Synthesis of some fused heterocyclic systems and their nucleoside candidates

Article abstract of DOI:10.1007/s11164-012-1006-y

A series of pyridofuro compounds were synthesized from 4-(4-chlorophenyl)- 1,2-dihydro-2-oxo-6-(thiophen-2-yl)pyridine-3-carbonitrile (1) as starting material. Alkylation of 1 with ethyl bromoacetate gave the corresponding ester 2, which was condensed with hydrazine hydrate to afford the corresponding acid hydrazide derivative 3. Thrope-Ziegler cyclization of 2 with sodium methoxide gave furo[2,3-b]pyridine derivative 4, which was reacted with thiosemicarbazide, allyl isothiocyanate, formamide or hydrazine hydrate to give furopyridine derivatives 5-8, respectively. The latter compound 8 was cyclized with acetylacetone or formic acid to give the corresponding compounds 9 and 10, respectively. Furthermore, sulfurization of 1 with P₂S₅ gave the corresponding thioxopyridine 11, which was reacted with glycosyl (or galactosyl) bromide, morpholine or piperidine to give the corresponding thioglycoside 12a,b and Mannich base 14a,b derivatives. The deacetylation of 12a,b gave the corresponding deacetylated thioglycosides 13a,b, respectively. All the newly synthesized compounds were characterized by the elemental analyses and spectroscopic evidences (IR, ¹H- and ¹³C NMR).

Full text of DOI:10.1007/s11164-012-1006-y

Res Chem Intermed
DOI 10.1007/s11164-012-1006-y
Synthesis of some fused heterocyclic systems
and their nucleoside candidates
•
Hassan A. El-Sayed Said A. Said
Abd El-Galil E. Amr
•
Received: 9 December 2012 / Accepted: 27 December 2012
Ó Springer Science+Business Media Dordrecht 2013
Abstract A series of pyridofuro compounds were synthesized from 4-(4-chloro-
phenyl)-1,2-dihydro-2-oxo-6-(thiophen-2-yl)pyridine-3-carbonitrile (1) as starting
material. Alkylation of 1 with ethyl bromoacetate gave the corresponding ester 2,
which was condensed with hydrazine hydrate to afford the corresponding acid
hydrazide derivative 3. Thrope-Ziegler cyclization of 2 with sodium methoxide
gave furo[2,3-b]pyridine derivative 4, which was reacted with thiosemicarbazide,
allyl isothiocyanate, formamide or hydrazine hydrate to give furopyridine deriva-
tives 5–8, respectively. The latter compound 8 was cyclized with acetylacetone or
formic acid to give the corresponding compounds 9 and 10, respectively. Further-
more, sulfurization of 1 with P2S5 gave the corresponding thioxopyridine 11, which
was reacted with glycosyl (or galactosyl) bromide, morpholine or piperidine to give
the corresponding thioglycoside 12a,b and Mannich base 14a,b derivatives. The
deacetylation of 12a,b gave the corresponding deacetylated thioglycosides 13a,b,
respectively. All the newly synthesized compounds were characterized by the ele-
1
mental analyses and spectroscopic evidences (IR, H- and 13C NMR).
Keywords Pyridine-2(1H)-one ꢀ Furo[2,3-b]pyridine ꢀ Thioglycoside ꢀ
Mannich bases
H. A. El-Sayed ꢀ S. A. Said
Department of Chemistry, Faculty of Science, Zagazig University, Zagazig, Egypt
A. E.-G. E. Amr (&)
Pharmaceutical Chemistry Department, Drug Exploration and Development Chair,
College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
e-mail: aamr1963@yahoo.com
A. E.-G. E. Amr
Applied Organic Chemistry Department, National Research Center, El Dokki, Cairo, Egypt
123

H. A. El-Sayed et al.
Introduction
Furopyridines and heterocycles derived from them are found to be associated with
diverse pharmacological activities [1–4]. They are also reported to possess
significant antipsychotic [5], antianaphlactic [3], antiproliferative [6], anticonvul-
sant [7], and anthelmintic [8] activities, and they can be used as calcium influx
promoters [9], HIV-1 nonnucleoside reverse transcriptase inhibitors [10], acetyl-
cholinesterase inhibitors [11], antioxidant, anti-inflammatory [12], broad-spectrum
human herpes virus polymerase inhibitors [13], anticancer [14], and 5-HT6receptor
antagonists [15]. Moreover, 2-thioxopyridines and their derivatives have been
evaluated to possess good antimicrobial [16], antiviral [17, 18], and anti-
inflammatory activity [19]. On the other hand, glycosylsulfanyl heterocycles have
attracted much attention because of their biological activity as antitumor [20],
antimicrobial [21, 22], antiviral [23], and in particular their inhibition of the activity
of enzymes [24–31]. In view of these reports and as a continuation of our research
program in the chemistry of pyridines [32], we report here the synthesis of
additional new numbers of these derivatives that are required in medicinal chemistry
programs.
Results and discussion
4-(4-Chlorophenyl)-2-oxo-6-(thien-2-yl)-1,2-dihydropyridine-3-carbonitrile (1) was
synthesized as starting material according to the literature procedure [32].
Alkylation of 1 with ethyl bromoacetate in the presence of K2CO3 in DMF
afforded the corresponding ethyl ester derivative 2 (Scheme 1). The IR spectrum of
ester 2 showed an absorption band at 1732 cm-1 characteristic for (C=O, ester), in
addition to the disappearance of the amide carbonyl band, which means the
formation of an O-alkylated derivative and not the N-analogues. Its 1H NMR
spectrum showed triplet, quartet, and singlet signals at d 1.24, 4.21, and 5.11 ppm
corresponding to OC2H5 and CH2O protons, respectively. 13C NMR spectrum of 2
showed four signals at d 14.15, 60.76, 63.67, and 167.9 ppm corresponding to
(C2H5), CH2O ,and (C=O, ester), respectively.
Cl
Cl
CN
O
CN
O
K2CO3/dry DMF
r.t./2h
+
Br
CO2Et
N
H
N
CO2Et
S
S
2
1
Scheme 1 Synthetic pathway for compound 2
123

