Synthesis of some new chromeno[2,3-b]pyridine and [1,2,4]Triazolo[1,5-a]quinoline nucleoside analogues with expected biological activity

Article abstract of DOI:10.2174/1570178611666140304000403

Direct preparation of 2-amino-5,6,7,8-tetrahydro-4-(4-methoxyphenyl)-7,7-dimethyl-5-oxo-4H-chromene-3- carbonitrile (2) and 1,2-diamino-1,4,5,6,7,8-hexahydro-4-(4-methoxyphenyl)-7,7-dimethyl-5-oxo-3-quinolinecarbonitrile (11) which were utilized as starti

Full text of DOI:10.2174/1570178611666140304000403

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Letters in Organic Chemistry, 2015, 12, 13-20
13
Synthesis of Some New Chromeno[2,3-b]pyridine and [1,2,4]Triazolo[1,5-
a]quinoline Nucleoside Analogues with Expected Biological Activity
*
Amira A. Ghoneim and Ahmed F. El-Farargy
Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt
Received October 14, 2013: Revised December 12, 2013: Accepted February 21, 2014
Abstract: Direct preparation of 2-amino-5,6,7,8-tetrahydro-4-(4-methoxyphenyl)-7,7-dimethyl-5-oxo-4H-chromene-3-
carbonitrile (2) and 1,2-diamino-1,4,5,6,7,8-hexahydro-4-(4-methoxyphenyl)-7,7-dimethyl-5-oxo-3-quinolinecarbonitrile
(11) which were utilized as starting products for the synthesis of S-nucleoside analogues of kinds 10, 15 and C-nucleoside
analogues of types 12, 13 is presented in the current study. The antibacterial and antifungal activities of these new com-
pounds were evaluated. The structures of the new products were confirmed on the basis of elemental and spectral analysis
results.
Keywords: Chromeno[2,3-b]pyridines, [1,2,4]triazolo[1,5-a]quinolines, L-rhamnopyranosyl bromide, antimicrobial activity.
INTRODUCTION
due to their documented biological activities [38]. Sugar
moieties linking to these structures would enhance their pen-
etration into cells, and therefore contribute to their activities.
Recently, chromene derivatives have attracted much at-
tention, as they exhibited a wide range of biological activi-
ties, such as antifungal, antibacterial [1-5], antioxidative [6],
antileishmanial [7], antitumor [8], hypotensive [9], antipro-
liferation [10], local anaesthetic [11], antiallergenic [12, 13],
central nervous system (CNS) activities and effects [14], as
well as efficacious in the treatment of Alzheimer’s disease
RESULTS AND DISCUSSION
(
4-Methoxybenzylidene)malononitrile 1 was reacted with
5
,5-dimethylcyclohexane-1,3-dione in refluxing ethanol con-
taining catalytic piperidine to give a yellow solid of 2-
amino-5,6,7,8-tetrahydro-4-(4-methoxyphenyl)-7,7-dimeth-
yl-5-oxo-4H-chromene-3-carbonitrile 2 [39,40] (Scheme 1).
[
15] and schizophrenia disorder [16]. On this basis, it was of
great importance to prepare fused chromene derivatives
which have platelet antiaggregating, local anaesthetic [17-
1
9] and antihistaminic activities [20]. Recently, the current
Refluxing of the compound 2 with ethyl acetoacetate in
the presence of pyridine gives the corresponding cyclized
product 3-acetyl-4-amino-8,9-dihydro-5-(4-methoxyphenyl)-
interest in 5,6,7,8-tetrahydro-4H-chromene derivatives bear-
ing nitrile functionality, especially 2-amino-5-oxo-5,6,7,8-
tetrahydro-4H-chromene-3-carbonitriles, has emerged for
their potential application in the treatment of human neu-
rodegenerative disorders [21]. A large number of nucleoside
analogues showed different biological activities. Most im-
portantly they could exhibit antitumor [22] and antiviral ac-
tivities [23] which encouraged us to prepare the correspond-
ing chromene S-nucleoside analogues. On the other hand,
quinoline derivatives possess diverse pharmacological activi-
ties, including antimicrobial [24], antimalarial [25], antiviral
8
,8-dimethyl-1H-chromeno[2,3-b]pyridine-2,6-dione
3.
Similarly, compound 2 with ethyl cyanoacetate in hot
ethanol containing catalytic triethylamine gives 4-amino-
2
2
,5,6,7,8,9-hexahydro-5-(4-methoxyphenyl)-8,8-dimethyl-
,6-dioxo-1H-chromeno[2,3-b]pyridine-3-carbonitrile
4
(
Scheme 1).
