Use of silica gel-supported aluminium chloride as reusable catalyst for expeditious synthesis of a novel series of 11-amino-12-aryl-hexahydro-5-oxa-6,13-diaza-indeno[1,2-b]anthracene derivatives

Article abstract of DOI:10.1007/s11164-014-1768-5

Abstract Efficient synthesis of a novel series of 11-amino-12-aryl-hexahydro-5-oxa-6,13-diaza-indeno[1,2-b]anthracene derivatives has been achieved by cyclocondensation of 2-amino-4,5-dihydro-4-arylpyrano[3,2-b]indole-3-carbonitriles and cyclohexanone in

Full text of DOI:10.1007/s11164-014-1768-5

Res Chem Intermed
DOI 10.1007/s11164-014-1768-5
Use of silica gel-supported aluminium chloride
as reusable catalyst for expeditious synthesis of a novel
series of 11-amino-12-aryl-hexahydro-5-oxa-6,13-diaza-
indeno[1,2-b]anthracene derivatives
•
Majid Ghashang Syed Sheik Mansoor
Krishnamoorthy Aswin
•
Received: 13 March 2014 / Accepted: 8 July 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract Efficient synthesis of a novel series of 11-amino-12-aryl-hexahydro-5-
oxa-6,13-diaza-indeno[1,2-b]anthracene derivatives has been achieved by cyclo-
condensation of 2-amino-4,5-dihydro-4-arylpyrano[3,2-b]indole-3-carbonitriles and
cyclohexanone in the presence of silica gel-supported aluminium chloride (SiO2–
AlCl3) as catalyst under thermal conditions. Thorough optimization of the experi-
mental conditions enabled significant rate enhancement and excellent yields. The
starting
2-amino-4,5-dihydro-4-arylpyrano[3,2-b]indole-3-carbonitriles
were
obtained by one-pot triphenylphosphine-catalyzed multicomponent condensation of
3-hydroxyindole, malononitrile, and aromatic aldehydes. The structures of all the
synthesized compounds were established by use of advanced spectroscopic
techniques.
Keywords Triphenylphosphine (PPh3) Á Pyrano[3,2-b]indole-3-carbonitrile Á
11-Amino-12-aryl-hexahydro-5-oxa-6,13-diaza-indeno[1,2-b]anthracene Á Silica
gel-supported aluminium chloride
Introduction
Multicomponent reactions (MCRs) are special, synthetically useful, organic
reactions in which three or more different starting materials react to form a final
product in a one-pot procedure. Such reactions are atom-efficient because,
M. Ghashang
Faculty of Sciences, Najafabad Branch, Islamic Azad University, Najafabad, Esfahan, Iran
S. S. Mansoor (&) Á K. Aswin
Bioactive Organic Molecule Synthetic Unit, Research Department of Chemistry, C. Abdul Hakeem
College, Melvisharam 632 509, Tamil Nadu, India
e-mail: smansoors2000@yahoo.co.in
123

M. Ghashang et al.
essentially, all the parts of the starting materials are incorporated into the final
product. MCRs have been successfully used to generate highly diverse combina-
torial libraries for high-throughput screening of biological and pharmacological
activity. MCRs comply with the principles of green chemistry, in terms of economy
of steps, and with many of the stringent criteria of ideal organic synthesis. These
reactions are effective in building highly functionalized small organic molecules
from readily available starting materials in a single step with inherent flexibility
which enables creation of molecular complexity and diversity coupled with
minimization of time, labor, cost, and waste production [1]. Hence, the development
of multi-component reaction procedures for synthesis of heterocyclic compounds
has attracted substantial interest in modern organic synthesis [2, 3].
Compounds containing the 4H-pyran structure are important because of their
interesting pharmacological and biological properties, and many of these com-
pounds have pharmaceutical applications. They are widely used as antimicrobial
[4], antiviral [5], mutagenic [6], cancer therapy [7], and antitumor [8] agents. Some
of these compounds have photochemical activity [9]. Therefore, synthesis of such
compounds has attracted much interest.
Considering the broad range of biological activity of indoles and a-pyrones [10–
12], it was believed that combining both these structures in one compound could
result in substantial improvement in the biological activity of such compounds.
Consequently, many methods have been developed for synthesis of such
compounds, including use of KH2PO4/ultrasonic irradiation-catalyzed multicom-
ponent synthesis [13], immobilized ionic liquid-catalyzed synthesis [14], intramole-
cular hetero-Diels–Alder cycloaddition [15], and gold(III) chloride-catalyzed
regioselective synthesis [16]. However, these methods often suffer from one or
more disadvantages and most give only moderate yields even after prolonged
reaction time. This clearly indicates that development of efficient and eco-
sustainable methods for synthesis of pyranoindole derivatives is still required.
In recent years triphenylphosphine (PPh3) has attracted much interest in a variety
of organic reactions because of the experimental simplicity of its reactions [17, 18].
We have reported use of PPh3 for synthesis of 3,4-dihydropyrimidine-2-(1H)-ones/
thiones/imines [19] and 4,6-diphenyl-3,4-dihydropyrimidine-2(1H)-thione [20]. We
continue to be interested in developing environmentally benign processes for
synthesis of biologically active molecules [21–25], and in this manuscript report the
use of PPh3 in the three-component reaction of aryl aldehydes, 3-hydroxyindole, and
malononitrile for synthesis of novel 2-amino-4,5-dihydro-4-arylpyrano[3,2-
b]indole-3-carbonitrile derivatives in aqueous ethanol at 60 °C (Scheme 1). This
is a one-pot reaction which is not only operationally simple but also consistently
gives the corresponding products in good to excellent yields.
Pyranopyridines are important heterocyclic compounds with diverse biological
activity, for example anti-bacterial [26], antimyopic [27], anti-proliferative [28],
cancer chemopreventive [29], and antiasthmatic [30].
Pyridine, and compounds containing this structure, for example pyranopyridines,
are of interest in organic synthesis and many strategies have been adopted for their
synthesis [31–33]. Among the different approaches used for synthesis of pyridines,
¨
Friedlander annulation reactions of these heterocycles and some of their derivatives
123

An expeditious synthesis of a novel series
NC
CN
R
2
CHO
PPh3 (5 mol%)
+
OH
H
CN
N
EtOH - H2O (1:1)
60 oC
R
O
4a-l
NH2
1a-l
N
H
3
Scheme 1 Synthesis of 2-amino-4,5-dihydro-4-phenylpyrano[3,2-b]indole-3-carbonitrile derivatives
R
R
O
NH2
SiO2-AlCl3
Reflux
H
N
H
N
CN
+
CH2Cl2
O
N
O
NH2
4a-l
5
6a-l
Scheme 2 Synthesis of 11-amino-12-aryl-7,8,9,10,12,13-hexahydro-5-oxa-6,13-diaza-indeno[1,2-b]
anthracene derivatives
¨
are simple and straightforward. Among a variety of Friedlander syntheses,
cyclocondensation of o-aminobenzonitrile with ketones has been little investigated,
because of such problems as requirement for prolonged reaction times, use of
hazardous reagents, and low yields [34–38]. Development of an efficient and
convenient procedure for synthesis of compounds containing the pyridine group, for
example pyranopyridines, is therefore of substantial interest.
We have achieved facile, rapid, and high-yielding synthesis of a series of
11-amino-12-aryl-7,8,9,10,12,13-hexahydro-5-oxa-6,13-diaza-indeno[1,2-b]anthra-
cenes (6a-l) by cyclocondensation of 2-amino-4,5-dihydro-4-arylpyrano[3,2-
b]indole-3-carbonitrile derivatives 4a-l with cyclohexanone in the presence of
silica gel-supported aluminium chloride (SiO2–AlCl3) in CH2Cl2 under reflux in
dichloromethane (Scheme 2).
Experimental
Chemicals and apparatus
Chemicals were purchased from Merck, Fluka, and Aldrich. All yields refer to
isolated products unless otherwise stated. 1H NMR (500 MHz) and 13C NMR
123

