Synthesis of new derivatives of thieno[2,3-b]pyridine fused with octyl ring

Article abstract of DOI:10.1002/jhet.5570440310

(Chemical Equation Presented) Derivatives of thiophene, thieno[2,3-b]pyridine, thieno[5′,4′:4,5]pyrimido[3,2-a]pyridine and thiepine fused with octyl ring have been synthesized and tested for antimicrobial and antifungal activities. The structure of the newly synthesized compounds have been established on the basis of their analytical and spectral data.

Full text of DOI:10.1002/jhet.5570440310

May-Jun 2007
561
Synthesis of New Derivatives of Thieno[2,3-b]pyridine Fused with
Octyl Ring
Fatima A. Al-Omran* and Adel A. El-Khair
Chemistry Department, Faculty of Science, Kuwait University,
P. O. Box 5969, 13060 Safat, Kuwait.
Received April 19, 2006
NH2
CN
NNHPh
PhN N+Cl-
CNCH2X
S
N
H
CN
S
Y
S
CN
NH2
NH2
Derivatives of thiophene, thieno[2,3-b]pyridine, thieno[5',4':4,5]pyrimido[3,2-a]pyridine and thiepine
fused with octyl ring have been synthesized and tested for antimicrobial and antifungal activities. The
structure of the newly synthesized compounds have been established on the basis of their analytical and
spectral data.
J. Heterocyclic Chem., 44, 561 (2007).
heterocycles in the hope of obtaining compounds of
potential antimicrobial and antifungal activities. To
prepare this novel class of compounds we used new 2-
aminocycloocta[b]thiophene-3-carbonitrile as the key
intermediate.
INTRODUCTION
Pharmacological studies of the thieno[2,3-b]pyridine
derivatives have been shown to posses a variety of
pharmacological activities such as antibacterial [1,2], anti-
hypertensive and vasodilator activities [3]. Some thieno-
[2,3-b]pyridine derivatives are useful as gonadotropin-
RESULTS AND DISCUSSION
releasing hormone antagonists [4-9].
Others were
prepared as anti-inflammatory agents, particularly for
treating arthritis and bone resorption inhibiting agents
[10]. It was interesting to study unreported tri- and tetra-
cyclic compounds containing nitrogen and sulfur
The key intermediate 2 used in our experiments has
been prepared according to Gewald’s reaction [11] by
refluxing the cyclooctanone 1 with malononitrile in N,N-
dimethylformamide (DMF) in the presence of elemental
Scheme 1
NH2
CN
CH2(CN)2
DMF, pip. reflux
S
S
N
NH2
3
NH2
CN
PhCOCH2CN, DMF
pip. reflux, HCl
O
.HCl
CN
N
Ph
CH2(CN)2,sulfur
4
DMF,(Et)3N
reflux
S
NH2
NH2
1
2
CN
CNCH2COOEt, DMF
pip. reflux
S
N
H
O
5
NH2
CN
H2NCSCH2CN, DMF
pip. reflux
S
N
H
S
6

562
F. A. Al-Omran and A. A. El-Khair
Vol 44
sulfur and a catalytaic amount of triethylamine.
The
in DMF and the presence of a catalytic amount of
piperidine gave a brown crystalline product identified as
4-amino-2-oxo-1H,2H-cycloocta[b]thieno[2,3-b]pyridine-
3-carbonitrile 5 and 4-amino-2-thioxo-1H,2H-cycloocta-
[b]thieno[2,3-b]pyridine-3-carbonitrile 6, respectively in
good yield similar to that which recently has been
reported from our laboratories [12]. The structures of 5
structure of 2 was established on the basis of spectral data
and formula confirm by elemental analysis. Thus, the ir
spectrum of compound 2 showed a strong absorption band
at ꢀ 2195, 3428 and 3333 cmꢁ1 corresponding to nitrile
and amino groups, respectively. The absence of the
carbonyl group absorption, in the ir spectrum, indicates
that the carbonyl group is involved in the reaction.
and
6 were established via their analytical and
The reactivity of the thiophene 2 toward active
methylene nitriles was investigated. Thus, treatment of 2
with malononitrile in refluxing DMF and in presence of a
catalytic amount of piperidine gave the 2,4-diaminocyclo-
octa[b]thieno[2,3-b]pyridine-3-carbonitrile 3 (Scheme 1).
The structure of the latter product was established on the
basis of its elemental analysis and spectral data. Thus, the
1H nmr spectrum of the reaction product 3 revealed,
besides the aliphatic multiplet, two types of D2O-
exchangeable protons at ꢂ 3.53 and 7.95 ppm for the two
amino groups.
Treatment of compound 2 with benzoylacetonitrile in
DMF at refluxed afforded the corresponding 4-amino-2-
phenylcycloocta[b]thieno[2,3-b]pyridine-3-carbonitrile
hydrochloride 4 in good yield. The structure of the latter
product was established on the basis of its spectral data
and molecular analysis. Thus the ir spectrum of the
reaction product showed an absorption bands at 3423,
3334 cmꢁ1 for the amino group in addition to a strong
absorption band at 2195 cmꢁ1 for the cyano group.
spectroscopic data. The mass spectrum of 5 revealed a
molecular ion peak m/z at 273. The H nmr spectrum of
1
the reaction product showed in addition to the aliphatic
signals, two singlet signal at ꢂ 6.88 and 11.97 ppm
assigned to the NH2 and NH group. The latter two
signals underwent a facile hydrogen deuterium exchange
upon addition of deuterium oxide.
On the other hand, treatment of 2 with enaminones 7a-b
afforded the corresponding enaminones 8a-b (cf. Scheme
2). The formation of 8a-b are assumed to proceed via
addition of amino group in compound 2 to the enamino
double bond of 7 followed by elimination of a
dimethylamine molecule. The structure of products 8a-b
1
were assigned as the Z-form based on H nmr which
revealed olefinic protons as two doublets at ꢂ 6.97 and
7.66 ppm with J=10 Hz as required for such Z-coupled
protons. Predominance of the Z form rather than the E
form is attributed to fixation through hydrogen bonding.