Compound 4 was allowed to react with ethyl chloroace-
tate in DMF in the presence of catalytic amount of potassium
carbonate to yield the corresponding compound 5 by electro-
philic attack. Compound 5 was reacted with hydrazine hy-
drate in ethanol giving hydrazide 6. The IR spectrum of the
latter compound revealed the appearance of three absorption
[
26], antitumor [27], immunomodulatory [28], caspase-3
inhibiting [29], antileishmanial [30], local anesthetic [31],
antiarrhythmic [32] and antiinflammatory activities [33].
Here we report, the synthesis of the novel 1,2-diamino-
-
1
2
bands at 3420, 3220, and 3159 cm due to NH and NH
1
,4,5,6,7,8-hexahydro-4-(4-methoxyphenyl)-7,7-dimethyl-5-
functions and the mass spectrum showed a peak correspond-
oxo-3-quinolinecarbonitrile (11) which was allowed to react
with D-glucose and L-rhamnose to form C-nucleosides.
+
ing to molecular ion at m/z = 463 (M ). Subsequently, treat-
ment of hydrazide derivative 6 with D-glucose in refluxing
ethanol and glacial acetic acid yields the corresponding hy-
drazone 7. Its structure was established on the basis of the
Furthermore, the synthesis [34, 35] of C-nucleosides and
their acyclic [36,37] analogues also received much attention
-
1
appearance of NH absorption band at 3154 cm and a car-
-
1
1
bonyl group at 1684 cm in the IR spectrum, whereas H
NMR spectrum revealed the presence of a signal due to
CH=N at 7.43 ppm.
*
Address correspondence to this author at the Chemistry Department, Fac-
ulty of Science, Zagazig University, Zagazig, Egypt; Tel: +886-34279455;
Fax: +886-34279455; E-mail: aa_amiraatef@yahoo.com
1
875-6255/15 $58.00+.00
© 2015 Bentham Science Publishers

1
4
Letters in Organic Chemistry, 2015, Vol. 12, No. 1
Ghoneim and El-Farargy
Me
Me
O
Ar
CN
N
H CO
3
CHO
2
CH (CN)2
O
O
O
NH2
H CO
3
piperidine
N
2COOEt
2
1
COCH
h
Me
din
e /7
N
pyri
3
t
O
Ar
O
NH2
NCCH COOEt
COMe
2
O
H
/
E
t
E
N
H
O
3
O
Ar
NH2
CN
O
N
O
H
4
t
COOE
2
H
C
Cl
O
Ar
O
NH2
O
Ar
NH2
N
NH NH2
CN
2
CN
N
O
COOEt
O
O
CONHNH2
6
5
D-glucose
O
Ar
NH2
CN
O
N
O
CONHN CH(CHOH) CH OH
4 2
7
Ar
=
OMe
Scheme 1.
Reaction of 2-((4-amino-3-cyano-6,7,8,9-tetrahydro-5-(4-
methoxyphenyl)-8,8-dimethyl-6-oxo-5H-chromeno[2,3-b]
pyridin-2-yl)oxy)acetohydrazide 6 with phenyl isothiocy-
anate in absolute ethanol at reflux produced the correspond-
ing hydrazinecarbothioamide 8 in a good yield. The structure
of 8 was confirmed by the IR spectral data, which displayed
dium hydroxide. When compound 9 was subjected to cou-
pling with 2,3,4-tri-O-acetyl-ꢀ-L-rhamnopyranosyl bromide
in the presence of potassium hydroxide using ethanol as the
solvent, compound 10 was afforded in 66-70% yield
(Scheme 2).
-
1
Compound 2 reacted with hydrazine hydrate in the pres-
ence of pyridine through the ring opening of chromene. The
reaction is presumed to occur via nucleophilic attack of
the ring, then cyclization to form 1,2-diaminoquinoline
characteristic absorption bands in the region 3420-3154 cm
-
1
-1
2
for NH and NH , 1694 cm for CO and 1348-1335 cm cor-
responding to CS vibrations. The synthesis of compound 9
was achieved by the cyclization of 8 in the presence of so-

Synthesis of Some New Chromeno[2,3-b]pyridine
Letters in Organic Chemistry, 2015, Vol. 12, No. 1
15
O
Ar
O
NH2
N
CN
O
Ar
O
NH2
PhNCS
CN
O
C
O
NHNH2
S
N
O
C
O
NHNH
C
NHPh
6
8
NaOH /reflux
O
Ar
NH2
O
Br
CN
O
Ar
O
NH2
N
N
AcO
OAc
O
N
CN
O
OAc
N
N
N
Ph
S
N
SH
O
N
O
Ph
9
AcO
OAc
OAc
Ar =
OMe
1
0
Scheme 2.