M. Ghashang et al.
(125 MHz) spectra were obtained by use of a Bruker DRX-500 Avance at ambient
temperature and with TMS as internal standard. In 1H NMR spectra, the J values are
expressed in Hz. FT-IR spectra were obtained as KBr discs by use of a Shimadzu
spectrometer. Mass spectra were determined on a Varian Saturn 2000 GC–MS
instrument. Elemental analysis was performed with a Perkin–Elmer 2400 CHN
elemental analyzer.
General procedure for synthesis of pyrano[3,2-b]indole derivatives
A mixture of aldehyde (1 mmol), 3-hydroxyindole (1 mmol), malononitrile
(1.1 mmol), and PPh3 (5 mol %) in EtOH-H2O (1:1) (5 mL) was stirred at 60 °C
(Scheme 1). The reaction was monitored by TLC and, after completion of the
reaction, the reaction mixture was washed with water and extracted with
dichloromethane. The organic phase was dried over Na2SO4 and the solvent was
removed under reduced pressure. The crude product obtained was purified by
column chromatography on silica gel with n-hexane–ethyl acetate (9:1) as mobile
phase.
Spectral data for the pyrano[3,2-b]indole derivatives (4a-l)
2-Amino-4,5-dihydro-4-phenylpyrano [3,2-b]indole-3-carbonitrile (4a)
1
IR (KBr, cm-1): 3,282 and 3,250 (–NH2), 2,221 (–CN), 1,669 (–NH); H NMR
(500 MHz, DMSO-d6) d: 5.29 (s, 1H, CH), 6.82 (bs, 2H, NH2), 6.89–7.04 (m, 2H,
Ar–H); 7.11–7.21 (m, 5H, Ar–H); 7.44 (d, 1H, J = 7.4, Ar–H); 7.72 (d, 1H,
J = 7.8, Ar–H), 9.88 (bs, 1H, NH) ppm; 13C NMR (125 MHz, DMSO-d6) d: 29.8,
59.1, 103.4, 111.7, 116.9, 120.6, 122.5, 125.5, 128.0, 128.7, 130.3, 130.7, 135.2,
135.4, 137.6, 176.7 ppm; MS (ESI): m/z 288 (M ? H)?; Anal. Calcd for
C18H13N3O: C, 75.25; H, 4.56; N, 14.63 %. Found: C, 75.20; H, 4.54; N, 14.55 %.
2-Amino-4,5-dihydro-4-(4-nitrophenyl)-pyrano[3,2-b]indole-3-carbonitrile (4b)
1
IR (KBr, cm-1): 3,268 and 3,240 (–NH2), 2,211 (–CN), 1,664 (–NH); H NMR
(500 MHz, DMSO-d6) d: 5.29 (s, 1H, CH), 6.71 (bs, 2H, NH2), 6.81–6.95 (m, 2H,
Ar–H); 7.11–7.24 (m, 4H, Ar–H); 7.49 (d, 1H, J = 7.4, Ar–H); 7.78 (d, 1H,
J = 7.8, Ar–H), 9.80 (bs, 1H, NH) ppm; 13C NMR (125 MHz, DMSO-d6) d: 31.6,
59.7, 102.6, 110.5, 117.6, 120.5, 122.4, 125.0, 128.0, 128.6, 130.6, 131.3, 135.3,
136.2, 137.9, 177.4 ppm; MS (ESI): m/z 333 (M ? H)?; Anal. Calcd for
C18H12N4O3: C, 65.06; H, 3.61; N, 16.87 %. Found: C, 65.02; H, 3.53; N, 16.78 %.
2-Amino-4,5-dihydro-4-(4-chlorophenyl)-pyrano[3,2-b]indole-3-carbonitrile (4c)
1
IR (KBr, cm-1): 3,270 and 3,232 (–NH2), 2,215 (–CN), 1,663 (–NH); H NMR
(500 MHz, DMSO-d6) d: 5.19 (s, 1H, CH), 6.81 (bs, 2H, NH2), 6.90–7.01 (m, 2H,
Ar–H); 7.08–7.17 (m, 4H, Ar–H); 7.39 (d, 1H, J = 7.4, Ar–H); 7.80 (d, 1H,
J = 7.8, Ar–H), 9.77 (bs, 1H, NH) ppm; 13C NMR (125 MHz, DMSO-d6) d: 30.5,
123

An expeditious synthesis of a novel series
60.6, 103.2, 111.2, 118.1, 121.5, 122.4, 125.9, 127.5, 128.5, 130.2, 131.2, 135.0,
135.7, 138.1, 176.1 ppm; MS (ESI): m/z 322.5 (M ? H)?; Anal. Calcd for
C18H12ClN3O: C, 67.19; H, 3.73; N, 13.06 %. Found: C, 67.17; H, 3.66; N,
12.98 %.
2-Amino-4,5-dihydro-4-(4-N,N-dimethylaminophenly)-pyrano[3,2-b]indole-3-
carbonitrile(4d)
1
IR (KBr, cm-1): 3,280 and 3,246 (–NH2), 2,216 (–CN), 1,655 (–NH); H NMR
(500 MHz, DMSO-d6) d: 2.88 (s, 6H, N(CH3)2), 5.27 (s, 1H, CH), 6.87 (bs, 2H,
NH2), 6.93–7.05 (m, 2H, Ar–H); 7.13–7.31 (m, 4H, Ar–H); 7.50 (d, 1H, J = 7.4,
Ar–H); 7.78 (d, 1H, J = 7.8, Ar–H), 9.81 (bs, 1H, NH) ppm; 13C NMR (125 MHz,
DMSO-d6) d: 31.1, 42.7, 60.4, 103.7, 111.7, 118.1, 121.3, 122.3, 125.0, 127.5,
128.4, 130.7, 131.3, 135.7, 136.2, 138.5, 177.2 ppm; MS (ESI): m/z 331 (M ? H)?;
Anal. Calcd for C20H18N4O: C, 72.72; H, 5.45; N, 16.96 %. Found: C, 72.66; H,
5.38; N, 16.89 %.
2-Amino-4,5-dihydro-4-(4-methylphenyl)-pyrano[3,2-b]indole-3-carbonitrile (4e)
1
IR (KBr, cm-1): 3,262 and 3,233 (–NH2), 2,213 (–CN), 1,665 (–NH); H NMR
(500 MHz, DMSO-d6) d: 2.23 (s, 3H, CH3), 5.17 (s, 1H, CH), 6.85 (bs, 2H, NH2),
6.93–7.05 (m, 2H, Ar–H); 7.11–7.19 (m, 4H, Ar–H); 7.50 (d, 1H, J = 7.4, Ar–H);
7.87 (d, 1H, J = 7.8, Ar–H), 9.89 (bs, 1H, NH) ppm; 13C NMR (125 MHz, DMSO-
d6) d: 18.9, 30.7, 61.0, 102.5, 111.4, 117.7, 121.3, 122.4, 125.3, 127.6, 128.5, 130.2,
131.1, 135.0, 135.5, 138.0, 176.5 ppm; MS (ESI): m/z 302 (M ? H)?; Anal. Calcd
for C19H15N3O: C, 75.75; H, 4.98; N, 13.95 %. Found: C, 75.76; H, 4.92; N,
13.84 %.
2-Amino-4,5-dihydro-4-(4-bromophenyl)-pyrano[3,2-b]indole-3-carbonitrile (4f)
1
IR (KBr, cm-1): 3,277 and 3,244 (–NH2), 2,214 (–CN), 1,659 (–NH); H NMR
(500 MHz, DMSO-d6) d: 5.19 (s, 1H, CH), 6.77 (bs, 2H, NH2), 6.85–6.97 (m, 2H,
Ar–H); 7.16–7.27 (m, 4H, Ar–H); 7.55 (d, 1H, J = 7.4, Ar–H); 7.80 (d, 1H,
J = 7.8, Ar–H), 9.84 (bs, 1H, NH) ppm; 13C NMR (125 MHz, DMSO-d6) d: 30.7,
58.9, 103.3, 110.6, 117.6, 121.1, 122.2, 125.4, 128.1, 128.4, 130.1 130.7, 135.5,
135.9, 138.0, 177.4 ppm; MS (ESI): m/z 366.9 (M ? H)?; Anal. Calcd for
C18H12BrN3O: C, 59.03; H, 3.28; N, 11.48 %. Found: C, 58.97; H, 3.29; N,
11.36 %.
2-Amino-4,5-dihydro-4-(2-nitrophenyl)-pyrano[3,2-b]indole-3-carbonitrile (4g)
1
IR (KBr, cm-1): 3,277 and 3,246 (–NH2), 2,219 (–CN), 1,660 (–NH); H NMR
(500 MHz, DMSO-d6) d: 5.33 (s, 1H, CH), 6.71 (bs, 2H, NH2), 6.91–7.02 (m, 2H,
Ar–H); 7.08–7.24 (m, 4H, Ar–H); 7.44 (d, 1H, J = 7.4, Ar–H); 7.70 (d, 1H,
J = 7.8, Ar–H), 9.88 (bs, 1H, NH) ppm; 13C NMR (125 MHz, DMSO-d6) d: 31.6,
59.5, 102.4, 110.6, 117.8, 121.2, 122.4, 125.2, 128.1, 128.4, 130.1, 130.5, 135.6,
123