The mass spectrum of 8b revealed a molecular ion peak
m/z at 336 (Scheme 2).
In a similar manner, treatment of compound 2 with
ethyl cyanoacetate or cyanothioacetamide under refluxing
Compound 10 could be obtained in situ via a one step
process by the treatment of 2 with 3-dimethylamino-1-(2'-
Scheme 2
CN
N
Ar
O
NMe2
7a-b
H
S
O
EtOH, DMF, reflux
8
Ar
a: Ar =
b: Ar =
7-8:
S
C H
CN
6
5
S
NH2
2
O
CN
CN
Ar
N
H
1)7a; EtOH/DMF,reflux
N
H
S
2)CH2(CN2)2,reflux
9
NH
O
CN
Ar
N
N
H
S
10
Ar=
9,10:
S

May-Jun 2007
Synthesis of New Derivatives of Thieno[2,3-b]pyridine Fused with Octyl Ring
563
thienyl)-2-propenone 7a in refluxing ethanol and DMF
followed by treatment of the reaction mixture with
malononitrile. The formation of 10 is assumed to
proaceed via non-isolated intermediate 9 followed by an
intramolecular cyclization under these reaction conditions
to afford theinopyrimidopyridine derivative 10.
Analytical and spectral data are consistent with the
assigned structure (see Experimental).
Treatment of compound 2 with benzylidenemalono-
nitrile in refluxing DMF and in the presence of a catalytic
amount of piperidine afforded 3,4-dihydrothieno[2,3-b]-
pyridine derivative 11 in good yield. The structure of the
latter compound was confirmed on the basis of elemental
analysis and spectral data. The mass spectrum of 11
revealed a molecular ion peak with m/z 360. Compound
11 is assumed to take place via initial Michael addition of
the amino group in compound 2 to an activated double
bond in benzylidenemalononitrile followed by cyclization
to afford 11. The formed adduct did not aromatize by
losing hydrogen cyanide. Perhaps in this case,11 is a
more stable product than the product that would be
obtained by elimination of hydrogen cyanide 12. Similar
dihydrothieno[2,3-b]pyridine formations have been
reported in Ref. [12].
thiourea in refluxing ethanol and DMF followed by
treatment of the reaction mixture with phenacyl bromide.
The structure was confirmed by analytical and spectral
data. The ir spectrum revealed the disappearance of the
bands corresponding the 3428 and 3333 cm-1 corre-
1
sponding to the NH2 group. The H nmr spectrum also
lacked the NH2 signal and showed a multiplet at ꢀ 7.32 -
7.89 ppm for aromatic protons in addition to a new singlet
one at ꢀ 7.23 ppm which integrates for one proton and is
attributed to the 5-H of the thiazoline ring proton and
other resonance at ꢀ 11.92 ppm was assigned to the NH
proton. The latter signal underwent a facile hydrogen
deuterium exchange upon addition of deuterium oxide.
Notably a literature survey revealed that thiazoline
derivatives are biological interesting candidates [13-14].
Upon fusion of 2 with acetylacetone, a crystalline-
brown colored product was formed. The mass spectrum
revealed a molecular ion peak with m/z 288. Although
the thieno[2,3-b]pyridine derivative 15 would seem to be
a reasonable possible structure, the 2-(4'-oxo-2'-penten-2-
yl)-aminocycloocta[b]thiophene-3-carbonitrile
14 was
actually assigned for this product on the basis of ir and 1H
nmr spectra. The ir spectrum for 14 revealed the presence
of cyano and carbonyl absorption bands at ꢁmax 2195 and
1665 cm-1, respectively. The lower frequency of carbonyl
group attributed to both hydrogen bonding and to the
Thiazol-2-ylidene derivative 13 could be obtained in
situ via a one step process by the treatment of 2 with
Scheme 3
NH2
N
CN
Ph
O
NH
S
12
S
N
Me
18
NH2
CN
CN
CN
O
PhCH=C(CN)2
DMF, pip. reflux
S
N
H
Me
S
N
Ph
17
11
cyclohexanone
AcOH, reflux
2
O
CN
N
H
N
Ph
NH2CSNH2
PhCOCH2Br
NH
S
S
N
S
H
CN
N
13
16
H
S
O
O
Me
Me
Me
14
NH2
N
S
Me
15

564
F. A. Al-Omran and A. A. El-Khair
Vol 44
conjugated double bond readily allowed for the exclusion
of structure 15. In an attempt to obtain the thieno[2,3-
b]pyridine derivative 15, compound 14 was subjected to
reflux for a greater length of time, however, again it was
shown to be unsuccessful as the cyano absorption band
was observed in the ir spectrum.
Treatment of 2 with benzenediazonium chloride in
strong basic medium furnished a single product, identified
as acyclic hydrazone derivative 19 in good yield. In an
attempt to cyclized 19 to the thienopyridazinone
derivative 20 upon refluxing in acetic acid and
hydrochloric acid mixture was unsuccessful [15]. The
reactivity of the acyclic hydrazone 19 toward dimethyl-
acetylene dicarboxylate DMAD was investigated. Thus
treatment of 19 with DMAD in a mixture of acetic acid
and dioxan afforded the thiepine derivative 23 in good
yield. The latter compound is believed to be formed via
intermediates 21 and 22 (cf. Scheme 4). Similar
formation of thiepine has been reported from our
laboratories [16-18] as well as Dopp et al. [19]. The
structure of the isolated product 23 was confirmed on the
basis of elemental analysis and spectral data.
Upon fusion either of cyclohexanone 1a or cyclo-
octanone 1b with each of 1H-benzotriazol-1-yl acetic acid
hydrazine 24a or cyano acetic acid hydrazine 24b at
130°C afforded the corresponding hydrazone 25a-d in
good yield. Structures 25a-d were established on the basis
of their elemental analysis and spectral data. Treatment
of each 25b or 25d with dimethylformamide dimethyl-
acetal (DMF DMA) in dry xylene at reflux, afforded the
enaminones 26a-b in good yield and not the prazolo
derivative 27. The proposed structure of enaminone was
confirmed based on elemental analysis (Scheme 5).