-
1
-1
O
Ar
O
2
Ar
NH group, 3105 cm due to CH aromatic bonds, 2920 cm
O
-
1
CN
due to CH aliphatic bonds, 2023 cm due to CN group.
CN
NH .NH / H O
2
2
2
The IR spectrum of 13 showed absorption bands at 3400
-
1
-1
-O
cm due to OH groups, 3232 cm due to NH group, 2925
NH2
NH2
-
1
-
1
N+
cm due to CH aliphatic bonds, 2225 cm due to CN group.
H
H
NH2
Compound 11 underwent cyclization with carbon disul-
fide giving the corresponding triazolo[1,5-a]quinoline de-
rivative 14. The heterocyclic compound 14 was reacted with
2
,3,4-tri-O-acetyl-ꢀ-L-rhamnopyranosyl bromide in the pres-
ence of potassium hydroxide in acetone and was stirred at
room temperature for 17 h to give the corresponding S-
glycosylated nucleoside 15 in good yield (Scheme 4).
O
Ar
O
Ar
CN
Antimicrobial Activity: Some new synthesized com-
pounds were tested for their antibacterial activities using two
bacterial strains, namely Staphylococcus aureus which is
Gram (+) bacterium and Esherichia coli which is Gram (–)
bacterium. In addition, the antifungal activity was also tested
using Aspergillus flavus and Candida albicans. The tested
compounds were dissolved in DMSO to get 30 mg/mL con-
centration and the disc diffusion method [41] was used. The
inhibition zone was measured in mm at the end of an incuba-
tion period of 48 h at 37 °C, and using an inhibition zone
diameter in mm/mg sample as criterion for the antimicrobial
activity. DMSO showed no inhibition zones. The bactericide
chloramphenicol (10 μg/mL) was used as reference for the
potency evaluation of the tested compounds under the same
conditions. Flucanazole (25 μg/mL) was used as standard
antifungal (positive control) while DMSO was used as nega-
tive control. The results are depicted in Table 1. The tested
products 7, 10, 12, and 15 exhibited antimicrobial effect.
Products 3 and 4 had moderate activity against both Gram
(+) and Gram (-) bacteria.
CN
N
NH2
OH
NH2
NH2
NH
NH
2
1
1
Ar
=
OMe
Scheme 3.
derivative 11. The suggested mechanism for the formation of
compound 11 is outlined in Scheme 3.
It was very interesting to study the condensation reaction
of 11 with D-glucose and L-rhamnose in the presence of
methanolic iodine and diluted acetic acid at room tempera-
ture under stirring for 22 h, which afforded compounds 12
and 13 (Scheme 4). The IR spectrum of 12 showed absorp-
-
1
-1
tion bands at 3363 cm due to OH groups, 3126 cm due to

1
6
Letters in Organic Chemistry, 2015, Vol. 12, No. 1
Ghoneim and El-Farargy
O
Ar
CN
N
N
H
O
NH
Ac
il.
,
d
2
I
,
e
(CHOH)4
os
luc
D-g
12 CH OH
2
O
Ar
O
Ar
O
O
Ar
CN
CN
CN
L-rhamnose, I , dil.AcOH
2
NH NH /Pyridine
2
2
N
NH2
N
NH2
N
2
NH2
NH
11
C
S
2
/
(CHOH)4
CH3
KOH/ e
tha
Ar
=
OMe
no
l
13
O
Ar
CN
O
Br
O
Ar
CN
N
N
AcO
OAc
HN
OAc
acetone / KOH
N
S
NH
S
O
HN
AcO
OAc
14
OAc
1
5
Scheme 4.
Table 1. Screening for antimicrobial activity of the tested compounds.
