Synthesis of novel pyrano[2,3-b]pyridines from α,α′- bis(substituted-benzylidene)cycloalkanones

Article abstract of DOI:10.1002/jhet.1612

In this paper, we describe a two-step synthesis of a series of tacrine analogues. In the first step, α,α'-bis(substituted-benzylidene) cycloalkanones are reacted with malononitrile to afford 2-amino-3-cyano-4H- pyrans. The second step involves the convers

Full text of DOI:10.1002/jhet.1612

0
Month 2013 Synthesis of Novel Pyrano[2,3-b]pyridines from a,a -Bis(substituted-ben-
zylidene)cycloalkanones
a
a
a
b
b
Mohammad Ali Bigdeli, * Katayon Marjani, Elinaz Farokhi, Enayatollah Sheikhhosseini, and Dadkhoda Ghazanfari
a
Faculty of Chemistry, Tarbiat Moallem University, 49 Mofateh Street, Tehran, Iran
b
Faculty of Science, Department of Chemistry, Kerman Branch, Islamic Azad University, Kerman, Iran
*
E-mail: mabig397@yahoo.com
Received October 24, 2011
DOI 10.1002/jhet.1612
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
In this paper, we describe a two-step synthesis of a series of tacrine analogues. In the first
step, a,a’-bis(substituted-benzylidene)cycloalkanones are reacted with malononitrile to afford
2
-amino-3-cyano-4H-pyrans. The second step involves the conversion of pyrans to pyrano
[
2,3-b]pyridines with the use of AlCl as catalyst.
3
J. Heterocyclic Chem., 00, 00 (2013).
Pyranopyridines are important motifs that find wide appli-
cations in drugs and pharmaceuticals [1]. They are present in
the framework of numerous biologically active alkaloids such
as ribalinine, geibalasine, and flindersine [2]. Pyranopyridines
exhibit a wide range of drug activities such as anti-allergic,
psychotropic, anti-inflammatory, and estrogenic properties
important acid catalysis function in these reactions [20]. A
series of heterocycles (2a–2h) were prepared and converted
to the corresponding novel pyrano[2,3-b]pyridines (3a–3j).
Reaction times in our work are shorter than previously
reported [21], and work-up procedures do not require col-
umn chromatography. The reactions seem to show similar
results (65–80%) irrespective of the ring size of the cycloalk-
anones under investigation. Use of different aryl groups does
not affect the yields. The yields for naphthyl derivatives are,
however, lower relative to the phenyl analogues.
[
3]. On the other hand, benzopyrano pyridines possess anti-
proliferative [4], cancer chemopreventive [5], anti-bacterial
including anti-tubercular) [6], anti-myopic [7], anti-histamic
8], hypotensive [9], anti-rheumatic [10], and anti-asthmatic
(
[
activities [11]. In recent years, much attention has been
devoted to the synthesis of tacrine (9-amino-1,2,3,4-tetrahy-
droacridine) commercially knows as THA. Tacrine is an
approved drug for the treatment of Alzheimer disease [12].
Various methods have been reported for the synthesis of
this drug [13], but the Friedländer [14] reaction is the most
popular and convenient approach to the synthesis of
polysubstituted pyridines involving the annulation of
o-aminoaryl ketones with carbonyl compounds having a
reactive a-methylene group [15]. Lewis acids have been
reported to catalyze this reaction [16].
CONCLUSIONS
In conclusion, we have applied the Michael addition–
cyclization reaction to a new type of a,b-unsaturated
starting materials and have found that these compounds
react favorably to give the corresponding 2-amino-3-
cyano-4H pyrans. Finally, we have used AlCl to transform
3
these 4H-pyrans to novel pyrano[2,3-b]pyridines (tacrine
analogues) via the Friedländer reaction with promising
drug potentials. In both steps of the synthesis, the reaction
conditions are mild and yields are high.
As a part of our ongoing research on heterocyclic com-
pounds of biological significance [17], we have carried
out a two-step reaction setup for the synthesis of some
novel tacrine analogues (Scheme 1).
EXPERIMENTAL
General procedure for the synthesis of 2-amino-3-cyano-4H-
0
pyrans (2a–2h). a,a -Bis(substituted-benzylidene)cycloalkanones
(
RESULTS AND DISCUSSION
1.0 eq.), malononitrile (1.2 eq.), and catalytic amount of piperidine
0
were refluxed in ethanol for 2–5 h. After cooling, the solvent was
distilled and the residue was recrystallized from ethanol. The results
are tabulated in Table 1.
a,a -Bis(substituted-benzylidene)cycloalkanones
(1)
were prepared and employed as starting materials with the
use of a previously described method [18]. On the basis of
previous reports [19] on systems similar to ours (2a–2h),
a possible mechanism for the (2) to (3) transformation is
shown in (Scheme 2). It is clear that AlCl3 plays an
(
7E)-2-Amino-7-benzylidene-4,5,6,7-tetrahydro-4-phenyl-
ꢀ
cyclopenta[b]pyran-3-carbonitrile (2a).
mp 228–230 C; IR (KBr): 3447, 3328, 3246, 3202, 2914,
mp 228 C; Ref.
