A simple and convenient approach to the Friedl?nder synthesis of pyrano[2,3-b]pyridines

Article abstract of DOI:10.1016/j.tet.2009.08.025

SnCl₂·2H₂O mediated efficient synthesis of pyrano[2,3-b]pyridines was achieved by the Friedla?nder reaction of 2-amino-3-cyano-4H-pyrans with cyclopentanone/cyclohexanone under solvent-free condition.

Full text of DOI:10.1016/j.tet.2009.08.025

Tetrahedron 65 (2009) 8524–8530
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
¨
A simple and convenient approach to the Friedlander synthesis
of pyrano[2,3-b]pyridines
*
Nagarajan Panneer Selvam, Thelagathoti Hari Babu, Paramasivan T. Perumal
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020, Tamilnadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 April 2009
Received in revised form 25 July 2009
Accepted 7 August 2009
Available online 13 August 2009
SnCl2$2H2O mediated efficient synthesis of pyrano[2,3-b]pyridines was achieved by the Friedla¨nder
reaction of 2-amino-3-cyano-4H-pyrans with cyclopentanone/cyclohexanone under solvent-free
condition.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Recently, SnCl2$2H2O16 has emerged both as the medium and
catalyst in various organic transformations. In view of its inherent
The presence of pyranopyridine scaffold in the frame work of
several biologically active naturally occurring alkaloids of plant
origin1 has enthused researchers to synthesize and study their
potential biological activities. They are known to possess anti-
allergic, anti-inflammatory, and estrogenic properties.2 In addition,
benzopyrano[2,3-b]pyridines exhibit anti-proliferative,3 cancer
chemopreventive,4 anti-bacterial (including anti-tubercular),5 anti-
myopic,6 anti-histamic,7 hypotensive,8 anti-rheumatic,9 and anti-
asthmatic activities.10
Despite numerous methods reported such as Skraup, Do¨bner-
von Miller, and Combes,11 the Friedla¨nder annulation is the most
simple and straightforward approach for the synthesis of poly-
substituted pyridines and related azaheterocycles. Friedla¨nder an-
nulation is acid or base catalyzed annulation of o-aminoaryl
properties like reusability, greater selectivity, operational simplic-
ity, non-corrosiveness, low cost, and ease of isolation, various
synthetic transformations were accomplished. Previously, our
group demonstrated the utility of SnCl2$2H2O as an alternative to
ionic liquid17d and employed it as a reaction medium for carrying
out various organic transformations. As part of our current studies
on the design of new routes for the preparation of biologically ac-
tive heterocyclic compounds,17 we herein disclose a simple and
convenient method for the synthesis of pyrano[2,3-b]pyridines by
Friedla¨nder reaction mediated by SnCl2$2H2O under solvent-free
condition (Scheme 1).
R
R
NH2
O
ketones with carbonyl compounds containing a reactive
a-methy-
SnCl H O
2.2
2
CN
+
lene group. Among various Friedla¨nder syntheses, cyclo-
condensation of o-aminobenzonitrile with various ketones has
been less explored. Previous investigation12,13 on condensation of
these derivatives required prolonged reaction times, use of haz-
ardous reagents and limits the large scale application. In view of its
immense biological applications, the development of simple and
convenient protocol is of considerable interest.
( )n
neat, 110 °C
4-5h
( )n
O
N
O
NH2
Scheme 1.
2. Results and discussion
In our initial endeavor, we investigated the reaction of 1a with
cyclohexanone 2a using various Lewis acid catalysts in different
solvents (methanol, ethanol, and 1,2-dichloroethane) and neat at
reflux or at 100 ꢀC (Scheme 2 and Table 1). After systematic
screening, we observed that tinchloride dihydrate gave moderate
yield under solvent-free condition with equimolar amount of cat-
alyst at 100 ꢀC. Then, we optimized the reaction condition by in-
creasing/decreasing the catalyst loading and temperature. The best
result was obtained when the reaction was carried out with
SnCl2$2H2O (also serving as reaction medium) under solvent-free
condition at 110 ꢀC. Further increase of temperature did not
Over the past few years, organic reactions under solvent-free
conditions have gained much popularity.14 Solvent-free reactions
are not only of interest from ecological point of view, but in many
cases, also offer several synthetic advantages like higher yields,
reduced pollution, low cost, improved selectivities, and simplicity
in process and handling.15
* Corresponding author. Tel.: þ91 44 24911386; fax:þ91 44 24911589.
E-mail address: ptperumal@gmail.com (P.T. Perumal).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.025

N.P. Selvam et al. / Tetrahedron 65 (2009) 8524–8530
8525
Cl
multiplets at
d
1.72, 2.26, and 2.83. Signals at
d
154.2 (–C]N), 160.4
Cl
(–C–NH2), 22.3–32.4 (–CH2 groups) in the 13C NMR spectrum
confirmed that cyclohexanone reacted with –NH2 and –CN of py-
ran. Mass analysis also supported the structural assignment.
A mechanistic rationalization for the reaction is given in Scheme 5.
O
O
O
NH2
N
CN
various conditions
O
O
+
O
NH2
O
3. Conclusion
1a
2a
3a
In summary, we have developed a simple and convenient
method for the synthesis of highly substituted pyranopyridines
from 2-amino-3-cyano-4H-pyrans and cyclohexanone/cyclo-
pentanone using inexpensive and commercially available
SnCl2$2H2O under solvent-free condition. The major advantage of
this protocol is that SnCl2$2H2O (as reaction medium) can be
recycled upto three times without much change in yield. The
generality of the reaction was also extended to the synthesis of
naphthopyranopyridines in moderate yields.
Scheme 2.
improve the product yield or increase the reaction rate. We also
studied the recyclability of SnCl2$2H2O as reaction medium.