Inhibition zone diameter(mm/mg of sample)
Fungus
Bacterium
C. albicans
A. flavus
S. aureus (G+)
E. coli (Gꢀ)
Sample
1
1
1
1
1
6
9
7
8
12
6
10
10
17
12
10
8
3
4
11
5
7
6
7
10
12
13
15
1
1
1
0
6
2
6
13
8
10
13
-
12
21
-
11
21
-
-
Chloramphenicol
Fluconazole
1
0
19
EXPERIMENTAL SECTION
tus in capillaries and are uncorrected. IR spectra were ob-
tained in the solid state as potassium bromide discs using a
Perkin-Elmer model 1430 spectrometer. H NMR spectra
General Procedures. Melting points were determined on
Electrothermal IA 9,100 series digital melting point appara-
1

Synthesis of Some New Chromeno[2,3-b]pyridine
Letters in Organic Chemistry, 2015, Vol. 12, No. 1
17
were recorded on a Varian/Gemini 200 MHz spectrometer in
2-((4-Amino-3-cyano-6,7,8,9-tetrahydro-5-(4-methoxy-
DMSO-d
6
as a solvent and TMS as an internal standard
phenyl)-8,8-dimethyl-6-oxo-5H-chromeno[2,3-b]pyridin-
(
chemical shifts in ꢀ, ppm). Mass spectra were measured on
2-yl)oxy)acetohydrazide (6)
an instrument VG-7035 at 70 or 15 eV. Elemental analyses
were performed at the Microanalytical Centre, Cairo Univer-
sity, and Giza, Egypt.
The reaction of 5 (1 mmol) with hydrazine hydrate (10
mL) in ethanol (30 mL) was heated under reflux for 4 h. The
reaction mixture was allowed to cool at room temperature
and poured onto water (100 mL). The solid formed was col-
lected by filtration, dried, and crystallized from ethanol to
give compound 6 as yellow powder in 83% yield, mp 243-
3
-Acetyl-4-amino-8,9-dihydro-5-(4-methoxyphenyl)-8,8-
dimethyl-1H-chromeno[2,3-b]pyridine-2,6-dione (3)
A mixture of 2 (1 mmol) and ethyl acetoacetate (1 mmol)
in 50 mL of pyridine was refluxed for 7 h, then the reaction
mixture was poured onto ice water and neutralized with hy-
drochloric acid, filtered, and recrystallized from ethanol to
2
245 °C. IR: 3420, 3220, 3159 (NH, NH, NH ), 2187(CN),
1685, 1664 (C=O) cm . H NMR: 8.22 (d, 2H, H-Ar), 8.05
-
1 1
(br s, 1H, NH, D O exchangeable), 7.32 (d, 2H, H-Ar), 6.79
2
(br s, 2H, NH , D O exchangeable), 3.94 (s, 1H, CH), 3.55
2
2
o
give compound 3. Yield: 56%, mp 168-170 C. IR (KBr):
(
(
3
br s, 2H, NH
s, 2H, CH
H, CH ), 1.04 (s, 3H, CH
calcd for C24 :C, 62.19; H, 5.44; N, 15.11. Found: C,
2.23; H, 5.41; N, 15.31.
2
, D
2
3
O exchangeable), 3.23 (s, 3H, OCH ), 2.10
-
1 1
3
414, 3124 (NH, NH
NMR: ꢀ 10.21 (s, 1H, NH), 7.14 (d, 2H, H-Ar), 6.80 (d, 2H,
H-Ar), 5.60 (s, 2H, NH ), 4.30 (s, 1H, CH), 3.76 (s, 3H,
OCH ), 2.13 (s, 3H, CH ), 2.45 (s, 2H, CH ), 1.83 (s, 2H,
CH ), 1.10 (s, 3H, CH ), 1.02 (s, 3H, CH ). MS: M 408
). Anal. calcd. for C23 : C, 67.73; H,
2
), 1681 (C=O), 1215 (C–O) cm . H
2
), 2.03 (s, 2H, CH
2 2
), 1.96 (s, 2H, CH ), 1.12 (s,
3
3
). MS m/z = 463 (M+). Anal.
2
25 5 5
H N O
3
3
2
6
+
2
3
3
(
C
23
H
24
N
2
O
6
24 2 6
H N O
5
.92; N, 6.86. Found: C, 67.46; H, 5.83; N, 6.32.
2-((4-Amino-3-cyano-6,7,8,9-tetrahydro-5-(4-methoxy-
phenyl)-8,8-dimethyl-6-oxo-5H-chromeno[2,3-b]pyridin-
2
-yl)oxy)-N'-((2S,3R,4R,5R)-2,3,4,5,6-pentahydroxyhexy-
4
-Amino-2,5,6,7,8,9-hexahydro-5-(4-methoxyphenyl)-8,8-
lidene)acetohydrazide (7)
dimethyl-2,6-dioxo-1H-chromeno[2,3-b]pyridine-3-
carbonitrile (4)
A mixture of compound 6 (1 mmol), D-glucose (1
mmol), ethanol (30 mL), and a catalytic amount of glacial
acetic acid (3 drops) was heated at 80 °C for 2 h. The formed
precipitate was filtered off, dried, and recrystallized from
To a solution of 2 (1 mmol) in absolute ethanol (30 mL)
and triethylamine (5 mL), ethyl cyanoacetate (1 mmol) was
added and the reaction mixture was refluxed for 7 h, then left
to cool at room temperature, poured onto cold water and
neutralized with diluted hydrochloric acid to complete pre-
cipitation. The solid obtained was filtered off, washed with
water, dried well, and recrystallized from methanol to give
o
ethanol to give compound 7. Yield: 43%, mp 205-207 C.