M. Ghashang et al.
136.4, 137.6, 176.8 ppm; MS (ESI): m/z 333 (M ? H)?; Anal. Calcd for
C18H12N4O3: C, 65.06; H, 3.61; N, 16.87 %. Found: C, 65.011; H, 3.54; N,
16.88 %.
2-Amino-4,5-dihydro-4-(4-cyanophenyl)-pyrano[3,2-b]indole-3-carbonitrile (4h)
1
IR (KBr, cm-1): 3,263 and 3,235 (–NH2), 2,223 (–CN), 1,677 (–NH); H NMR
(500 MHz, DMSO-d6) d: 5.19 (s, 1H, CH), 6.71 (bs, 2H, NH2), 6.83–6.97 (m, 2H,
Ar–H); 7.10–7.31 (m, 4H, Ar–H); 7.58 (d, 1H, J = 7.4, Ar–H); 7.87 (d, 1H,
J = 7.8, Ar–H), 9.81 (bs, 1H, NH) ppm; 13C NMR (125 MHz, DMSO-d6) d: 31.3,
59.5, 102.4, 110.4, 116.7, 117.5, 120.5, 122.3, 125.7, 128.5, 128.9, 130.4 130.8,
135.4, 135.8, 138.0, 177.2 ppm; MS (ESI): m/z 313 (M ? H)?; Anal. Calcd for
C19H12N4O: C, 73.07; H, 3.85; N, 17.95 %. Found: C, 73.05; H, 3.77; N, 17.88 %.
2-Amino-4,5-dihydro-4-(3-methylphenyl)-pyrano[3,2-b]indole-3-carbonitrile (4i)
1
IR (KBr, cm-1): 3,259 and 3,245 (–NH2), 2,210 (–CN), 1,679 (–NH); H NMR
(500 MHz, DMSO-d6) d: 2.24 (s, 3H, CH3), 5.22 (s, 1H, CH), 6.79 (bs, 2H, NH2),
6.88–6.98 (m, 2H, Ar–H); 7.07–7.19 (m, 4H, Ar–H); 7.59 (d, 1H, J = 7.4, Ar–H);
7.84 (d, 1H, J = 7.8, Ar–H), 9.84 (bs, 1H, NH) ppm; 13C NMR (125 MHz, DMSO-
d6) d: 18.9, 30.1, 59.7, 102.7, 110.5, 117.9, 121.5, 122.5, 125.6, 127.8, 128.7, 130.4,
131.2, 135.3, 135.9, 137.9, 177.4 ppm; MS (ESI): m/z 302 (M ? H)?; Anal. Calcd
for C19H15N3O: C, 75.75; H, 4.98; N, 13.95 %. Found: C, 75.73; H, 4.91; N,
13.84 %.
2-Amino-4,5-dihydro-4-(2-chlorophenyl)-pyrano[3,2-b]indole-3-carbonitrile (4j)
1
IR (KBr, cm-1): 3,275 and 3,241 (–NH2), 2,212 (–CN), 1,663 (–NH); H NMR
(500 MHz, DMSO-d6) d: 5.19 (s, 1H, CH), 6.88 (bs, 2H, NH2), 6.95–7.07 (m, 2H,
Ar–H); 7.13–7.19 (m, 4H, Ar–H); 7.42 (d, 1H, J = 7.4, Ar–H); 7.87 (d, 1H,
J = 7.8, Ar–H), 9.83 (bs, 1H, NH) ppm; 13C NMR (125 MHz, DMSO-d6) d: 31.2,
60.9, 103.4, 111.3, 117.9, 121.4, 122.6, 125.3, 127.3, 128.1, 130.2, 131.4, 135.4,
136.0, 138.3, 176.9 ppm; MS (ESI): m/z 322.5 (M ? H)?; Anal. Calcd for
C18H12ClN3O: C, 67.19; H, 3.73; N, 13.06 %. Found: C, 67.15; H, 3.67; N,
12.97 %.
2-Amino-4,5-dihydro-4-(3-bromophenyl)-pyrano[3,2-b]indole-3-carbonitrile (4k)
1
IR (KBr, cm-1): 3,269 and 3,240 (–NH2), 2,218 (–CN), 1,659 (–NH); H NMR
(500 MHz, DMSO-d6) d: 5.29 (s, 1H, CH), 6.79 (bs, 2H, NH2), 6.87–6.99 (m, 2H,
Ar–H); 7.11–7.24 (m, 4H, Ar–H); 7.54 (d, 1H, J = 7.4, Ar–H); 7.81 (d, 1H,
J = 7.8, Ar–H), 9.92 (bs, 1H, NH) ppm; 13C NMR (125 MHz, DMSO-d6) d: 30.1,
59.4, 102.1, 110.4, 117.3, 121.0, 122.3, 125.4, 128.4, 128.7, 130.0 130.6, 135.5,
135.9, 137.3, 176.2 ppm; MS (ESI): m/z 366.9 (M ? H)?; Anal. Calcd for
C18H12BrN3O: C, 59.03; H, 3.28; N, 11.48 %. Found: C, 58.91; H, 3.22; N,
11.44 %.
123

