
electrophilic reaction. From research in the literature, we
envisage that cyanuric chloride under aqueous conditions
Bioevaluation methods
In vitro assay for evaluation of antimalarial activity. The
compounds were evaluated for antimalarial activity against
both chloroquininesensitive 3D7 (CQ-S) and chloroquinine-
resistant K1 (CQ-R) strains of Plasmodium falciparum using
malaria SYBR Green I nucleic acid staining dye-based uores-
cence assay as described by Singh et al.27 The stock solution (5
mg mLꢁ1) was prepared in DMSO and test dilutions were
prepared in culture medium (RPMI-1640-FBS). Chloroquine was
used as a reference drug. The compounds were tested in 96-well
plates (in duplicate wells). A parasitized cell suspension (1.0%)
containing 0.8% parasitemia was used. The plates were incu-
bated at 37 ꢀC in a CO2 incubator in an atmosphere of 5% CO2
Table 4 Synthesis of spiro-oxyindoles 13a–d via the Pictet–Spengler reactiona
Entry
Indoline-2,3-dione and analogues
X
R1
Yieldb (%)
13a
13b
13c
13d
Indoline-2,3-dione (12a)
H
H
CH3
CH3
H
66
69
72
68
1-Ethylindoline-2,3-dione (12b)
1-Methylindoline-2,3-dione (12c)
1-Ethylindoline-2,3-dione (12b)
Et
Me
Et
a
Reaction conditions: 6 or 7 (0.5 mmol), indole-2,3-dione and its analogues (12a–c) (0.5 mmol), cyanuric chloride (20 mol%), TBAB (2.0 eq.), H2O
b
(0.64 M) at 90 ꢀC for 3.0 h. Isolated yield.
Scheme 2 Synthesis of the proposed tricyclic substrate (19, 20) for Pictet–Spengler cyclisation.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 26757–26770 | 26761

View Article Online
RSC Advances
Paper
Table 5 Synthesis of IBT polyheterocycles (21a–f) via the Pictet–Spengler reactiona
Entry
Aryl aldehyde
Y
Yieldb (%)
21a
21b
21c
21d
21e
21f
Benzaldehyde (8a)
H
H
H
CH3
CH3
CH3
76
83
78
78
76
78
4-Nitrobenzaldehyde (8b)
4-Methoxybenzaldehyde (8d)
4-Nitrobenzaldehyde (8b)
4-Methoxybenzaldehyde (8d)
4-Bromobenzaldehyde (8j)
a
Reaction conditions: 19 or 20 (0.5 mmol), aryl aldehyde (8a-b or 8d or 8j) (0.5 mmol), cyanuric chloride (20 mol%), TBAB (2.0 eq.), H2O (0.64 M) at
b
90 ꢀC for 2.0 h. Isolated yield.
Table 6 Synthesis of IBT polyheterocycles (22a–c) using acetophenonesa
Entry
Acetophenones
Yieldb (%)
22a
22b
22c
Acetophenone (10a)
1-(4-Nitrophenyl)ethanone (10b)
1-(4-Methoxyphenyl)ethanone (10c)
76
78
74
a
Reaction conditions: 19 (0.5 mmol), Ar ketone (10a–c) (0.5 mmol), cyanuric chloride (20 mol%), TBAB (2.0 eq.), H2O (0.64 M) at 80 ꢀC for 2.0 h.
Isolated yield.
b
and air mixture. Aer 72 h, 100 mL of lysis buffer containing 2ꢂ described by Sashidhara et al.28 The cells were incubated with
concentration of SYBR Green-I (Invitrogen) was added to each compound dilutions for 72 h and 3-(4,5-dimethylthiazol-2-yl)-
well and incubated for 1 h at 37 ꢀC. Relative uorescence units 2,5-diphenyltetrazolium bromide (MTT) was used as the
(RFU) of the wells were measured at 485 ꢃ 20 nm excitation and reagent for the detection of cytotoxicity. The 50% cytotoxic
530 ꢃ 20 nm emission using the uorescence plate reader concentration (CC50
) was determined using non-linear
(FLUOstar, BMG LabTech). Data were transferred into a graphic regression analysis using a pre-programmed Excel spread-
programme (EXCEL) and the concentration values corre- sheet. The Selectivity Index was calculated as SI equals
sponding to 50% growth inhibition of the parasite (IC50) were CC50/IC50
.
obtained by Logit regression analysis using a pre-programmed
Excel spreadsheet.
To assess their potential biological activities, subsets of the
synthesized compounds were evaluated for their in vitro anti-
In vitro assay for evaluation of cytotoxic activity. Cytotoxicity malarial activity against CQ-S 3D7 and CQ-R K1 strains of P.
of the compounds was evaluated using a Vero cell line (C falciparum and their cytotoxicity toward the VERO cell line
1008; Monkey kidney broblast) following the method (Table 7). Compounds 9j, 9l, 9m, 9p, 11a, 11b, 11d, 11f and 13a
26762 | RSC Adv., 2014, 4, 26757–26770
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
Fig. 3 Proposed mechanism for synthesis of different polyheterocycles.
Table 7 In vitro antimalarial activity of compounds against 3D7 and K1
strains of P. falciparum and their cytotoxicity against the VERO cell line
Conclusion
In summary, we have developed a mild protocol for the
synthesis of annulated polyheterocycles through Pictet–Spen-
gler type 6-endo cyclisation reactions under aqueous conditions.
The process is applicable to a variety of aryl/HetAr/metallocene
aldehydes, ketones, and indoline-2,3-diones. High yields, mild
reaction conditions, operational simplicity and minimum
environmental pollution are the key features of our method-
ology that make it useful for the construction of pharmaceuti-
cally important heterocycles, demonstrated by the observation
of moderate anti-plasmodial activity in vitro.
a
IC50 (mM)
Comp. no.
CQ-S (3D7)
CQ-R (K1)
CC50b (mM)
9a
9b
9c
9d
9e
9f
9j
9l
3.40
4.62
>5.0
1.24
2.05
3.04
2.83
0.99
0.75
1.07
0.56
1.71
0.20
0.48
0.22
0.84
1.04
1.12
0.005
NDc
ND
ND
ND
ND
34.54
66.63
104.92
24.23
21.94
37.10
43.36
31.92
25.57
33.98
13.01
28.47
50.17
42.16
32.28
20.92
73.02
80.76
125
ND
0.53
1.02
0.56
ND
0.67
ND
0.50
0.27
0.50
0.96
1.87
ND
9m
9n
9p
Experimental section
General
9q
11a
11b
11d
11f
13a
13b
CQd
Melting points are uncorrected and were determined in capil-
lary tubes on a precision melting point apparatus containing
silicon oil. Infrared (IR) spectra were recorded on an FTIR
spectrophotometer Shimadzu 8201 PC and are reported in
terms of frequency of absorption (cmꢁ1). 1H-NMR and 13C-NMR
spectra were recorded either on a Bruker DPX-200, a Bruker
Advance DRX-300 FT or a Bruker Advance DRX-400 FT spec-
trometer. Nuclear magnetic resonance (NMR) spectra were
recorded on 300 MHz and 400 MHz spectrometers for 1H-NMR
and 50, 75, 100 MHz for 13C-NMR in deuterated chloroform
(CDCl3) or deuterated dimethylsulfoxide (DMSO-d6) with tri-
0.15
a
IC50 (mM): concentration corresponding to 50% growth inhibition of
b
the parasite.
CC50 (mM): concentration corresponding to 50%
toxicity. ND: not done. Biological activity of the standard drug
chloroquine.
c
d
exhibited low micromolar antiplasmodial activity against methylsilane (TMS) as the internal reference wherever
both strains, which were comparable to chloroquine for the mentioned. Chemical shis (d) are reported in parts per million
CQ-resistant organism and were much less active than chloro- (ppm) for 1H-NMR and 13C-NMR spectra. Coupling constants, J,
quine for the CQ-sensitive parasite.
are reported in hertz (Hz). Multiplicities are reported as follows:
singlet (s), broad (br), doublet (d), triplet (t), quartet (q), and
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 26757–26770 | 26763

View Article Online
RSC Advances
Paper
multiplet (m). The high-resolution mass spectroscopy (HRMS) 7.13 (t, J ¼ 7.2 Hz, 1H), 6.77 (d, J ¼ 7.6 Hz, 2H), 2.47 (s, 3H) ppm;
spectra were recorded as electrospray ionization (ESI)-HRMS on 13C-NMR (CDCl3, 75 MHz): d 147.7, 146.5, 145.2, 135.0, 130.2,
an Agilent 6520 Q-TOF, LC-MS/MS mass spectrometer. The 130.1, 128.5, 127.6, 127.2, 124.4, 117.6, 116.9, 112.4, 107.3, 21.4
progress of the reaction was routinely monitored by thin-layer ppm; HRMS (ESI) calculated for [M + H]+: C16H14N3S: 280.0908,
chromatography (TLC) on pre-coated silica gel plates. Column actual: 280.0917.
chromatography was performed over silica gel. All the solvents
and chemicals were used as procured from the suppliers.