-
1 1
2
IR: 3420, 3154 (NH, NH ), 2187(CN), 1684 (C=O) cm . H
NMR: ꢀ 8.58 (s, 1H, NH), 7.43 (m, 1H, N=CH), 7.23 (d, 2H,
H-Ar), 6.80 (d, 2H, H-Ar), 5.2-5.5 and 3.7-3.9 (two m, 8H,
o
H-2`-5`, H
able), 4.99 (s, 2H, NH
OCH ), 2.11 (s, 2H, CH
CH ), 1.04 (s, 3H, CH ). Anal. calcd. for C30
57.59; H, 5.64; N, 11.19. Found. C, 57.96; H, 6.03; N, 11.21.
2
-6`, OCH
2
), 5.2-4.3 (m, 5 x OH, D
), 4.74 (s, 1H, CH), 3.43 (s, 3H,
), 1.86 (s, 2H, CH ), 1.13 (s, 3H,
2
O exchange-
compound 4. Yield: 53-60%, mp 187-189 C. IR: 3420, 3154
-
1 1
(
(
2
CH
CH
NH, NH
s, 1H, NH), 7.23 (d, 2H, H-Ar), 6.80 (d, 2H, H-Ar), 6.30 (s,
H, NH ), 4.74 (s, 1H, CH), 3.43 (s, 3H, OCH ), 2.11 (s, 2H,
), 1.86 (s, 2H, CH ), 1.13 (s, 3H, CH ), 1.04 (s, 3H,
). MS m/z = 391 (M+). Anal. calcd. for C22 : C,
2
), 2187 (CN), 1684 (C=O) cm . H NMR: ꢀ 9.12
2
3
2
2
3
3
35 5
H N O10: C,
2
3
2
3
2
3
21 3 4
H N O
6
7.51; H, 5.41; N, 10.74. Found:C, 64.46; H, 5.93; N, 10.12.
2
-(2-((4-Amino-3-cyano-6,7,8,9-tetrahydro-5-(4-methoxy-
phenyl)-8,8-dimethyl-6-oxo-5H-chromeno[2,3-b]pyridin-
2-yl)oxy)acetyl)-N-phenylhydrazinecarbothioamide (8)
Ethyl 2-((4-amino-3-cyano-6,7,8,9-tetrahydro-5-(4-me-
thoxyphenyl)-8,8-dimethyl-6-oxo-5H-chromeno[2,3-b]
pyridin-2-yl)oxy)acetate (5)
A mixture of 6 (1 mmol) and phenyl isothiocyanate (1
mmol) in 50 mL of DMF containing a catalytic amount of
triethylamine (4 drops) was refluxed for 5 h and then left to
cool at room temperature. The reaction mixture was poured
into cold water for complete precipitation, and then the solid
was filtered off, washed with water, dried well and recrystal-
A solution of 4 (1 mmol) in 250 mL of dry DMF was
o
heated at 80–85 C with ethyl chloroacetate (1 mmol) in an
oil bath in the presence of anhydrous potassium carbonate
(
0.11 mmol). The reaction mixture was cooled and poured
onto ice water. A pale yellow crystalline solid was separated,
filtered, washed thoroughly first with cold water and then
with cold ethanol, recrystallized from 95% ethanol. Yield
lized from aqueous methanol to give compound 8. Yield:
o
6
(
2%, mp 263-265 C. IR: 3420, 3154 (NH, NH
2
), 2187
-1 1
CN), 1694 (C=O), 1356 (C=S) cm . H NMR: ꢀ 11.59 (br s,
o
7
1
2
0%, mp 273-275 C. IR: 3433, 3135 (NH
2
), 2213 (CN),
1
2
H, NH), 10.40 (br s, 1H, NH), 8.12 (s, 1H, NH), 7.23 (d,
H, H-Ar), 7.1-7.0 (m, 5H, PhNH), 6.80 (d, 2H, H-Ar), 6.21
1
712 (C=O), 1664. H NMR: ꢀ 7.13 (d, 2H, H-Ar), 6.88 (d,
H, H-Ar), 5.30 (s, 2H, NH ), 4.93 (s, 2H, CH ), 4.34 (s, 1H,
), 3.23 (s, 3H, OCH ), 2.23 (s, 2H,
), 1.24 (t, 3H, CH ), 1.12 (s, 3H,
2
2
(
3
3
s, 2H, NH
2
), 4.74 (s, 1H, CH), 4.22 (s, 2H, OCH
), 2.11 (s, 2H, CH ), 1.86 (s, 2H, CH
), 1.04 (s, 3H, CH ). MS m/z = 598 (M+). Anal.