An expeditious synthesis of a novel series
2-Amino-4,5-dihydro-4-(4-fluorophenyl)-pyrano[3,2-b]indole-3-carbonitrile (4l)
1
IR (KBr, cm-1): 3,279 and 3,239 (–NH2), 2,219 (–CN), 1,666 (–NH); H NMR
(500 MHz, DMSO-d6) d: 5.16 (s, 1H, CH), 6.79 (bs, 2H, NH2), 6.91–7.04 (m,
2H,Ar–H); 7.11–7.23 (m, 4H, Ar–H); 7.48 (d, 1H, J = 7.4, Ar–H); 7.80 (d, 1H,
J = 7.8, Ar–H), 9.90 (bs, 1H, NH) ppm; 13C NMR (125 MHz, DMSO-d6) d: 30.2,
60.2, 102.1, 110.4, 117.9, 121.2, 122.6, 125.5, 127.4, 128.8, 130.3, 131.4, 135.6,
136.3, 138.7, 177.3 ppm; MS (ESI): m/z 306 (M ? H)?; Anal. Calcd for
C18H12FN3O: C, 70.82; H, 3.93; N, 13.77 %. Found: C, 70.69; H, 3.81; N, 13.69 %.
Preparation of SiO2–AlCl3
˚
Anhydrous AlCl3 (5.1 g) was added to silica gel (Merck, grade 60, 230–400 A,
washed with 1 M HCl, and dried under vacuum at 80 °C for 72 h; 10.2 g) in carbon
tetrachloride (30 mL). The mixture was stirred by use of a magnetic stirrer under
reflux for 2 days, in an N2 atmosphere, then filtered, washed with 50 mL dry CCl4,
and dried under vacuum at 60 °C for 3 h. The determined loading of AlCl3 was
1.3 mmol/g [39].
General procedure for synthesis of substituted hexahydro-5-oxa-6,13-diaza-
indeno[1,2-b]anthracenes
A mixture of substituted 2-amino-4,5-dihydro-4-phenylpyrano [3,2-b]indole-3-
carbonitrile 4 (1 mmol), cyclohexanone 5 (1.3 mmol), and SiO2–AlCl3 (0.12 mmol)
in CH2Cl2 (5 mL) was stirred at reflux (Scheme 2). After completion of the reaction
(monitored by TLC), the catalyst was isolated by filtration and washed with CH2Cl2.
The reaction mixture was poured into a beaker containing ice-cold water. The
mixture was extracted with CH2Cl2 (3 9 15 mL), dried over anhydrous Na2SO4,
and filtered. The solvent was evaporated under reduced pressure and the resulting
crude product was purified by column chromatography (40 % ethyl acetate in
hexane) to afford pure product 6. Spent catalyst from different experiments was
washed with ether and used again without further drying. The activity of the catalyst
was unaffected, even after five cycles.
Spectral data for 11-amino-12-aryl-hexahydro-5-oxa-6,13-diaza-indeno[1,2-
b]anthracene derivatives (6a-l)
11-Amino-12-aryl-7,8,9,10,12,13-hexahydro-5-oxa-6,13-diaza-indeno[1,2-
b]anthracene (6a)
1
IR (KBr, cm-1): 3,402, 3,372, 2,929, 1,677, 1,630, 1,466, 1,244, 1,169; H NMR
(500 MHz, DMSO-d6) d: 1.77 (m, 4H, CH2), 2.11 (m, 2H, CH2), 2.40 (m, 2H, CH2),
5.28 (s, 1H, CH), 5.58 (s, 2H, NH2), 6.94–7.02 (m, 2H, Ar–H); 7.17–7.29 (m, 5H,
Ar–H); 7.47 (d, 1H, J = 7.2, Ar–H); 7.70 (d, 1H, J = 7.8, Ar–H), 9.85 (bs, 1H, NH)
ppm; 13C NMR (125 MHz, DMSO-d6) d: 23.1, 27.3, 31.2, 32.2, 34.7, 103.5, 105.6,
110.9, 117.0, 121.1, 123.0, 127.8, 128.5, 130.1, 131.0, 134.9, 135.5, 137.1, 157.7,
123

M. Ghashang et al.
161.0, 166.4 ppm; MS (ESI): m/z 368 (M ? H)?; Anal. Calcd for C24H21N3O: C,
78.45; H, 5.76; N, 11.44 %. Found: C, 78.36; H, 5.73; N, 11.39 %.
11-Amino-12-(4-nitrophenyl)-7,8,9,10,12,13-hexahydro-5-oxa-6,13-diaza-
indeno[1,2-b]anthracene (6b)
1
IR (KBr, cm-1): 3,408, 3,363, 2,937, 1,670, 1,628, 1,469, 1,242, 1,173; H NMR
(500 MHz, DMSO-d6) d: 1.80 (m, 4H, CH2), 2.12 (m, 2H, CH2), 2.42 (m, 2H, CH2),
5.21 (s, 1H, CH), 5.56 (s, 2H, NH2), 6.88–7.03 (m, 2H, Ar–H); 7.13–7.27 (m, 4H,
Ar–H); 7.42 (d, 1H, J = 7.4, Ar–H); 7.77 (d, 1H, J = 8.0, Ar–H), 9.87 (bs, 1H, NH)
ppm; 13C NMR (125 MHz, DMSO-d6) d: 22.4, 27.5, 31.0, 32.4, 35.0, 104.0, 105.4,
110.8, 117.3, 121.3, 123.2, 127.9, 128.6, 130.3, 131.2, 135.2, 135.7, 137.0, 157.9,
160.6, 166.8 ppm; MS (ESI): m/z 413 (M ? H)?; Anal. Calcd for C24H20N4O3: C,
69.89; H, 4.89; N, 13.58 %. Found: C, 69.80; H, 4.87; N, 13.54 %.
11-Amino-12-(4-chlorophenyl)-7,8,9,10,12,13-hexahydro-5-oxa-6,13-diaza-
indeno[1,2-b]anthracene (6c)
1
IR (KBr, cm-1): 3,419, 3,367, 2,939, 1,669, 1,622, 1,464, 1,233, 1,172; H NMR
(500 MHz, DMSO-d6) d: 1.79 (m, 4H, CH2), 2.16 (m, 2H, CH2), 2.43 (m, 2H, CH2),
5.27 (s, 1H, CH), 5.63 (s, 2H, NH2), 6.95–7.06 (m, 2H, Ar–H); 7.15–7.32 (m, 4H,
Ar–H); 7.45 (d, 1H, J = 7.2, Ar–H); 7.75 (d, 1H, J = 8.0, Ar–H), 9.86 (bs, 1H, NH)
ppm; 13C NMR (125 MHz, DMSO-d6) d: 23.0, 27.6, 31.3, 32.3, 35.0, 104.1, 105.3,
111.3, 116.6, 120.5, 123.2, 128.4, 128.8, 130.2, 131.0, 134.8, 135.3, 137.3, 157.8,
160.4, 166.7 ppm; MS (ESI): m/z 402 (M ? H)?; Anal. Calcd for C24H20ClN3O: C,
71.73; H, 5.02; N, 10.46 %. Found: C, 71.66; H, 4.99; N, 10.40 %.
11-Amino-12-(4-N,N-dimethylaminophenyl)-7,8,9,10,12,13-hexahydro-5-oxa-6,13-
diaza-indeno[1,2-b]anthracene (6d)
1
IR (KBr, cm-1): 3,422, 3,370, 2,930, 1,666, 1,634, 1,465, 1,235, 1,170; H NMR
(500 MHz, DMSO-d6) d: 1.78 (m, 4H, CH2), 2.10 (m, 2H, CH2), 2.41 (m, 2H, CH2),
2.79 (s, 6H, N(CH3)2), 5.32 (s, 1H, CH), 5.60 (s, 2H, NH2), 6.87–7.00 (m, 2H, Ar–
H); 7.14–7.30 (m, 4H, Ar–H); 7.52 (d, 1H, J = 7.4, Ar–H); 7.74 (d, 1H, J = 7.8,
Ar–H), 9.89 (bs, 1H, NH) ppm; 13C NMR (125 MHz, DMSO-d6) d: 22.7, 28.0,
31.0, 32.1, 34.7, 43.5, 103.5, 105.5, 111.5, 116.5, 120.6, 122.8, 128.3, 128.9, 130.6,
130.9, 135.3, 135.7, 137.6, 158.2, 160.7, 165.8 ppm; MS (ESI): m/z 411 (M ? H)?;
Anal. Calcd for C26H26N4O: C, 76.07; H, 6.38; N, 13.65 %. Found: C, 76.00; H,
6.31; N, 13.59 %.
11-Amino-12-(4-methylphenyl)-7,8,9,10,12,13-hexahydro-5-oxa-6,13-diaza-
indeno[1,2-b]anthracene (6e)
1
IR (KBr, cm-1): 3,416, 3,368, 2,944, 1,675, 1,630, 1,467, 1,237, 1,175; H NMR
(500 MHz, DMSO-d6) d: 1.79 (m, 4H, CH2), 2.09 (m, 2H, CH2), 2.20 (s, 3H, CH3),
123