Heating compound
2 with cyclohexanone under
refluxed in the presence of acetic acid afforded a product
with the potential structure N-acetamido derivative 17
rather than spiro compound 16. The structural assignment
is based on analytical data. The presence of cyano
absorption in the ir spectrum at ꢀmax 2219 cm-1 which
readily excluded the possibility of 16. Again, compound 17
was refluxed for a greater length of time in an attempt to
obtain the thienopyrimidine derivative 18, however again it
was found to be unsuccessful as the cyano absorption band
was observed in the ir spectrum (Scheme 3).
Scheme 4
S
N
H2N
NPh
O
20
AcOH/HCl
Scheme 5
O
+ -
PhN NCl
EtOH
O
S
+
2
DMF, NaOH
X
NNHPh
+
NH2HN
H2N
CN
(CH2)n
24
1
19
a: X=Bt
b: X=CN
a: n=0
b: n=3
DMAD
AcOH, dioxan, reflux
fused
130°C
O
X
Me2N
NNH
NMe2
MeO2C
MeO2C
O
NNHPh
CN
X
N.NH
S
26
a: X=Bt
b: X=CN
NH2
25 b or d
DMF DMA
21
reflux
xylene,
(CH2)n
O
25
X
Me2N
N
a: n=0; X=Bt
N
b: n=3; X=Bt
c: n=0; X=CN
d: n=3; X=CN
MeO2C
MeO2C
MeO2C
MeO2C
NNHPh
CN
S
H2N
S
NNHPh
NH2
27
CN
24-27: X=Bt=Benzotriazol-1-yl
22
23

May-Jun 2007
Synthesis of New Derivatives of Thieno[2,3-b]pyridine Fused with Octyl Ring
565
1.25-1.50 (m, 8H, 6-, 7-, 8-, and 9-H), 2.47 (t, 2H, CH2, J=4
Hz), 2.56 (t, 2H, CH2, J=4 Hz), 3.53 (br.s, 2H, NH2, D2O
exchangeable), 7.95 ppm (br.s, 2H, NH2, D2O exchangeable).
Anal. Calcd. for C14H16N4S (272.30): C, 61.76; H, 5.92; N,
20.58. Found: C, 61.72; H, 5.78; N, 20.34.
4-Amino-2-phenyl-5,6,7,8,9,10-hexahydrocycloocta[b]-
thieno[2,3-b]pyridine-3-carbonitrile hydrochloride (4). A
mixture of 2 (2.06 g, 10 mmoles) and benzoylacetonitrile (1.45
Biological Activity. The biological activities of some
of the newly synthesized compounds were screened for
antifungal activity against Aspergillus niger and
Penicillium sp while the antibacterial activity was tested
against Escherichia coli, Staphylococcus aureas and
Saccharomyces cerivisiae. Most of the test sample
showed bacterial and fungicidal activity (Table 1).
Table 1
In vitro antimicrobial and fungicidal activities [a] of some newly synthesized compounds [b].
Compound
Escherichia
coli
Staphylococcus
aureus
Saccharomyces
cerivisiae
Aspergillus
niger
Penicillium sp
2
4
6
10
25a
25b
6.0
10.0
9.0
3.0
7.0
8.0
7.0
1.0
3.0
9.0
8.0
15.0
-
3.0
-
-
-
-
-
-
-
-
-
-
9.0
-
-
2.0
7.0
-
[a] Diameter (in mm) of growth inhibition zones; [b] The data expected by the mean.
g, 10 mmoles) in DMF (20 mL) containing piperidine (1.0 mL)
was refluxed for 3 hours. The reaction was left to cool at room
temperature, then poured onto ice-cold water and neutralized
with 10% HCl. The solid product, so formed, was collected by
filtration and recrystallized from EtOH as brown crystal, 2.69 g
(73%), mp. 103-105°C; ir: ꢁ 3428, 3334 (NH2), 2925, 2847
(CH2), 2195 (CN), 1619(C=N) cmꢂ1; 1H nmr (DMSO-d6): ꢀ
1.38-1.52 (m, 8H, 6-, 7-, 8-, and 9-H), 2.48 (t, 2H, CH2, J=5
Hz), 2.55 (t, 2H, CH2, J=5 Hz), 6.87 (br.s, 2H, NH2), 7.49-7.95
ppm (m, 5H, phenyl protons). Anal. Calcd. for C20H20ClN3S
(369.91): C, 64.94; H, 5.44; N, 11.35. Found: C, 64.85; H, 5.32;
N, 11.26.
4-Amino-2-oxo-1H,2H-5,6,7,8,9,10-hexahydrocycloocta[b]-
thieno[2,3-b]pyridine-3-carbonitrile (5). A mixture of 2 (2.06
g, 10 mmoles) and ethyl cyanoacetate (1.13 g, 10 mmoles) in
DMF (20 mL) containing piperidine (1.0 mL) was refluxed for
3 hours. The reaction mixture was left to cool at room temper-
ature, then poured onto ice-cold water. The solid product, so
formed, was collected by filtration and recrystallized from
EtOH as brown crystal, 1.99 g (73%), mp 93-95 °C; ir: ꢁ 3427,
3333 (NH2), 3218 (NH), 2924, 2848 (CH2), 2195 (CN), 1620
(CO) cmꢂ1. 1H nmr (DMSO-d6): ꢀ 1.34-1.52 (m, 8H, 6-, 7-, 8-,
and 9-H), 2.45-2.54 (m, 4H, 5- and 10-H), 6.88 (br.s, 2H, NH2,
D2O exchangeable), 11.97 ppm (br.s, 1H, NH, D2O
exchangeable); 13C nmr (DMSO-d6): ꢀ 25.9, 26.1, 26.3, 26.4,
30.6, 32.1 (6CH2), 116.4, 117.5, 119.8, 131.3, 134.9, 146.2,
162.4 (aromatic carbons & CN), 163.3 (CO) ppm; ms: m/z 273
(M+). Anal. Calcd. for C14H15N3OS (273.27): C, 61.53; H, 5.53;
N, 15.37. Found: C, 61.34; H, 5.23; N, 15.33.