ꢀ
2842, 2196, 1683, 1638, 1587, 1490, 1451, 1408, 1382, 1106,
©
2013 HeteroCorporation

M. A. Bigdeli, K. Marjani, E. Farokhi, E. Sheikhhosseini, and D. Ghazanfari
Vol 000
ꢁ
1 1
7
2
(
(
1
1
00 cm ; H NMR (300 MHz, CDCl ): d = 2.18 (1H, m, CH);
(8E)-2-Amino-5,6,7,8-tetrahydro-4-(naphthalen-2-yl)-8-
((naphthalen-6-yl)methylene)-4H-chromene-3-carbonitrile
(2c). mp 244–245 C; IR (KBr): 3457, 3326, 3256, 3211, 3184,
3
.33 (1H, m, CH); 2.39 (2H, m, CH ); 4.24 (1H, s, CH); 4.63
2
13
ꢀ
2H, s, NH
2
); 6.44 (1H, s, CH); 7.18–7.39 (10H, Ar); C NMR
): d = 26.9, 28.0, 41.0, 60.8, 117.2, 119.9,
21.7, 126.5, 127.4, 127.8, 128.1, 128.5, 128.8, 136.7, 137.2,
41.5, 146.3, 159.9 ppm. Anal. Calcd for C H N O: C, 80.96;
75 MHz, CDCl
3
3051, 2918, 2905, 2851, 2195, 1674, 1643, 1596, 1410, 1130,
ꢁ
1 1
879, 759 cm
3
; H NMR (300 MHz, CDCl ): d =1.60 (2H, m,
CH ); 1.91 (2H, m, CH ); 2.64 (1H, m, CH); 2.79 (1H, m, CH);
2
2
18
2
2
2
H, 5.56; N, 8.58%. Found: C, 80.89; H, 5.49; N, 8.50%.
4.1 (1H, s, CH); 4.55 (2H, s, NH ); 7.06 (1H, s, CH); 7.38–7.86
2
(14H, Ar); C NMR (75 MHz, CDCl ): d = 23.0, 24.6, 31.6, 42.8,
3
13
(
8E)-2-Amino-8-benzylidene-5,6,7,8-tetrahydro-4-phenyl-4H-
ꢀ
ꢀ
chromene-3-carbonitrile (2b). mp 230 C; Ref. mp 230–231 C;
58.0, 110.8, 117.6, 122.6, 123.4, 123.7, 124.0, 124.5, 124.8, 126.3,
126.5, 126.8, 127.3, 128.0, 130.4, 130.5, 130.6, 130.8, 132.6,
140.3, 140.5, 140.8, 160.0. Anal. Calcd for C H N O: C, 84.52;
IR (KBr): 3431, 3337, 3047, 3023, 2945, 2921, 2844, 2830, 2188,
ꢁ
1 1
1
669, 1636, 1619, 1412, 1131, 700 cm ; H NMR (300 MHz,
CDCl ): d = 1.55 (2H, m, CH ); 1.99 (2H, m, CH ); 2.52 (1H, m,
CH ); 2.67 (1H, m, CH ); 3.96 (1H, s, CH); 4.50 (2H, s, NH );
.87 (1H, s, CH); 7.21–7.38 (10H, Ar); C NMR (75MHz,
CDCl ): d = 22.2, 27.0, 27.4, 43.5, 60.4, 115.2, 119.8, 122.6,
31 24 2
3
2
2
H, 5.49; N, 6.36%. Found: C, 84.46; H, 5.50; N, 6.40%.
2
2
2
(8E)-2-Amino-5,6,7,8-tetrahydro-6-methyl-4-(naphthalen-2-
yl)-8-((naphthalen-6-yl)methylene)-4H-chromene-3-carbonitrile
13
6
ꢀ
(2d). mp 194–196 C; IR (KBr): 3457, 3327, 3210, 3184, 3049,
3
1
26.81, 127.3, 127.9, 128.1, 128.7, 129.2, 129.4, 137.0, 159.0 ppm.
3017, 2951, 2901, 2868, 2828, 2191, 1671, 1640, 1595, 1410,
ꢁ
1 1
1
129, 758 cm ; H NMR (300 MHz, CDCl
CH ); 1.61 (1H, m, CH); 1.86 (1H, m, CH); 1.94 (1H, dd, J =2.1,
2 Hz, CH); 2.15 (1H, dd, J = 1.5, 11.4 Hz, CH); 2.91 (1H, d,
3
): d = 0.84 (3H, m,
Scheme 1. Synthesis of tacrine analogues from α,α’-bis(substituted-
3
1
benzylidene)cycloalkanones.
J =15Hz, CH); 4.14 (1H, s, CH); 4.57 (2H, s, NH ); 7.07 (1H, s,
2
Ar
O
Ar NH2
O
13
CH); 7.37–7.87 (14H, Ar); C NMR (75 MHz, CDCl ): d =20.9,
CN
3
CH2(CN)2
piperidin,
Z
AlCl3
Z
28.9, 34.8, 35.2, 36.1, 43.4, 60.4, 114.5, 119.8, 122.9, 125.6,
125.8, 126.0, 126.2, 126.7, 126.8, 127.6, 127.9, 128.0, 128.1,
128.8, 129.8, 132.2, 133.2, 134.5, 139.8, 158.9, 159.0 ppm. Anal.
n
Ar
Ar
ClCH CH Cl
2
2
n
Z
O
NH2
O
N
EtOH,reflux
reflux
Ar
Ar
Calcd for C H N O: C, 84.55; H, 5.77; N, 6.16%. Found: C,
(
1)
(2)
(3)
32 26 2
84.50; H, 5.76; N, 6.15%.