Synthesis of some fused heterocyclic systems
Condensation of ester 2 with hydrazine hydrate afforded the corresponding acid
hydrazide derivative 3 (Scheme 2). The IR spectrum of 3 showed absorption bands at
1636 and 3416 cm-1 characterized to amid carbonyl, NH, and NH2 groups,
1
respectively. Its H NMR spectrum showed two singlets at d 4.62 and 8.48 ppm
corresponding to NH2 and NH protons, respectively. 13C NMR spectrum of 3 showed
the disappearance of the ethoxy carbon atoms. Upon treatment of ester 2 with sodium
methoxide in methanol, it underwent interamolecular Thrope-Ziegler condensation to
furnish ethyl 3-amino-4-(4-chlorophenyl)-6-(thien-2-yl)furo[2,3-b]pyridine-2-car-
boxylate (4) (Scheme 2). The IR spectrum of compound 4 showed an absorption
band at 1734 and 3449 cm-1 characteristic for carbonyl ester and NH2, in addition to
the disappearance of the C:N band. Its 1H NMR spectrum showed triplet, quartet,
and singlet broad signals at d 1.20, 4.10, and 5.03 ppm corresponding to ethoxy and
NH2 protons, respectively, with the disappearance of the signal of the CH2O protons.
Heterocyclization of furo[2,3-b]pyridine 4 with thiosemicarbazide, allylisothiocya-
nate, and formamide afforded 5-(3-amino-4-(4-chlorophenyl)-6-(thien-2-yl)furo[2,3-
b]pyridin-2-yl)-4H-1,2,4-triazole-3-thiol (5), 3-allyl-9-(4-chlorophenyl)-4-oxo-
1,2,3,4-tetrahydro-7-(thien-2-yl)-2-thioxopyrido[30,20:4,5]furo[3,2-d]pyrimidine (6),
and 9-(4-chlorophenyl)-4-oxo-3,4-dihydro-7-(thien-2-yl)pyrido-[30,20:4,5]furo[3,2-
d]pyrimidine (7), respectively (Scheme 2). The IR spectra of compounds 5–7
showed the absence of a carbonyl ester band and the presence of bands at
3444–3448 cm-1 corresponding to NH groups, in addition, two bands at 1638 and
1654 cm-1 corresponded to the amide carbonyl of compounds 6 and 7, respectively.
1
The H NMR spectrum of triazole derivative 5 showed two singlets at d 8.79 and
13.21 ppm corresponding to NH and SH protons. The H NMR spectrum of allyl
1
derivative 6 showed two doublet signals at d 4.8 and 5.23 ppm with coupling
constants 5.43 and 10.14 Hz, corresponding to NCH2 and Ha, respectively, in
addition, there was a doublet signal at d 5.31 ppm with a coupling constant 17.5 Hz
for Hb, and a multiplet signal at d 5.80 ppm for Hc. Its 13C NMR spectrum showed
signals at d 62.91, 110.9, and 118.0 ppm corresponding to NCH2, (=CH2), and (CH=),
1
respectively. The H NMR spectrum of furopyrimidine 7 showed two singlets at d
4.94 and 7.69 ppm for the NH and pyrimidine-H-2 protons, respectively.
Condensation of ester 4 with hydrazine hydrate afforded the acid hydrtazide
derivative 8, which was cyclized with acetyl acetone and formic acid and gave (3-
amino-4-(4-chlorophenyl)-6-(thien-2-yl)furo[2,3-b]pyridin-2-yl)(3,5-dimethyl-1H-
pyrazol-1-yl)methanone (9) and 9-(4-chlorophenyl)-3-formylamino-4-oxo-3,4-dihy-
dro-7-(thien-2-yl)pyrido[30,20:4,5]furo[3,2-d]pyrimidine
(10),
(Scheme 3). The IR spectra of compounds 9 and 10 showed absorption bands at
respectively
1619 and 1694 cm-1, respectively, corresponding to the amide carbonyl. The H
1
NMR spectrum of pyrazole derivative 9 showed three singlets at 2.27, 2.87, and
6.25 ppm corresponding to 2CH3 protons and a pyrazole ring proton, respectively,
while the 1H NMR spectrum of compound 10 showed three singlets at d 7.81, 9.8, and
10.01 ppm corresponding to pyrimidine-H-2, CHO, and NH protons, respectively.
Sufurization of 1 with P2S5 gave the corresponding thioxopyridine derivative 11,
which was glycosylated with 2,3,4,6-tetra-O-acetyl-a-D-gluco/galactopyranosyl bor-
mide to give the corresponding thioglycosides 12a,b, respectively (Scheme 4). The IR
spectrum of 12a showed characteristic absorption band at 1750 cm-1 corresponding
123