EXPERIMENTAL
All melting points are uncorrected. The ir spectra (KBr) were
recorded on a Perkin Elmer 2000 FT-IR spectrophotometer. 1H
nmr and 13C nmr spectra were recorded on a Brucker 400 MHz
spectrometer in DMSO-d6 or CDCl3 as solvent using TMS as
internal standard, ꢀ TMS = 0.00 ppm. Mass spectra were
measured on GC/MS VS Autospec Q. Microanalyses were
performed on a CHNS-LECO 932 analyzer. Abbreviation: EtOH
= ethanol, Et3N = triethylamine, DMF = N,N-dimethylform-
amide, DMSO-d6 = dimethyl-d6-sulfoxide, TMS = tetramethyl-
silane, DMA DMF = N,N-dimethylformamide dimethylacetal;
DMAD = dimethylacetylene dicarboxylate.
2-Amino-4,5,6,7,8,9-hexahydrocycloocta[b]thiophene-3-
carbonitrile (2). A mixture of 1 (1.32 g, 10 mmoles), malono-
nitrile (0.66 g, 10 mmoles) and elemental sulfur (0.32 g, 10
mmoles) in DMF (30 mL) containing Et3N (1.0 mL) was heated
under refluxed for 6 hours. The reaction mixture was left to cool
at room temperature and then pour onto ice cold water. The
solid product, so formed, was collected by filtration and
recrystallized from EtOH as brown crystal, 1.46 g (71%), mp
81-820C; ir: ꢁ 3428, 3333 (NH2), 2924, 2846 (CH2), 2195 (CN),
1620 (C=C) cmꢂ1; H nmr (DMSO-d6): ꢀ 1.15-1.51 (m, 8H, 5-,
1
6-, 7-. and 8-H), 2.47 (t, 2H, CH2, J=5 Hz), 2.55 (t, 2H, CH2,
J=5 Hz), 6.84 ppm (br.s, 2H, NH2); 13C nmr (DMSO-d6): ꢀ 26.0,
26.1, 26.3, 26.4, 30.5, 36.1 (6CH2), 115.8, 117.4, 126.4, 134.9,
163.3 ppm (thiophene carbons & CN). Anal. Calcd. for
C11H14N2S (206.24): C, 64.06; H, 6.84; N, 13.58. Found: C,
64.30; H, 6.82; N, 13.38.
2,4-Diamino-5,6,7,8,9,10-hexahydrocycloocta[b]thieno[2,3-
b]pyridine-3-carbonitrile (3). A mixture of 2 (2.06 g, 10
mmoles) and malononitrile (0.66 g, 10 mmoles) in DMF (20
mL) containing piperidine (1.0 mL) was refluxed for 3 hours.
The reaction was left to cool at room temperature, then poured
onto ice-cold water. The solid product, so formed, was collected
by filtration and recrystallized from EtOH as brown crystal,
1.60 g (59%), mp. 90-92°C; ir: ꢁ 3431-3335 (2NH2), 2925, 2848
4-Amino-2-thioxo-1H,2H-5,6,7,8,9,10-hexahydrocycloocta-
[b]thieno[2,3-b]pyridine-3-carbonitrile (6). A mixture of
2
(2.06 g, 10 mmoles) and cyanothioacetamide (1.00 g, 10
mmoles) in DMF (20 mL) containing piperidine (1.0 mL) was
refluxed for 3 hours. The reaction mixture was left to cool at
room temperature, then poured onto ice-cold water. The solid
product, so formed, was collected by filtration and recrystallized
from EtOH as brown crystal, 2.19 g (76%), mp 130-132 °C. ir:
ꢁ 3427, 3333 (NH2), 2923, 2847 (CH2), 2195 (CN) cmꢂ1; 1H
1
(CH2), 2194 (CN), 1619 (C=N) cmꢂ1; H nmr (DMSO-d6): ꢀ

566
F. A. Al-Omran and A. A. El-Khair
Vol 44
nmr (DMSO-d6): ꢀ 1.33-1.52 (m, 8H, 6-, 7-, 8-, and 9-H),
2.47(t, 2H, CH2, J=5 Hz), 2.55 (t, 2H, CH2, J=5Hz), 6.88 (br.s,
2H, NH2, D2O exchangeable), 11.9 ppm (br.s, 2H, NH, D2O
exchangeable). Anal. Calcd. For C14H15N3S2 (289.28): C, 58.12;
H, 5.23; N, 14.53. Found: C, 58.25; H, 5.27; N, 14.29.
General Procedure for the Preparation 8a-b. A mixture of
2 (2.06 g, 10 mmoles) and either of each 7a (1.81 g, 10
mmoles) or 7b (1.75 g, 10 mmoles) in a mixture of EtOH (20
mL) and DMF (10 mL) was refluxed for 3 hours. The reaction
was left to cool at room temperature. The solid product, so
formed, was collected by filtration and reacrystallized from a
mixture of EtOH/DMF (2:1).
2-[3'-Oxo-3'-(2-thienyl)propenyl]amino-4,5,6,7,8,9-hexa-
hydrocycloocta[b]thiophene-3-carbonitrile (8a). This
compound was obtained as brown crystal, 2.20 g (71%), mp.