S: C, 62.19; H, 5.05; N, 14.04; S, 5.36.
Found: C, 62.34; H, 5.13; N, 14.12; S, 5.66.
2
), 3.43 (s,
), 1.13 (s,
CH), 3.93 (q, 2H, OCH
2
3
H, OCH
H, CH
3
2
2
CH
CH
2
), 1.79 (s, 2H, CH
), 1.04 (s, 3H, CH
: C, 65.40; H, 5.70; N, 8.80. Found: C, 65.44;
H, 5.68; N, 8.76.
2
3
3
3
3
3
). MS m/z = 477 (M+) Anal. calcd.
30 6 5
calcd. for C31H N O
27 3 6
for C26H N O

1
8
Letters in Organic Chemistry, 2015, Vol. 12, No. 1
Ghoneim and El-Farargy
4
1
-Amino-6,7,8,9-tetrahydro-2-((5-mercapto-4-phenyl-4H-
,2,4-triazol-3-yl)methoxy)-5-(4-methoxyphenyl)-8,8-di-
2 2 3
was quenched by addition of Na S O (2 mL of saturated
aqueous solution), and the mixture was concentrated under
reduced pressure to give crude product which was washed
successively with water and methanol, then recrystallized
from ethanol to give 12 as yellow powder, 68% yield, mp
methyl-6-oxo-5H-chromeno[2,3-b]pyridine-3-carbonitrile
9)
(
A mixture of 8 (1 mmol) in ethanolic NaOH (100 mL,
%) was heated under reflux for 4 h. The reaction mixture
2
2
7
4
3
12-214 °C. IR: 3432, 3363 (OH), 3126 (NH), 3105, 2920,
023 (CN), 1687 (CO) cm . H NMR: ꢀ 10.12 (s, 1H, NH),
.07 (d, 2H, H-Ar), 6.83 (d, 2H, H-Ar), 5.49 (m, 1H, H-2`),
5
-1 1
was left to cool to room temperature, then poured into ice
cold water (50 mL) and neutralized with dilute hydrochloric
acid; the separated material was filtered off and recrystal-
lized from ethanol to give compound 9. MS m/z = 580 (M+).
Anal. calcd. for C31
S, 5.52. Found: C, 64.36; H, 4.69; N, 14.32; S, 5.40.
.74 (s, 1H, CH), 4.41 (m, 1H, H-3`), 4.30 (m, 2H, H
.78 (m, 1H, H-4`), 3.59 (m, 5H, 5 x OH, D O exchange-
), 2.31 (s, 2H, CH ), 1.89 (s, 2H,
), 1.04 (s, 3H, CH ).
2
-5`),
2
able), 3.43 (s, 3H, OCH
CH ), 1.13 (s, 3H, CH
3
2
28 6 4
H N O S: C, 64.12; H, 4.86; N, 14.47;
2
3
3
1
,5,6,7,8,9-Hexahydro-2-((S,S,S,S)-1,2,3,4-tetrahydroxy-
(
3R,4R,5S,6S)-2-((5-(((4-Amino-3-cyano-6,7,8,9-tetrahy-
pentyl)-5-(4-methoxyphenyl)-8,8-dimethyl-6-oxo-[1,2,4]
triazolo[1,5-a]quinoline-4-carbonitrile (13)
dro-5-(4-methoxyphenyl)-8,8-dimethyl-6-oxo-5H-chro-
meno[2,3-b]pyridin-2-yl)oxy)methyl)-4-phenyl-4H-1,2,4-
triazol-3-yl)thio)-3,4,5,6-tetrahydro-6-methyl-2H-pyran-
It was prepared by the same conditions used for the com-
3
,4,5-triyl triacetate (10)
pound 12. The product was crystallized from methanol to
give 13 as yellow powder. Yield: 78%, mp 203-205 °C. IR:
Compound 9 (2 mmol) was dissolved in a solution of
-1
3
400 (OH), 3232 (NH), 2925, 2225 (CN), 1684 (C=O) cm .