General procedure 3
1-(2,2-Dibromovinyl)-2-nitrobenzene (7). To a chilled solu-
tion of triphenylphosphine (3.934 g, 15.0 mol) in DCM (40 mL),
Synthesis of 6-phenyl-5,6b,11-triaza-benzo[a]uorenes (9a–
carbon tetrabromide (CBr4) (9.948 g, 30 mol) was added in s). To a solution of Pictet–Spengler substrate (6 or 7) (0.96
fractions for 15 minutes. To this solution, 2-nitrobenzaldehyde mmol) in water (1.5 mL), each one of the desired aromatic
(2.266 g, 15.0 mmol) in DCM (10 mL) was added dropwise aldehydes (8a–o) (1 eq.) was added followed by addition of tetra-
(through a dropping funnel) for 15 minutes at 0 ꢀC and the n-butylammonium bromide (2.0 eq.). The reaction mixture was
reaction was allowed to run for 4 h at ambient temperature. stirred for 15 minutes followed by addition of cyanuric chloride
Aer completion (monitored by TLC), the reaction mixture was (0.19 mmol, 20 mol%) at 90 ꢀC. The reaction was allowed to run
poured into hexane and the precipitated triphenylphosphine for 1.5 h. Aer completion (monitored by TLC), the reaction
oxide was ltered using sintering. This ltrate was concentrated mixture was poured into water and extracted with ethyl acetate
under reduced pressure followed by column chromatography (20 mL ꢂ 3). The combined organic layers were washed with
using 60–120 mesh silica gel with CHCl3 as eluent, to obtain the brine, dried over anhydrous Na2SO4, concentrated under
intermediate 7 as a yellow solid (3.90 g, yield 85%).23
reduced pressure and the crude product was puried by column
chromatography using 60–120 mesh silica gel with 3% MeOH–
CHCl3 as eluent to obtain good to excellent yields of the Pictet–
Spengler products 9a–s.
General procedure 1
Synthesis of intermediates 4, 5, 17 and 18. To a stirred
solution of different 2-amino pyridines (1 or 2) (10.0 mmol) or 2-
amino benzothiazoles (14 or 15) (10.0 mmol) in dime-
thylformamide (DMF; 8 mL), NaHCO3 (40.0 mmol) was added
followed by addition of 1-(2,2-dibromovinyl)-2-nitrobenzene (7)
(10.0 mmol), and the reaction was allowed to run for 6 h at
120 ꢀC. Aer completion (monitored by TLC), the reaction
mixture was poured into water and extracted with ethyl acetate
(40 mL ꢂ 4), the organic layer was dried over Na2SO4 and
evaporated under reduced pressure followed by column chro-
matography using 60–120 mesh silica gel with 20% ethyl
acetate–hexane as eluent to obtain the solid products (4, 5, 17
and 18) with yields of 75–85%.24
6-Phenyl-5,6b,11-triaza-benzo[a]uorene (9a). The title
compound was obtained according to general procedure 3
using substrate 6 as an off-white solid. Yield: 0.23ꢁg1, 82%; mp:
214–217 ꢀC; IR (KBr): n 1386, 1489, 3023 cm
;
1H-NMR
(CDCl3, 400 MHz): d 8.81 (d, J ¼ 7.9 Hz, 1H), 8.32 (d, J ¼ 8.2
Hz, 1H), 8.05 (d, J ¼ 6.9 Hz, 1H), 7.95 (d, J ¼ 9.1, 1H), 7.82 (t, J
¼ 7.1, 1H), 7.73 (br, 3H), 7.66–7.61 (m, 3H), 7.54 (t, J ¼ 7.5,
1H), 6.80 (t, J ¼ 6.8, 1H) ppm; 13C-NMR (CDCl3, 50 MHz): d
149.6, 148.2, 147.2, 145.0, 138.2, 129.9, 129.6, 129.5, 129.3,
128.9, 128.7, 127.1, 126.5, 122.6, 121.4, 120.3, 117.9, 112.0
ppm; HRMS (ESI) calculated for [M
296.1183, actual: 296.1178.
+
H]+: C20H14N3:
6-(4-Nitro-phenyl)-5,6b,11-triaza-benzo[a]uorene (9b). The
title compound was obtained according to general procedure 6
as a pale-yellow solid. Yield: 0.29 g, 90%; mp: >250 ꢀC; IR (KBr):
General procedure 2
Synthesis of intermediates 6, 7, 19 and 20. To a solution of n 1384, 1600, 3019 cmꢁ1; 1H-NMR (CDCl3, 300 MHz): d 8.83 (d,
intermediates 4 or 5 or 17 or 18 (10.0 mmol) in acetic acid (10 J ¼ 7.2 Hz, 1H), 8.53 (d, J ¼ 8.4 Hz, 2H), 8.30 (d, J ¼ 7.8 Hz, 1H),
mL), Fe powder (50.0 mmol) was added. The reaction mixture 8.04–7.96 (m, 4H), 7.86–7.75 (m, 2H), 7.61 (t, J ¼ 7.8, 1H), 6.89
was heated at 90 ꢀC for 40 minutes. Aer completion of the (t, J ¼ 6.9, 1H) ppm; 13C-NMR (CDCl3, 75 MHz): d 149.9, 148.7,
reaction (indicated by a change in colour of the reaction mixture 147.8, 145.5, 145.0, 144.7, 139.4, 130.4, 130.3, 129.8, 129.4,
from brown to yellow and monitored by TLC), the reaction 127.4, 126.8, 124.6, 122.9, 118.5, 112.7 ppm; HRMS (ESI)
mixture was ltered through a celite pad followed by neutrali- calculated for [M
+
H]+: C20H13N4O2: 341.1039, actual:
sation with 10% sodium bicarbonate solution and extracted 341.1032.
with ethyl acetate (40 mL ꢂ 3). The combined organic layer was
6-(4-Flouro-phenyl)-5,6b,11-triaza-benzo[a]uorene (9c). The
dried over Na2SO4, concentrated under reduced pressure and title compound was obtained according to general procedure 6
the crude product was puried by column chromatography as a brown solid. Yield: 0.24 g, 82%; mp: 209–212 ꢀC; IR (KBr): n
using 60–120 mesh silica gel with ethyl acetate–hexane (30%) as 1384, 1612, 3021 cmꢁ1; 1H-NMR (CDCl3, 300 MHz): d 8.81 (d, J ¼
eluent to get the intermediates 6, 7, 19, and 20 as brown solids 8.1 Hz, 1H), 8.30 (d, J ¼ 7.4 Hz, 1H), 8.07 (d, J ¼ 5.7, 1H), 7.96 (d,
(yield 78–84%).
J ¼ 8.1, 1H), 7.80–7.74 (m, 4H), 7.57 (t, J ¼ 7.5, 1H), 7.37 (t, J ¼
2-(3-Methyl-imidazo[2,1-b]-benzothiazol-6-yl)-phenylamine (7). 7.8, 2H), 6.84 (t, J ¼ 5.1, 1H) ppm; 13C-NMR (CDCl3, 50 MHz): d
The title compound was obtained according to general proce- 161.1, 149.7, 147.3, 147.0, 144.9, 134.4, 130.8, 130.7, 130.0,
dure 2 as a brown solid. Yield: 2.17 g, 78%; mp: 140–143 ꢀC; IR 129.5, 129.0, 126.9, 126.7, 122.6, 121.3, 118.0, 116.6, 116.2, 112.1
(KBr): n 761, 1215, 1388, 1614, 3020, 3432 cmꢁ1 1H-NMR ppm; HRMS (ESI) calculated for [M + H]+: C20H13FN3: 314.1094,
,
(CDCl3, 300 MHz): 7.87 (s, 1H), 7.51–7.47 (m, 3H), 7.26 (s, 1H), actual: 314.1116.
26764 | RSC Adv., 2014, 4, 26757–26770
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
6-(4-Methoxy-phenyl)-5,6b,11-triaza-benzo[a]uorene (9d). The
RSC Advances
procedure 3 as a yellow solid. Yield: 0.28 g, 82%; mp: >250 ꢀC; IR
(KBr): n 1389, 1648, 3021 cmꢁ1; H-NMR (CDCl3, 300 MHz): d
1
title compound was obtained according to general procedure 3
as an off-white solid. Yield: 0.24 g, 77%; mp: 224–227 ꢀC; IR
8.80 (d, J ¼ 7.8 Hz, 1H), 8.67 (s, 1H), 8.50 (d, J ¼ 7.9 Hz, 1H), 8.28
(d, J ¼ 8.1, 1H), 8.14 (d, J ¼ 7.1, 1H), 7.90–7.72 (m, 5H), 6.69 (d, J
¼ 7.0, 1H), 2.51 (s, 3H) ppm; 13C-NMR (CDCl3, 75 MHz): d 150.4,
148.7, 147.9, 145.0, 144.8, 142.4, 140.1, 135.1, 130.4, 129.5,
129.3, 127.1, 125.6, 124.5, 124.3, 122.9, 121.5, 119.9, 116.6,
115.5, 21.9 ppm; HRMS (ESI) calculated for [M + H]+:
1
(KBr): n 1384, 1610, 3019 cmꢁ1; H-NMR (CDCl3, 300 MHz): d
8.82 (d, J ¼ 7.5 Hz, 1H), 8.32 (d, J ¼ 7.9 Hz, 1H), 8.20 (d, J ¼ 6.7,
1H), 7.97 (d, J ¼ 9.0, 1H),7.81–7.68 (m, 4H), 7.58 (t, J ¼ 7.8, 1H),
7.19 (d, J ¼ 8.0, 2H), 6.85 (t, J ¼ 6.7, 1H), 3.97 (s, 3H) ppm; 13C-
NMR (CDCl3, 50 MHz): d 160.8, 149.7, 148.2, 147.4, 145.2, 130.7,
130.2, 130.0, 129.6, 128.9, 127.3, 126.5, 122.7, 121.4, 120.6,
118.1, 114.8, 112.0 ppm; HRMS (ESI) calculated for [M + H]+:
C
21H15N4O2: 355.1195, actual: 355.1237.
6-(4-Cyano-phenyl)-9-methyl-5,6b,11-triaza-benzo[a]uorene (9j).