143-145 °C; ir: ꢁ 3427-3215 (NH), 2923, 2849 (CH2), 2195
(CN), 1623 (CO) cmꢂ1; 1H nmr (DMSO-d6): ꢀ 1.36 – 1.56 (m,
8H, 5-, 6-, 7-, and 8-H), 2.62-2.65 (m, 4H, 4- and 9-H), 6.97 (d,
1H, olefinic proton, J=9 Hz), 7.66 (d, 1H, olefinic proton, J=9
Hz), 7.23-7.96 (m, 3H, thienyl protons), 11.03 ppm (br.s, 1H,
NH). Anal. Calcd. for C18H18N2S2O (342.36): C, 63.15; H, 5.30;
N, 8.18. Found: C, 63.14; H, 5.10; N, 8.38.
2-[3'-Oxo-3'-phenylpropenyl]amino-4,5,6,7,8,9-hexahydro-
cycloocta[b]thiophene-3-carbonitrile (8b). This compound
was obtained as brown crystal; 2.28 g (68%), mp. 155-157°C;
ir: ꢁ 3333-3215 (NH), 2925, 2849 (CH2), 2207 (CN), 1633
(CO)cmꢂ1; 1H nmr (DMSO-d6): ꢀ 1.06-1.60 (m, 8H, 5-, 6-, 7-,
and 8-H), 2.65-2.77 (m, 4H, 4- and 9-H), 6.97 (d, 1H, olefinic
proton, J=10 Hz), 7.56 (d, 1H, olefinic proton, J=10 Hz), 7.51-
7.99 (m, 5H, phenyl protons), 11.03 ppm (br.s, 1H, NH); ms:
m/z 336 (M+). Anal. Calcd. for C20H20N2SO (336.36): C, 71.41;
H, 5.99; N, 8.32. Found: C, 71.32; H, 5.71; N, 8.21.
2H, CH2, J=5 Hz), 2.73 (t, 2H, CH2, J=5 Hz), 7.44-7.97 (m,
5H, phenyl protons), 8.66 ppm (br.s, 2H, NH2); ms: m/z 360
(M+). Anal. Calcd. for C21H20N4S (360.48): C, 69.97; H, 5.59; N,
15.54. Found: C, 69.88; H, 5.49; N, 15.32.
2-(2',3'-Dihydro-4'-phenylthiazol-2'-ylidene)amino-4,5,6,
7,8,9-hexahydrocycloocta[b]thiophene-3-carbonitrile (13). A
solution of 2 (2.06 g, 10 mmoles) and thiourea (0.76 g, 10
mmoles) in a mixture of DMF (20 mL) and EtOH (10 mL) was
refluxed for 3 hours. To the reaction mixture, phenacyl
bromide (1.99 g, 10 mmoles) was added and refluxed for 1 hour,
then allowed to cool at room temperature. The solid product, so
formed, was collected by filtration and recrystallized from a
mixture of EtOH/DMF (1:2) as brown crystal, 2.15 g (59%),
mp. 80-82°C; ir: ꢁ 3429-3216 (NH), 2924, 2848 (CH2), 2195
1
(CN), 1620(C=N) cmꢂ1; H nmr (DMSO-d6): ꢀ 1.03-1.42 (m,
8H, 5-, 6-, 7-, and 8-H), 2.39-2.45 (m, 4H, 4- and 9-H), 7.23 (s,
1H, 5'-H thiazoline proton), 7.32-7.89 (m. 5H, phenyl protons),
11.92 ppm (s, 1H, NH, D2O exchangeable); 13C nmr (DMSO-
d6) ꢀ 18.7, 25.3, 26.0, 30.2, 31.8, 32.1 (6CH2), 117.4, 120.5,
128.6, 129.5, 130.0, 130.5, 131.4, 134.7, 144.7, 159.8, 162.8,
171.0 ppm (aromatic carbons & CN). Anal. Calcd. for
C20H19N3S2 (365.38): C, 65.74; H, 5.24; N, 11.50. Found: C,
65.64; H, 5.14; N, 11.68.
2-(4'-Oxo-2'-penten-2-yl)amino-4,5,6,7,8,9-hexahydro-
cycloocta[b]thiophene-3-carbonitrile (14). A mixture of
2
(2.06 g, 10 mmoles) and acetylacetone (1.34 g, 10 mmoles) was
fused at 130°C in oil bath for 10 minutes. The fused product
was dissolved in anhydrous DMF (10 mL), then poured onto ice
cold water. The solid product, so formed, was collected by
filtration and recrystallized from a mixture of EtOH/DMF (2:1)
as brown solid; 2.37 (78%), mp. 96-98°C; ir: ꢁ 3428-3218
1
(NH), 2924, 2847 (CH2), 2195 (CN), 1619 (CO) cmꢂ1; H nmr
13-Imino-1-oxo-3-(2-thienyl)-1H,5H,13H-7,8,9,10,11,12-hexa-
hydrocycloocta[b]thieno[5',4':4,5]pyrimido[3,2-a]pyridine-2-
carbonitrile (10). A solution of 2 (2.06 g, 10 mmoles) and 7a
(1.81 g, 10 mmoles) in a mixture of EtOH (20 mL) and DMF
(10 mL) was refluxed for 3 hours. To the reaction mixture
malononitrile (0.66 g, 10 mmoles) was added and refluxed for 3
hours, then poured onto ice-cold water. The solid product, so
formed, was collected by filtration and recrystallized from a
mixture of EtOH/DMF (2:1) as brown crystal, 2.35 (63%), mp
90-92°C; ir: ꢁ 3401-3193 (2NH), 2922, 2849 (CH2), 2196 (CN),
1647 (CO) cmꢂ1; 1H nmr (DMSO-d6): ꢀ 1.03-1.53 (m, 8H, 8-, 9-,
10- and 11-H), 2.47-2.56 (m, 4H, 7- and 12-H), 7.17-7.77 (m,
3H, thienyl protons), 8.10 (s, 1H, 4-H pyridine proton), 11.02 (s,
1H, NH, D2O-exchangeable), 12.47 ppm (s, 1H, NH, D2O-
exchangeable); 13C nmr (DMSO-d6); ꢀ 25.86, 25.96, 26.05,
26.41, 30.26, 32.17 (6CH2), 117.35, 119.66, 120.23, 128.84,
129.97, 130.32, 131.76, 133.62, 134.39, 137.00, 144.02, 153.89,
159.04, 163.72, 165.94 ppm (aromatic carbons, CO & CN).