KOH (2 mmol) in ethanol (25 mL). After stirring of the mix-
ture at room temperature for 30 min, 2,3,4-tri-O-acetyl-ꢀ-L-
rhamnopyranosyl bromide (2 mmol) was added. The reaction
mixture was stirred at room temperature for 48 h. The mix-
ture was concentrated and washed with water. The crude
30 4 6
MS m/z = 482 (M+). Anal. calcd. for C25H N O : C, 62.23;
H, 6.27; N, 11.61. Found: C, 62.69; H, 6.12; N, 11.39.
1,2,3,5,6,7,8,9-Octahydro-5-(4-methoxyphenyl)-8,8-dime-
thyl-6-oxo-2-thioxo-[1,2,4]triazolo[1,5-a]quinoline-4-car-
bonitrile (14)
product was purified by flash column chromatography.
o
Yield: 66-70%, mp 210-212 C. IR: 3436, 3144 (NH
2
), 2187
-
1 1
(
7
5
(
3
2
CH
(
9
CN), 1684 (C=O) cm . H NMR: ꢀ 7.7-7.3 (m, 5H, PhNH),
A mixture of 11 (1 mmol) and carbon disulfide (1 mmol)
in ethanolic potassium hydroxide (1 mmol) was refluxed for
.23 (d, 2H, H-Ar), 6.80 (d, 2H, H-Ar), 6.30 (s, 2H, NH
2
),
.09 (d, 1H, H-1`), 4.74 (s, 1H, CH), 4.36 (2H, OCH ), 3.87
2
5
h, after cooling the reaction mixture was poured onto ice.
dd, 1H, H-4`), 3.68 (dd, 1H, H-5`), 3.6-3.4 (m, 2H, H-2`,3`),
The solid obtained was filtered, washed with water, and
.43 (s, 3H, OCH
.11, 2.05, and 1.99 (three s, 9H, 3 x CH
), 1.13 (s, 3H, CH ), 1.04 (s, 3H, CH
M+). Anal. calcd. for C43 11S: C, 60.55; H, 5.20; N,
3
), 2.30 (s, 3H, H
3
-6'), 2.11 (s, 2H, CH
CO), 1.86 (s, 2H,
). MS m/z = 852
2
),
crystallized from DMF to give compound 14 as yellow crys-
o
3
tals, yield 75%, mp 233-235 C. IR: 3431, 3254 (NH), 2157
-1 1
2
3
3
(
1
CN), 1689 (C=O), 1346 (C=S) cm . H NMR: ꢀ 9.80 and
0.03 (two br s, 2H, 2NH), 7.22 (d, 2H, H-Ar), 6.83 (d, 2H,
H-Ar), 4.74 (s, 1H, CH), 3.32 (s, 3H, OCH ), 2.41 (s, 2H,
), 1.04 (s, 3H,
). MS m/z = 380 (M+). Anal. calcd. for C20 S: C,
44 6
H N O
.85; S, 3.76. Found: C, 60.36; H, 5.49; N, 9.20; S, 3.32.
3
CH
CH
2
3
2 3
), 1.89 (s, 2H, CH ), 1.13 (s, 3H, CH
20 4 2
H N O
1
7
,2-Diamino-1,4,5,6,7,8-hexahydro-4-(4-methoxyphenyl)-
,7-dimethyl-5-oxoquinoline-3-carbonitrile (11)
6
3.14; H, 5.30; N, 14.73; S, 8.43. Found: C, 63.54; H, 5.13;
N, 14.42; S, 8.66.
A mixture of 2 (1 mmol) and hydrazine hydrate (10 mL)
in pyridine (30 mL) was heated under reflux for 4 h. The
reaction mixture was allowed to cool at room temperature,
poured onto water (100 mL), and neutralized with hydro-
chloric acid. The solid formed was collected by filtration,
dried, and crystallized from ethanol, to give compound 11 as
(
3R,4R,5S,6S)-2-((4-Cyano-1,5,6,7,8,9-hexahydro-5-(4-
methoxyphenyl)-8,8-dimethyl-6-oxo-[1,2,4]triazolo[1,5-
a]quinolin-2-yl)thio)-3,4,5,6-tetrahydro-6-methyl-2H-
pyran-3,4,5-triyl triacetate (15)
o
brown powder. Yield: 63%, mp 145-147 C. IR: 3410, 3154
To a solution of 14 (1 mmol) in aqueous potassium hy-
droxide (0.73 g in 10 mL of distilled water), a solution of
2,3,4-tri-O-acetyl-ꢁ-L-rhamnopyranosyl bromide (1 mmol)
in acetone (40 mL) was added. The reaction mixture was
stirred at room temperature for 24 h (under TLC control).