The title compound was obtained according to general procedure
3 as a beige solid. Yield: 0.27 g, 86%; mp: >250 C; IR (KBr): n
C
21H21N2O4: 365.1501, actual: 365.1501.
6-(Ferrocenyl)-5,6b,11-triaza-benzo[a]uorene (9e). The title
ꢀ
1384, 1650, 2265, 3019 cmꢁ1; 1H-NMR (CDCl3, 300 MHz): d 8.78
(d, J ¼ 7.4 Hz, 1H), 8.26 (d, J ¼ 7.8 Hz, 1H), 7.96–7.67 (m, 8H), 6.67
(d, J ¼ 6.4, 1H), 2.49 (s, 3H) ppm; 13C-NMR (CDCl3, 75 MHz): d
150.5, 148.1, 145.5, 145.1, 143.0, 142.2, 133.1, 130.0, 129.7, 129.2,
127.1, 125.8, 122.8, 121.7, 120.0, 118.5, 116.7, 115.3, 113.6, 21.9
ppm; HRMS (ESI) calculated for [M + H]+: C22H15N4: 335.1297,
actual: 335.1294.
6-(4-Isopropyl-phenyl)-9-methyl-5,6b,11-triaza-benzo[a]uorene
(9k). The title compound was obtained according to general
procedure 3 as a beige solid. Yield: 0.28 g, 83%; mp: 237–240 ꢀC;
IR (KBr): n 1386, 1655, 3019 cmꢁ1, 1H-NMR (CDCl3, 300 MHz): d
8.75 (d, J ¼ 7.2 Hz, 1H), 8.28 (d, J ¼ 8.0 Hz, 1H), 8.00 (d, J ¼ 6.9
Hz, 1H), 7.77–7.62 (m, 5H), 7.48 (d, J ¼ 7.7, 2H), 6.60 (d, J ¼ 6.60,
1H), 3.10–3.01 (m, 1H), 2.45 (s, 3H), 1.36 (s, 3H), 1.34 (s, 3H)
ppm; 13C-NMR (CDCl3, 75 MHz): d 153.2, 150.6, 150.3, 148.2,
147.7, 145.3, 141.7, 136.0, 129.7, 128.9, 128.8, 127.4, 126.5,
126.4, 122.8, 121.6, 120.5, 116.3, 114.8, 31.8, 24.1, 21.9 ppm;
HRMS (ESI) calculated for [M + H]+: C24H22N3: 352.1814, actual:
352.1839.
6-(4-Bromo-phenyl)-9-methyl-5,6b,11-triaza-benzo[a]uorene (9l).
The title compound was obtained according to general procedure
3 as a white solid. Yield: 0.32 g, 86%; mp: 218–221 ꢀC; IR (KBr): n
1384, 1651, 3023 cmꢁ1; 1H-NMR (CDCl3, 300 MHz): d 8.80 (d, J ¼
7.5 Hz, 1H), 8.30 (d, J ¼ 7.6 Hz, 1H), 7.99 (d, J ¼ 7.0 Hz, 1H), 7.82–
7.63 (m, 7H), 6.70 (d, J ¼ 7.2, 1H), 2.52 (s, 3H) ppm; 13C-NMR
(CDCl3, 75 MHz): d 150.5, 150.1, 148.1, 147.6, 145.1, 141.5, 135.8,
129.5, 128.7, 127.3, 126.3, 126.2, 122.6, 121.4, 120.4, 116.1, 114.6,
21.7 ppm; HRMS (ESI) calculated for [M + H]+: C21H15BrN3:
388.0449, actual: 388.0468.
6-(4-N,N-Dimethylamino-phenyl)-9-methyl-5,6b,11-triaza-benzo-
[a]uorene (9m). The title compound was obtained according to
general procedure 3 as a yellow solid. Yield: 0.25 g, 75%; mp:
235–238 ꢀC; IR (KBr): n 1384, 1610, 3019 cmꢁ1; 1H-NMR (CDCl3,
300 MHz): d 8.77 (d, J ¼ 7.6 Hz, 1H), 8.30–8.23 (m, 2H), 7.79–7.61
(m, 5H), 6.95 (d, J ¼ 8.2 Hz, 2H), 6.66 (d, J ¼ 6.3 Hz, 1H), 3.11 (s,
6H), 2.50 (s, 3H) ppm; 13C-NMR (CDCl3, 50 MHz): d 151.3, 150.1,
148.7, 147.6, 145.3, 141.4, 131.0, 129.9, 128.9, 128.6, 126.6,
125.9, 122.6, 121.3, 120.7, 116.1, 114.5, 112.5, 40.5, 21.8 ppm;
HRMS (ESI) calculated for [M + H]+: C23H21N4: 353.1766, actual:
353.1760.
compound was obtained according to general procedure 3 as a
black solid. Yield: 0.28 g, 75%; mp: 216–219 ꢀC; IR (KBr): n 1384,
1
1640, 3019 cmꢁ1; H-NMR (CDCl3, 300 MHz): d 8.75 (d, J ¼ 7.8
Hz, 1H), 8.50 (d, J ¼ 6.6 Hz, 1H), 8.31 (d, J ¼ 8.2 Hz, 1H), 7.88 (d,
J ¼ 8.9 Hz, 1H), 7.81 (t, J ¼ 7.4 Hz, 1H), 7.71 (t, J ¼ 7.4 Hz, 1H),
7.51 (t, J ¼ 7.0 Hz, 1H), 6.81 (t, J ¼ 6.6 Hz, 1H), 4.73 (s, 2H), 4.51
(s, 2H), 4.47 (s, 5H) ppm; 13C-NMR (CDCl3, 75 MHz): d 149.2,
146.3, 145.2, 139.2, 129.5, 129.4, 128.5, 127.8, 126.1, 122.5,
122.0, 121.3, 117.7, 111.3, 87.2, 70.6, 70.3, 68.7, ppm; HRMS
(ESI) calculated for [M + H]+: C24H18FeN3: 404.0850, actual:
404.0844.
6-(Phenyl)-9-methyl-5,6b,11-triaza-benzo[a]uorene (9f). The
title compound was obtained according to general procedure 3
as an orange solid. Yield: 0.24 g, 82%; mp: 217–220 ꢀC; IR (KBr):
1
n 1384, 1485, 1652, 3019 cmꢁ1; H-NMR (CDCl3, 300 MHz): d
8.78 (d, J ¼ 6.4 Hz, 1H), 8.29 (d, J ¼ 6.2 Hz, 1H), 7.90 (d, J ¼ 5.7,
1H), 7.78–7.62 (m, 8H), 6.61 (d, J ¼ 5.8, 1H), 2.47 (s, 3H) ppm;
13C-NMR (CDCl3, 50 MHz): d 150.3, 148.0, 147.7, 145.1, 141.7,
138.5, 129.6, 129.4, 128.9, 126.4, 126.3, 122.8, 121.6, 120.4,
116.3, 114.8, 21.8 ppm; HRMS (ESI) calculated for [M + H]+:
C
21H16N3: 310.1344, actual: 310.1339.
6-(4-Nitro-phenyl)-9-methyl-5,6b,11-triaza-benzo[a]uorene (9g).
The title compound was obtained according to genꢀeral procedure
3 as a yellow solid. Yield: 0.31 g, 92%; mp: >250 C; IR (KBr): n
1384, 1653, 2924 cmꢁ1; 1H-NMR (CDCl3, 400 MHz): d 8.79 (d, J ¼
7.8 Hz, 1H), 8.52 (d, J ¼ 8.4 Hz, 2H), 8.27 (d, J ¼ 8.2, 1H), 7.98 (d, J
¼ 8.4, 2H), 7.88 (d, J ¼ 7.0, 1H), 7.83 (t, J ¼ 7.2, 1H), 7.76 (t, J ¼ 7.5,
1H), 7.69 (s, 1H), 6.68 (d, J ¼ 7.0, 1H), 2.50 (s, 3H) ppm; 13C-NMR
(CDCl3, 50 MHz): compound is too insoluble to record a carbon
NMR spectrum; HRMS (ESI) calculated for [M + H]+: C21H15N4O2:
355.1195, actual: 355.1193.
6-(2-Nitro-phenyl)-9-methyl-5,6b,11-triaza-benzo[a]uorene (9h).
The title compound was obtained according to genꢀeral procedure
3 as a yellow solid. Yield: 0.26 g, 77%; mp: >250 C; IR (KBr): n
1389, 1648, 3021 cmꢁ1; 1H-NMR (CDCl3, 400 MHz): d 8.80 (d, J ¼
8.1 Hz, 1H), 8.35 (d, J ¼ 8.1 Hz, 1H), 8.20 (d, J ¼ 8.0 Hz, 1H), 7.90
(t, J ¼ 7.4 Hz, 1H), 7.83–7.66 (m, 5H), 7.53 (d, J ¼ 7.0, 1H), 6.62 (d,
J ¼ 6.9, 1H), 2.48 (s, 3H) ppm; 13C-NMR (CDCl3, 75 MHz): d 150.4,
148.2, 147.1, 144.7, 144.2, 143.3, 134.7, 132.9, 131.8, 131.3, 129.5,
129.0, 127.4, 125.5, 125.3, 122.8, 121.6, 120.8, 116.2, 21.9 ppm;
HRMS (ESI) calculated for [M + H]+: C21H15N4O2: 355.1195,
actual: 355.1236.
6-(4-Methoxy-phenyl)-9-methyl-5,6b,11-triaza-benzo[a]uorene
(9n). The title compound was obtained according to general
procedure 3 as a brown solid. Yield: 0.25 g, 78%; mp: >250 ꢀC; IR
6-(3-Nitro-phenyl)-9-methyl-5,6b,11-triaza-benzo[a]uorene (9i).