SnCl2$2H2O is insoluble in dichloromethane. This property was
utilized in recycling the reaction medium. Since SnCl2$2H2O is in-
soluble in dichloromethane, it was used to bring out the organic
part from the reaction mixture. Thus, dichloromethane leaves the
SnCl2$2H2O in reaction vessel, which was recycled for further re-
actions (three times). The yield did not vary much while recycling
the reaction medium and the yields were found to be 56, 55, and 53,
respectively.
4. Experimental
4.1. Materials and methods
SnCl2$2H2O, NH2SO3H, CAN, and FeCl3 were obtained from S.D.
Fine Chem. Ltd. Bi(OTf)3, In(OTf)3, InCl3, and BiCl3 were purchased
from Aldrich and used as received. All melting points were un-
corrected. IR spectra were recorded on a Perkin Elmer FT-IR spec-
trophotometer. 1H and 13C NMR spectra were recorded in CDCl3
using TMS as an internal standard on JEOL spectrometer at
500 MHz and 125 MHz and Bruker spectrometer at 300 MHz and
75 MHz, respectively. Mass spectra were recorded by electrospray
ionization method on Thermo Finnegan Mass spectrometer. Ele-
mental analyses were recorded using a Thermo Finnegan FLASH EA
1112 CHN analyzer. Column chromatography was performed on
silica gel (100–200 mesh, SRL, India). Analytical TLC was performed
on precoated plastic sheets of silica gel G/UV-254 of 0.2 mm
thickness (Macherey-Nagel, Germany).
Table 1
Catalyst and solvent screening
Entry
Catalyst
Yielda (%)
MeOH
EtOH
DCE
Neat
1
2
3
4
5
6
7
8
InCl3
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
5
8
d
In(OTf)3
SnCl2.2H2O
NH2SO3H
CAN
BiCl3
Bi(OTf)3
FeCl3
d
45
d
d
5
10
6
54
Trace
d
10
12
12
a
All reactions were performed with 100 mol % catalyst at reflux or 100 ꢀC for 5 h.
Table 2 summarizes our results on the Friedla¨nder reaction of
various 2-amino-3-cyano-4H-pyrans18 with cyclohexanone/cyclo-
pentanone under optimized condition (Scheme 3). The reaction
was amenable to wide variations in 2-amino-3-cyano-4H-pyrans
and afforded the corresponding highly substituted pyranopyridines
3a–l in moderate yields.
4.2. General procedure for the synthesis of pyranopyridines
To a two-neck round-bottomed flask fitted with a mechanical
stirrer and oil bath, 2 g of SnCl2$2H2O was added and stirred at 50 ꢀC.
SnCl2$2H2O became viscous liquid. To this viscous liquid, 2-amino-
3-cyano-4H-pyran 1 (1 mmol) and cyclohexanone 2a (1.1 mmol)
were added and stirred at same temperature for about 15 min. Then
stirring was continued at 110 ꢀC until the disappearance of starting
materials, as indicated by TLC. After the completion of the reaction,
the reaction mixture was allowed to cool to 40 ꢀC and triturated
with dichloromethane (3ꢂ15 mL) and stirred for 10 min. The organic
layer thus obtained was washed twice with water and with satu-
rated sodium chloride solution, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The crude product was pu-
rified through column chromatography (40% ethyl acetate in pe-
troleum ether). The round-bottom flask, which contains the
SnCl2$2H2O was again utilized for recycling the reaction medium
(successfully recycled three times). The same procedure was fol-
lowed for the synthesis of naphthopyranopyridines 5a–e.
The structures of all products 3a–l were confirmed by IR, 1H
NMR, 13C NMR, mass, and elemental analysis. In the IR spectrum of
3a, disappearance of –CN group and a peak at 1638 cmꢁ1 (–C]N–)
confirmed the formation of pyridine ring. Absorptions at 3435,
3349, and 1209 cmꢁ1 indicated the presence of –NH2 and –C–O–C-
groups, respectively. Signals at
d 150.2 (–C]N), 154.2 (–C–NH2),
22.3–32.4 (–CH2 groups) in the 13C NMR spectrum confirmed that
cyclohexanone reacted with –NH2 and –CN of 2-amino-3-cyano-
4H-pyran. The 1H NMR spectrum of 3a displayed signals at
d 1.76,
2.20, and 2.71 (–CH2 protons of cyclohexyl ring) and 4.03 (–NH2
protons, D2O exchangeable). Mass analysis also supported the
structural assignment.
To further explore the potential of this protocol, we investigated
the reaction of 2-amino-3-cyano chromenes with cyclohexanone/
cyclopentanone and obtained the corresponding naphthopyr-
anopyridines 5a–e in moderate yields (Scheme 4 and Table 3).