Anal. Calcd. for C21H18N4S2O (406.39): C, 62.06; H, 4.46; N,
13.79. Found: C, 61.86; H, 4.46; N, 13.82.
(DMSO-d6): ꢀ 1.34-1.52 (m, 8H, 5-, 6-, 7-, and 8-H), 1.53 (s,
3H, CH3), 2.15 (s, 3H, CH3), 2.46-2.16 (m, 4H, 4-, and 9-H),
6.90 (s, 1H, 3’-H), 7.95 ppm (br.s, 1H, NH); ms: m/z 288 (M+).
Anal. Calcd. for C16H20N2OS (288.36): C, 66.44; H, 6.99; N,
9.71. Found: C, 66.53; H, 6.92; N, 9.75.
2-Acetamido-4,5,6,7,8,9-hexahydrocycloocta[b]thiophene-
3-carbonitrile (17). A solution of 2 (2.06 g, 10 mmoles) in
acetic acid(20 mL) was treated with cyclohexanone (0.98 g, 10
mmoles). The reaction was refluxed for 10 hours and poured
onto ice-cold water. The solid product, so formed, was collected
by filtration and recrystallized from EtOH as brown crystal,
1.68 g (68%), mp. 101-102°C; ir: ꢁ 3263-3215 (NH), 2924,
2849 (CH2), 2219 (CN), 1691 (CO) cmꢂ1; 1H nmr (DMSO-d6): ꢀ
1.31-1.54 (m, 8H, 5-, 6-, 7-, and 8-H), 2.17 (s, 3H, CH3), 2.61-
2.64 (t, 2H, CH2, J=5 Hz), 2.69-2.72 (t, 2H, CH2, J=5 Hz),
11.52 ppm (s, 1H, NH); 13C nmr (DMSO-d6): ꢀ 23.0, 25.9,
26.06, 27.3, 30.2, 31.2, 32.2 (6CH2 & CH3), 115.3 (CN), 120.3,
130.6, 134.7, 147.4 (thiophene carbons), 169.31 ppm (CO).
Anal. Calcd. for C13H16N2OS (248.27): C, 62.89; H, 6.50; N,
11.28. Found: C, 63.05; H, 6.32; N, 11.25.
4-Amino-3H,4H-5,6,7,8,9,10-hexahydrocycloocta[b]thieno-
[2,3-b]pyridine-3,3-dicarbonitrile (11). A mixture of 2 (2.06
g, 10 mmol) and benzylidenemalononitrile (1.54 g, 10 mmol) in
DMF (20 mL)containing piperidine (1.0 mL) was refluxed for
5 hours. The reaction mixture was left to cool at room
temperature. The solid product, so formed, was collected by
filtration and recrystallized from DMF as brown crystal, 2.30 g
(64%), mp. 132-134°C; ir: ꢁ 3336, 3206 (NH2), 2923, 2823
2-Amino-4-phenylhydrazo-4H-5,6,7,8,9-pentahydrocyclo-
octa[b]thiophene-3-carbonitrile (19). To a cold solution 0 °C
of 2 (2.05 g, 10 mmoles) in a mixture of EtOH (20 mL) and
DMF (10 mL) containing NaOH (0.50 g), benzenediazonium
chloride (1.28 g, 10 mmoles) was added with continuous
stirring. The reaction mixture was stirred at room temperature
for 2 hours. The solid product, so formed, was collected by
filtration and recrystallized from a mixture of EtOH/DMF (2:1)
as brown crystal, 1.80 g (64%), mp. 103-105°C; ir: ꢁ 3443-
3168 (NH2 & NH), 2916, 2850 (CH2), 2210 (CN), 1649
1
(CH2), 2199 (2CN), 1623 (C=N) cmꢂ1; H nmr (DMSO-d6): ꢀ
1.34-1.63 (m, 8H, 6-, 7-, 8-, and 9-H), 2.46 (s, 1H, 4-H), 2.55 (t,

May-Jun 2007
Synthesis of New Derivatives of Thieno[2,3-b]pyridine Fused with Octyl Ring
567
(C=N) cmꢀ1; 1H nmr (DMSO-d6): ꢁ 1.33-1.61 (m, 6H, 6-, 7-,
and 8-H), 2.47-2.56 (m, 2H, CH2), 2.64-2.76 (m, 2H, CH2),
7.31-7.39 (m, 5H, phenyl protons), 8.86 (br.s, 2H, NH2, D2O
exchangeable), 11.91 ppm (br.s, 1H, NH, D2O exchangeable).
Anal. Calcd. for C17H18N4S (310.35): C, 65.79; H, 5.85; N,
18.05. Found: C, 65.80; H, 5.87; N, 18.29.
and 8-H), 4.00 (s, 2H, CH2CN), 10.63 ppm (br.s, 1H, NH, D2O
exchangeable). Anal. Calcd. for C11H17N3O (207.27): C, 63.74;
H, 8.27; N, 20.27. Found: C, 63.94; H, 8.26; N, 20.22.
General Procedure for the Preparation of 26a-d. A
solution of each 24b or 24d (10 mmoles) and DMF DMA (1.33 g,
10 mmoles) in xylene (20 mL) was refluxed for 6 hours. The
reaction mixture was cool at room temperature. The solvent was
evaporated under reduced pressure. The solid product, so formed,
was collected by filtration and recrystallized from EtOH.
N-(2'-Benzotriazol-1-yl-1'-oxoethyl)-2,8-dimethylamino-
methylidenyl-2,8-dihydro-1H-cyclooctanone hydrazone (26a).