The title compound was obtained according to general
1
(KBr): n 1215, 1390, 1507, 1609, 3020 cmꢁ1; H-NMR (CDCl3,
300 MHz): d 8.64 (d, J ¼ 7.5 Hz, 1H), 8.26 (d, J ¼ 8.1 Hz, 1H),
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 26757–26770 | 26765

View Article Online
RSC Advances
Paper
7.75–7.64 (m, 4H), 7.46 (s, 1H), 7.12 (d, J ¼ 8.5, 2H), 6.87 (d, J ¼ 131.3, 129.8, 129.6, 128.8, 128.6, 127.3, 127.0, 126.6, 125.9,
8.5, 1H), 6.06 (d, J ¼ 8.5, 1H), 3.94 (s, 3H), 2.38 (s, 3H) ppm; 13C- 124.8, 122.7, 121.7, 116.1, 114.8, 21.7 ppm; HRMS (ESI) calcu-
NMR (CDCl3, 75 MHz): d 160.9, 157.6, 150.5, 146.5, 144.2, 134.9, lated for [M + H]+: C25H18N3: 360.1501, actual: 360.1492.
133.1, 131.2, 131.0, 129.2, 128.3, 127.1, 126.5, 124.2, 123.9,
122.1, 120.8, 116.2, 114.4, 55.7, 21.0 ppm; HRMS (ESI) calcu-
lated for [M + H]+: C22H18N3O: 340.1540, actual: 340.1543.
General procedure 4
4-(9-Methyl-5,6b,11-triaza-benzo[a]uoren-6-yl)-phenol
(9o).
Synthesis of 5,6-dihydro-5,6b,11-triaza-benzo[a]uorene
The title compound was obtained according to general proce- (11a–f). To a solution of Pictet–Spengler substrate (6 or 7) (0.96
dure 3 as a white solid. Yield: 0.22 g, 72%; mp: >250 ꢀC; IR (KBr): mmol) in water (1.5 mL), each one of the desired acetophenones
1
n 1384, 1650, 3019, 3416 cmꢁ1; H-NMR (CDCl3, 300 MHz): d (10a–e) (1.0 eq.) was added followed by addition of TBAB (2.0
10.78 (s, 1H), 9.44 (d, J ¼ 9.0 Hz, 1H), 8.94 (d, J ¼ 6.0 Hz, 2H), eq.). The reaction mixture was stirred for 15 minutes followed
8.59–8.51 (m, 3H), 8.42 (d, J ¼ 9.0, 2H), 7.85 (d, J ¼ 6.0, 2H), 7.77 by addition of cyanuric chloride (0.14 mmol, 15 mol%) at 80 ꢀC.
(d, J ¼ 9.0, 1H), 3.31 (s, 3H) ppm; 13C-NMR (CDCl3, 50 MHz): The reaction was allowed to run for 1.5 h. Aer completion
compound is too insoluble to record a carbon NMR spectrum; (monitored by TLC), the reaction mixture was poured into water
HRMS (ESI) calculated for [M + H]+: C21H16N3O: 326.1293, and extracted with ethyl acetate (20 mL ꢂ 3). The combined
actual: 326.1329.
organic layers were washed with brine solution and dried over
6-(3,4,5-Trimethoxy-phenyl)-9-methyl-5,6b,11-triaza-benzo[a]- anhydrous Na2SO4. The crude product was puried by column
uorene (9p). The title compound was obtained according to chromatography using 60–120 mesh silica gel with 1% MeOH–
general procedure 3 as a beige solid. Yield: 0.30 g, 79%; mp: 212– CHCl3 as eluent to obtain a good to excellent yield of the Pictet–
214 ꢀC; IR (KBr): n 1215, 1325, 1385, 1464, 1586, 1651, 3019 cmꢁ1
;
Spengler products 11a–f.
6-Methyl-6-(phenyl)-5,6-dihydro-5,6b,11-triaza-benzo[a]uorene
1H-NMR (CDCl3, 300 MHz): d 8.78 (d, J ¼ 7.6 Hz, 1H), 8.30 (d, J ¼
7.5 Hz, 1H), 7.99 (d, J ¼ 6.8 Hz, 1H), 7.78–7.68 (m, 3H), 6.91 (s, (11a). The title compound was obtained according to general
2H), 6.67 (d, J ¼ 6.6, 1H), 3.96 (s, 3H), 3.90 (s, 6H), 2.50 (s, 3H) procedure 4 as a gray solid. Yield: 0.24 g, 82%; mp: 245–247 ꢀC;
ppm; 13C-NMR (CDCl3, 50 MHz): d 154.2, 153.4, 150.3, 147.7, IR (KBr): n 1384, 1620, 3019, 3412 cmꢁ1; H-NMR (CDCl3, 300
1
145.0, 141.8, 139.1, 133.9, 129.6, 128.8, 126.5, 122.7, 121.6, 120.2, MHz): d 7.96 (d, J ¼ 7.1 Hz, 1H), 7.65–7.59 (m, 3H), 7.37 (br, 3H),
116.3, 114.8, 105.8, 61.2, 56.5, 21.9 ppm; HRMS (ESI) calculated 7.20 (d, J ¼ 6.4, 1H), 7.08 (br, 2H), 6.82 (t, J ¼ 7.1, 1H), 6.52 (d, J
for [M + H]+: C24H22N3O3: 400.1661, actual: 400.1652.
¼ 5.9, 2H), 4.25 (s, 1H), 2.04 (s, 3H) ppm; 13C-NMR (CDCl3, 50
6-(4-Flouro-phenyl)-9-methyl-5,6b,11-triaza-benzo[a]uorene (9q). MHz): d 145.8, 143.9, 141.7, 139.2, 137.4, 129.1, 128.9, 128.2,
The title compound was obtained according to general procedure 3 126.9, 124.4, 123.3, 123.0, 120.3, 118.0, 116.9, 115.0, 114.1,
as a beige solid. Yield: 0.26 g, 83%; mp: 175–177 ꢀC; IR (KBr) 1504, 113.0, 112.4, 58.8, 25.7 ppm; HRMS (EI) calculated for [M + H]+:
1653, 3026 cmꢁ1; 1H-NMR (CDCl3, 300 MHz): d 8.79 (d, J ¼ 7.8 Hz,
1H), 8.30 (d, J ¼ 8.0 Hz, 1H), 7.94 (d, J ¼ 6.9 Hz, 1H), 7.83–7.71 (m,
C
21H18N3: 312.1501, actual: 312.1507.
6-Methyl-6-(4-nitro-phenyl)-5,6-dihydro-5,6b,11-triaza-benzo[a]-
5H), 7.38 (t, J ¼ 8.4, 2H), 6.67 (d, J ¼ 6.3, 1H), 2.51 (s, 3H) ppm; 13C- uorene (11b). The title compound was obtained according to
NMR (CDCl3, 50 MHz): d 150.3, 147.6, 146.8, 145.0, 142.0, 136.3, general procedure 4 as a gray solid. Yield: 0.29 g, 86%; mp: >250
134.5, 130.9, 130.8, 144.7, 141.9, 129.5, 128.9, 126.8, 125.7, 123.5, ꢀC; IR (KBr): n 1384, 1622, 3019, 3409 cmꢁ1; 1HNMR (CDCl3, 300
122.6, 121.5, 119.6, 116.2, 115.0, 21.7 ppm; HRMS (ESI) calculated MHz): d 8.23 (d, J ¼ 9.0 Hz, 2H), 7.97 (d, J ¼ 7.2 Hz, 1H), 7.78 (d, J
for [M + H]+: C21H15FN3: 328.1250, actual: 328.1244.
¼ 8.2, 2H), 7.68 (d, J ¼ 9.2, 1H), 7.24 (d, J ¼ 7.2, 1H), 7.16–7.09
6-(4-Pyridyl)-9-methyl-5,6b,11-triaza-benzo[a]uorene (9r). The (m, 2H), 6.89 (t, J ¼ 7.2, 1H), 6.61 (t, J ¼ 8.2, 2H), 4.27 (s, 1H),
title compound was obtained according to general procedure 3 2.16 (s, 3H) ppm; 13C-NMR (CDCl3 + deuterated methanol
as a brown solid. Yield: 0.24 g, 82%; mp: 217–219 ꢀC; IR (KBr): n (CD3OD), 50 MHz): d 157.4, 151.7, 150.9, 147.6, 142.9, 133.9,
1384, 1653, 3019 cmꢁ1; 1H-NMR (CDCl3, 300 MHz): d 8.91 (d, J ¼ 132.5, 129.4, 129.1, 128.9, 127.2, 124.2, 121.9, 121.7, 119.9,
5.2 Hz, 2H), 8.74 (d, J ¼ 7.8 Hz, 1H), 8.24 (d, J ¼ 8.1 Hz, 1H), 7.89 117.9, 117.6, 63.3, 30.9 ppm; HRMS (ESI) calculated for [M + H]+:
(d, J ¼ 7.0 Hz, 1H), 7.80–7.68 (m, 4H), 7.61 (s, 1H), 6.61 (d, J ¼
C
21H17N4O2: 357.1352, actual: 357.1360.