H. A. El-Sayed et al.
Ar
CN
O
NH2NH2.H2O
EtOH
N
CONHNH2
S
3
2
Ar
N
NH2
CO2Et
MeONa
O
S
4
HCONH2
NH2CSNHNH2
Pyridine
CH2=CHCH2NCS
CH3CN/K2CO3
Hb
S
Ar
N
NH2
Ar
N
Ar
HN
Ha
N
N
NH
N
Hc
Cl
O
N
H
SH
O
O
O
O
N
N
S
5
6
S
S
7
Ar =
Scheme 2 Synthetic pathway for compounds 3–7
to the acetyl carbonyl groups and the 1H NMR spectra of 12a,b showed the anomeric
proton of the sugar moiety at d 6.40 and 6.09 ppm as doublet, with coupling constants
8.78 and 8.76 Hz, respectively, indicating the b-orientation of the thioglycosidic bond.
The attachment of the glycosyl residues to the sulfur rather than to the nitrogen has
been supported by the value of the chemical shift of the anomeric protons which
otherwise should appear at a lower field. The anomeric proton of b-N-glucosides
having an adjacent C=S, was reported to appear at higher chemical shift (d
6.9–7.2 ppm) due to the anisotropic deshielding effect of the C=S. Furthermore, the
13C NMR spectrum of 12a,b showed a signals at d 81.5 and 80.2 ppm, respectively,
corresponding to the anomeric carbons, in addition to, the absence of C=S carbon peak
indicates that the attachment of the sugar at the sulfur atom and not the nitrogen atom.
When the glycosides 12a,b were treated with triethyamine in the presence of a few
drops of water in methanol, the deacetylated thioglycoside derivatives 13a,b were
obtained in good yields (Scheme 4). The IR spectra of compounds 13a,b showed
123

Synthesis of some fused heterocyclic systems
4
Ar
N
NH2
CH3
acetyl-
NH2NH2.H2O
EtOH
acetone
N
N
EtOH
O
Ar
O
NH2
CH3
S
9
CONHNH2
O
N
Ar
H
N
N
S
N
8
CHO
HCOOH
O
O
Ar =
Cl
N
S
10
Scheme 3 Synthetic pathway for compounds 8–10
characteristic absorption bands corresponding to the OH groups at 3423 and
3421 cm-1, respectively, and their 1H NMR agreed with the assigned structures.
Transformation of 4-(4-chlorophenyl)-6-(thien-2-yl)-2-thioxo-1,2-dihydropyri-
dine-3-carbonitrile (11) into Mannich bases is an important reaction to confirm
the regeio-selectivity of the previous glycosylation reaction at the sulfur atom and
not the nitrogen atom. The one-pot multi-component Mannich reaction involved the
thioxopyridine derivative 11, the formaldehyde and the secondary amines (namely,
morpholine and pipridine) in ethanol at room temperature to give the corresponding
Mannich base derivatives 14a,b (Scheme 4). The IR spectrua of compounds
14a,b showed absorption bands at 1353 and 1372 cm-1 corresponding to the amidic
thiocarbonyl (C=S). Their 13C NMR spectra showed absorption peaks at d 185.2 and
183.5 ppm corresponding to C=S carbon.
Experimental
All melting points are uncorrected and were measured using an Electro thermal IA 9100
apparatus. TLC was performed on Merck Silica Gel 60F254 with detection by UV light and
by charring for glycosides after seperating with 10 % EtOH solution of H2SO4. The IR
spectra were recorded on a Pye Unicam Sp-3-300 or a Shimadzu FTIR 8101 PC infrared
spectrophotometer. The 1Hand13C NMR spectra were determined with a JEOL-JNM-LA
500 MHz spectrometer. The chemical shifts are expressed on the d(ppm) scale using TMS
as the standard reference. Elemental analysis determined on a Perkin Elmer 240
(microanalysis), Microanalysis Center, Cairo University, Cairo, Egypt.
Ethyl 2-(4-(4-chlorophenyl)-3-cyano-6-(thien-2-yl)pyridin-2-yloxy)acetate (2)
A mixture of pyridin-2(1H)-one (1) (0.01 mol) and anhydrous potassium carbonate
(0.01 mol) in dry DMF (15 mL) was stirred for 1 h, then (0.011 mol) of ethyl
123

H. A. El-Sayed et al.
Ar
CN
N
OH
S
O
S
"R
R'
HO
OH
13a, R' = OH, R" = H
13b, R' = H, R" = OH
Et3N/H2O
MeOH
Ar
R"
OAc
O
CN
1
R'
AcO
AcO
P2S5/pyr.
6h
Br
k2CO3/Aceone/DMF
N
OAc
S
S
O
"R
R'
Ar
OAc
AcO
Ar
CN
S
12a, R' = OAc, R" = H
12b, R' = H, R" = OAc
N
H
S
CN
S
CH2O,
11
HN
X
N
EtOH/r.t. 2h
S
Ar =
Cl
N
X
14a, X = O
14b, X = CH2
Scheme 4 Synthetic pathway for compounds 11–14
bromoacetate was added. The reaction mixture was stirred for an additional 2 h at
room temperature, filtered off, concentrated under reduced pressure, and poured into
ice water. The obtained product was filtered off, dried, and crystallized from ethanol
to give the title product 2 as pale yellow crystals. Yield 95 %, mp 135–136 °C. IR
1
(KBr, cm-1): 2219 (C:N) and 1732 (C=O, ester). H NMR (DMSO-d6, ppm):
d = 1.24 (t, 3H, J = 7.0 Hz, CH3CH2), 4.21 (q, 2H, J = 7.0 Hz, CH2CH3), 5.11 (s,
2H, CH2), 7.25 (t, 1H, J = 4.55, 3.62 Hz, thiophene-H), 7.69 (d, 2H, J = 8.50 Hz,
Ar–H), 7.77 (d, 2H, J = 8.50 Hz, Ar–H), 7.83 (s, 1H, pyridine-H-5), 7.86 (d, 1H,
J = 4.55 Hz, thiophene-H), 8.13 (d, 1H, J = 3.62 Hz, thiophene-H). 13C NMR
(DMSO-d6, ppm): d = 14.15 (CH3CH2), 60.76 (CH3CH2), 63.67 (CH2), 91.1,
123