This compound was obtained as yellow crystal; 2.94 g (72%),
mp. 161-1620C; ir: ꢂ 3412, 3215 (NH), 2977, 2853 (CH2), 1684
(CO) cmꢀ1; 1H nmr (DMSO-d6): ꢁ 1.27-1.66 (m, 2H, 5-H), 1.73-
1.86 (m, 4H, 4- and 6-H), 2.41-2.54 (m, 4H, 3- and 7-H), 2.76
(s, 6H, N(CH3)2); 2.96 (s, 6H, N(CH3)2); 5.80 (s, 2H, CH2-Bt),
7.34-7.52 (m, 4H, benzotriazolyl protons), 7.85 (s, 2H, ylidene
protons), 8.83 ppm (br.s, 1H, NH), ms: m/z 409 (M+). Anal.
Calcd. for C22H31N7O (409.51): C, 64.60; H, 7.56; N, 23.96.
Found: C, 64.51; H, 7.50; N, 23.76.
Dimethyl-2-amino-11-cyano-10-phenylhydrazo-10H-
5,6,7,8,9-pentahydrocycloocta[c]thiepine-3,4-dicarboxylate
(23). A mixture of 19 (3.11 g, 10 mmoles) in dioxan (25 mL)
containing acetic acid (2 mL)and DMAD (1.23 g, 10 mmoles)
was refluxed for 5 hours. The reaction mixture was evaporated
under vacuo and recrystallized from a mixture of DMF/EtOH
(2:1) as brown crystal, 32.5 g (72%), mp. 103-105°C, ir: ꢂ
3429-3217 (NH2 & NH), 2924, 2850 (CH2), 2200 (CN), 1735
1
(2CO ester), 1618(C=N) cmꢀ1, H nmr (DMSO-d6): ꢁ 1.34-1.57
(m, 6H, 6-, 7-, and 8-H), 2.46-2.67 (m, 4H, 5-, and 9-H), 3.67 (s,
3H, OCH3), 3.71 (s, OCH3), 7.31-7.39 (m, 5H, phenyl protons),
9.84 (br.s, 1H, NH, D2O exchangeable), 11.9 ppm (br.s, 2H,
NH2, D2O exchangeable). Anal. Calcd. for C23H24N4O4S
(452.45): C, 61.05; H, 5.35; N, 12.38. Found: C, 61.13; H, 5.35;
N, 12.38.
N-(2'-cyano-1'-oxoethyl)-2,8-dimethylaminomethylidenyl-
2,8-dihydro-1H-cyclooctanone hydrazone hydrochloride
(26b). This compound was obtained as yellow crystal; 2.15 g
(61%), mp. 102-104°C, ir: ꢂ 3381 (NH), 2924, 2855 (CH2),
General Procedure for the Preparation of 25a-d.
A
mixture of either 1a or 1b (10 mmoles) and each of 24a or 24b
(10 mmoles) was fused at 130-140°C for 5 minutes. The fused
product was dissolved in EtOH (10 mL) and refluxed for 1 hour.
The solid product, so formed, was collected by filtration and
recrystallized from EtOH.
N-(2'-Benzotriazol-1-yl-1'-oxoethyl)-1H-cyclohexanone
hydrazone (25a). This compound was obtained as yellow
crystals, 1.97 g (73%), mp. 150-152°C; ir: ꢂ 3226-3112 (NH),
2924, 2853 (CH2), 1693 (CO), 1649 (C=N) cmꢀ1; 1H nmr
(DMSO-d6): ꢁ 1.51-1.66 (m, 6H, 3-, 4-, and 5-H), 2.24-2.31 (m,
4H, 2-, and 6-H), 5.88 (s, 2H, CH2-Bt), 7.38-8.06 (m, 4H,
benzotriazolyl protons), 10.9 ppm (br..s, 1H, NH, D2O
exchangeable), ms: m/z 271 (M+). Anal. Calcd. for C14H17N5O
(271.32): C, 61.97; H, 6.32; N, 25.82. Found: C, 61.88; H, 6.22;
N, 25.72.
N-(2'-Benzotriazol-1-yl-1'-oxoethyl)-1H-cyclooctanone
hydrazone (25b). This compound was obtained as yellow
crystals, 2.13 g (75%), mp. 201-202°C; ir: ꢂ 3339-3187 (NH),
2925, 2859 (CH2), 1682 (CO), 1634 (C=N) cmꢀ1; 1H nmr
(DMSO-d6): ꢁ 1.38-1.75 (m, 10H, 3-, 4-, 5-, 6- and 7-H), 2.31-
2.45 (m, 4H, 2-, and 8-H), 5.87 (s, 2H, CH2-Bt), 7.39-8.04 (m,
4H, benzotriazolyl protons), 10.72 ppm (br.s, 1H, NH); 13C
nmr (DMSO-d6): ꢁ 25.7, 27.7, 28.2, 36.9 (4CH2), 49.9 (CH2-
Bt), 111.9, 119.9, 124.7, 128.2, 134.9, 146.0 (benzotriazolyl
carbons), 161.3 (C-1), 168.3 ppm (CO). Anal. Calcd. for
C16H21N5O (299.37): C, 64.19; H, 7.07; N, 23.39. Found: C,
64.29; H, 7.01; N, 23.27.
N-(2'-Cyano-1'-oxoethyl)-1H-cyclohexanone hydrazone
(25c). This compound was obtained as yellow crystals, 2.54 g
(75%), mp. 230-232°C; ir: ꢂ 3339-3223 (NH), 2932, 2858
(CH2), 2196 (CN), 1689 (CO), 1645 (C=N) cmꢀ1; 1H nmr
(DMSO-d6): ꢁ 1.09-1.50 (m, 6H, 3-, 4-, and 5-H), 2.22-2.30 (m,
4H, 2- and 6-H), 4.02 (s, 2H, CH2CN), 10.52 ppm (br.s, 1H, NH,
D2O exchangeable). Anal. Calcd. for C9H13N3O (179.22): C,
60.31; H, 7.31; N, 23.44. Found: C, 60.21; H, 7.23; N, 23.34.