7.0, 1H), 2.45 (s, 3H) ppm; 13C-NMR (CDCl3, 75 MHz): d 150.7,
6-Methyl-6-(4-methoxy-phenyl)-5,6-dihydro-5,6b,11-triaza-benzo-
150.1, 147.7, 146.2, 144.8, 144.7, 141.9, 129.5, 128.9, 126.8, [a]uorene (11c). The title compound was obtained according to
125.7, 123.5, 122.6, 121.5, 119.6, 116.2, 115.0, 21.7 ppm; HRMS general procedure 4 as a gray solid. Yield: 0.26 g, 82%; mp: 248–
(ESI) calculated for [M + H]+: C20H15N4: 311.1297, actual: 251 ꢀC; IR (KBr): n 1217, 1384, 1622, 3019, 3409 cmꢁ1, 1H-NMR
311.1266.
(CDCl3, 300 MHz): d 7.96 (d, J ¼ 7.0 Hz, 1H), 7.68 (d, J ¼ 8.1 Hz,
6-(1-Naphthyl)-9-methyl-5,6b,11-triaza-benzo[a]uorene (9s). 1H), 7.54 (d, J ¼ 7.0, 2H), 7.21 (d, J ¼ 6.4, 1H), 7.09 (d, J ¼ 7.0,
The title compound was obtained according to general proce- 2H), 6.90 (d, J ¼ 7.0, 2H), 6.82 (t, J ¼ 7.0, 1H), 6.54 (t, J ¼ 6.5, 2H),
dure 3 as a beige solid. Yield: 0.30 g, 87%; mp: 239–241 C; IR 4.15 (s, 1H), 3.79 (s, 3H), 2.00 (s, 3H) ppm; 13C-NMR (CDCl3 +
ꢀ
(KBr): n 1387, 1504, 1653, 3026 cmꢁ1 1H-NMR (CDCl3, 300 CD3OD, 50 MHz): d 163.6, 149.8, 147.7, 143.6, 141.6, 141.4, 136.1,
;
MHz): d 8.85 (d, J ¼ 7.0 Hz, 1H), 8.35 (d, J ¼ 7.8 Hz, 1H), 8.12 (d, J 133.9, 132.7, 129.6, 128.7, 127.8, 127.0, 125.4, 121.2, 120.9, 119.1,
¼ 7.5 Hz, 1H), 8.02 (d, J ¼ 8.4 Hz, 1H), 7.84–7.69 (m, 4H), 7.64 (s, 118.6, 117.8, 117.5, 62.6, 59.9, 27.2 ppm; HRMS (ESI) calculated
1H), 7.55 (t, J ¼ 7.1, 1H), 7.43 (d, J ¼ 8.1, 1H), 7.34 (t, J ¼ 7.2, 1H), for [M + H]+: C22H20N3O: 342.1606, actual: 342.1617.
7.11 (d, J ¼ 6.9, 1H), 6.37 (d, J ¼ 6.6, 1H), 2.40 (s, 3H) ppm; 13C-
6-Methyl-6-(4-bromo-phenyl)-5,6-dihydro-5,6b,11-triaza-benzo-
NMR (CDCl3, 50 MHz): d 150.2, 146.6, 145.2, 141.7, 135.3, 133.7, [a]uorene (11d). The title compound was obtained according to
26766 | RSC Adv., 2014, 4, 26757–26770
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
general procedure 4 as a brown solid. Yield: 0.31 g, 84%; mp: ppm; 13C-NMR (CDCl3, 50 MHz): d 180.4, 151.2, 147.9, 146.3,
>250 ꢀC; IR (KBr): n 1384, 1650, 3019, 3412 cmꢁ1 1H-NMR 144.8, 143.8, 135.3, 134.8, 133.7, 130.7, 129.4, 127.9, 127.7,
;
(CDCl3, 300 MHz): d 8.03 (d, J ¼ 6.7 Hz, 1H), 7.87 (d, J ¼ 8.6 Hz, 127.1, 121.9, 119.5, 119.3, 118.5, 118.0, 117.7, 115.6, 68.2 ppm;
1H), 7.50 (br, 3H), 7.28 (br, 3H), 7.13 (t, J ¼ 6.7, 1H), 6.84 (t, J ¼ HRMS (ESI) calculated for [M + H]+: C21H15N4O: 339.1246,
7.7, 1H), 6.75 (t, J ¼ 6.7, 1H), 6.60 (d, J ¼ 8.6, 1H), 4.50 (s, 1H), actual: 339.1247.
2.07 (s, 3H) ppm; 13C-NMR (CDCl3, 50 MHz): compound is
6-Spiro-indol-2(N-ethyl)-one-5,6-dihydro-5,6b,11-triaza-benzo-
insoluble and a carbon NMR spectrum could not be recorded; [a]uorine (13b). The title compound was obtained according to
HRMS (ESI) calculated for [M + H]+: C21H17BrN3: 390.0606, general procedure 5 as a yellow solid. Yield: 0.24 g, 69%; mp:
1
228–230 C; IR (KBr): n 1384, 1611, 1721, 3019 cmꢁ1; H-NMR
ꢀ
actual: 390.0608.
6-Methyl-6-(phenyl)-5,6-dihydro-9-methyl-5,6b,11-triaza-benzo- (CDCl3, 300 MHz): d 7.95 (d, J ¼ 7.3 Hz, 1H), 7.62 (d, J ¼ 9.0 Hz,
[a]uorene (11e). The title compound was obtained according to 1H), 7.43–7.38 (m, 2H), 7.12–7.00 (m, 4H), 6.88 (m, 2H), 6.61 (d,
general procedure 4 as a brown solid. Yield: 0.27 g, 88%; mp: J ¼ 7.8 Hz, 1H), 6.52 (t, J ¼ 6.7 Hz, 1H), 4.55 (s, 1H), 3.94–3.73
1
210–213 C; IR (KBr): n 1384, 1651, 3019, 3411 cmꢁ1; H-NMR (m, 2H), 1.37 (t, J ¼ 7.1, 3H) ppm; 13C-NMR (CDCl3, 50 MHz): d
ꢀ
(CDCl3, 400 MHz): d 7.93 (d, J ¼ 7.7 Hz, 1H), 7.60 (d, J ¼ 7.7 Hz, 173.5, 146.8, 141.5, 141.4, 140.4, 130.8, 129.0, 126.2, 124.3,
2H), 7.37–7.28 (m, 4H), 7.07 (d, J ¼ 7.1, 2H), 6.81 (t, J ¼ 7.1, 1H), 123.9, 123.0, 122.5, 118.8, 117.5, 115.5, 113.2, 113.0, 112.6,
6.51 (d, J ¼ 8.2, 1H), 6.34 (d, J ¼ 6.6, 1H), 4.24 (s, 1H), 2.29 (s, 109.0, 63.3, 35.1, 12.7 ppm; HRMS (ESI) calculated for [M + H]+:
3H), 2.03 (s, 3H) ppm; 13C-NMR (CDCl3, 100 MHz): d 146.4,
C
23H19N4O: 367.1559, actual: 367.1552.
144.2, 141.6, 137.3, 135.3, 128.8, 128.1, 126.9, 122.8, 122.5,
6-Spiro-indol-2(N-methyl)-one-5,6-dihydro-9-methyl-5,6b,11-tri-
119.8, 117.9, 115.5, 114.8, 112.9, 58.8, 25.8, 21.2 ppm; HRMS aza-benzo[a]uorine (13c). The title compound was obtained
(ESI) calculated for [M + H]+: C22H20N3: 326.1657, actual: according to general procedure 5 as a yellow solid. Yield: 0.25 g,
326.1672.
72%; mp: >250 ꢀC; IR (KBr): n 1385, 1617, 1719, 3020 cmꢁ1; 1H-
6-Methyl-6-(2-thiophenyl)-5,6-dihydro-5,6b,11-triaza-benzo[a]- NMR (CDCl3, 300 MHz): d 7.92 (d, J ¼ 7.3 Hz, 1H), 7.42–7.35 (m,
uorene (11f). The title compound was obtained according to 3H), 7.07 (br, 2H), 6.99 (d, J ¼ 7.7 Hz, 1H), 6.87 (t, J ¼ 7.3, 1H),
general procedure 4 as a yellow solid. Yield: 0.25 g, 83%; mp: 6.69 (d, J ¼ 6.8 Hz, 1H), 6.60 (d, J ¼ 6.9 Hz, 1H), 6.35 (d, J ¼ 6.9
1
187–189 C; IR (KBr): n 1384, 1653, 3019, 3408 cmꢁ1; H-NMR Hz, 1H), 4.68 (s, 1H), 3.26 (s, 3H), 2.29 (s, 3H) ppm; 13C-NMR
ꢀ
(CDCl3, 300 MHz): d 7.98 (d, J ¼ 7.2 Hz, 1H), 7.68 (d, J ¼ 8.8 Hz, (CDCl3, 75 MHz): d 174.2, 147.1, 142.6, 141.3, 139.9, 136.0,
1H), 7.44 (d, J ¼ 6.4 Hz, 1H), 7.35 (d, J ¼ 4.6 Hz, 1H), 7.17–7.08 131.0, 129.1, 129.0, 126.0, 124.2, 123.2, 121.9, 119.1, 115.9,
(m, 3H), 7.02 (br, 1H), 6.88 (t, J ¼ 7.2, 1H), 6.60 (d, J ¼ 7.5, 2H), 115.6, 113.3, 112.4, 109.0, 63.4, 26.6, 21.3 ppm; HRMS (ESI)
4.43 (s, 1H), 2.09 (s, 3H) ppm; 13C-NMR (CDCl3, 100 MHz): d calculated for [M + H]+: C23H19N4O: 367.1559, actual: 367.1550.