An expeditious synthesis of a novel series
2.39 (m, 2H, CH2), 5.31 (s, 1H, CH), 5.57 (s, 2H, NH2), 6.93–7.07 (m, 2H, Ar–H);
7.13–7.29 (m, 4H, Ar–H); 7.49 (d, 1H, J = 7.4, Ar–H); 7.82 (d, 1H, J = 7.8, Ar–
H), 9.92 (bs, 1H, NH) ppm; 13C NMR (125 MHz, DMSO-d6) d: 18.4, 23.1, 27.5,
30.9, 32.6, 34.5, 103.7, 105.8, 111.4, 116.8, 120.8, 122.6, 128.4, 128.9, 130.5,
131.0, 134.8, 135.6, 137.4, 158.4, 161.2, 165.7 ppm; MS (ESI): m/z 382 (M ? H)?;
Anal. Calcd for C25H23N3O: C, 78.71; H, 6.08; N, 11.02 %. Found: C, 78.66; H,
6.02; N, 10.98 %.
11-Amino-12-(4-bromophenyl)-7,8,9,10,12,13-hexahydro-5-oxa-6,13-diaza-
indeno[1,2-b]anthracene (6f)
1
IR (KBr, cm-1): 3,410, 3,355, 2,931, 1,680, 1,626, 1,464, 1,231, 1,177; H NMR
(500 MHz, DMSO-d6) d: 1.81 (m, 4H, CH2), 2.10 (m, 2H, CH2), 2.40 (m, 2H,
CH2), 5.28 (s, 1H, CH), 5.60 (s, 2H, NH2), 6.87–6.99 (m, 2H, Ar–H); 7.17–7.33
(m, 4H, Ar–H); 7.50 (d, 1H, J = 7.2, Ar–H); 7.80 (d, 1H, J = 8.0, Ar–H), 9.94
(bs, 1H, NH) ppm; 13C NMR (125 MHz, DMSO-d6) d: 22.6, 27.4, 30.8, 32.5,
34.6, 103.9, 105.7, 111.6, 117.3, 120.9, 122.7, 127.7, 128.5, 130.4, 130.9, 135.3,
135.7, 137.5, 158.0, 160.8, 166.4 ppm; MS (ESI): m/z 447 (M ? H)?; Anal.
Calcd for C24H20BrN3O: C, 64.58; H, 4.52; N, 9.41 %. Found: C, 64.50; H,
4.51; N, 9.39 %.
11-Amino-12-(2-nitrophenyl)-7,8,9,10,12,13-hexahydro-5-oxa-6,13-diaza-
indeno[1,2-b]anthracene (6g)
1
IR (KBr, cm-1): 3,400, 3,360, 2,935, 1,681, 1,629, 1,466, 1,240, 1,166; H NMR
(500 MHz, DMSO-d6) d: 1.84 (m, 4H, CH2), 2.12 (m, 2H, CH2), 2.46 (m, 2H,
CH2), 5.25 (s, 1H, CH), 5.64 (s, 2H, NH2), 6.95–7.06 (m, 2H, Ar–H); 7.16–7.34
(m, 4H, Ar–H); 7.51 (d, 1H, J = 7.2, Ar–H); 7.74 (d, 1H, J = 8.0, Ar–H), 9.90
(bs, 1H, NH) ppm; 13C NMR (125 MHz, DMSO-d6) d: 22.8, 27.2, 31.3, 32.3,
34.8, 104.0, 105.6, 111.8, 116.8, 120.5, 122.9, 128.2, 128.6, 130.0, 130.8, 135.5,
135.9, 137.3, 158.1, 160.7, 166.7 ppm; MS (ESI): m/z 413 (M ? H)?; Anal.
Calcd for C24H20N4O3: C, 69.89; H, 4.89; N, 13.58 %. Found: C, 69.84; H,
4.907; N, 13.51 %.
11-Amino-12-(4-cyanophenyl)-7,8,9,10,12,13-hexahydro-5-oxa-6,13-diaza-
indeno[1,2-b]anthracene (6h)
1
IR (KBr, cm-1): 3,413, 3,367, 2,928, 1,680, 1,631, 1,473, 1,235, 1,168; H NMR
(500 MHz, DMSO-d6) d: 1.83 (m, 4H, CH2), 2.11 (m, 2H, CH2), 2.43 (m, 2H,
CH2), 5.22 (s, 1H, CH), 5.59 (s, 2H, NH2), 6.88–7.01 (m, 2H, Ar–H); 7.19–7.35
(m, 4H, Ar–H); 7.54 (d, 1H, J = 7.4, Ar–H); 7.70 (d, 1H, J = 7.8, Ar–H), 9.96
(bs, 1H, NH) ppm; 13C NMR (125 MHz, DMSO-d6) d: 23.0, 28.2, 31.2, 32.0,
34.9, 103.6, 105.4, 110.5, 116.6, 117.2, 121.2, 123.1, 128.3, 128.8, 130.4, 130.9,
134.9, 135.3, 137.7, 157.8, 161.2, 165.9 ppm; MS (ESI): m/z 393(M ? H)?; Anal.
Calcd for C25H20N4O: C, 76.51; H, 5.14; N, 14.28 %. Found: C, 76.44; H, 5.10;
N, 14.25 %.
123