Synthesis of some fused heterocyclic systems
112.7, 114.8 (C:N), 128.9, 129.0, 130.5, 131.8, 134.2, 135.1, 148.0, 142.0, 152.6,
155.1, 162.8 and 167.9 (Ar–C and C=O). Anal. Calcd. for C20H15ClN2O3S (398.86):
C, 60.22; H, 3.79; N, 7.02;. Found: C, 60.19; H, 3.83; N, 7.09.
2-(4-(4-Chlorophenyl)-3-cyano-6-(thien-2-yl)pyridin-2-yloxy)acetohydrazide
(3)
A mixture of compound 2 (0.01 mol) and hydrazine hydrate 98 % (1 mL, 0.04 mol)
in absolute ethanol (25 mL) was refluxed for 1 h. After cooling, the formed
precipitate was filtered off, dried, and crystallized from methanol to give compound
3 as yellow crystals. Yield 80 %, mp 192–194 °C. IR (KBr, cm-1): 3416 (NH and
NH2), 2206 (C:N) and 1636 (C=O, amide). 1H NMR (DMSO-d6, ppm): d = 4.62
(s, 2H, NH2), 4.98 (s, 2H, CH2), 7.31 (t, 1H, J = 4.12, 3.24 Hz, thiophene-H), 7.65
(d, 2H, J = 8.0 Hz, Ar–H), 7.70 (d, 2H, J = 8.0 Hz, Ar–H), 7.72 (s, 1H, pyridine-
H-5), 7.80 (d, 1H, J = 4.12 Hz, thiophene-H), 8.03 (d, 1H, J = 3.24 Hz, thiophene-
H), 8.48 (s, 1H, NH). 13C NMR (DMSO-d6, ppm): d = 65.1 (CH2), 107.6, 113.0,
115.2 (C:N), 128.0, 128.6, 128.7, 130.2, 130.5, 134.6, 141.1, 144.8, 154.6, 156.2,
161.4 and 166.3 (Ar–C and C=O). Anal. Calcd. for C18H13ClN4O2S (384.84): C,
56.18; H, 3.40; N, 14.56. Found: C, 56.23; H, 3.44; N, 14.55.
Ethyl 3-amino-4-(4-chlorophenyl)-6-(thien-2-yl)furo[2,3-b]pyridine-2-
carboxylate (4)
Compound 2 (0.01 mol) was suspended in sodium methoxide solution (0.12 g sodium
in 30 mL methanol) and heated under reflux for 30 min. The reaction mixture was
cooled, poured into ice water and acidified with HCl; the formed solid was filtered off,
dried, and crystallized from ethanol to give compound 4 as pale yellow crystals; Yield
78 %, mp 231–233 °C. IR (KBr, cm-1): 3449 (NH2) and 1734 (C=O, ester). 1H NMR
(DMSO-d6, ppm): d = 1.20 (t, 3H, J = 7.14 Hz, CH3CH2), 4.10 (q, 2H, J = 7.14 Hz,
CH2CH3), 5.03 (s, 2H, NH2), 7.23 (t, 1H, J = 4.58, 3.50 Hz, thiophene-H), 7.68 (d,
2H, J = 8.0 Hz, Ar–H), 7.77 (d, 2H, J = 8.0 Hz, Ar–H), 7.81 (s, 1H, pyridine-H-5),
7.83 (d, 1H, J = 4.58 Hz, thiophene-H), 8.09 (d, 1H, J = 3.50 Hz, thiophene-H). 13
C
NMR (DMSO-d6, ppm): d = 16.02 (CH3CH2), 63.5 (CH3CH2), 91.1, 112.0, 112.5,
127.5, 128.9, 129.0, 130.4, 131.3, 131.6, 134.3, 135.1, 142.1, 152.6, 155.0, 163.0 and
169.3 (Ar–C and C=O). Anal. Calcd. for C20H15ClN2O3S (398.86): C, 60.22; H, 3.79;
N, 7.02. Found: C, 60.20; H, 3.76; N, 6.97.
5-(3-Amino-4-(4-chlorophenyl)-6-(thien-2-yl)furo[2,3-b]pyridin-2-yl)-4H-1,2,4-
triazole-3-thiol (5)
A mixture of compound 4 (0.01 mol) and thiosemicarbazide (0.015 mol) in pyridine
(30 mL) was refluxed for 6 h. The reaction mixture was cooled, poured into ice
water and acidified with HCl, the formed solid was filtered off, dried, and
crystallized from ethanol to give compound 5 as yellow crystals; Yield 82 %, mp
1
125–127 °C. IR (KBr, cm-1): 3444 (NH and NH2). H NMR (DMSO-d6, ppm):
d = 5.05 (s, 2H, NH2), 7.24 (t, 1H, J = 4.57, 3.50 Hz, thiophene-H), 7.69 (d, 2H,
123