2
a-2h(Table 1)
3a-3j(Table2)
(8E)-2-Amino-6-ethyl-5,6,7,8-tetrahydro-4-(naphthalen-2-yl)-
8
(
-((naphthalen-6-yl)methylene)-4H-chromene-3-carbonitrile
ꢀ
2e). mp 205–207 C; IR (KBr): 3457, 3329, 3254, 3212, 3048,
2
955, 2900, 2872, 2864, 2822, 2195, 1673, 1642, 1595, 1409,
ꢁ
1 1
Scheme 2. Proposed mechanism.
1136, 747 cm ; H NMR (300 MHz, CDCl
CH ); 1.12 (2H, m, CH ); 1.27 (2H, m, CH ); 1.98 (1H, m, CH);
.99 (2H, m, CH ); 4.14 (1H, d, J= 3.9 Hz, CH); 4.56 (2H, d,
3
): d =0.68 (3H, m,
3
2
2
1
2
13
AlCl
3
J=7.5Hz, NH ); 7.07 (1H, s, CH); 7.25–7.87 (14H, Ar); C NMR
2
Ar
O
Ar
O
Ar
O
AlCl
3
O
(75 MHz, CDCl ): d = 11.3, 28.2, 32.7, 33.2, 33.8, 35.0, 35.5, 43.4,
3
CN
CN
N
C N
AlCl
3
60.6, 114.4, 114.5, 122.9, 123.1, 126.0, 126.2, 126.7, 127.4, 127.6,
127.6, 127.9, 128.1, 128.9, 129.6, 129.8, 132.2, 132.9, 133.2,
.
.
N: H
2
N
H
28 2
133.4, 139.9, 158.8 ppm. Anal. Calcd for C33H N O: C, 84.58; H,
Ar
Ar
Ar
6.02; N, 5.98%. Found: C, 84.48; H, 6.08; N, 5.90%.
(
8E)-2-Amino-8-benzylidene-5,6,7,8-tetrahydro-6-methyl-4-
AlCl
3
ꢀ
phenyl-4H-chromene-3-carbonitrile (2f). mp 201–203 C; IR
KBr): 3431, 3338, 3026, 2947, 2850, 2826, 2189, 1672, 1638,
619, 1593, 1414, 1150, 699cm ; H NMR (300 MHz, CDCl ):
3
Ar NH
Ar NH
2
(
1
H
ꢁ
1 1
d = 0.86 (3H, t, J = 6.59Hz, CH ); 1.63 (3H, m, CH ); 2.17 (1H,
O
N
O
N
3 2
m, CH ); 2.80 (1H, m, CH ); 3.93 (1H, s, CH); 4.49 (2H, s, NH );
2
2
2
Ar
Ar
Table 1
0
Preparation of 2-amino-3-cyano-4H-pyrans from a,a -bis(substituted-benzylidene)cycloalkanones.
ꢀ
Product
Ar
Z
Time (h)
Yield (%)
mp ( C)
2
2
2
2
2
2
2
2
a
b
c
d
e
f
g
h
C
C
C
C
C
C
6
H
H
5
CH
CH
CH
CH(Me)–CH
CH(Et)–CH
CH(Me)–CH
2
2
2
1
1
3
4
5
3
4
3
75
80
80
61
60
70
87
80
228
(228–230)
230
(230–231)
244–245
194–196
205–207
a
6
5
CH
CH
2
10
10
10
6
H
7
7
7
2
a
H
H
2
2
H
5
2
o-BrC
p-CF
6
H
4
CH
CH
2
CH
CH
2
3
C
6
H
4
2
2
a
mp References [22,23].
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

0
Month 2013
Pyrano[2,3-b]pyridines from a,a -Bis(substituted-benzylidene)cycloalkanones
1
3
6
.87 (1H, s, CH); 7.21–7.39 (10H, Ar); C NMR (75 MHz,
128.2, 128.3, 129.1, 137.8, 138.0, 142.2, 147.3, 151.6, 153.9,
CDCl ): d = 20.2, 32.4, 32.7, 36.8, 45.7, 54.7, 110.4, 123.3, 123.5,
156.0, 160.5 ppm. Anal. Calcd for C H N O: C, 82.73; H,
3
28 26 2
1
1
7
24.4, 124.6, 126.7, 126.9, 128.4, 128.8, 130.6, 130.7, 142.5,
45.7, 158.8. Anal. Calcd for C24 O: C, 81.33; H, 6.26; N,
.90%. Found: C, 81.28; H, 6.24; N, 7.87%.
8E)-8-(2-Bromobenzylidene)-2-amino-4-(2-bromophenyl)-
6.45; N, 6.89%. Found: C, 82.68; H, 6.40; N, 6.83%.