150.1, 146.2, 141.2, 137.4, 129.0, 127.3, 126.5, 124.8, 124.4,
6-Spiro-indol-2(N-ethyl)-one-5,6-dihydro-9-methyl-5,6b,11-tri-
123.3, 122.9, 119.8, 118.5, 117.1, 115.6, 113.3, 112.4, 59.9, 27.4 aza-benzo[a]uorine (13d). The title compound was obtained
ppm; HRMS (ESI) calculated for [M + H]+: C19H16N3S: 318.1065, according to general procedure 5 as a yellow solid. Yield: 0.24 g,
actual: 318.1080.
68%; mp: 232–234 ꢀC; IR (KBr): n 1386, 1622, 1718, 3020 cmꢁ1
;
1H-NMR (CDCl3, 300 MHz): d 7.91 (d, J ¼ 7.3 Hz, 1H), 7.41–7.35
(m, 3H), 7.07–6.98 (m, 3H), 6.86 (t, J ¼ 7.3 Hz, 1H), 6.74 (d, J ¼
6.7 Hz, 1H), 6.60 (d, J ¼ 7.8 Hz, 1H), 6.34 (d, J ¼ 6.4 Hz, 1H), 4.65
General procedure 5
Synthesis of spirooxyindoles (13a–d). To a solution of Pictet– (s, 1H), 3.90–3.72 (m, 2H), 2.28 (s, 3H), 1.35 (t, J ¼ 6.9 Hz, 1H),
Spengler substrate (6 or 7) (0.96 mmol) in water (1.5 mL), ppm; 13C-NMR (CDCl3, 75 MHz): d 173.6, 147.3, 141.4, 140.1,
indoline-2,3-dione or N-substituted indoline-2,3-dione (1.0 eq.) 135.4, 130.7, 129.4, 128.8, 126.1, 123.8, 123.0, 121.7, 118.7,
was added followed by addition of TBAB (2.0 eq.). The reaction 116.0, 115.7, 115.2, 113.2, 112.5, 109.0, 63.4, 35.0, 21.2, 12.7
mixture was stirred for 15 minutes followed by addition of ppm; HRMS (ESI) calculated for [M + H]+: C24H21N4O: 381.1715,
cyanuric chloride (0.19 mmol, 20 mol%) at 90 ꢀC. The reaction actual: 381.1719.
was allowed to run for 3.0 h. The progress of the reaction was
monitored by TLC. Aer completion, the reaction mixture was
General procedure 6
poured into water and was extracted with ethyl acetate (20 mL ꢂ
5). The combined organic layers were washed with saturated
Synthesis of 6-(phenyl)-(11-S)-5,6b,12-triaza-benzo[a]uo-
brine solution and dried over anhydrous Na2SO4. The crude renes (21a–f). To a solution of Pictet–Spengler substrate (19 or
product was puried by column chromatography using 60–120 20) (0.96 mmol) in water (1.5 mL), each one of the desired
mesh silica gel with 3% MeOH–CHCl3 as eluent to obtain a good aromatic aldehydes (1.0 eq.) was added followed by addition of
yield of the Pictet–Spengler product (13a–d).
TBAB (2.0 eq.). The reaction mixture was stirred for 15 minutes
6-Spiro-indol-2(1H)-one-5,6-dihydro-5,6b,11-triaza-benzo[a]- followed by addition of cyanuric chloride (0.15 mmol, 20 mol%)
uorine (13a). The title compound was obtained according to at 90 ꢀC. The reaction was allowed to run for 2.0 h. Aer
general procedure 5 as a yellow solid. Yield: 0.21 g, 66%; mp: completion (monitored by TLC), the reaction mixture was
244–246 ꢀC; IR (KBr): n 1384, 1639, 1724, 3019, 3417 cmꢁ1; 1H- poured into water and extracted with ethyl acetate (20 mL ꢂ 3).
NMR (CDCl3, 300 MHz): d 10.50 (s, 1H), 7.83 (s, 1H), 7.71 (d, J ¼ The combined organic layers were washed with brine solution,
7.4 Hz, 1H), 7.50 (d, J ¼ 9.0 Hz, 1H), 7.29–7.21 (m, 2H), 7.10 (t, J dried over anhydrous Na2SO4, concentrated under reduced
¼ 7.5, 1H), 6.98 (br, 4H), 6.65 (t, J ¼ 7.5, 1H), 6.58 (t, J ¼ 6.8, 1H) pressure and the crude product was puried by column
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 26757–26770 | 26767

View Article Online
RSC Advances
Paper
chromatography using 60–120 mesh silica gel using 30% ethyl
acetate–hexane as eluent to obtain a good yield of the Pictet–
Spengler products (21a–f).
6-(4-Bromo-phenyl)-7-methyl-(11-S)-5,6b,12-triaza-benzo[a]uo-
rene (21f). The title compound was obtained according to
general procedure 6 as a beige solid. Yield: 0.25 g, 78%; mp:
>250 ꢀC; IR (KBr): n 1384, 1645, 3019 cmꢁ1; 1H-NMR (CDCl3, 300
MHz): d 8.65 (d, J ¼ 7.8 Hz, 1H), 8.25 (d, J ¼ 8.0 Hz, 1H), 7.75–
7.66 (m, 4H), 7.63 (d, J ¼ 7.7, 2H), 7.49 (s, 1H), 6.92 (d, J ¼ 8.4,
1H), 6.01 (d, J ¼ 8.4, 1H), 2.40 (s, 3H) ppm; 13C-NMR (CDCl3, 100
MHz): d 158.1, 150.9, 148.0, 145.4, 144.4, 139.6, 135.4, 132.3,
131.6, 131.2, 129.5, 128.7, 127.3, 127.0, 124.3, 124.1, 124.0,
122.2, 121.0, 115.9, 21.3 ppm; HRMS (ESI) calculated for [M +
H]+: C23H15BrN3S: 444.0170, actual: 444.0236.
6-(Phenyl)-(11-S)-5,6b,12-triaza-benzo[a]uorine (21a). The
title compound was obtained according to general procedure 6
as an orange solid. Yield: 0.19 g, 76%; mp: 175–177 ꢀC; IR (KBr):
n 1384, 1653, 3019 cmꢁ1; 1H-NMR (CDCl3, 300 MHz): d 8.67 (d, J
¼ 7.8 Hz, 1H), 8.29 (d, J ¼ 8.1 Hz, 1H), 7.78–7.59 (m, 8H), 7.25 (s,
1H), 7.01 (t, J ¼ 7.9, 1H), 5.96 (d, J ¼ 8.4, 1H) ppm; 13C-NMR
(CDCl3, 75 MHz): d 158.0, 150.8, 146.9, 144.4, 140.8, 133.4,
129.8, 129.7, 129.5, 129.3, 129.2, 128.6, 126.9, 126.3, 124.9,
124.0, 122.2, 121.0, 116.5 ppm; HRMS (ESI) calculated for [M +
H]+: C22H14N3S: 352.0908, actual: 352.0926.
General procedure 7
6-(4-Nitro-phenyl)-(11-S)-5,6b,12-triaza-benzo[a]uorene (21b).
The title compound was obtained according to general proce-
Synthesis of 6-(phenyl)-5,6-dihydro-(11-S)-5,6b,12-triaza-
dure 6 as a brown solid. Yield: 0.24 g, 83%; mp: 175–177 ꢀC; IR benzo[a]uorines (22a–c). To a solution of Pictet–Spengler
(KBr): n 1348, 1521, 1654, 3019 cmꢁ1 1H-NMR (CDCl3, 300 substrate (19 or 20) (0.96 mmol) in water (1.5 mL), each one of
;
MHz): d 8.68 (d, J ¼ 7.6 Hz, 1H), 8.48 (d, J ¼ 8.1 Hz, 2H), 8.26 (d, J the acetophenones (10a–c) (1.0 eq.) was added followed by
¼ 7.8 Hz, 1H), 7.98 (d, J ¼ 8.1 Hz, 2H), 7.81–7.71 (m, 3H), 7.33 (t, addition of TBAB (2.0 eq.). The reaction mixture was stirred for
J ¼ 7.4, 1H), 7.09 (t, J ¼ 8.5, 1H), 6.15 (d, J ¼ 8.6 Hz, 1H) ppm; 15 minutes followed by addition of cyanuric chloride (0.15
13C-NMR (CDCl3, 75 MHz): d 158.5, 151.4, 148.6, 146.8, 144.5, mmol, 20 mol%) at 80 C. The reaction was allowed to run for
ꢀ
139.1, 133.0, 131.1, 129.6, 129.0, 127.6, 129.3, 125.3, 124.5, 2.0 h. Aer completion of the reaction (monitored by TLC), the
124.2, 123.4, 122.3, 121.1, 119.8, 115.8 ppm; HRMS (ESI) reaction mixture was poured into water and extracted with ethyl
calculated for [M
397.0805.
+
H]+: C22H13N4O2S: 397.0759, actual: acetate (20 mL ꢂ 3). The combined organic layers were washed
with brine solution and dried over anhydrous Na2SO4. The
6-(4-Methoxy-phenyl)-(11-S)-5,6b,12-triaza-benzo[a]uorene (21c). crude product was puried by column chromatography using
The title compound was obtained according to general procedure 60–120 mesh silica gel with 30% ethyl acetate–hexane as eluent
6 as a brown solid. Yield: 0.22 g, 78%; mp: 173–175 ꢀC; IR (KBr): n to get a good yield of the Pictet–Spengler product 22a–c.