H. A. El-Sayed et al.
J = 7.80 Hz, Ar–H), 7.74 (d, 2H, J = 7.80 Hz, Ar–H), 7.79 (s, 1H, pyridine-H-5),
7.84 (d, 1H, J = 4.57 Hz, thiophene-H), 8.10 (d, 1H, J = 3.50 Hz, thiophene-H),
8.79 (s, 1H, NH), 13.21 (s, 1H, SH). 13C NMR (DMSO-d6, ppm): d = 91.16, 112.5,
127.6, 128.3, 128.9, 129.0, 129.8, 130.5, 131.7, 132.0, 134.3, 135.1, 138.0, 142.1,
152.6, 155.1 and 163.0 (Ar–C). Anal. Calcd. for C19H12ClN5OS2 (425.91): C,
53.58; H, 2.84; N, 16.44; Found: C, 53.60; H, 2.81; N, 16.47.
3-Allyl-9-(4-chlorophenyl)-4-oxo-1,2,3,4-tetrahydro-7-(thien-2-yl)-2-
thioxopyrido[30,20:4,5]furo-[3,2-d]pyrimidine (6)
A mixture of furopyridine 4 (0.01 mol), allyl isothiocyanate (0.011 mol) and anhydrous
potassium carbonate (0.012 mol) in dry acetonitrile (30 mL) was refluxed for 12 h. The
reaction mixture was concentrated under reduced pressure, cooled, and poured into ice
water; the formed solid was filtered off, dried, and crystallized from ethanol to give
compound 6 as yellow crystals. Yield 65 %, mp 130–132 °C. IR (KBr, cm-1): 3438
(NH), 1638 (C=O, amide). 1H NMR (DMSO-d6, ppm): d = 4.8 (d, 2H, J = 5.43 Hz,
NCH2), 5.23 (d, 1H, J = 10.14 Hz, H-a), 5.31 (d, 1H, J = 17.5 Hz, H-b), 5.80 (m, 1H,
H–c), 7.18 (t, 1H, J = 4.83, 3.72 Hz, thiophene-H), 7.75 (d, 2H, J = 7.84 Hz, Ar–H),
7.78 (d, 2H, J = 7.84 Hz, Ar–H), 7.80 (s, 1H, pyridine-H-8), 7.84 (d, 1H, J = 4.83 Hz,
thiophene-H), 8.15 (d, 1H, J = 3.72 Hz, thiophene-H), 10.2 (s, 1H, NH). 13C NMR
(DMSO-d6, ppm): d = 62.91 (NCH2), 110.9 (=CH2), 118.0 (CH =), 128.1, 128.6,
128.9, 129.2, 129.8, 130.0, 130.4, 131.7, 132.1, 134.0, 135.1, 142.8, 148.2, 153.3, 155.5,
160.2 and 168.3 (Ar–C, C=O and C=S). Anal. Calcd. for C22H14ClN3O2S2 (451.95): C,
58.47; H, 3.12; N, 9.30. Found: C, 58.46; H, 3.15; N, 9.28.
9-(4-Chlorophenyl)-4-oxo-3,4-dihydro-7-(thien-2-yl)pyrido[30,20:4,5]furo[3,2-
d]pyrimidine (7)
A solution of furopyridine 4(0.01 mol) in formamide (20 mL) was heated under reflux for
4 h. The reaction mixture was cooled andpoured intoice water; the formedprecipitate was
filtered off, dried, and crystallized from ethanol to give compound 7 as yellow crystals.
Yield 70 %, mp 163–165 °C. IR (KBr, cm-1): 3448 (NH) and 1654 (C=O, amide). 1H
NMR (DMSO-d6, ppm): d = 7.23 (t, 1H, J = 5.0, 3.50 Hz, thiophene-H), 7.69 (s, 1H,
pyrimidine-H-2), 7.76 (d, 2H, J = 8.50 Hz, Ar–H), 7.81 (d, 2H, J = 8.50 Hz, Ar–H),
7.82 (s, 1H, pyridine-H-8), 7.84 (d, 1H, J = 5.0 Hz, thiophene-H), 8.06 (d, 1H,
J = 3.5 Hz, thiophene-H), 10.25 (s, 1H, NH). 13C NMR (DMSO-d6, ppm): d = 91.8,
112.1, 128.2, 128.9, 129.6, 130.4, 131.5, 132.7, 134.4, 135.0, 142.2, 148.3, 152.6, 154.9,
155.6, 162.9 and 168.8 (Ar–C and C=O). Anal. Calcd for C19H10ClN3O2S (379.82): C,
60.08; H, 2.65; N, 11.06. Found: C, 60.11; H, 2.61; N, 11.08.
3-Amino-4-(4-chlorophenyl)-6-(thien-2-yl)furo[2,3-b]pyridine-2-
carbohydrazide (8)
A mixture of furopyridine 4 (0.01 mol) and hydrazine hydrate 98 % (1 mL, 0.04 mol)
in absolute ethanol was refluxed for 3 h, then the reaction mixture was cooled, the
formed precipitate was filtered off, dried, and crystallized from methanol to give
123