M. Ghashang et al.
11-Amino-12-(3-methylphenyl)-7,8,9,10,12,13-hexahydro-5-oxa-6,13-diaza-
indeno[1,2-b]anthracene (6i)
1
IR (KBr, cm-1): 3,417, 3,372, 2,930, 1,676, 1,630, 1,472, 1,237, 1,170; H NMR
(500 MHz, DMSO-d6) d: 1.77 (m, 4H, CH2), 2.07 (m, 2H, CH2), 2.28 (s, 3H, CH3),
2.37 (m, 2H, CH2), 5.30 (s, 1H, CH), 5.61 (s, 2H, NH2), 6.90–7.03 (m, 2H, Ar–H);
7.15–7.29 (m, 4H, Ar–H); 7.49 (d, 1H, J = 7.2, Ar–H); 7.69 (d, 1H, J = 7.8, Ar–
H), 9.89 (bs, 1H, NH) ppm; 13C NMR (125 MHz, DMSO-d6) d: 19.0, 22.5, 27.7,
31.5, 32.5, 35.2, 103.9, 105.5, 110.8, 117.3, 121.4, 123.0, 128.4, 128.9, 130.6,
131.2, 135.5, 135.8, 137.8, 157.9, 161.0, 165.8 ppm; MS (ESI): m/z 382 (M ? H)?;
Anal. Calcd for C25H23N3O: C, 78.71; H, 6.08; N, 11.02 %. Found: C, 78.63; H,
6.07; N, 11.00 %.
11-Amino-12-(2-chlorophenyl)-7,8,9,10,12,13-hexahydro-5-oxa-6,13-diaza-
indeno[1,2-b]anthracene (6j)
1
IR (KBr, cm-1): 3,421, 3,364, 2,932, 1,674, 1,632, 1,470, 1,233, 1,171; H NMR
(500 MHz, DMSO-d6) d: 1.80 (m, 4H, CH2), 2.11 (m, 2H, CH2), 2.40 (m, 2H, CH2),
5.27 (s, 1H, CH), 5.64 (s, 2H, NH2), 6.92–7.06 (m, 2H, Ar–H); 7.12–7.30 (m, 4H,
Ar–H); 7.48 (d, 1H, J = 7.4, Ar–H); 7.71 (d, 1H, J = 7.8, Ar–H), 9.87 (bs, 1H, NH)
ppm; 13C NMR (125 MHz, DMSO-d6) d: 22.4, 27.5, 31.6, 32.7, 35.0, 103.7, 105.9,
110.9, 116.7, 121.0, 122.5, 127.7, 128.4, 130.3, 131.3, 135.6, 135.9, 137.4, 158.0,
160.5, 166.4 ppm; MS (ESI): m/z 402 (M ? H)?;Anal. Calcd for C24H20ClN3O: C,
71.73; H, 5.02; N, 10.46 %. Found: C, 71.64; H, 5.03; N, 10.44 %.
11-Amino-12-(3-bromophenyl)-7,8,9,10,12,13-hexahydro-5-oxa-6,13-diaza-
indeno[1,2-b]anthracene (6k)
1
IR (KBr, cm-1): 3,424, 3,360, 2,937, 1,672, 1,627, 1,464, 1,237, 1,173; H NMR
(500 MHz, DMSO-d6) d: 1.85 (m, 4H, CH2), 2.17 (m, 2H, CH2), 2.47 (m, 2H, CH2),
5.26 (s, 1H, CH), 5.60 (s, 2H, NH2), 6.88–7.00 (m, 2H, Ar–H); 7.16–7.33 (m, 4H,
Ar–H); 7.47 (d, 1H, J = 7.4, Ar–H); 7.73 (d, 1H, J = 8.0, Ar–H), 9.91 (bs, 1H, NH)
ppm; 13C NMR (125 MHz, DMSO-d6) d: 22.3, 27.6, 31.3, 32.5, 35.2, 103.5, 104.9,
111.4, 116.9, 120.8, 122.7, 128.4, 128.8, 130.4, 130.9, 134.7, 135.5, 137.3, 158.5,
160.7, 166.9 ppm; MS (ESI): m/z 447 (M ? H)?; Anal. Calcd for C24H20BrN3O: C,
64.58; H, 4.52; N, 9.41 %. Found: C, 64.54; H, 4.53; N, 9.35 %.
11-Amino-12-(4-fluorophenyl)-7,8,9,10,12,13-hexahydro-5-oxa-6,13-diaza-
indeno[1,2-b]anthracene (6l)
1
IR (KBr, cm-1): 3,411, 3,362, 2,940, 1,673, 1,625, 1,463, 1,235, 1,175; H NMR
(500 MHz, DMSO-d6) d: 1.81 (m, 4H, CH2), 2.15 (m, 2H, CH2), 2.45 (m, 2H, CH2),
5.28 (s, 1H, CH), 5.63 (s, 2H, NH2), 6.87–7.03 (m, 2H, Ar–H); 7.17–7.31 (m, 4H,
Ar–H); 7.52 (d, 1H, J = 7.2, Ar–H); 7.75 (d, 1H, J = 8.0, Ar–H), 9.89 (bs, 1H, NH)
ppm; 13C NMR (125 MHz, DMSO-d6) d: 22.2, 27.9, 30.7, 32.4, 34.7, 103.8, 104.8,
111.6, 117.4, 120.9, 122.8, 128.2, 128.6, 130.5, 131.1, 135.3, 135.7 137.7, 158.2,
123

An expeditious synthesis of a novel series
160.9, 166.0 ppm; MS (ESI): m/z 386 (M ? H)?; Anal. Calcd for C24H20FN3O: C,
74.79; H, 5.23; N, 10.90 %. Found: C, 74.73; H, 5.19; N, 10.85 %.
Results and discussion
Herein we report a green, efficient, and rapid procedure, with SiO2–AlCl3 as
catalyst, for synthesis of 11-amino-12-aryl-hexahydro-5-oxa-6,13-diaza-indeno[1,2-
b]anthracene derivatives in excellent yields by reaction of 2-amino-4,5-dihydro-4-
phenylpyrano[3,2-b]indole-3-carbonitrile derivatives and cyclohexanone. To syn-
thesize the 2-amino-4,5-dihydro-4-phenyl-pyrano[3,2-b]indole-3-carbonitrile deriv-
atives, we investigated the three-component condensation of benzaldehyde 1a,
malononitrile 2, and 3-hydroxyindole 3, as model reaction, in the presence of
5 mol% PPh3 as catalyst, under different conditions at 60 °C (Table 1).
Initially, we tested the effect of different solvents. Use of 1,4-dioxane, CH2Cl2,
water, and ethanol was investigated (Table 1, entries 1–4). Reaction without solvent
at 60 °C was not very successful (Table 1, entry 5). Reaction under reflux in protic
solvents, for example H2O or EtOH, gave better yields (Table 1, entries 3 and 4).
Hence, the model reaction was studied at different EtOH–H2O solvent mixtures.
When the reaction was performed in EtOH–H2O (30:70 v/v) and EtOH–H2O (70:30
v/v) the yield was 73 and 85 % respectively (Table 1, entries 6 and 8). EtOH–H2O
(50:50 v/v) was proved to be the most suitable solvent for this condensation in terms
of yield and reaction time (Table 1, entry 7). We also evaluated the amount of PPh3
required for the reaction. It was found that when the amount of catalyst was reduced
from 5 to 2 mol%, the yield decreased from 92 to 77 % (Table 1, entry 9). Use of
5 mol% of PPh3 maintained the yield at 92 %, so this amount is sufficient to
promote the reaction. In the presence of more than this amount of catalyst, neither
Table 1 Synthesis of 2-amino-4,5-dihydro-4-phenyl-pyrano[3,2-b]indole-3-carbonitrile (4a) in the pre-
sence of PPh3 as catalyst under different reaction conditions
Entry
Solvent
Amount of PPh3
catalyst (mol%)
Time (min)
Yield (%)a
1
2
1,4-Dioxane
5
5
5
5
5
5
5
5
2
8
120
120
120
120
120
60
52
61
70
76
33
73
92
85
77
92
CH2Cl2
3
H2O
4
EtOH
5
None
6
EtOH–H2O (30:70 v/v)
EtOH–H2O (50:50 v/v)
EtOH–H2O (70:30 v/v)
EtOH–H2O (50:50 v/v)
EtOH–H2O (50:50 v/v)
7
40
8
60
9
40
10
40
Reaction conditions: benzaldehyde (1 mmol), 3-hydroxyindole (1 mmol), malononitrile (1.1 mmol) at
60 °C
a
Isolated yield
123

M. Ghashang et al.
yield nor the reaction time was improved (Table 1, entry 10). Thus, the best result
was obtained by use of 5 mol% catalyst in 50 % aqueous ethanol under reflux
(Table 1, entry 7).
It is worth mentioning that it has previously been reported [12] that use of
ultrasonic irradiation with KH2PO4 as catalyst resulted in no reaction in the
presence of proton acids and classical Lewis acids, for example AlCl3, ZnCl2,
TsOH, NH2SO3H, Cu(OTf)2, and Zn(OTf)2, as catalysts. Hence, we used PPh3 as
catalyst in 50 % aqueous ethanol under thermal conditions, which enabled synthesis
of the expected products in excellent yields. To show that PPh3 is an efficient
catalyst, we conducted the model reaction in the presence of AlCl3, ferric hydrogen
sulfate Fe(HSO4)3), hexadecyldimethylbenzyl ammonium bromide (HDMBAB),
KF/Al2O3, and NaHCO3 as catalysts (Table 2, entries 1–5). Yields were lower than
when PPh3 was used.
Encouraged by the success of this three-component reaction, synthesis of diverse
2-amino-4,5-dihydro-4-phenyl-pyrano[3,2-b]indole-3-carbonitrile derivatives 4a-l
was undertaken. Aromatic aldehydes bearing electron-withdrawing and electron-
donating groups were found to result in very good yields (Table 3, entries 1–12).
The mechanism proposed for preparation of the 2-amino-4,5-dihydro-4-phenyl-
pyrano[3,2-b]indole-3-carbonitrile derivatives is illustrated in Scheme 3. Olefin-
ation of the aldehydes with malononitrile is induced by activation of the aldehydes
by PPh3, producing intermediate a. This intermediate undergoes coupling with
malononitrile to form 2-arylidenemalononitrile, with loss of the Ph3P. 2-Arylid-
enemalononitrile is not sufficiently reactive to react with Ph3P, and attachment of
1H-indol-3-ol occurs, giving intermediate b. Activation of the nitrile group by Ph3P
(intermediate c), hydrogen shift, and cyclization, with loss of Ph3P, results in
formation of intermediate d, which is converted into the desired product via a 1,3
hydrogen shift.
Because catalyst reusability is extremely important in commercial applications,
recovery and reusability of the PPh3 was investigated. After completion of the
reaction, the reaction mixture was cooled to ambient temperature, CH2Cl2 was
added, and the PPh3 was isolated by filtration. The recycled catalyst has been used
Table 2 Evaluation of the activity of different catalysts in the condensation of benzaldehyde, malono-
nitrile, and 3-hydroxyindole in EtOH–H2O (50:50 v/v) at 60 °C
Entry
Catalyst
Amount of
catalyst (mol%)
Time (min)
Yield (%)a
1
2
3
4
5
6
AlCl3
10
10
10
10
10
5
120
120
180
180
240
40
48
54
69
74
59
92
Fe(HSO4)3
HDMBAB
KF–Al2O3
NaHCO3
PPh3
Reaction conditions: benzaldehyde (1 mmol), 3-hydroxyindole (1 mmol), malononitrile (1.1 mmol) at
60 °C
a
Isolated yield
123