The structures of all products 5a–e were confirmed by IR, 1H
NMR, 13C NMR, mass, and elemental analysis. The IR spectrum of 5e
showed absorptions at 3483, 3397, and 1109 cmꢁ1 indicating the
presence of –NH2 and –C–O–C-groups, respectively. Disappearance
of –CN group and a peak at 1628 cmꢁ1 (–C]N–) confirmed the
formation of pyridine ring. In the 1H NMR spectrum, –NH2 protons
4.2.1. Ethyl 5-amino-4-(4-chlorophenyl)-2-methyl-6,7,8,9-tetrahydro-
4H-pyrano[2,3-b]quinoline-3-carboxylate (3a). Off white solid; mp
138–140 ꢀC; Rf 0.65 (40% EtOAc/petroleum ether); IR nmax (KBr):
3435, 3349, 2928, 1685,1638,1571, 1447,1295,1209,1057, 833 cmꢁ1
;
1H NMR (500 MHz, CDCl3)
(m, 4H, –CH2), 2.20 (m, 2H, –CH2), 2.42 (s, 3H, –CH3), 2.71 (m, 2H,
–CH2), 4.03 (br s, 2H, D2O exchangeable, –NH2), 4.09 (m, 2H,
–OCH2CH3), 4.80 (s, 1H, –CH), 7.18 (m, 4H, –Ar–H); 13C NMR
d
: 1.22 (t, 3H, J¼6.9 Hz, –OCH2CH3), 1.76
appeared as a broad singlet at
d 4.19 (D2O exchangeable) and the
methylene protons (–CH2) of cyclohexyl ring were seen as
(125 MHz, CDCl3) d: 14.2, 19.8, 22.3, 22.5, 22.9, 32.4, 37.9, 60.4, 99.2,

8526
N.P. Selvam et al. / Tetrahedron 65 (2009) 8524–8530
Table 2
Synthesis of pyrano[2,3-b]pyridines 3a–l
Entry
2-Amino-3-cyano-4H-pyrans (1)
Cyclic ketone (2)
Product (3)a
Time (h)
Yieldb (%)
Cl
Cl
O
O
O
NH2
N
CN
1
4.5
58
H3C
O
H3C
O
CH3
CH3
1a
O
NH2
O
2a
3a
NO2
NO2
NH2
O
O
O
CN
H3C
O
H3C
O
2
4.5
60
CH3
1b
O
NH2
CH3
O
N
2a
3b
F
F
O
O
O
NH2
N
H3C
CN
H3C
O
O
CH3
3
4.2
64
CH3
O
NH2
O
2a
1c
3c
Cl
O
Cl
O
O
O
NH2
CH3
CH3
CH3
CN
4
4.5
64
O
O
CH3
CH3
1d
NH2
CH3
O
3d
N
2a
Cl
Cl
Cl
Cl
NH2
O
O
O
H3C
CN
H3C
5
4.5
62
O
O
CH3
CH3
1e
O
NH2
O
N
2a
3e
NO2
NO2
O
O
NH2
N
O
CN
CH3
CH3
CH3
CH3
6
4.2
60
O
O
NH2
2a
1f
3f
NO2
NO2
O
O
O
NH2
N
7
CN
4.0
65
2a
O
O
NH2
3g
1g

N.P. Selvam et al. / Tetrahedron 65 (2009) 8524–8530
8527
Table 2 (continued)
Entry
2-Amino-3-cyano-4H-pyrans (1)
Cyclic ketone (2)
Product (3)a
Time (h)
Yieldb (%)
NO2
NO2
O
O
O
NH2
CN
8
4.0
65
O
1h
NH2
O
N
2a
3h
NO2
NO2
NH2
O
O
O
O
O
CN
CH3
CH3
CH3
CH3
9
5.0
62
O
NH2
O
N
2a
3i
1i
Cl
Cl
Cl
Cl
O
NH2
O
CN
10
5.0
63
CH3
CH3
CH3
CH3
O
N
O
NH2
2a
1j
3j
Cl
Cl
O
O
NH2
N
H3C
CN
H3C
11
4.5
62
O
O
CH3
CH3
O
NH2
2b
O
1k
3k
NO2
NO2
O
O
O
NH2
N
12
5.0
63
CN
CH3
CH3
CH3
CH3
2a
O
NH2
O
1l
31
a
All products were characterized by IR, 1H NMR, 13C NMR, mass spectral, and elemental analysis.
Isolated yield.
b
106.4, 113.7, 128.7, 129.8, 132.8, 142.4, 150.2, 154.2, 154.3, 160.1, 166.7;
204–206 ꢀC; Rf 0.57 (40% EtOAc/petroleum ether); IR nmax (KBr):
MS (ESI LCQ-MS): m/z 399 [Mþ1]þ. Anal. Calcd for C22H23N2O3Cl: C,
3438, 3340, 2932, 1686, 1642, 1529, 1353, 1230, 1065, 801,
66.24; H, 5.81; N, 7.02%. Found: C, 66.41; H, 5.77; N, 7.04%.
685 cmꢁ1
;
1H NMR (500 MHz, CDCl3)
d
: 1.24 (t, 3H, J¼7.7 Hz,
–OCH2CH3), 1.78 (m, 4H, –CH2), 2.33 (m, 2H, –CH2), 2.46 (s, 3H,
–CH3), 2.74 (m, 2H, –CH2), 4.11 (br s, 2H, D2O exchangeable, –NH2),
4.12 (m, 2H, –OCH2CH3), 4.95 (s, 1H, –CH), 7.42 (t,1H, J¼8.4 Hz, –Ar–
4.2.2. Ethyl 5-amino-2-methyl-4-(3-nitrophenyl)-6,7,8,9-tetrahydro-
4H-pyrano[2,3-b]quinoline-3-carboxylate (3b). Off white solid; mp
R
NH2
R
R
NH2
R
O
O
O
O
CN
2
SnCl2. H2O
CN
.
SnCl2 2H2O
+
+
( )n
( )n
neat, 110 °C
4-5h
( )n
neat, 110 °C
4-5h
( )n
O
N
O
N
O
NH2
O
1
NH2
2
4
2
5a-e
3a-l
Scheme 4.
Scheme 3.

8528
N.P. Selvam et al. / Tetrahedron 65 (2009) 8524–8530
Table 3
Synthesis of naphthopyranopyridines 5a–e
Entry
2-Amino-3-cyano chromenes (4)
Cyclic ketone (2)
Product (5)a
Time (h)
Yieldb (%)
NO2
NO2
NH2
O
CN
1
3.5
62
O
NH2
O
N
2a
5a
4a
Cl
Cl
O
NH2
N
CN
2
3
4
4.0
60
2b
O
4b
NH2
O
5b
NO2
NO2
O
NH2
N
CN
3.0
64
2b
O
NH2
O
5c
4c
NO2
NO2
NH2
O
CN
4.0
60
O
4d
Cl
NH2
O
N
2a
5d
Cl
O
NH2
N
Cl
Cl
5
CN
4.0
60
O
NH2
2a
O
5e
4e
a
All products were characterized by IR, 1H NMR, 13C NMR, mass spectral, and elemental analysis.