Synthesis of some fused heterocyclic systems
compound 8 as yellow crystals. Yield 75 %, mp 178–180 °C. 1H NMR (DMSO-d6,
ppm): d = 4.09 (s, 2H, furan-NH2), 4.63 (s, 2H, NHNH2), 7.25 (t, 1H, J = 5.12,
3.71 Hz, thiophene-H), 7.68 (d, 2H, J = 8.26 Hz, Ar–H), 7.74 (d, 2H, J = 8.26 Hz,
Ar–H), 7.80 (s, 1H, pyridine-H-5), 7.85 (d, 1H, J = 5.12 Hz, thiophene-H), 8.06 (d,
1H, J = 3.71 Hz, thiophene-H), 8.48 (s, 1H, NH). 13C NMR (DMSO-d6, ppm):
d = 92.8, 112.8, 127.5, 128.1, 128.7, 129.4, 129.6, 131.4, 131.9, 132.6, 135.0, 135.3,
141.2, 154.4, 159.8 and 168.5 (Ar–C and C=O). Anal. Calcd for C18H13ClN4O2S
(384.84): C, 56.18; H, 3.40; N, 14.56. Found: C, 65.15; H, 3.42; N, 14.59.
(3-Amino-4-(4-chlorophenyl)-6-(thien-2-yl)furo[2,3-b]pyridin-2-yl)(3,5-
dimethyl-1H-pyrazol-1-yl)methanone (9)
A mixture of hydrazide 8 (0.01 mol) and acetylacetone (0.02 mol) in ethanol (30 mL)
was heated under reflux for 8 h. The reaction mixture was cooled and poured into ice
water. The formed precipitate was filtered off, dried, and crystallized from ethanol to
givecompound9asyellowcrystals. Yield81 %,mp148–150 °C.IR(KBr,cm-1):3433
(NH2) and 1619 (C=O, amide). 1H NMR (DMSO-d6, ppm): d = 2.27 (s, 3H, CH3), 2.87
(s, 3H, CH3), 4.92(s, 2H, NH2), 6.25(s, 1H, pyrazole-H), 7.24(t, 1H, J = 4.96, 3.85 Hz,
thiophene-H), 7.64 (d, 2H, J = 8.0 Hz, Ar–H), 7.84(d, 2H, J = 8.0 Hz, Ar–H), 7.88 (s,
1H, pyridine-H-5), 7.96 (d, 1H, J = 4.96 Hz, thiophene-H), 8.16 (d, 1H, J = 3.85 Hz,
thiophene-H). 13C NMR (DMSO-d6, ppm): d = 12.82, 13.32 (2CH3), 98.9, 109.3,
127.9, 128.5, 128.8, 129.2, 129.4, 130.1, 130.8, 131.5, 134.4, 135.0, 141.5, 141.9, 149.5,
152.6, 152.9, 155.6 and 168.7 (Ar–C and C=O). Anal. Calcd for C23H17ClN4O2S
(448.92): C, 61.54; H, 3.82; N, 12.48. Found: C, 61.57; H, 3.80; N, 12.51.
9-(4-Chlorophenyl)-3-formylamino-4-oxo-3,4-dihydro-7-(thien-2-
yl)pyrido[30,20:4,5]furo[3,2-d]pyrimidine (10)
A solution of hydrazide 8 (0.01 mol) in formic acid (20 mL) was heated under reflux
for 3 h. The reaction mixture was cooled and poured into ice water. The formed
precipitate was filtered off, dried, and recrystallized from ethanol to give compound
10 as yellow crystals. Yield 67 %, mp 160–162 °C. IR (KBr, cm-1): 3434 (NH) and
1694 (C=O, amide). 1H NMR (DMSO-d6, ppm): d = 7.22 (t, 1H, J = 4.82, 3.64 Hz,
thiophene-H), 7.56 (d, 2H, J = 8.0 Hz, Ar–H), 7.69 (d, 2H, J = 8.0 Hz, Ar–H), 7.75
(s, 1H, pyridine-H-8), 7.81 (s, 1H, pyrimidine-H-2), 7.88 (d, 1H, J = 4.82 Hz,
thiophene-H), 8.07 (d, 1H, J = 3.64 Hz, thiophene-H), 9.8 (s, 1H, NH), 10.09 (s, 1H,
CHO). 13C NMR (DMSO-d6, ppm): d = 113.3, 127.5, 127.6, 127.9, 128.4, 128.6,
128.8, 129.0, 129.3, 129.5, 130.4, 130.6, 131.2, 143.9, 152.4, 154.0, 160.8 and 166.8
(Ar–C, HC=O and C=O). Anal. Calcd for C20H11ClN4O3S (422.84): C, 56.81; H,
2.62; N, 13.25. Found: C, 56.79; H, 2.63; N, 13.28.
4-(4-Chlorophenyl)-2-(20,30,40,60-tetra-O-acetyl-b-D-glycopyranosylmercapto)-
6-(thien-2-yl)nicotinonitrile (12a,b)
A mixture of pyridin-2-thione (11) (0.01 mol) and anhydrous potassium carbonate
(0.01 mol) was stirred in dry acetone/DMF (15 mL) for 1 h, then 0.011 mol of
123