An expeditious synthesis of a novel series
Table 3 Synthesis of 2-amino-4,5-dihydro-4-phenyl-pyrano[3,2-b]indole-3-carbonitrile derivatives from
aromatic aldehydes, 3-hydroxyindole, and malononitrile with PPh3 (5 mol%) as catalyst
Entry
Aldehyde
Product
Time (min)
Yield (%)b
H
CN
N
O
NH2
4a
CHO
NO2
1
40
92
NO2
H
CN
N
O
NH2
4b
CHO
Cl
2
3
30
90
91
Cl
H
CN
N
O
NH2
4c
CHO
30
N(CH3)2
N(CH3)2
H
CN
N
O
NH2
4d
CHO
CH3
4
50
50
85
86
CH3
H
CN
N
O
NH2
4e
CHO
Br
5
Br
H
CN
N
O
NH2
4f
CHO
6
7
30
40
91
NO2
H
N
CN
NO2
O
NH2
4g
CHO
89
123

M. Ghashang et al.
Table 3 continued
Entry
Aldehyde
Product
Time (min)
Yield (%)b
CN
CN
H
N
CN
O
NH2
4h
CHO
8
40
50
88
87
CH3
CH3
H
CN
N
O
NH2
4i
CHO
9
Cl
H
N
CN
Cl
Br
O
NH2
4j
CHO
10
11
50
30
87
Br
H
CN
N
O
NH2
4k
CHO
89
F
F
H
N
CN
NH
O
12
2l
30
92
4l
CHO
Reaction conditions: aromatic aldehyde (1 mmol), 3-hydroxyindole (1 mmol), malononitrile (1.1 mmol),
PPh3 (5 mol%) in EtOH–H2O (50:50 v/v) at 60 °C
a
Isolated yield
in the next run. The PPh3 catalyst could be reused four times without any loss of its
activity (Fig. 1).
After synthesis of the 2-amino-4,5-dihydro-4-aryl-pyrano[3,2-b]indole-3-carbo-
nitrile derivatives 4a-l, we synthesized 11-amino-12-aryl-hexahydro-5-oxa-6,13-
123

An expeditious synthesis of a novel series
O
Ar
PPh3
+
Ar-CHO + Ph3P
a
OH
+ a
NC
CN
NC
CN
Ar
PPh3
CN
CN
H
Ar
+ OH
NC
Ar
CN
CN
PPh3
PPh3
-Ph3P
O
CN
OH
CN
CN
Ar
NH
+
Ar
NH
b
N
NC
OH
Ph3P
OH
C
CN
CN
Ph3P
Ar
Ar
NH
NH
c
NH
NH
O
Ph3P
O
C
CN
- Ph3P
CN
Ar
d
Ar
N
H
NH
1,3-H shift
NH2
CN
O
Ar
N
H
Scheme 3 Proposed mechanism for preparation of 2-amino-4,5-dihydro-4-phenyl-pyrano[3,2-b]indole-
3-carbonitrile derivatives
123

M. Ghashang et al.
diaza-indeno[1,2-b]anthracene derivatives 6a-l. To optimize the reaction conditions,
we initially investigated synthesis of the pyranopyridine 6a by reaction of 4a with
cyclohexanone 5, with AlCl3 as catalyst, in CH2Cl2 under reflux. The product was
obtained in 62 % yield in 2.0 h (Table 4, entry 1).
Aluminium chloride is one of the most widely used Lewis acids. It is very active,
soluble in many organic solvents, and inexpensive. Unfortunately, it is often too
powerful as an acid, giving unwanted side reactions. When the reaction is complete,
the only viable method for separating the aluminium chloride is by use of a
destructive water quench, leading to large volumes of hazardous waste. Thus, use of
aluminium chloride can lead to violations of several of the principles of green
chemistry by release into the environment of hazardous substances, by use of
volatile organic solvents, by use of reagent-like quantities that are lost on work up,
and as a result of unselective reactions that do not lead to maximum incorporation of
the starting materials in the product. There have been several attempts to
immobilize aluminium chloride to help overcome these problems.
A literature survey revealed that the acidic properties of AlCl3 change when it is
supported on the surface of solid material such as silica, resulting in a material with
strong Brønsted and Lewis acidity [40]. Thus our use as catalyst of SiO2–AlCl3
prepared by addition of anhydrous AlCl3 to silica gel in CCl4 under reflux [39].
We then performed the reaction with SiO2–AlCl3 (0.12 mmol) as catalyst in
CH2Cl2 under reflux, and the desired pyranopyridine 6a was formed in 88 % in
1.2 h (Table 4, entry 2). We then optimized the quantity of catalyst. Reducing the
molar proportion of SiO2–AlCl3 substantially reduced the yield of 6a (Table 4,
entries 3 and 4) whereas increasing the molar proportion did not improve the yield
(Table 4, entry 5). No products were detectable when other Lewis acids, for
example CaCl2, Bi(NO3)3, BiCl3, Cu(OTf)2, InCl3, and FeCl3 (Table 4, entries
94
93
92%
Recycling of PPh3
92
91
90%
90
89%
89
88
87%
87
86
85
84
1
2
3
4
Number of Runs
Fig. 1 Recyclability of the catalyst. PPh3 could be reused four times as catalyst without loss of its
activity in the synthesis of 2-amino-4,5-dihydro-4-phenyl-pyrano[3,2-b]indole-3-carbonitrile
123