Isolated yield.
b
H), 7.58 (d, 1H, J¼7.7 Hz, –Ar–H), 8.03 (d, 1H, J¼8.4 Hz, –Ar–H), 8.19
(s, 1H, –Ar–H); 13C NMR (125 MHz, CDCl3)
: 14.3, 17.6, 23.7, 32.5,
34.7, 60.8, 98.4, 105.8, 114.0, 121.7, 122.9, 123.9, 129.4, 137.6, 146.1,
148.2, 150.1, 154.3, 154.8, 161.3, 166.5; MS (ESI LCQ-MS): m/z 410
[Mþ1]þ. Anal. Calcd for C22H23N3O5: C, 64.54; H, 5.66; N, 10.26%.
Found: C, 64.63; H, 5.69; N, 10.24%.
d
SnCl2.2H2O
SnCl2.2H2O
SnCl2.2H2O
Ar
O
Ar
O
Ar
O
N
N
O
CN
CN
-H2O
OH
+
( )n
( )n
N
H
NH2
( )n
SnCl2.2H2O
Ar HN
4.2.3. Methyl 5-amino-4-(3-fluorophenyl)-2-methyl-6,7,8,9-tetrahy-
dro-4H-pyrano[2,3-b]quinoline-3-carboxylate (3c). Yellow solid; mp
222–224 ꢀC; Rf 0.61 (40% EtOAc/petroleum ether); IR nmax (KBr):
3453, 3372, 2932, 1692, 1643, 1446, 1380, 1295, 1234, 1064,
SnCl2.2H2O
Ar NH2
Ar
O
N
( )n
( )n
( )n
774 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d: 1.63 (m, 4H, –CH2), 2.34 (m,
O
N
O
N
N
H
3 and 5
2H, –CH2), 2.44 (s, 3H, –CH3), 2.74 (m, 2H, –CH2), 3.75 (s, 3H, –OCH3),
4.02 (s, 2H, D2O exchangeable, NH2), 4.85 (s, 1H, –CH), 6.88 (t, 1H,
Scheme 5.

N.P. Selvam et al. / Tetrahedron 65 (2009) 8524–8530
8529
J¼8.4 Hz, –Ar–H), 6.97 (d,1H, J¼9.2 Hz, –Ar–H), 7.08 (d,1H, J¼6.9 Hz,
–Ar–H), 7.19 (s, 1H, –Ar–H); 13C NMR (75 MHz, CDCl3)
: 19.8, 22.3,
22.5, 22.9, 29.7, 32.4, 38.2, 51.4, 99.0, 106.1, 113.7, 114.1, 115.3, 123.9,
130.1, 146.5, 150.3, 154.2, 160.4 (JC–F¼240.2 Hz), 163.8, 167.2; MS (ESI
LCQ-MS): m/z 369 [Mþ1]þ. Anal. Calcd for C21H21N2O3F: C, 68.46; H,
5.75; N, 7.60%. Found: C, 68.62; H, 5.80; N, 7.67%.
2H, –CH2), 2.33 (m, 2H, –CH2), 2.75 (m, 2H, –CH2), 4.06 (s, 2H, D2O
d
exchangeable, –NH2), 5.00 (s, 1H, –CH), 7.51 (d, 2H, J¼8.4 Hz, –Ar–
H), 8.09 (d, 2H, J¼8.4 Hz, –Ar–H); 13C NMR (75 MHz, CDCl3)
d: 21.4,
21.9, 22.4, 32.1, 33.9, 34.8, 34.9, 33.1, 52.7, 111.3, 113.8, 114.6, 123.8,
130.1, 144.1, 153.4, 154.3, 160.2, 164.3, 198.6; MS (ESI LCQ-MS): m/z
392 [Mþ1]þ. Anal. Calcd for C22H21N3O4: C, 67.51; H, 5.41; N,10.74%.
Found: C, 67.83; H, 5.40; N, 10.69%.
4.2.4. Isopropyl 5-amino-4-(4-chlorophenyl)-2-methyl-6,7,8,9-tetra-
hydro-4H-pyrano[2,3-b]quinoline-3-carboxylate (3d). Pale brown
solid; mp 130–132 ꢀC; Rf 0.52 (40% EtOAc/petroleum ether); IR nmax
(KBr): 3441, 3365, 2928, 1689, 1642, 1452, 1371, 1297, 1211, 1098,
4.2.9. 11-Amino-3,3-dimethyl-12-(3-nitrophenyl)-3,4,7,8,9,10-hexa-
hydro-2H-chromeno[2,3-b]quinolin-1(12H)-one (3i). White solid;
mp 290–292 ꢀC [lit:19 293 ꢀC]; Rf 0.46 (40% EtOAc/petroleum
ether); IR nmax (KBr): 3424, 3387, 2935, 1637, 1564, 1535, 1421, 1370,
1060, 834 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d: 1.16 (d, 3H, J¼6.1 Hz,
–CH3), 1.22 (d, 3H, J¼6.1 Hz, –CH3), 1.76 (m, 4H, –CH2), 2.29 (m, 2H,
–CH2), 2.41 (s, 3H, –CH3), 2.71 (m, 2H, –CH2), 4.03 (s, 2H, D2O ex-
changeable, –NH2), 4.78 (s, 1H, –CH), 4.97 (m,1H, –OCH(CH3)2), 7.20
1232, 1032, 580 cmꢁ1 1H NMR (500 MHz, CDCl3)
; d: 1.08 (s, 3H,
–CH3), 1.24 (s, 3H, –CH3), 1.82 (m, 4H, –CH2), 2.23 (m, 4H, –CH2),
2.57 (m, 2H, –CH2), 2.77 (m, 2H, –CH2), 4.07 (br s, 2H, D2O ex-
changeable, –NH2), 4.98 (s, 1H, –CH), 7.41 (t, 1H, J¼7.7 Hz, –Ar–H),
7.70 (d, 1H, J¼7.7 Hz, –Ar–H), 8.02 (d, 1H, J¼8.4 Hz, –Ar–H), 8.18 (s,
(s, 4H, –Ar–H); 13C NMR (75 MHz, CDCl3)
d: 18.3, 22.4, 22.6, 22.9,
32.5, 37.5, 99.3, 106.6, 113.8, 128.3, 129.1, 129.5, 132.9, 142.4, 150.3,
154.3, 159.3, 166.3; MS (ESI LCQ-MS): m/z 412 [Mþ1]þ. Anal. Calcd
for C23H25N2O3Cl: C, 66.90; H, 6.10; N, 6.78%. Found: C, 67.12; H,
6.14; N, 6.81%.