N-(2'-Cyano-1'-oxoethyl)-1H-cyclooctanone hydrazone
(25d). This compound was obtained as yellow crystals, 1.26 g
(61%), mp. 242-243°C; ir: ꢂ 3200 (NH), 2932, 2857 (CH2),
2256 (CN), 1665 (CO), 1633 (C=N) cmꢀ1; 1H nmr (DMSO-d6): ꢁ
1.34-1.71 (m, 10H, 3-, 4-, 5-, 6- and 7-H), 2.25-2.41 (m, 4H, 2-,
1
2180 (CN), 1693 (CO) cmꢀ1; H nmr (DMSO-d6): ꢁ 1.35-1.47
(m, 2H, 5-H), 1.68-1.71 (m, 4H, 4- and 6-H), 2.31-2.83 (m, 4H,
3- and 7-H), 2.77 (s, 6H, N(CH3)2), 2.95 (s, 6H, N(CH3)2), 4.00
(s, 2H, CH2CN), 7.75 (s, 2H, ylidene protons), 9.10 ppm (br.s,
sH, NH); ms: m/z 317 (M+-HCl). Anal. Calcd. for C17H28ClN5O
(353.83): C, 57.70; H, 7.97; N, 19.79. Found: C, 57.72; H,
7.82; N, 19.69.
Biological Testing. The newly synthesized compounds were
tested against the specified microorganism, using 400 μg/mL
(w/v) solutions in sterile dimethyl-d6-sulfoxide (DMSO).
A
solution of the tested compound (1.0 mL) was poured aseptically
in a well of 6 mm diameter made by a Cork borer in the nutrient
agar medium for bacterial test and Sabourand agar for fungal
test. After placing the same volume in wells of all tested
microorganism, nutrient agar plates were incubated at 37 °C for
24 hours and Sabourand dextrose agar plates were incubated at
25 °C for 48 hours. The diameter of zones inhibition was
measured in millimeters and the results are shown in Table 1.
The least concentration, which showed inhibitory effect on any
specific microorganism, was considered as the minimum
inhibitory concentration (MIC) which was determined using
streptomycin (50 μg/mL) as the references.
Acknowledgement. This work was financed by the
University of Kuwait research grant SC08/00. We are grateful
to the Faculty of Science, Chemistry Department, SAF facility
for the spectral and analytical data (Project G 01/01 & G 03/01).
REFERENCES
*
Corresponding Author: E-mail: chesc@kuc01.kuniv.edu.kw
[1] Shraideh, Z.; Sallal, A.-K. Biomed. Lett. 1997, 54, 233.
[2] Bompart, J.; Giral, L.; Malicorne, G.; Puygrenier, M. Eur. J.
Med. Chem. 1987, 22, 139.
[3] Adachi, I.; Yamamori, T.; Hiramatsu, Y.; Sakai, K.; Mihara,
S.-I.; Kawakami, M.; Masui, M.; Uno, O.; Ueda, M. Chem. Pharm.
Bull. 1988, 36(11), 4389.
[4] Furuya, S.; Choh, N.; Kato, K.; Hinuma, S. PCT Int. Appl.
WO, 95, 28, 405; Chem. Abstr. 1996, 124, 202226t.

568
F. A. Al-Omran and A. A. El-Khair
Vol 44
[5] Cho, N.; Harada, M.; Imaeda, T.; Imada, T.; Matsumoto, H.;
[12] Al-Omran, F.A.; El-Khair, A.A. J. Heterocyclic Chem.,
2004, 41, 909.
[13] Hassan, H.Y.; El-Koussi, N.A.; Farghaly, Z.S. Chem.
Pharm. Bull. 1998, 46(5), 863.
[14] Abdelhamid, A.O.; Al-Shehri, S.M. J. Chem. Research (S),
1997, 240; J. Chem. Research (M), 1997, 1681.
[15] Al-Omran, F.A.; Al-Awadhi, N.; Elassar, A.A.; El-Khair,
A.A. J. Chem. Research(S), 2000, 20; J. Chem. Research (M), 2000,
237.
Hayase, Y.; Sasaki, S.; Furuya, S.; Suzuki, N.; Okubo, S.; Ogi, K.;
Endo, S.; Onda H.; Fujino, M. J. Med. Chem. 1998, 41, 4190.
[6] Miki, S.; Fukuoka, K.; Akita, M.; KawaKami, J.; Furuya, S.;
Ishimaru, Y. PCT Int. Appl. WO, 99, 09, 033 ; Chem. Abstr. 1999, 130,
196644h.
[7] Suzuki, N.; Matsumoto, H.; Furuya, S. Eur. Pat. Appl. 1997,
781, 774; Chem. Abstr. 1997, 127, 135807e.
[8] Furuya, S.; Choh, N.; Suzuki, N.; Imada, T. PCT Int.
Appl.WO, 00, 00, 493; Chem. Abstr., 2000, 132, 64179s.
[16] Al-Omran, F.A.; Khalik, M.M.A.; Al-Awadhi, H.; Elnagdi,
M.H. Tetrahedron, 1996, 52, 11915.
[9]
Furuya, S.; Matsumoto, H.; Hayase, Y.; Suzuki, N.; Imada,
T. PCT Int. Appl. WO, 97, 41, 126; Chem. Abstr. 1998, 128, 13211f .
[10] Sohda, T.; Makino, H.; Baba, A. PCT Int Appl. WO, 96, 14,
319; Chem. Abstr. 1996, 125, 114583x.
[17] Al-Omran, F.A. Sulfur Letters. 2000, 23(6), 275.
[18] Al-Omran, F.A.; El-Khair, A.A. J. Heterocyclic Chem., 2004,
41, 327.
[11] Gewald, K.; Schinke, E.; Bottcher, H. Chem. Ber. 1966,
99, 94.
[19] Bonguen, E. N.; Fondjo, E. S.; Fomum, Z. T.; Dopp, D. J.
Chem. Soc. Perkin Trans. 1994, 1, 2191.