1
1348, 1521, 1654, 3019 cmꢁ1; H-NMR (CDCl3, 300 MHz): d 8.63
6-Methyl-6-(phenyl)-5,6-dihydro-(11-S)-5,6b,12-triaza-benzo[a]-
(d, J ¼ 7.2 Hz, 1H), 8.26 (d, J ¼ 7.6 Hz, 1H), 7.73–7.66 (br, 5H), 7.25 uorine (22a). The title compound was obtained according to
(s, 1H), 7.11–6.85 (m, 3H), 6.20 (d, J ¼ 8.2, 1H), 3.93 (s, 3H) ppm; general procedure 7 as a brown solid. Yield: 0.20 g, 76%; mp:
13C-NMR (CDCl3, 100 MHz): d 161.0, 148.9, 148.3, 146.7, 141.7, 236–238 C; IR (KBr): n 1384, 1653, 3021, 3407 cmꢁ1; H-NMR
1
ꢀ
132.0, 131.9, 131.1, 130.8, 130.5, 128.2, 127.5, 126.4, 125.5, 124.5, (CDCl3, 300 MHz): d 7.80 (d, J ¼ 7.4 Hz, 1H), 7.63 (t, J ¼ 7.8 Hz,
123.7, 114.5, 113.1, 110.1, 55.8 ppm; HRMS (ESI) calculated for [M 3H), 7.41–7.31 (m, 3H), 7.16 (t, J ¼ 7.1, 1H), 7.04–6.94 (m, 2H),
+ H]+: C23H16N3OS: 382.1014, actual: 382.1063.
6.80 (d, J ¼ 7.3, 1H), 6.47 (d, J ¼ 8.0, 2H), 4.08 (s, 1H), 2.10 (s, 3H)
6-(4-Nitro-phenyl)-7-methyl-(11-S)-5,6b,12-triaza-benzo[a]uo- ppm; 13C-NMR (CDCl3, 75 MHz): d 149.7, 145.9, 140.2, 140.0,
rene (21d). The title compound was obtained according to 132.3, 130.3, 130.1, 130.0, 129.3, 128.4, 128.2, 128.0, 126.9,
general procedure 6 as an orange solid. Yield: 0.24 g, 79%; mp: 125.8, 124.1, 122.0, 118.0, 114.3, 112.5, 59.9, 32.1 ppm; HRMS
>250 ꢀC; IR (KBr): n 1384, 1653, 3019 cmꢁ1; 1H-NMR (CDCl3, 300 (ESI) calculated for [M + H]+: C23H18N3S: 368.1221, actual:
MHz): d 8.66 (d, J ¼ 7.7 Hz, 1H), 8.47 (d, J ¼ 8.4 Hz, 2H), 8.25 (d, J 368.1269.
¼ 7.9 Hz, 1H), 7.97 (d, J ¼ 8.4 Hz, 2H), 7.79–7.69 (m, 2H), 7.51 (s,
6-Methyl-6-(4-nitro-phenyl)-5,6-dihydro-(11-S)-5,6b,12-triaza-
1H), 6.87 (d, J ¼ 8.3, 1H), 5.98 (d, J ¼ 8.5, 1H), 2.40 (s, 3H) ppm; benzo[a]uorine (22b). The title compound was obtained
13C-NMR (CDCl3, 75 MHz): d 158.3, 151.0, 148.6, 146.7, 144.3, according to general procedure 7 as a brown solid. Yield: 0.24 g,
143.8, 135.6, 131.0, 130.8, 129.4, 128.8, 127.4, 127.2, 124.5, 78%; mp: >250 ꢀC; IR (KBr): n 1384, 1653, 3019, 3409 cmꢁ1; 1H-
124.1, 123.3, 122.2, 121.0, 115.3, 21.1 ppm; HRMS (ESI) calcu- NMR (CDCl3, 300 MHz): 8.26 (d, J ¼ 7.9 Hz, 2H), 7.81–7.76 (m,
lated for [M + H]+: C23H15N4O2S: 411.0916, actual: 411.0919.
3H), 7.65 (d, J ¼ 8.1 Hz, 1H), 7.20 (d, J ¼ 7.5, 1H), 7.07 (t, J ¼ 6.3,
6-(4-Methoxy-phenyl)-7-methyl-(11-S)-5,6b,12-triaza-benzo[a]- 2H), 6.84 (t, J ¼ 7.3, 1H), 6.50 (t, J ¼ 6.7, 2H), 4.04 (s, 1H), 2.22 (s,
uorene (21e). The title compound was obtained according to 3H) ppm; 13C-NMR (CDCl3, 75 MHz): d 152.2, 151.7, 147.3,
general procedure 6 as a brown solid. Yield: 0.23 g, 79%; mp: 140.4, 139.6, 131.9, 130.1, 128.5, 127.7, 126.1, 125.9, 124.5,
>250 ꢀC; IR (KBr): n 1387, 1647, 3022 cmꢁ1; 1H-NMR (CDCl3, 300 122.3, 122.1, 121.0, 118.9, 118.4, 113.6, 112.5, 59.6, 32.0 ppm;
MHz): d 8.64 (d, J ¼ 7.5 Hz, 1H), 8.26 (d, J ¼ 8.1 Hz, 1H), 7.75– HRMS (ESI) calculated for [M + H]+: C23H17N4O2S: 413.1072,
7.60 (m, 4H), 7.46 (s, 1H), 7.11 (d, J ¼ 8.5, 2H), 6.87 (d, J ¼ 8.5, actual: 413.1128.
1H), 6.05 (d, J ¼ 8.5, 1H), 3.94 (s, 3H), 2.37 (s, 3H) ppm; 13C-NMR
6-Methyl-6-(4-methoxy-phenyl)-5,6-dihydro-(11-S)-5,6b,12-tri-
(CDCl3, 100 MHz): d 160.9, 157.7, 150.5, 146.5, 144.2, 134.9, aza-benzo[a]uorine (22c). The title compound was obtained
133.1, 131.2, 131.1, 129.2, 128.3, 127.1, 126.5, 124.2, 123.9, according to general procedure 7 as a brown solid. Yield: 0.22 g,
122.1, 120.8, 116.2, 114.4, 55.7, 21.0 ppm; HRMS (ESI) calcu- 74%; mp: 246–247 ꢀC; IR (KBr): n 1384, 1653, 3019, 3407 cmꢁ1
;
lated for [M + H]+: C24H18N3OS: 396.1171, actual: 396.1171.
1H-NMR (CDCl3, 400 MHz): d 7.78 (d, J ¼ 7.7 Hz, 1H), 7.58 (d, J ¼
26768 | RSC Adv., 2014, 4, 26757–26770
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
8.3 Hz, 1H), 7.52 (d, J ¼ 8.9 Hz, 1H), 7.15 (t, J ¼ 7.2, 1H), 7.02 (t, J
¼ 7.7, 2H), 6.89 (d, J ¼ 8.3, 1H), 6.77 (t, J ¼ 7.8, 1H), 6.54 (d, J ¼
8.3, 1H), 6.44 (d, J ¼ 8.4, 1H), 3.77 (s, 3H), 2.06 (s, 3H) ppm; 13C-
NMR (CDCl3, 75 MHz): d 159.4, 149.6, 140.1, 138.3, 132.3, 130.3,
130.1, 130.0, 129.8, 128.1, 128.0, 125.9, 124.1, 121.9, 117.8,
115.8, 114.5, 112.4, 59.4, 55.4, 32.0 ppm; HRMS (ESI) calculated
for [M + H]+: C24H20N3OS: 398.1327, actual: 398.1380.
D. C. Mohan, S. N. Rao and S. Adimurthy, J. Org. Chem.,
2013, 78, 1266–1272; (e) C. Enguehard, F. Fauvelle,
J. Debouzy, A. Peinnequin, I. Thery, V. Dabouis and
A. Gueiffier, Eur. J. Pharm. Sci., 2005, 24, 219–227; (f)
H. D. Langtry and P. Beneld, Zolpidem, 1990, 40, 291–313;
(g) M. A. Ismail, R. K. Arafa, T. Wenzler, R. Brun,
F. A. Tanious, W. D. Wilson and D. W. Boykin, Bioorg. Med.
Chem., 2008, 16, 683–691.
7 (a) T. H. Al-Tel, R. A. Al-Qawasmeh and R. Zaarour, Eur. J.
Med. Chem., 2011, 46, 1874–1881; (b) A. Andreani,
M. Granaiola, A. Leoni, A. Locatelli, R. Morigi,
M. Rambaldi, L. Varoli, D. Lannigan, J. Smith, D. Scudiero,
S. Kondapaka and R. H. Shoemaker, Eur. J. Med. Chem.,
2011, 46, 4311–4323; (c) S. D. Barchechath, R. I. Tawatao,
M. Corr, D. A. Carson and H. B. Cottam, J. Med. Chem.,
2005, 48, 6409–6422.
8 J. M. Chezal, E. Moreau, O. Chavignon, C. Lartigue,
Y. Blacheb and J. C. Teulade, Tetrahedron, 2003, 59, 5869–
5878.
9 P. K. Adhikary and S. K. Das, J. Med. Chem., 1976, 19, 1352–
1354.
Acknowledgements
Two of the authors AKP and RS are thankful to CSIR, New Delhi
for Senior Research Fellowships (SRFs). We also thank SAIF
division, CSIR-CDRI for the analytical facilities. The CDRI
communication number is 8715.
References
1 (a) V. Polshettiwar and R. S. Varma, Aqueous Microwave
Assisted Chemistry, 2010, pp. 91–122; (b) Organic Synthesis
in Water, ed. P. A. Grieco, Blackie A & P, London, 1998; (c)
R. N. Butler and A. G. Coyne, Chem. Rev., 2010, 110, 6302–
6337; (d) Organic Reactions in Water, ed. U. M Lindstrom, 10 M. V. Chiesa, P. J. Zimmermann, C. Brehm, W. A. Simon,
Blackwell Publishing, Oxford, 2007; (e) F. I. McGonagle,
H. F. Sneddon, C. Jamieson and A. J. B. Watson, ACS
Sustainable Chem. Eng., 2014, 2, 523–532.