H. A. El-Sayed et al.
glucosyl/or galactosyl bromide was added. The reaction mixture was stirred
overnight at room temperature, and then refluxed for 3–5 h, filtered off, and the
solvent was evaporated under reduced pressure; the obtained products were dried
and crystallized from the ethanol to give compounds 12a,b.
4-(4-Chlorophenyl)-2-(20,30,40,60-tetra-O-acetyl-b-D-glucopyranosylmercapto)-
6-(thien-2-yl)nicotinonitrile (12a)
Orange crystals, yield 76 %, mp 140–142 °C. IR (KBr, cm-1): 2216 (C:N) and
1
1750 (C=O, acetoxy). H NMR (DMSO-d6, ppm): d = 1.87, 1.98, 2.08 and 2.17
(4 s, 12H, 4 CH3CO), 3.95 (dd, 1H, J5 ,6 = 4.34, J6 ,6 = 12.07 Hz, H-60), 4.12 (dd,
0
0
0
00
1H, J5 ,6 = 4.15, J6 ,6 = 12.07 Hz, H-600), 4.52 (m, 1H, H-50), 5.25 (t, 1H,
0
0
0
00
J = 9.12 Hz, H-40), 5.48 (dd, 1H, J1 ,2 = 8.78, J2 ,3 = 9.52 Hz, H-20), 5.59 (dd,
0
0
0
0
1H, J2 ,3 = 9.52, J3 ,4 = 9.12 Hz, H-30), 6.40 (d, 1H, J1 ,2 = 8.78 Hz, H-10), 7.29
(t, 1H, J = 5.18, 3.63 Hz, thiophene-H), 7.70 (d, 2H, J = 7.92 Hz, Ar–H), 7.76 (d,
2H, J = 7.92 Hz, Ar–H), 7.81 (s, 1H, pyridine-H-5), 7.95 (d, 1H, J = 5.18 Hz,
thiophene-H), 8.15 (d, 1H, J = 3.63 Hz, thiophene-H). 13C NMR (DMSO-d6, ppm):
d = 19.9, 20.2, 20.3 and 20.4 (4CH3CO), 61.6 (C-60), 66.1 (C-40), 67.7 (C-30), 70.9
(C-20), 73.8 (C-50), 82.5 (C-10), 114.1 (C:N), 117.2, 128.9, 129.0, 129.1, 130.5,
130.6, 132.0, 132.2, 134.1, 135.2, 141.6, 153.9, 157.5, 169.0, 169.6, 170.2 and 171.0
(Ar–C, C=N and 4 C=O). Anal. Calcd. for C30H27ClN2O9S2 (659.13): C, 54.67; H,
4.13; N, 4.25. Found: C, 54.71; H, 4.10; N, 4.21.
0
0
0
0
0
0
4-(4-Chlorophenyl)-2-(20,30,40,60-tetra-O-acetyl-b-D-galactopyranosylmercapto)-
6-(thien-2-yl)nicotinonitrile (12b)
Orange crystals, yield 78 %, mp 191–193 °C. 1H NMR (DMSO-d6, ppm): d = 2.0,
0
0
2.04, 2.05 and 2.12 (4 s, 12H, 4 CH3CO), 4.05 (dd, 1H, J5 ,6 = 5.26,
J6 ,6 = 11.25 Hz, H-60), 4.12 (dd, 1H, J5 ,6 = 6.30, J6 ,6 = 11.25 Hz, H-600),
0
00
0
00
0
00
4.25 (m, 1H, H-50), 5.09 (t, 1H, J3 ,2 = 9.58, J3 ,4 = 2.81 Hz, H-30), 5.28 (t, 1H,
0
0
0
0
J2 ,1 = 8.96, J2 ,3 = 9.58 Hz, H-20), 5.62 (t, 1H, J4 ,3 = 2.81, J4 ,5 = 2.38 Hz,
0
0
0
0
0
0
0
0
H-40), 6.09 (d, 1H, J1 ,2 = 8.96, Hz, H-10), 7.29 (t, 1H, J = 5.16, 4.45 Hz,
thiophene-H), 7.68 (d, 2H, J = 8.50 Hz, Ar–H), 7.77 (d, 2H, J = 8.50 Hz, Ar–H),
7.92 (d, 1H, J = 5.16 Hz, thiophene-H), 7.99 (s, 1H, pyridine-H5), 8.20 (d, 1H,
J = 4.45 Hz, thiophene-H). 13C NMR (DMSO-d6, ppm): d = 20.04, 20.30, 20.35
and 20.60 (4CH3CO), 61.6 (C-60), 67.9 (C-40), 68.6 (C-20), 73.1 (C-30), 75.4 (C-50),
80.2 (C-10), 102.8, 115.1, 115.4 (C:N), 128.9, 129.1, 129.4, 130.5, 132.1, 134.1,
135.2, 142.1, 153.0, 154.0, 159.1, 169.3, 169.5, 169.8 and 170.3 (Ar–C, C=N and
4C=O). Anal. Calcd. for C30H27ClN2O9S2 (659.13): C, 54.67; H, 4.13; N, 4.25.
Found: C, 54.65; H, 4.18; N, 4.23.
0
0
4-(4-Chlorophenyl)-2-(b-D-glycopyranosylmercapto)-6-(thien-2-
yl)nicotinonitrile (13a,b)
Triethylamine (1 mL) was added to a solution of glycosides 12a,b (0.01 mol) in
methanol (20 mL) and a few drops of water. The reaction mixture was stirred
123