H N
22 2
(4E)-4-Benzylidene-2,3,4,7,8,9,10,12-octahydro-12-phenyl-1H-
ꢀ
mp 213–215 C; IR
chromeno[2,3-b]quinolin-11-amine (3b).
(KBr): 3478, 3384, 3205, 3058, 3022, 2928, 2858, 2834, 1624,
(
ꢁ
1
1
5
2
1
,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (2g).
mp
1598, 1575, 1451, 1421, 1384, 1253, 1200, 697 cm
; H
ꢀ
19–221 C; IR (KBr): 3448, 3331, 2197, 1667, 1637, 1599,
NMR (300 MHz, acetone-d ): d = 0.85 (2H, m, CH ), 1.59 (4H,
6
2
ꢁ
1 1
486, 1419, cm ; H NMR (300 MHz, CDCl
3
): d = 1.60–2.70
2 2 2
m, CH ), 1.74 (4H, m, CH ), 2.63 (2H, m, CH ), 2.69 (2H, m,
(
6H, m, aliph.); 3.94 (1H, s); 4.56 (2H, s, NH ); 6.79 (1H, s,
2 2
CH ), 4.45 (2H, s, NH ), 4.89 (1H, s, CH), 7.18 (1H, s, CH),
2
1
3
13
CH); 7.11–7.48 (8H, Ar); C NMR (75 MHz, CDCl ): d = 22.1,
7.20–7.43 (10 H, Ar);
C NMR (75 MHz, acetone-d6):
3
2
1
7.0, 27.3, 43.1, 59.9, 115.1, 119.7, 120.8, 121.3, 121.7, 129.6,
29.8, 130.8, 131.3, 131.9, 135.7, 141.4, 141.8, 158.8 ppm.
d = 23.6, 27.7, 28.1, 30.3, 30.5, 33.0, 43.9, 99.4, 112.9, 115.8,
123.0, 127.2, 127.3, 127.7, 128.9, 129.4, 130.0, 131.6, 138.4,
142.9, 144.7, 151.8, 156.2, 160.46 ppm. Anal. Calcd for
C H N O: C, 82.43; H, 7.16; N, 6.63%. Found: C, 82.39; H,
Anal. Calcd for C23
Found: C, 55.17; H, 3.31; N, 5.62%.
8E)-8-(4-(trifluoromethyl)benzylidene)-2-amino-4-(4-(trifluoro-
2 2
H18Br N O: C, 55.42; H, 3.61; N, 5.62%.
29 30 2
(
7.12; N, 6.59%.
methyl)phenyl)-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile
(
4E)-2,3,4,7,8,9,10,12-Octahydro-12-(naphthalen-2-yl)-4-
ꢀ
(
1
2h). mp 263–265 C; IR (KBr): 3450, 3333, 2190, 1668, 1640,
(
1
(naphthalen-2-yl)methylene)-1H-chromeno[2,3-b]quinolin-
1-amine (3c). mp 143–145 C; IR (KBr): 3457, 3327, 2951,
2828, 1671, 1640, 1595, 1410, 1129, 758 cm ; H NMR
(300 MHz, MeOH-d ): d = 1.50 (2H, m, CH ); 1.83 (4H, m,
ꢁ
1
1
598, 1480, 1418, cm
;
H NMR (300 MHz, MeOH-d
6
):
ꢀ
ꢁ
1
1
d = 1.58–1.71 (4H, m, CH ); 1.82–1.90 (1H, m, CH); 2.06–2.15
2
(
1H, m, CH); 2.95 (2H, s, NH ); 4.10 (1H, s, CH); 7.06 (1H, s,
2
6
2
1
3
CH); 7.42–7.66 (8H, Ar); C NMR (75 MHz, MeOH-d
6
):
CH
2
2 2
); 2.16 (4H, m, CH ); 2.54 (2H, m, CH ); 2.78 (2H, m,
d = 23.3, 24.1, 25.2, 45.0, 57.0, 117.0, 121.5, 122.7, 126.0,
CH ); 3.67 (2H, s, NH ); 4.60 (1H, s, CH); 7.29–7.85 (14H, Ar);
2
2
13
1
1
3
2
26.1, 126.6, 127.5, 129.6, 130.2, 130.6, 132.8, 142.5, 142.7,
49.6, 162.0ppm. Anal. Calcd for C H F N O: C, 63.03; H,
.81; F, 23.93; N, 5.88; O, 3.36%. Found: C, 63.00; H, 3.78; F,
3.89; N, 5.81; O, 3.31%.
7
.93 (1H, s, CH); C NMR (75 MHz, MeOH-d ): d = 21.9, 22.3,
23.0, 23.3, 26.4, 27.8, 28.1, 28.1, 42.2, 45.1, 98.9, 114.4, 117.8,
24.8, 126.4, 127.1, 127.3, 127.6, 128.3, 128.5, 128.5, 128.6,
28.7, 128.8, 128.9, 129.2, 130.2, 130.4, 135.7, 139.1, 146.2,
6
2
5
18
6
2
1
1
General procedure for the synthesis of pyrano[2,3-b]pyridines
152.0, 158.5 ppm. Anal. Calcd for C37H N O: C, 85.35; H,
6.19; N, 5.38%. Found: C, 85.30; H, 6.12; N, 5.31%.