1H, –Ar–H); 13C NMR (75 MHz, CDCl3)
d: 21.2, 21.4, 21.9, 26.1, 28.0,
31.1, 32.7, 40.2, 43.0, 49.5, 97.2, 112.1, 113.0,120.5, 122.2, 144.9, 146.8,
150.5, 152.5, 153.0, 164.3, 195.2; MS (ESI LCQ-MS): m/z 420 [Mþ1]þ.
Anal. Calcd for C24H25N3O4: C, 68.72; H, 6.01; N, 10.02%. Found: C,
69.01; H, 6.04; N, 10.09%.
4.2.5. Methyl 5-amino-4-(2,4-dichlorophenyl)-2-methyl-6,7,8,9-tetra-
hydro-4H-pyrano[2,3-b]quinoline-3-carboxylate (3e). Light brown
solid; mp 222–224 ꢀC; Rf 0.57 (40% EtOAc/petroleum ether); IR nmax
(KBr): 3483, 3396, 2934, 1713, 1642, 1451, 1397, 1224, 1064, 1099,
4.2.10. 11-Amino-12-(2,4-dichlorophenyl)-3,3-dimethyl-3,4,7,8,9,10-
hexahydro-2H-chromeno[2,3-b]quinolin-1(12H)-one (3j). Pale yel-
low solid; mp 282–284 ꢀC; Rf 0.49 (40% EtOAc/petroleum ether); IR
nmax (KBr): 3404, 3348, 2933, 1649, 1369, 1230, 1168, 1039, 852,
845, 655 cmꢁ1 1H NMR (500 MHz, CDCl3)
; d: 1.65 (m, 2H, –CH2),
1.83 (m, 2H, –CH2), 2.31 (m, 2H, –CH2), 2.48 (s, 3H, –CH3), 2.69 (m,
2H, –CH2), 3.63 (s, 3H, –OCH3), 4.40 (s, 2H, D2O exchangeable,
567 cmꢁ1 1H NMR (500 MHz, CDCl3)
; d: 0.97 (s, 3H, –CH3), 1.09 (s,
–NH2), 5.21 (s,1H, –CH), 7.14 (m, 2H, –Ar–H), 7.29 (s,1H, –Ar–H); 13
C
3H, –CH3), 1.78 (m, 4H, –CH2), 2.32 (m, 4H, –CH2), 2.56 (m, 2H,
–CH2), 2.72 (m, 2H, –CH2), 4.38 (s, 2H, D2O exchangeable, –NH2),
5.19 (s, 1H, –CH), 7.12 (d, 2H, J¼8.4 Hz, –Ar–H), 7.31 (s, 1H, –Ar–H);
NMR (75 MHz, CDCl3) d: 22.4, 22.9, 32.0, 34.8, 50.8, 98.9, 105.8,
113.4, 129.2, 132.3, 140.7, 150.4, 154.1, 154.2, 161.7, 162.7, 167.0; MS
(ESI LCQ-MS): m/z 419 [Mþ1]þ. Anal. Calcd for C21H20N2O3Cl2: C,
60.15; H, 4.81; N, 6.68%. Found: C, 60.28; H, 4.83; N, 6.71%.
13C NMR (75 MHz, CDCl3)
d: 18.4, 21.8, 28.4, 32.3, 34.7, 47.1, 54.3,
61.2, 111.8, 113.4, 115.4, 126.8, 130.1, 133.1, 136.4, 136.7, 150.1, 154.9,
160.2, 164.8, 198.3; MS (ESI LCQ-MS): m/z 443 [Mþ1]þ. Anal. Calcd
for C24H24N2O2Cl2: C, 65.02; H, 5.46; N, 6.32%. Found: C, 65.28; H,
5.49; N, 6.31%.
4.2.6. 1-(5-Amino-2-methyl-4-(3-nitrophenyl)-6,7,8,9-tetrahydro-
4H-pyrano[2,3-b]quinolin-3-yl)ethanone (3f). Pale brown solid; mp
238–240 ꢀC; Rf 0.62 (40% EtOAc/petroleum ether); IR nmax (KBr):
3433, 3357, 2925, 1706, 1631, 1528, 1351, 682 cmꢁ1
;
1H NMR
4.2.11. 10-Amino-8-(4-chlorophenyl)-6-methyl-1,2,3,8-tetrahydro-5-
oxa-4-aza-cyclopenta[b]naphthacene-7-carboxylic acid methyl ester
(3k). Off white solid; mp 182–184 ꢀC; Rf 0.59 (40% EtOAc/petro-
leum ether); IR nmax (KBr): 3461, 3336, 2956, 1714, 1559, 1446, 1208,
(500 MHz, CDCl3) d: 1.80 (m, 4H, –CH2), 2.33 (m, 5H, –CH3 and
–CH2), 2.49 (s, 3H, acetyl–CH3), 2.75 (m, 2H, –CH2), 4.10 (br s, 2H,
D2O exchangeable, –NH2), 5.06 (s, 1H, –CH), 7.41 (t, 1H, J¼7.7 Hz,
–Ar–H), 7.63 (d, 1H, J¼7.7 Hz, –Ar–H), 8.02 (d, 1H, J¼8.4 Hz, –Ar–H),
1096, 820 cmꢁ1 1H NMR (500 MHz, CDCl3)
; d: 1.72 (s, 3H, –CH3),
8.15 (s, 1H, –Ar–H); 13C NMR (75 MHz, CDCl3)
d
: 18.3, 21.3, 22.8,
1.96 (m, 2H, –CH2), 2.58 (m, 2H, –CH2), 2.93 (m, 2H, –CH2), 3.86 (s,
3H, –OCH3), 4.13 (br s, 2H, D2O exchangeable, –NH2), 4.89 (s, 1H,
–CH), 6.97 (d, 2H, J¼7.7 Hz, –Ar–H), 7.15 (d, 2H, J¼7.7 Hz, –Ar–H);
23.6, 32.3, 38.6, 110.4, 114.6, 115.3, 128.3, 130.1, 136.2, 139.4, 149.4,
153.4, 155.1, 156.3, 166.4, 198.6; MS (ESI LCQ-MS): m/z 380 [Mþ1]þ.