W. Kromer, S. Postius, A. Palmer and W. Buhr, Tricyclic
imidazopyridines, Patent application WO 2005/090358,
2005.
2 (a) D. G. Blackmond, A. Armstrong, V. Coombe and A. Wells, 11 (a) N. Chandaka, J. K. Bhardwaj, R. K. Sharma and
Angew. Chem., Int. Ed., 2007, 46, 3798–3800; (b) C. J. Li, Chem.
Rev., 2005, 105, 3095–3166; (c) U. M. Lindstrom, Chem. Rev.,
2002, 102, 2751–2772.
3 T. Dwars, E. Paetzold and G. Oehme, Angew. Chem., Int. Ed.,
2005, 44, 7174–7199.
4 (a) A. M. Palmer, B. Grobbel, C. Jecke, C. Brehm,
P. J. Zimmermann, W. Buhr, M. P. Feth, W. A. Simon and
W. Kromer, J. Med. Chem., 2007, 50, 6240–6264; (b)
A. Goblyos, Z. G. Gao, J. Brussee, R. Connestari,
S. N. Santiago, K. Ye, A. P. Ijzerman and K. A. Jacobson, J.
P. K. Sharma, Eur. J. Med. Chem., 2013, 59, 203–208; (b)
Q. Chao, K. G. Sprankle, R. M. Grotzfeld, A. G. Lai,
T. A. Carter, A. M. Velasco, R. N. Gunawardane,
M. D. Cramer, M. F. Gardner, J. James, P. P. Zarrinkar,
H. K. Patel and S. S. Bhagwat, J. Med. Chem., 2009, 52,
7808–7816; (c) P. K. Sahu, P. K. Sahu, S. K. Gupta,
D. Thavaselvam and D. D. Agarwal, Eur. J. Med. Chem.,
2012, 54, 366–378; (d) N. Karalıa, O. Guzel, N. Ozsoy,
S. Ozbey and A. Salman, Eur. J. Med. Chem., 2010, 45,
1068–1077.
Med. Chem., 2006, 49, 3354–3361; (c) C. M. Miller and 12 N. Amino, Y. Ideyama, M. Yamano, S. Kuromitsu, K. Tajinda,
F. O. McCarthy, RSC Adv., 2012, 2, 8883–8918; (d)
K. Samizu, A. Matsuhisa, M. Kudoh and M. Shibasaki,
R. M. Kumbhare, K. V. Kumar, M. J. Ramaiah, T. Dadmal,
Cancer Lett., 2006, 238, 119–127.
S. N. C. V. L. Pushpavalli, D. Mukhopadhyay, B. Divyab, 13 B. K. S. Yeung, B. Zou, M. Rottmann, S. B. Lakshminarayana,
T. A. Devi, U. Kosurkar and M. P. Bhadra, Eur. J. Med.
Chem., 2011, 46, 4258–4266; (e) Z. Jin, Nat. Prod. Rep., 2011,
28, 1143–1191.
5 (a) D. Izuhara and T. M. Swager, J. Am. Chem. Soc., 2009, 131,
17724–17725; (b) S. J. Kim and E. T. Kool, J. Am. Chem. Soc.,
S. H. Ang, S. Y. Leong, J. Tan, J. Wong, S. K. Maerki, C. Fischli,
A. Goh, E. K. Schmitt, P. Krastel, E. Francotte, K. Kuhen,
D. Plouffe, K. Henson, T. Wagner, E. A. Winzeler,
F. Petersen, R. Brun, V. Dartois, T. T. Diagana and
T. H. Keller, J. Med. Chem., 2010, 53, 5155–5164.
2006, 128, 6164–6171; (c) M. Zajac, P. Hrobarik, P. Magdolen, 14 (a) A. Pictet and T. Spengler, Pictet–Spengler reaction, Ber.
P. Foltınova and P. Zahradnık, Tetrahedron, 2008, 64, 10605–
10618.
6 (a) For a general review on the chemistry of imidazopyridine
Dtsch. Chem. Ges., 1911, 44, 2030–2036; (b) For reviews on
the Pictet–Spengler reaction see: J. Royer, M. Bonin and
L. Micouin, Chem. Rev., 2004, 104, 2311–2352.
derivatives, see: F. Couty and G. Evano, in Comprehensive 15 (a) E. David, S. P. Rostainga and M. Lemaire, Tetrahedron,
Heterocyclic Chemistry III, ed. A. R. Katritzky, C. A.
Ramsden, E. F. V. Scriven and R. J. K. Taylor, Elsevier,
Oxford, 2008, vol. 11, pp. 409–499, For biological activity of
imidazopyridine derivatives, see:; (b) T. Okubo,
R. Yoshikawa, S. Chaki, S. Okuyamac and A. Nakazato,
2007, 63, 8999–9006; (b) P. K. Agarwal, S. K. Sharma,
D. Sawant and B. Kundu, Tetrahedron, 2009, 65, 1153–
1161; (c) D. Bonnet and A. Ganesan, J. Comb. Chem., 2002,
4, 546–548; (d) D. J. Cheng, H. B. Wu and S. K. Tian, Org.
Lett., 2011, 13, 5636–5639.
Bioorg. Med. Chem., 2004, 12, 3569–3580; (c) T. S. Harrison 16 S. Sharma, B. Saha, D. Sawant and B. Kundu, J. Comb. Chem.,
and G. M. Keating, CNS Drugs, 2005, 19, 65–89; (d)
2007, 9, 783.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 26757–26770 | 26769

View Article Online
RSC Advances
Paper
17 (a) N. Sunduru, N. S. Palne, P. M. S. Chauhan and S. Gupta, 21 A. Sharma, M. Singh, N. N. Rai and D. Sawant, Beilstein J. Org.
Eur. J. Med. Chem., 2009, 44, 2473–2481; (b) A. Kumar, Chem., 2013, 9, 1235–1242.
K. Srivastava, S. R. Kumar, M. I. Siddiqi, S. K. Puri, 22 A. K. Pandey, R. Sharma, R. Shivahare, A. Arora, N. Rastogi,
J. K. Sexana and P. M. S. Chauhan, Eur. J. Med. Chem.,
2011, 46, 676–690; (c) N. Sunduru, L. Gupta, K. Chauhan,
S. Gupta and P. M. S. Chauhan, J. Org. Chem., 2013, 78, 1534–
1546.
N. N. Mishra, P. K. Shukla and P. M. S. Chauhan, Eur. J. 23 A. R. Kunzer and M. D. Wendt, Tetrahedron Lett., 2011, 52,
Med. Chem., 2011, 46, 1232–1244; (d) R. Kumar, L. Gupta, 1815–1818.
P. Pal, S. Khan, N. Singh, S. B. Katiyar, S. Meena, J. Sarkar, 24 Z. Wu, Y. Pan and X. Zhou, Synthesis, 2011, 14, 2255–2259.
S. Sinha, J. K. Kanaujiya, S. Lochab, A. K. Trivedi and 25 (a) C. B. Cui, H. Kakeya and H. J. Osada, Tetrahedron, 1996,
P. M. S. Chauhan, Eur. J. Med. Chem., 2010, 45, 2265–2276.
18 M. Sharma, S. Pandey, K. Chauhan, D. Sharma, B. Kumar
and P. M. S. Chauhan, J. Org. Chem., 2012, 77, 929–937.
19 (a) L. D. Luca, G. Giacomelli and A. Porcheddu, J. Org. Chem.,
2001, 66, 7907–7909; (b) Y. Furuya, K. Ishihara and
H. Yamamoto, J. Am. Chem. Soc., 2005, 127, 11240–11241;
52, 12651–12666; (b) A. Jossang, P. Jossang, H. A. Hadi,
T. Sevenet and B. Bodo, J. Org. Chem., 1991, 56, 6527–6530;
(c) J. S. Shi, J. X. Yu, X. P. Chen and R. X. Xu, Acta
Pharmacol. Sin., 2003, 24, 97–101; (d) J. M. Polonsky,
M. A. Merrien, T. Prange and C. Pascard, J. Chem. Soc.,
Chem. Commun., 1980, 601–602.
(c) C. O. Kangani and B. W. Day, Org. Lett., 2008, 10, 2645– 26 M. A. Bigdeli, G. H. Mahdavinia, S. Jafari and H. Hazarkhani,
2648; (d) A. Porcheddu, G. Giacomelli and M. Salaris, J.
Org. Chem., 2005, 70, 2361–2363.
20 (a) A. Saito, J. Numaguchi and Y. Hanzawa, Tetrahedron Lett.,
Catal. Commun., 2007, 8, 2229–2231.
27 S. Singh, R. K. Srivastava, M. Srivastava, S. K. Puri and
K. Srivastava, Exp. Parasitol., 2011, 127, 318–321.
2007, 48, 835–839; (b) A. Saito, M. Takayama, A. Yamazaki, 28 K. V. Sashidhara, M. Kumar, R. K. Modukuri,
J. Numaguchi and Y. Hanzawa, Tetrahedron, 2007, 63,
4039–4047; (c) B. Saha, S. Sharma, D. Sawant and
B. Kundu, Tetrahedron Lett., 2007, 48, 1379–1383.
R. K. Srivastava, A. Soni, K. Srivastava, S. V. Singh,
J. K. Saxena, H. M. Gauniyal and S. K. Puri, Bioorg. Med.
Chem., 2012, 20, 2971–2981.
26770 | RSC Adv., 2014, 4, 26757–26770
This journal is © The Royal Society of Chemistry 2014