Synthesis of some fused heterocyclic systems
overnight at room temperature for 5 h, evaporated under reduced pressure, and the
residue was washed with methanol until the triethylamine was removed. The residue
was crystallized from ethanol to give compounds 13a,b.
4-(4-Chlorophenyl)-2-(b-D-glucopyranosylmercapto)-6-(thien-2-
yl)nicotinonitrile (13a)
Orange crystals, yield 88 %, mp 189–191 °C. IR (KBr, cm-1): 3423 (4 OH) and
2212 (C:N). 1H NMR (DMSO-d6, ppm): d = 3.04 (m, 6H, H-60, H-600, H-50, H-40,
H-30 and H-20), 3.45 (t, 1H, J = 3.52 Hz, OH-60), 4.27 (d, 1H, J = 4.23 Hz, OH-40),
5.10 (d, 1H, J = 4.20 Hz, OH-30), 5.43 (d, 1H, J = 4.54 Hz, OH-20), 5.98 (d, 1H,
J1 ,2 = 8.53 Hz, H-10), 7.21 (t, 1H, J = 4.92, 3.80 Hz, thiophene-H), 7.65 (d, 2H,
J = 8.40 Hz, Ar–H), 7.72 (d, 2H, J = 8.40 Hz, Ar–H), 7.90 (s, 1H, pyridine-H-5),
7.96 (d, 1H, J = 4.92 Hz, thiophene-H), 8.16 (d, 1H, J = 3.80 Hz, thiophene-H).
Anal. Calcd. for C22H19ClN2O5S2 (490.98): C, 53.82; H, 3.90; N, 5.71;. Found: C,
53.78; H, 3.92; N, 5.77.
0
0
4-(4-Chlorophenyl)-2-(b-D-galatcopyranosylmercapto)-6-(thien-2-
yl)nicotinonitrile (13b)
Orange crystals, yield 90 %, mp 205–207 °C. IR (KBr, cm-1):0 3421 (4 OH) and
2218 (C:N). 1H NMR (DMSO-d6, ppm): d = 3.21 (m, 3H, H-3 , H-60, H-60’), 3.50
(m, 3H, H-20, H-40, H-50), 4.52 (m, 2H,0 OH-40, OH-60), 4.80 (d, 1H, J = 5.12 Hz,
OH-30), 5.18 (d, 1H, J = 4.74 Hz, OH-2 ), 5.56 (d, 1H, J1 ,2 = 8.28 Hz, H-10), 7.19
(t, 1H, J = 4.90, 3.85 Hz, thiophene-H), 7.55 (d, 2H, J = 8.42 Hz, Ar–H), 7.68 (d,
2H, J = 8.42 Hz, Ar–H), 7.72 (s, 1H, pyridine-H-5), 7.75 (d, 1H, J = 4.90 Hz,
thiophene-H), 8.15 (d, 1H, J = 3.85 Hz, thiophene-H). Anal. Calcd. for
C22H19ClN2O5S2 (490.98): C, 53.82; H, 3.90; N, 5.71;. Found: C, 53.84; H, 3.93;
N, 5.70.
0
0
General synthetic procedure for Mannich bases (14a,b)
A mixture of 11a,b (0.01 mol), morpholine or piperidine (0.015 mol) and
formaldehyde (37 %, 1 mL) in ethanol (20 mL) was stirred at room temperature
for 2 h, then 10 mL of cooled water was added. The formed precipitate was filtered
off, dried, and crystallized from ethanol to give compounds 14a,b.
4-(4-Chlorophenyl)-1-(morpholinomethyl)-6-(thien-2-yl)-2-thioxo-1,2-
dihydropyridine-3-carbonitrile (14a)
Orange crystals, yield 90 %, mp 110–112 °C. IR (KBr, cm-1): 2214 (C:N) and
1
1353 (C=S). H NMR (DMSO-d6, ppm): d = 2.40 (t, 4H, J = 4.48 Hz, 2CH2-
morpholine), 3.56 (t, 4H, J = 4.48 Hz, 2CH2–morpholine), 5.25 (s, 2H, N–CH2–N),
7.23 (t, 1H, J = 5.0, 3.92 Hz, thiophene-H), 7.72 (d, 2H, J = 8.10 Hz, Ar–H), 7.79
(d, 2H, J = 8.10 Hz, Ar–H), 7.85 (s, 1H, pyridine-H-5), 8.13 (d, 1H, J = 5.0 Hz,
thiophene-H), 8.24 (d, 1 H, J = 3.92 Hz, thiophene-H). 13C NMR (DMSO-d6,
123

H. A. El-Sayed et al.
ppm): d = 51.5, 66.0 (4CH2-morpholine), 79.6 (N–CH2–N), 107.6, 115.6 (C:N),
117.2, 129.0, 129.2, 129.5, 130.5, 132.2, 135.3, 141.6, 153.3, 154.4 157.5 and 185.2
(Ar–C and C=S). Anal. Calcd. for C21H18ClN3OS2 (427.97): C, 58.94; H, 4.24; N,
9.82; Found: C, 58.96; H, 4.23; N, 9.80.
4-(4-Chlorophenyl)-1-(piperidin-1-ylmethyl)-6-(thien-2-yl)-2-thioxo-1,2-
dihydropyridine-3-carbonitrile (14b)
Orange crystals, yield 92 %, mp 170–172 °C. IR (KBr, cm-1): 2214 (C:N) and
1
1372 (C=S). H NMR (DMSO-d6, ppm): d = 1.50 (m, 6H, 3CH2-piperidine), 2.58
(t, 4H, J = 4.74 Hz, 2CH2-piperidine), 4.08 (s, 2H, N–CH2–N), 7.23 (t, 1H,
J = 4.97, 3.80 Hz, thiophene-H), 7.71 (d, 2H, J = 8.15 Hz, Ar–H), 7.78 (d, 2H,
J = 8.15 Hz, Ar–H), 7.82 (s, 1H, pyridine-H-5), 8.02 (d, 1H, J = 4.97 Hz,
thiophene-H), 8.12 (d, 1 H, J = 3.80 Hz, thiophene-H). 13C NMR (DMSO-d6,
ppm): d = 48.5, 50.8, 51.5 (5CH2-piperidine), 66.1 (N–CH2–N), 107.6, 115.6
(C:N), 117.2, 129.0, 129.2, 129.5, 130.5, 130.6, 132.2, 135.3, 141.6, 153.3, 154.4
and 183.5 (Ar–C and C=S). Anal. Calcd. for C22H20ClN3S2 (426.00): C, 62.03; H,
4.73; N, 9.86. Found: C, 62.05; H, 4.74; N, 9.82.
Acknowledgment The authors extend their appreciation to the Deanship of Scientific Research at King
Saud University for funding the work through the research group project No. RGP-VPP-0172.
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