Anal. Calcd for C21H21N3O4: C, 66.48; H, 5.58; N, 11.08%. Found: C,
66.72; H, 5.61; N, 11.04%.
13C NMR (75 MHz, CDCl3)
d: 18.4, 24.2, 24.8, 34.7, 52.6, 96.4, 104.7,
105.8, 114.2, 130.1, 132.3, 136.3, 152.6, 154.8, 155.7, 163.9, 165.1; MS
(ESI LCQ-MS): m/z 371 [Mþ1]þ. Anal. Calcd for C20H19N2O3Cl: C,
64.78; H, 5.16; N, 7.55%. Found: C, 64.93; H, 5.18; N, 7.49%.
4.2.7. 11-Amino-12-(3-nitrophenyl)-3,4,7,8,9,10-hexahydro-2H-chro-
meno[2,3-b]quinolin-1(12H)-one (3g). Pale yellow solid; mp 242–
244 ꢀC; Rf 0.50 (40% EtOAc/petroleum ether); IR nmax (KBr): 3468,
4.2.12. 11-Amino-3,3-dimethyl-12-(4-nitrophenyl)-3,4,7,8,9,10-hexa-
3365, 2931, 1631, 1530, 1351, 1192, 1076, 716 cmꢁ1
;
1H NMR
hydro-2H-chromeno[2,3-b]quinolin-1(12H)-one
(3l). Off white
(500 MHz, CDCl3)
d: 1.22 (m, 2H, –CH2), 2.02 (m, 4H, –CH2), 2.35 (m,
solid; mp: 322–324 ꢀC [lit:19 323–325 ꢀC]; Rf 0.49 (40% EtOAc/pe-
troleum ether); IR nmax (KBr): 3402, 3232, 2927, 1637, 1517, 1370,
4H, –CH2), 2.75 (m, 4H, –CH2), 4.15 (s, 2H, D2O exchangeable, –NH2),
5.02 (s, 1H, –CH), 7.40 (t, 1H, J¼7.7 Hz, –Ar–H), 7.69 (d, 1H, J¼7.7 Hz,
–Ar–H), 8.00 (d, 1H, J¼6.9 Hz, –Ar–H), 8.17 (s, 1H, –Ar–H); 13C NMR
1370, 1346, 1228, 1205, 1032, 802, 579 cmꢁ1 1H NMR (500 MHz,
;
CDCl3) d: 0.92 (s, 3H, –CH3), 1.07 (s, 3H, –CH3), 1.80 (m, 4H, –CH2),
(75 MHz, CDCl3)
d: 20.2, 22.8, 32.3, 33.6, 34.9, 36.9, 98.6, 114.1, 121.6,
2.13 (m, 4H, –CH2), 2.54 (m, 2H, –CH2), 2.74 (m, 2H, –CH2), 4.10 (br s,
2H, D2O exchangeable, –NH2), 4.98 (s, 1H, –CH), 7.50 (d, 2H,
J¼8.4 Hz, –Ar–H), 8.08 (d, 2H, J¼8.4 Hz, –Ar–H); 13C NMR (75 MHz,
122.8,124.1, 128.8,135.4,145.5,148.5, 150.7, 154.2,154.8,167.4, 197.0;
MS (ESI LCQ-MS): m/z 392 [Mþ1]þ. Anal. Calcd for C22H21N3O4: C,
67.51; H, 5.41; N, 10.74%. Found: C, 67.64; H, 5.42; N, 10.78%.
CDCl3) d: 18.6, 22.3, 22.5, 23.0, 32.5, 34.6, 98.6, 114.7, 126.3, 127.2,
134.1, 136.2, 152.3, 154.4, 156.8, 162.0; MS (ESI LCQ-MS): m/z 420
[Mþ1]þ. Anal. Calcd for C24H25N3O4: C, 68.72; H, 6.01; N, 10.02%.
Found: C, 68.99; H, 5.98; N, 10.09%.
4.2.8. 11-Amino-12-(4-nitrophenyl)-3,4,7,8,9,10-hexahydro-2H-
chromeno[2,3-b]quinolin-1(12H)-one (3h). Off white solid; mp 242–
244 ꢀC; Rf 0.52 (40% EtOAc/petroleum ether); IR nmax (KBr): 3410,
3368, 2930, 1637, 1564, 1520, 1348, 1190, 1074 cmꢁ1
;
1H NMR
4.2.13. 14-(3-Nitrophenyl)-9,11,12,14-tetrahydro-10H-7-oxa-8-aza-
(500 MHz, CDCl3)
d: 1.23 (m, 2H, –CH2), 1.81 (m, 6H, –CH2), 2.03 (m,
benzo[a]-naphthacen-13-ylamine (5a). Pale yellow solid; mp 284–

8530
N.P. Selvam et al. / Tetrahedron 65 (2009) 8524–8530
286 ꢀC [lit:20 287–289 ꢀC]; Rf 0.53 (40% EtOAc/petroleum ether); IR
nmax (KBr): 3456, 3324, 2928, 1654, 1535, 1349, 1233, 1082, 816,
–Ar–H), 7.73 (d, 1H, J¼8.4 Hz, –Ar–H), 8.12 (d, 1H, J¼8.4 Hz, –Ar–H),
8.61 (d, 1H, J¼8.4 Hz, –Ar–H); 13C NMR (125 MHz, CDCl3)
d: 22.3,
680 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d: 1.80 (m, 4H, –CH2), 2.34 (m,
22.8, 29.7, 32.4, 38.2, 99.0, 106.1, 113.7, 114.2, 115.3, 121.3, 122.4,
123.9, 125.6, 126.9, 128.2, 130.1, 132.0, 133.7, 143.4, 147.8, 150.3,
154.2, 160.4, 164.0; MS (ESI LCQ-MS): m/z 447 [Mþ1]þ. Anal. Calcd
for C26H20N2OCl2: C, 69.81; H, 4.51; N, 6.26%. Found: C, 70.13; H,
4.54; N, 6.30%.