An expeditious synthesis of a novel series
9–14), or other solvents, for example ethanol, methanol, and acetonitrile, were used
(Table 4, entries 6–8). It is concluded from the table that SiO2–AlCl3 in CH2Cl2
under reflux affords the best result. Unlike AlCl3, SiO2–AlCl3 is a milder catalyst
which forms no stable complex with the starting materials and/or products. The
efficiency of SiO2–AlCl3 may also be attributed to its large surface area and its
remarkable ability to act as a water scavenger.
Synthesis of a novel series of 11-amino-12-aryl-7,8,9,10,12,13-hexahydro-5-oxa-
6,13-diaza-indeno[1,2-b]anthracene derivatives 6a-l was achieved by cycloconden-
sation of 2-amino-4,5-dihydro-4-arylpyrano[3,2-b]indole-3-carbonitrile derivatives
4a–l with cyclohexanone in the presence of SiO2–AlCl3 in CH2Cl2 under reflux. The
results are given in Table 5. The progress of the reaction was monitored by TLC.
After completion of the reaction, the mixture was poured into a beaker containing
ice-cold water and extracted with CH2Cl2 (3 9 15 mL). The organic phase was
dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
The crude product was purified by column chromatography (with 40 % ethyl acetate
in hexane as mobile phase) to afford pure product 6 in good yield. It is important to
mention that under the reaction conditions investigated pyranopyridines 6 are
exclusively obtained as the only isolable product with no measurable side product.
A reasonable mechanism for preparation of 11-amino-12-aryl-7,8,9,10,12,13-
hexahydro-5-oxa-6,13-diaza-indeno[1,2-b]anthracene derivatives was proposed on
the basis of activation of cyclohexanone by SiO2–AlCl3 as the first step (Scheme 4).
Interaction of SiO2–AlCl3 with cyclohexanone depends on the ability of the catalyst
to act as a Brønsted or Lewis acid [40]. Subsequent intermolecular nucleophilic
attack by the NH2 group on the carbonyl carbon followed by dehydration produces
the intermediate 1, which is in equilibrium with the enamine 2. In the next step,
Table 4 Optimization of the reaction conditions using compound 4a as reference
Entry
Catalyst
Amount of catalyst
Solvent
Time (h)
Yield (%)a
1
AlCl3
1.2 equiv
0.12 mmol
0.08 mmol
0.10 mmol
0.14 mmol
0.12 mmol
0.12 mmol
0.12 mmol
1.5 equiv
1.5 equiv
1.5 equiv
1.5 equiv
1.5 equiv
1.5 equiv
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Ethanol
Methanol
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
2.0
1.2
1.8
1.4
1.2
3.0
3.0
3.0
2.0
2.0
2.0
2.0
2.0
2.0
62
88
58
71
87
–
2
SiO2–AlCl3
SiO2–AlCl3
SiO2–AlCl3
SiO2–AlCl3
SiO2–AlCl3
SiO2–AlCl3
SiO2–AlCl3
CaCl2
3
4
5
6
7
–
8
–
9
–
10
11
12
13
14
Bi(NO3)3
BiCl3
–
–
Cu(OTf)2
InCl3
–
–
FeCl3
–
Reaction conditions: compound 4a (1 mmol), cyclohexanone (1.3 mmol) in solvent (5 mL) at reflux
a
Isolated yield
123

M. Ghashang et al.
Table 5 Synthesis of 11-amino-12-aryl-7,8,9,10,12,13-hexahydro-5-oxa-6,13-diaza-indeno[1,2-b]anthracene
derivatives from compound 4 and cyclohexanone catalyzed by SiO2–AlCl3 (0.12 mmol)
Entry
Compound
Product
Time (h)
Yield (%)b
NH2
N
H
H
N
CN
N
O
NH2
O
4a
6a
1
1.2
88
NO2
NO2
NH2
H
H
N
CN
N
O
NH2
O
N
4b
6b
2
1.0
90
Cl
Cl
NH2
H
N
H
CN
N
O
NH2
O
N
4c
6c
3
1.0
91
N(CH3)2
N(CH3)2
NH2
H
H
N
CN
N
O
NH2
O
N
4d
6d
4
1.5
1.5
85
86
CH3
CH3
NH2
N
H
N
H
N
CN
O
NH2
O
4e
6e
5
6
Br
Br
NH2
N
H
N
H
N
CN
O
NH2
O
4f
6f
1.0
1.2
91
NO2
NH2
NO2
CN
H
N
H
N
O
NH2
O
N
4g
6g
7
89
123

An expeditious synthesis of a novel series
Table 5 continued
Entry
Compound
Product
Time (h)
Yield (%)b
CN
CN
NH2
N
H
H
N
CN
N
O
O
NH2
4h
6h
8
1.2
86
85
85
CH3
CH3
NH2
H
N
H
CN
N
O
NH2
O
N
4i
6i
9
1.5
1.2
Cl
Cl
NH2
H
N
H
CN
N
O
NH2
Br
O
N
4j
6j
10
11
Br
NH2
N
H
N
H
CN
N
O
NH2
O
4k
6k
1.2
1.0
92
F
F
NH2
H
N
H
CN
N
O
NH2
O
N
4l
6l
12
93
Reaction conditions: 4 (1 mmol), cyclohexanone (1.3 mmol), SiO2–AlCl3 (0.12 mmol) in CH2Cl2, at reflux
a
Isolated yield
activation of the nitrile group by SiO2–AlCl3 followed by intramolecular attachment
of the carbon nucleophile forms the intermediate 3, which is converted to the
desired product via imine–enamine equilibrium.
Ease of recycling of the catalyst is a valuable advantage of our method. In the reaction
of 4a with cyclohexanone, even after five cycles SiO2–AlCl3 still results in excellent
yields, implying that SiO2–AlCl3 can be reused without significant loss of activity (Fig. 2).
123

M. Ghashang et al.
O
O
SiO2-AlCl3
Cl
Cl
O
Al
H
O
O
O
O
O
O
Si
Si
Si
A
Ar
O
Ar
H
CN
N
H
N
CN
N
A
O
NH2
1
Ar
NH
N
H
Ar
N
H
CN
NH
N
SiO2-AlCl3
O
O
3
2
Ar
O
NH2
N
H
N
Scheme 4 Mechanism proposed for preparation of 11-amino-12-aryl-7,8,9,10,12,13-hexahydro-5-oxa-
6,13-diaza-indeno[1,2-b]anthracene derivatives
The nature of AlCl3 as a Lewis acid could be changed when it is supported on the
surfaceoftheSiO2. Aluminiumchlorideissoluble inmostorganicsolventsand,because
of its high activity, can react with the small water content of these solvents to form
Al(OH)3 as by-product. This results in strongly acidic media, because of quantitative
release of HCl into the reaction mixture, which results in unwanted side reactions. The
discovery of silica-supported aluminium chloride has overcome these problems. AlCl3
binds to the hydroxyl groups of the silica, forming proton-donating complexes. If the
supported catalyst is produced in toluene or CCl4 under reflux, SiO2–AlCl2 is formed,
with loss of HCl. Sites on the surface of SiO2–AlCl2 have strong Brønsted and Lewis
acidity. The Brønsted acidity of SiO2–AlCl2 commonly arises as a result of Lewis acid–
123

An expeditious synthesis of a novel series
90
89
88%
88
Recycling of SiO2-AlCl3
87%
87
86
85
84
83
82
81
80
85%
85%
83%
1
2
3
4
5
Number of Runs
Fig. 2 Recovery and reuse of the catalyst SiO2–AlCl3 in the synthesis of 11-amino-12-aryl-hexahydro-5-
oxa-6,13-diaza-indeno[1,2-b]anthracene in CH2Cl2 at reflux
Scheme 5 Brønsted acidity
arising as a result of the
Cl
Cl
inductive effect of Lewis acid–
base complexation
Al
O
OH
Si
O
O
O
O
Si
Si
base complexation (Scheme 5). Covalent bonding of AlCl3 with silica furnishes a
heterogeneous form of AlCl3 which can be recycled several times [40–43].
Conclusions
In conclusion, we report facile PPh3-catalyzed multicomponent condensation of
3-hydroxyindole, malononitrile, and aromatic aldehydes to afford 2-amino-4,5-
dihydro-4-phenyl-pyrano[3,2-b]indole-3-carbonitrile derivatives. Subsequent reac-
tion of these with cyclohexanone, in the presence of SiO2–AlCl3, furnishes novel
pyranopyridine derivatives. Advantages include improved yield, easier work-up,
shorter reaction time, and mild reaction conditions.
Acknowledgments The author Mansoor is grateful to the management of C. Abdul Hakeem College,
Melvisharam-632 509, Tamil Nadu, India, for facilities and support. Our sincere thanks are also due to
SAIF, Indian Institute of Technology, Madras, India, for recording spectral data.
123

M. Ghashang et al.
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