32 2
(
3a–3j).
2-Amino-3-cyano-4H-pyrans (1.0 eq.), cycloalkanone
(
1.2 eq.), and AlCl (1.2 eq.) were suspended in 1,2-dichloroethane
(4E)-2,3,4,7,8,9,10,12-Octahydro-2-methyl-12-(naphthalen-
2-yl)-4-((naphthalen-2-yl)methylene)-1H-chromeno[2,3-b]
quinolin-11-amine (3d). mp 249–251 C; IR (KBr): 3330,
3
(
10 Ml). The mixture was then refluxed for 3–5 h under nitrogen.
After cooling, the solvent was removed, the residue was washed
with petroleum ether, and the precipitate was recrystallized from
methanol. The results are tabulated in Table 2.
ꢀ
3205, 3050, 2925, 2857, 1640, 1607, 1462, 1325, 1124,
ꢁ
1 1
751 cm ; H NMR (300 MHz, MeOH-d ): d = 0.85 (3H, dd,
6
(
7E)-7-Benzylidene-4-phenyl-5,6-dihydrocyclopenta[e]-
J = 6.6, 18 Hz, CH ), 1.28 (4H, m, CH ), 1.84 (4H, m, CH ),
3
2
2
4
H-pyrano-[2,3-b]-(5,6,7,8-tetrahydro-4-aminoquinoline)
2.15 (2H, d, J = 3.3 Hz, CH ), 2.18 (2H, m, CH ), 3.35 (2H, s,
2 2
ꢀ
(
3a).
mp 144–146 C; IR (KBr): 3658, 3484, 3453, 3099,
NH
2
), 4.69 (1H, s, CH), 7.32 (1H, s, CH), 7.32–7.94 (14H, Ar),
13
2
6
937, 2921, 2878, 2851, 2406, 1642, 1593, 1573, 1445, 1382,
7.93 (1H, s, CH); C NMR (75 MHz, MeOH-d ): d = 22.3, 24.1,
6
ꢁ
1
1
95 cm
;
H NMR (300MHz, CDCl ): d = 1.83 (4H, m,
30.1, 30.6, 35.4, 36.1, 38.8, 42.5, 110.9, 114.4, 117.1, 126.5,
127.1, 127.3, 127.7, 128.1, 128.4, 128.6, 128.7, 128.8, 128.9,
129.2, 130.2, 130.4, 134.3, 134.6, 135.6, 142.2, 146.4, 156.8,
3
CH ), 2.27 (4H, m, CH ), 2.83 (4H, m, CH ), 3.95 (2H, s,
NH ), 4.56 (1H, s, CH), 6.81 (1H, s, CH), 7.13–7.40 (10H,
2
Ar); C NMR (75 MHz, CDCl
2
2
2
13
3
): d = 22.5, 22.8, 26.9, 28.0,
34 2
158.6, 164.8 ppm. Anal. Calcd for C38H N O: C, 85.36; H, 6.41;
3
2.3, 41.6, 97.9, 112.9, 117.6, 119.7, 125.9, 127.4, 127.8,
N, 5.24%. Found: C, 85.30; H, 6.36; N, 5.19%.
Table 2
Preparation of pyrano[2,3-b]pyridine catalyzed by AlCl
ꢀ
at 83 C under reflux.
3
ꢀ
Product
Ar
Z
Time (h)
Yield (%)
mp ( C)
a
3
3
3
3
3
3
3
3
3
3
a
C
C
C
C
C
C
6
H
H
5
CH
CH
CH
CH(Me)–CH
CH(Et)–CH
CH(Me)–CH
2
2
2
3
5
5
4
5
5
4
5
5
3
80
70
77
65
70
65
79
67
65
66
144–146
213–215
143–145
249–251
162–164
234–235
198–200
253–255
173–174
153–154
a
b
6
5
CH
CH
2
a
c
10
10
10
6
H
H
H
7
7
7
2
a
d
2
a
e
f
2
a
H
5
2
a
g
o-BrC
6
H
4
CH
CH
CH
CH
2
2
2
2
CH
CH
2
b
h
C
C
6
H
H
5
2
b
i
j
6
5
a
p-CF
3
C
6
H
4
CH
2
a
(
(
n = 2).
n = 1).
b
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. A. Bigdeli, K. Marjani, E. Farokhi, E. Sheikhhosseini, and D. Ghazanfari
Vol 000
(
4E)-2-Ethyl-2,3,4,7,8,9,10,12-octahydro-12-(naphthalen-2-
(4E)-4-(4-(Trifluoromethyl)benzylidene)-12-(4-(trifluoro-
methyl)phenyl)-2,3,4,7,8,9,10,12-octahydro-1H-chromeno-
[2,3-b]quinolin-11-amine (3j). mp 153–154 C; IR (KBr):
yl)-4-((naphthalen-2-yl)methylene)-1H-chromeno[2,3-b]
quinolin-11-amine (3e).