The solvent was evaporated under reduced pressure and the
crude product was filtered off and washed with distilled wa-
ter to remove KBr formed. The product was dried, and crys-
-
1
1
(
2
3
CH
CH
NH
2
), 2227 (CN), 1684 (C=O) cm . H NMR: ꢀ 7.07 (d,
H, H-Ar), 6.83 (d, 2H, H-Ar), 6.21 (s, 2H, NH ), 3.30 (s,
H, OCH ), 3.24 (s, 1H, CH), 2.32 (s, 2H, NH ), 2.11 (s, 2H,
), 1.04 (s, 3H,
2
3
2
2
3
), 1.86 (s, 2H, CH
).
2 3
), 1.13 (s, 3H, CH
1
,5,6,7,8,9-Hexahydro-2-((1S,2R,3R,4R)-1,2,3,4,5-penta-
o
tallized from hexane. Yield: 60%, mp 179-181 C. IR: 3419,
hydroxypentyl)-5-(4-methoxyphenyl)-8,8-dimethyl-6-oxo-
-1
1
3
(
132 (NH), 2187 (CN), 1684 (C=O) cm . H NMR: ꢀ 9.12
s, 1H, NH), 7.12 (d, 2H, H-Ar), 6.79 (d, 2H, H-Ar), 5.09 (d,
1H, H-1`), 4.34 (s, 1H, CH), 3.87 (dd, 1H, H-4`), 3.68 (dd,
1H, H-5`), 3.6-3.4 (m, 2H, H-2`,3`), 3.53 (s, 3H, OCH ),
[
1,2,4]triazolo[1,5-a]quinoline-4-carbonitrile (12)
Compound 11 (1 mmol) and D-glucose (1 mmol) were
dissolved in a solution of iodine (1 mmol) in acetic acid (5
mL) at room temperature until the D-glucose was completely
consumed as indicated by the TLC. The reaction mixture
3
2.71 (s, 2H, CH ), 2.11, 2.13, and 2.16 (three s, 9H, 3 x
CH CO), 1.86 (s, 2H, CH ), 1.15 (s, 3H, CH ), 1.04 (s, 3H,
2
3
2
3

Synthesis of Some New Chromeno[2,3-b]pyridine
Letters in Organic Chemistry, 2015, Vol. 12, No. 1
19
[13]
[14]
[15]
Coudert, P.; Couquelet, J.M.; Bastide, J.; Marion, Y.; Fialip, J.
Synthesis and antiallergic properties of some N-arylnitrones having
a furopyran structure. Ann. Pharm. Fr. 1988, 46, 91-96.
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CH
3
), 1.02 (s, 3H, CH
3
). MS m/z = 652 (M+). Anal. calcd.
36 4 9
for C32H N O
C, 58.91; H, 5.53; N, 8.51; S, 4.88.
S: C, 58.88; H, 5.56; N, 8.58; S, 4.91. Found:
CONFLICT OF INTEREST
The authors confirm that this article content has no con-
flict of interest.
[
16]
17]
Kesten, S.R.; Heffner, T.G.; Johnson, S.J.; Pugsley, T.A.; Wright,
J.L.; Wise, D.L. Design, Synthesis, and Evaluation of Chromen-2-
ones as Potent and Selective Human Dopamine D4 Antagonists. J.
Med. Chem., 1999, 42, 3718-3725.
Bargagna, A.; Longobardi, M.; Mariani, E.; Schenone, P.; Losasso,
C.; Esposito, G.; Falzarano, C.; Marmo, E. Reaction of ketenes
with N,N-disubstituted ꢀ-aminomethyleneketones. XXII. 2H,5H-
ACKNOWLEDGEMENTS
Declared none.
[
SUPPLEMENTARY MATERIAL
[1]benzothiopyrano[4,3-b]pyran derivatives with platelet antiag-
Supplementary material is available on the publisher’s
web site along with the published article.
gregating activity. Farmaco, 1990, 45, 405-413.
[
[
[
[
18]
19]
20]
21]
Bargagna, A.; Longobardi, M.; Mariani, E.; Schenone, P.; Cenico-
la, M.L.; Losasso, C.; Carnevale, M.; Marmo, E. Reaction of kete-
nes with N,N-disubstituted ꢀ-aminomethylene ketones. XXV.
Benzo[6,7]cyclohepta[1,2-b]pyran derivatives with platelet antiag-
gregating and other activities. Farmaco, 1991, 46, 461-475.
Bargagna, A.; Longobardi, M.; Mariani, E.; Schenone, P.; Rossi,
F.; D'amico, M.; Falzarano, C. Reaction of ketenes with N,N-
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