2H, –CH2), 2.75 (m, 2H, –CH2), 4.11 (br s, 2H, D2O exchangeable,
–NH2), 5.32 (s, 1H, –CH), 7.81 (m, 5H, –Ar–H), 8.01 (m, 4H, –Ar–H),
8.44 (s, 1H, –Ar–H); 13C NMR (125 MHz, CDCl3)
d: 22.4, 22.8, 26.4,
32.1, 34.8, 98.8, 105.4, 113.4, 115.2, 117.5, 121.5, 122.4, 122.8, 123.9,
126.6, 132.1, 133.2, 134.5, 142.3, 151.0, 154.5, 159.9, 163.7; MS (ESI
LCQ-MS): m/z 424 [Mþ1]þ. Anal. Calcd for C26H21N3O3: C, 73.74; H,
5.00; N, 9.92%. Found: C, 73.99; H, 5.04; N, 9.98%.
Acknowledgements
One of the author, N.P.S. thanks the Council of Scientific and
Industrial Research (CSIR), New Delhi for financial assistance.
4.2.14. 13-(4-Chlorophenyl)-9,10,11,13-tetrahydro-7-oxa-8-aza-benzo-
[a]-cyclopenta[l]anthracene-12-ylamine (5b). Off white solid; mp
214–216 ꢀC; Rf 0.61 (40% EtOAc/petroleum ether); IR nmax (KBr):
References and notes
3431, 3372, 2936, 1601, 1451, 1209, 1086, 823 cmꢁ1 1H NMR
;
1. (a) Ahmad, S. J. Nat. Prod. 1984, 47, 391; (b) Mitaka, S.; Skaltsounis, A.-L.; Till-
equin, F.; Koch, M.; Pusset, J.; Chauviere, G. J. Nat. Prod. 1985, 48, 772; (c) Ulu-
belen, A. Phytochemistry 1984, 23, 2123; (d) Tantivatana, P.; Ruangrungsi, N.;
Vaisiroiroj, V.; Lankin, D. C.; Bhacca, N. S.; Borris, R. P.; Cordell, G. A.; Johnson, L. F.
J. Org. Chem. 1983, 48, 268; (e) Munoz, M. A.; torres, R.; Cassels, B. K. J. Nat. Prod.
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2. (a) Faber, K.; Stueckler, H.; Kappe, T. J. Heterocycl. Chem. 1984, 21, 1171; (b)
Johnson, J. V.; Rauckman, S.; Beccanari, P. D.; Roth, B. J. Med. Chem. 1989, 32,
1942; (c) Yamada, N.; Kadowaki, S.; Takahashi, K.; Umeza, K. Biochem. Phar-
macol. 1992, 44, 1211.
(500 MHz, CDCl3) d: 1.96 (m, 2H, –CH2), 2.48 (m, 2H, –CH2), 2.68 (m,
2H, –CH2), 4.21 (m, 2H, D2O exchangeable, –NH2), 5.41 (s, 1H, –CH),
7.10 (m, 4H, –Ar–H), 7.42 (m, 6H, –Ar–H); 13C NMR (125 MHz,
CDCl3) d: 22.1, 22.9, 25.7, 34.6, 97.3, 106.4, 114.9, 117.4, 119.2, 121.8,
122.3, 126.3, 127.4, 127.8, 128.3, 129.4, 130.2, 134.2, 141.8, 153.8,
157.8, 162.4, 164.3; MS (ESI LCQ-MS): m/z 399 [Mþ1]þ. Anal. Calcd
for C25H19N2OCl: C, 75.28; H, 4.80; N, 7.02%. Found: C, 75.53; H,
4.84; N, 7.05%.
3. Kolokythas, G.; Pouli, N.; Marakos, P.; Pratsinis, H.; Kletsas, D. Eur. J. Med. Chem.
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Eds.; Pergamon:NewYork, NY,1996; Vol. 5, p 167;(b) Cho, C. S.; Oh, B. H.; Kim, T. J.;
Shim, S. C. J. Chem. Soc., Chem. Commun. 2000, 1885; (c) Jiang, B.; Si, Y. C. J. Org.
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Zhang, L. J.; Yang, X. Q.; Li, Q.; Wang, D.; Wang, C. X.; Shi, D. X.; Zhang, Q. Chin.
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13. (a) de los Rios, C.; Marco, J. L.; Carreiras, M. C.; Chinchon, P. M.; Garcia, A. G.;
Villarroya, M. Bioorg. Med. Chem. 2002, 10, 2077; (b) Marco, J. L.; de los Rios, C.;
Garcia, A. G.; Villarroya, M.; Carreiras, M. C.; Martins, C.; Eleuterio, A.; Morreale,
A.; Orozco, M.; Luque, J. Bioorg. Med. Chem. 2004, 12, 2199; (c) Leon, R.; Marco-
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4.2.15. 13-(4-Nitrophenyl)-9,10,11,13-tetrahydro-7-oxa-8-aza-benzo-
[a]-cyclopenta[l]anthracene-12-ylamine (5c). Pale brown solid; mp
202–204 ꢀC; Rf 0.57 (40% EtOAc/petroleum ether); IR nmax (KBr):
3451, 3341, 2940, 1611, 1534, 1358, 1440, 1198, 1091, 821 cmꢁ1 1H
;
NMR (500 MHz, CDCl3) d: 1.86 (m, 2H, –CH2), 2.48 (m, 2H, –CH2),
2.86 (m, 2H, –CH2), 4.31 (br s, 2H, D2O exchangeable, –NH2), 5.36 (s,
1H, –CH), 6.86 (d, 1H, J¼8.4 Hz, –Ar–H), 7.18 (m, 4H, –Ar–H), 7.40
(m, 3H, –Ar–H), 8.16 (d, 2H, J¼7.7 Hz, –Ar–H); 13C NMR (75 MHz,
CDCl3) d: 23.5, 24.8, 25.3, 34.8, 96.4, 106.8, 115.1, 117.8, 118.3, 122.4,
123.7, 124.2, 125.9, 126.2, 127.4, 129.4, 134.3, 144.9, 152.1, 155.7,
161.0, 164.3; MS (ESI LCQ-MS): m/z 410 [Mþ1]þ. Anal. Calcd for
C25H19N3O3: C, 73.34; H, 4.68; N,10.26%. Found: C, 73.57; H, 4.72; N,
10.31%.
4.2.16. 7-(3-Nitrophenyl)-9,10,11,12-tetrahydro-7H-14-oxa-13-aza-
benzo[a]naphthacen-8-ylamine (5d). Light green solid; mp 154–
156 ꢀC; Rf 0.51 (40% EtOAc/petroleum ether); IR nmax (KBr): 3454,
2930, 1609, 1529, 1380, 1347, 1103, 806, 679 cmꢁ1
;
1H NMR
(500 MHz, CDCl3) d: 1.71 (m, 4H, –CH2), 2.48 (m, 2H, –CH2), 2.88 (m,
2H, –CH2), 4.12 (br s, 2H, D2O exchangeable, –NH2), 5.21 (s, 1H,
–CH), 7.04 (d, 1H, J¼7.7 Hz, –Ar–H), 7.41 (m, 5H, –Ar–H), 7.68 (d, 1H,
J¼8.4 Hz, –Ar–H), 7.90 (s, 1H, –Ar–H), 8.02 (m, 2H, –Ar–H); 13C NMR
(75 MHz, CDCl3) d: 22.2, 22.5, 23.2, 32.0, 34.8, 97.4, 105.4, 115.2,
´
´
´
727; (f) Marco-Contelles, J.; Leon, R.; Lopez, M. G.; Garcıa, A. G.; Villarroya, M.
Eur. J. Med. Chem. 2006, 41, 1464.
115.8,116.1, 121.2, 123.6, 124.8, 126.4, 127.4, 129.2, 132.3, 134.7, 144.7,
148.9, 150.4, 156.4, 160.9, 164.9; MS (ESI LCQ-MS): m/z 424 [Mþ1]þ.
Anal. Calcd for C26H21N3O3: C, 73.74; H, 5.00; N, 9.92%. Found: C,
73.98; H, 5.06; N, 9.97%.
14. (a) Loh, T. P.; Huang, J. M.; Goh, S. H.; Vittal, J. J. Org. Lett. 2000, 29, 1291; (b)
Solvent-Free Organic Synthesis; Tanaka, K., Ed.; Wiley-VCH: Weinheim, 2003.
15. (a) Cave, G. W. W.; Raston, C. L.; Scott, J. L. Chem. Commun. 2001, 2159; (b)
Tanka, K.; Toda, F. Chem. Rev. 2000, 100, 1025.
16. (a) Bez, G.; Gogoi, D. Tetrahedron Lett. 2006, 47, 5155; (b) Tang, L.; Ding, L.;
Chang, W.-X.; Li, J. Tetrahedron Lett. 2006, 47, 303; (c) Yoo, C. L.; Fettinger, J. C.;
Kurth, M. J. J. Org. Chem. 2005, 70, 6941.
17. (a) Selvam, N. P.; Saravanan, C.; Muralidharan, D.; Perumal, P. T. J. Heterocycl.
Chem. 2006, 43, 1379; (b) Selvam, N. P.; Perumal, P. T. Tetrahedron 2008, 64,
2972; (c) Selvam, N. P.; Saranya, S.; Perumal, P. T. Can. J. Chem. 2008, 86, 32; (d)
Arumugam, P.; Perumal, P. T. Chem. Lett. 2006, 35, 635.
4.2.17. 7-(2,4-Dichlorophenyl)-9,10,11,12-tetrahydro-7H-14-oxa-13-
aza-benzo[a]naphthacen-8-ylamine (5e). Pale brown solid; mp
160–162 ꢀC; Rf 0.37 (40% EtOAc/petroleum ether); IR nmax (KBr):
3483, 3397, 3043, 1628, 1580, 1457, 1380, 1109, 866, 809 cmꢁ1 1H
;
NMR (500 MHz, CDCl3) d: 1.72 (m, 4H, –CH2), 2.26 (m, 2H, –CH2),
18. Kuthan, J. Adv. Heterocycl. Chem. 1995, 62, 20.
2.83 (m, 2H, –CH2), 4.19 (s, 2H, D2O exchangeable, –NH2), 5.78 (s,
1H, –CH), 7.04 (d, 1H, J¼8.4 Hz, –Ar–H), 7.11 (d, 1H, J¼8.4 Hz, –Ar–
H), 7.20 (d, 1H, J¼8.4 Hz, –Ar–H), 7.36 (m, 2H, –Ar–H), 7.48 (m, 1H,
19. Rafael, G.; Antonio, G.; Marco-Contelles, J. J. Chem. Res. 2006, 8, 536.
20. Jiarong, L.; Lijun, Z.; Daxin, S.; Qing, L.; Dong, W.; Chunxia, W.; Qi, Z.; Ling, Z.;
Yanqiu, F. Synlett 2008, 233.