ꢀ
ꢀ
mp 162–164 C; IR (KBr): 3332,
3
4
205, 3053, 2924, 2855, 1641, 1608, 1467, 1364, 752,
3467, 3393, 3295, 3156, 2943, 2860, 2841, 2563, 1667,
ꢁ
1
1
ꢁ1;
1
76 cm
;
6
H NMR (300 MHz, MeOH-d ): d = 0.66 (3H, m,
1641, 1611, 1470, 1435, 1332, 1029, 780 cm
H NMR
CH ); 0.74 (1H, m, CH); 1.19 (2H, m, CH ); 1.77 (4H, m, CH );
(300 MHz, MeOH-d ): d = 0.91 (2H, m, CH ); 1.21 (4H, m,
3
2
2
6
2
2
.21 (4H, m, CH ); 2.80 (2H, s, NH ); 2.98 (4H, m, CH ); 4.69
CH ); 1.72 (4H, m, CH ); 2.21 (4H, m, CH ); 2.69 (2H, m,
2 2 2
2
2
2
(
1H, d, J = 5.4 Hz, CH); 7.30 (1H, s, CH); 7.35–7.96 (14H, Ar).
2
NH ); 4.54 (1H, s, CH); 7.30 (1H, s, CH); 7.43–7.72 (8H,
Ar). C NMR (75 MHz, MeOH-d ): d = 23.6, 23.9, 28.0,
6
1
3
13
6
C NMR (75 MHz, MeOH-d ) d = 11.6, 21.9, 22.3, 23.1, 45.5,
1
1
1
5
14.5, 126.4, 127.2, 127.4, 127.7, 128.2, 128.3, 128.6, 128.7,
28.8, 128.9, 129.2, 130.2, 133.8, 134.7, 135.6, 142.2, 145.8,
28.5, 32.7, 43.7, 106.7, 119.8, 122.7, 123.6, 124.5, 124.7,
124.9, 126.0, 126.5, 128.9, 129.8, 130.8, 133.7, 135.7,
153.8, 155.6, 164.8 ppm. Anal. Calcd for C31H F N O: C,
26 6 2
66.90; H, 4.71; N, 5.03%. Found: C, 66.86; H, 4.69; N, 4.98%.
58.7 ppm. Anal. Calcd for C39
.11%. Found: C, 85.34; H, 6.57; N, 5.10%.
4E)-4-Benzylidene-2,3,4,7,8,9,10,12-octahydro-2-methyl-12-
36 2
H N O: C, 85.37; H, 6.61; N,
(
phenyl-1H-chromeno[2,3-b]quinolin-11-amine (3f). mp 234–
ꢀ
2
1
(
35 C; IR (KBr): 3478, 3391, 3200, 2925, 2868, 2829, 1623,
Acknowledgment. We gratefully acknowledge the financial support
from the research council of Tarbiat Moallem University.
ꢁ
1
1
597, 1575, 1446, 1421, 1381, 1246, 699 cm
): d = 0.87 (3H, d, J = 6.6 Hz, CH
m, CH), 1.79 (4H, m, CH ), 1.98 (2H, m, CH ), 2.17 (4H, m,
CH ), 2.76 (2H, m, CH ), 4.03 (2H, s, NH ), 4.19 (1H, s, CH),
;
H NMR
300 MHz, CDCl
3
3
), 1.61 (1H,
2
2
2
2
2
REFERENCES AND NOTES
1
3
7
.25 (1H, s, CH), 7.30 (10H, Ar); C NMR (75MHz, CDCl3):
d = 22.3, 22.5, 22.7, 28.5, 32.0, 34.5, 34.9, 43.5, 113.9, 117.3,
[1] (a) Elderfield, R. C. In Heterocyclic Compounds; John Wiley:
London, 1960; Vol. 4, Chapter 1, p 1; (b) Wright, C. W.; Addae-Kyereme,
J.; Breen, A. G.; Brown, J. E.; Cox, M. F.; Croft, S. L.; Gokcek, Y.;
Kendrick, H.; Phillips, R. M.; Pollet, P. L. J Med Chem 2001, 44, 3187;
1
1
19.4, 123.8, 126.3, 127.4, 127.9, 128.0, 128.4, 129.0, 129.4,
37.7, 142.9, 146.8, 154.9, 156.8, 160.8ppm. Anal. Calcd for
C H N O: C, 82.53; H, 7.39; N, 6.42%. Found: C, 82.47; H,
30 32 2
(c) Sahu, N. P.; Pal, C.; Mandal, N. B.; Benerjee, S.; Raha, M.; Kundu,
7.35; N, 6.39%.
A. P.; Basu, A.; Ghose, M.; Roy, K.; Bandyopadhyay, S. Bioorg Med
Chem 2002, 10, 1687; (d) Bringmann, G.; Reichert, Y.; Kane, V.
Tetrahedron 2004, 60, 3539; (e) Kournetsov, V. V.; Mendez, L. Y. V.;
Gomez, C. M. M. Curr Org Chem 2005, 9, 141.
(
4E)-4-(2-Bromobenzylidene)-12-(2-bromophenyl)-2,3,4,7,-
8
,9,10,12-octahydro-1H-chromeno[2,3-b]quinolin-11-amine
ꢀ
(
3g).
mp 198–200 C; IR (KBr): 3454, 3389, 3297, 3148,
[2] (a) Corral, R. A.; Orazi, O. O. Tetrahedron Lett 1967, 7, 583;
2
1
928, 2861, 2832, 2558, 1669, 1644, 1609, 1464, 1431, 1327,
ꢁ
1
1
(b) Sekar, M.; Prasad, K. J. R. J Nat Prod 1998, 61, 294; (c) Puricelli,
L.; Innocenti, G.; Delle Monache, G.; Caniato, R.; Filippini, R.;
Cappelletti, E. M. Nat Prod Lett 2002, 16, 95; (d) Marco, J. L.; Carreiras,
M. C. Mini Rev Med Chem 2003, 3, 518.
[3] (a) Yamada, N.; Kadowaki, S.; Takahashi, K.; Umezu, K.
Biochem Pharmacol 1992, 44, 1211; (b) Faber, K.; Stueckler, H.; Kappe,
T. J Heterocycl Chem 1984, 21, 1177; (c) Johnson, J. V.; Rauckmann, B.
S.; Baccanari, D. P.; Roth, B. J Med Chem 1989, 32, 1942; (d) Mohmed,
E. A. Chem Pap 1994, 48, 261.
023, 740 cm
;
H NMR (300 MHz, MeOH-d
); 1.82 (4H, m, CH ); 2.27 (4H, m, CH
); 5.01 (1H, s, CH); 7.06 (1H,
6
): d = 1.55
(
(
2H, m, CH
2H, s, NH
2
2
2
); 2.77
2
); 3.20 (4H, m, CH
2
1
3
s, CH); 7.12–7.62 (8H, Ar). C NMR (75 MHz, MeOH-d6):
d = 22.3, 23.1, 24.3, 27.5, 27.8, 27.9, 28.0, 29.5, 30.7, 41.7,
9
1
1
8.9, 114.6, 124.6, 125.2, 128.2, 130.0, 130.3, 131.1, 131.4,
32.0, 132.3, 133.8, 134.3, 138.1, 141.0, 142.5, 147.4, 152.5,
58,1 ppm. Anal. Calcd for C29H26Br N O: C, 60.23; H, 4.53;
2 2
[
4] Kolokythas, G.; Pouli, N.; Marakos, P.; Pratsinis, H.; Kletsas,
D. Eur J Med Chem 2006, 41, 71.
5] Azuine, M.A.; Tokuda, H.; Takayasu, J.; Enjyo, F.; Mukainaka,
N, 4.84%. Found: C, 60.17; H, 4.49; N, 4.79%.
8E)-8-Benzylidene-5,6,7,8-tetrahydro-4-phenyl-4H-chromeno-
2,3-b]-(5,6-dihydrocyclopenta[b]pyridine-4-amine) (3h). mp
(
[
[
2
2
T.; Konoshima, T.; Nishino, H.; Kapadia, G. J Pharmacol Res 2004,
49, 161.
ꢀ
53–255 C; IR (KBr): 3464, 3345, 3350, 3208, 2920, 2862,
ꢁ
1
1
[6] (a) Srivastava, S. K.; Tripathi, R. P.; Ramachandran, R. J Biol
833, 1671, 1636, 1594, 1413, 1130, 1034, 748 cm
; H
Chem 2005, 280, 30273–30281; (b) Brotz-Oesterhelt, H.; Knezevic, I.;
Bartel, S.; Lampe, T.; Warnecke-Eberz, U.; Ziegelbauer, K.; Habich, D.;
Labischinski, H. J Biol Chem 2003, 278, 39435; (c) Kumar, A.;
Srivastava, S.; Gupta, G.; Chaturvedi, V.; Sinha, S.; Srivastava, R. ACS
Comb Sci 2011, 13, 65.
[7] Toshiro, S.; Noriko,W. U.S. Patent 5,519,030, 1996.
[8] Ito, Y.; Kato, H.; Yasuda, S.; Kato, N.; Iwasaki, N.; Nishino,
H.; Takeshita, M. Jpn. Kokai Tokkyo Koho 1994, JP 06107664 A2
NMR (300 MHz, MeOH-d ): d = 1.62 (4H, m, CH ); 2.23
6
2
(
(
4H, m, CH ); 2.68 (4H, m, CH ); 3.03 (2H, m, NH ); 4.51
2
2
2
1
3
1H, s, CH); 7.09–7.38 (11H, Ar).
C NMR (75 MHz,
MeOH-d
6
): d = 23.1, 23.3, 27.9, 28.3, 28.5, 32.0, 42.3, 110,
, 114.4, 118.0, 124.5, 128.1, 128.9, 129.1, 129.3, 130.0,
30.3, 142.3, 147.4, 152.5, 157.1 ppm. Anal. Calcd for
O: C, 82.73; H, 6.45; N, 6.89%. Found: C, 82.68;
H, 6.42; N, 6.85%.
7E)-7-Benzylidene-4-phenyl-5,6-dihydrocyclopenta[e]-4H-
9
1
28 26 2
C H N
19940419.
[9] Goto, K.; Yaoka, O.; Oe, T. U.S. Patent 4, 555, 510, 1985.
(
[10] Maruyama, Y.; Goto, K.; Terasawa, M. Ger. Offen. 1981, DE
pyrano-[2,3-b]-(5,6-dihydrocyclopenta[b]pyridine-4-amine)
3010751 19810806.
ꢀ
(
3i). mp 173–174 C; IR (KBr): 3470, 3350, 3205, 3020, 3022,
[11] Ukawa, K.; Ishiguro, T.; Kuriki, H.; Nohara, A. Chem Pharm
2
1
924, 2856, 2830, 1619, 1596, 1570, 1446, 1421, 1380, 1248,
Bull (Tokyo) 1985, 33, 4432.
ꢁ
1 1
200, 687 cm ; H NMR (300 MHz, acetone-d ): d = 1.60 (2H,
2
); 2.08 (2H, m, NH ); 2.76 (8H, m, CH ); 3.55 (1H, s,
6
[12] (a) León, R.; Marco-Contelles, J.; García, A. G.; Villarroya, M.
Bioorg Med Chem 2005, 13, 1167; (b) León, R.; Ríos, C. D. L.; Marco-
Contelles, J.; Huertas, O.; Barril, X.; Luque, F. J.; Lopez, M. G.; García,
A. G.; Villarroya, M. Bioorg Med Chem 2008, 16, 7759.
m, CH
2
2
1
3
CH); 7.12–7.56 (11H, Ar). C NMR (75 MHz, acetone-d6):
d = 21.3, 24.6, 25.6, 26.9, 27.9, 28.4, 127.1, 128.7, 129.0,
[13] (a) Skraup, H. Chem Ber 1880, 13, 2086; (b) Hermecz, I.;
1
29.1, 129.4, 129.6, 130.0, 130.5, 131.7. Anal. Calcd for
O: C, 82.62; H, 6.16; N, 7.14%. Found: C, 82.60; H,
.13; N, 7.11%.
Kereszturi, G.; Vasvari-Debreczy, L. Adv Heterocycl Chem 1992, 54, 1;
(c) Pfitzinger, W. J Prakt Chem 1886, 33, 100; (d) Calaway, P. K.;
Henze, H. R. J Am Chem Soc 1939, 61, 1355; (e) Long, R.; Schofield,
27 24 2
C H N
6
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

0
Month 2013
Pyrano[2,3-b]pyridines from a,a -Bis(substituted-benzylidene)cycloalkanones
K. J Chem Soc 1953, 3161; (f) Baruah, B.; Bhuyan, P. J. Tetrahedron
009, 65, 7099; (g) Singh, B.; Chandra, A.; Upadhyay, Sh.; Singh, R.
M.; Puerta, M. C.; Valerga, P. Tetrahedron Lett 2008, 49, 6423.
14] (a) Friedlander, P. Chem Ber 1882, 15, 2572; (b) Fehnel, E. A.
J Org Chem 1966, 31, 2899.
15] (a) Lemport, P. S.; Bodrin, G. V.; Belyakov, A. I.; Petrovskii, P.
V.; Vologzhanina, A. V.; Nifant’ev, E. E. Mendeleev Commun. 2009, 19,
03; (b) Zolfigol, M. A.; Salehi, P.; Ghaderi, A.; Shiri, M. Catal Commun.
007, 8, 1214; (c) Ronco, C.; Jean, L.; Renard, P. Y. Tetrahedron 2010, 66,
399e7404; (d) Ronco, C.; Sorin, G.; Nachon, F.; Foucault, R.; Jean, L.;
Romieu, A.; Renard, P. Y. Bioorg Med Chem 2009, 17, 4523.
16] (a) Selvam, N. P.; Babu, Th. H.; Perumal, P. T. Tetrahedron
009, 65, 8524; (b) Li, J. R.; Zhang, L. J.; Yang, X. Q.; Li, Q.; Wang,
D.; Wang, Ch. X.; Shi, D. X.; Zhang, Q. Chin Chem Lett 2008, 19, 15;
c) Seeliger, F.; Berger, S. T. A.; Remennikov, G. Y.; Polborn, K.; Mayr,
H. J Org Chem 2007, 72, 9170.
17] (a) Bigdeli, M. A.; Moradi, Sh.; Nemati, F. J Mol Struct
THEOCHEM) 2008, 64, 860; (b) Bigdeli, M. A.; Dostmohamadi, H.;
Mahdavinia, G. H.; Nemati, F. J Heterocycl Chem 2008, 45, 1203; (c)
Bigdeli, M. A.; Sheikhhosseini, E.; Habibi, A.; Balalaei, S. Heterocycles
2011, 83, 1.
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Catal Commun 2007, 8, 2228.
2
[
[19] (a) Zhao, S. L.; Zheng, C. W.; Zhao, G. Tetrahedron:
Asymmetry 2009, 20, 1046; (b) Changsheng, Y.; Bei, J.; Tuanjie,
L.; Bingbin, Q.; Xiaodong, F.; Honghong, Zh.; Cuihua,W.; Shujiang, T.
Bioorg Med Chem Lett 2011, 21, 599; (c) Ye, Z.; Xu, R.; Shao, X.; Xu,
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P.; Venkateswara Rao, K. T.; Sai Prasad, P. S. Tetrahedron Lett 2008, 49,
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35, 1859.
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[
3
2
7
[
2
(
[
(
[22] Wang, X. S.; Shi, D. Q.; Tu, S. J Chin J Chem 2004, 122.
[23] Zhou, J. F. Synth Commun 2003, 33, 99.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet